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HEARING IMPAIRMENT, CARDIOVASCULAR DISEASE RISK FACTORS, METHYLMALONIC ACID, AND VITAMIN B12 STATUS IN OLDER ADULTS by SOHYUN PARK (Under the Direction of Mary Ann Johnson, Ph.D.) ABSTRACT Hearing impairment is a common chronic health condition in older adults and is associated with impaired quality of life. However, there is limited comprehensive research concerning interactions among poor diets and hearing loss. In the first study, the prevalence of hearing impairment and the relationship of Hearing Handicap Inventory for the Elderly with pure-tone average threshold (PTA) were evaluated. Approximately 63% of participants had hearing impairment in the best ear [PTA across 1, 2, and 4 kHz > 25 dB hearing level (HL)]. A moderate correlation was found between Hearing Handicap Inventory for the Elderly and PTA. In the second study, the relationship between hearing loss and cardiovascular disease (CVD) risk factors was examined. Low-density lipoprotein cholesterol, total cholesterol, and triglycerides were not significantly associated with hearing loss. However, PTA was significantly correlated with high-density lipoprotein (HDL) cholesterol in the poorest ear and total cholesterol/HDL cholesterol ratio in both ears. Participants with impaired hearing had significantly lower HDL cholesterol concentration than those with normal hearing (≤ 25 dB HL) in the worst ear. Participants with PTA > 40 dB HL had significantly lower HDL cholesterol level than those with PTA ≤ 40 dB HL in both ears. Thus, HDL cholesterol may be a modifiable risk factor for

hearing loss. In the third study, the relationship between age-related hearing loss (ARHL) and poor vitamin B12 status in older adults was examined, using multiple measures of vitamin B12 status and by repletion with a vitamin B12 supplement. A consistent relationship of vitamin B12 with auditory function was found in the worst ear. Participants with impaired hearing in the worst ear had a significantly higher prevalence of vitamin B12 deficiency, higher mean serum MMA concentration, higher prevalence of elevated MMA (> 271 nmol/L), and a nonsignificantly higher prevalence of low serum vitamin B12 than those with normal hearing (≤ 25 dB HL). Hearing thresholds were not improved in any group after three months of vitamin B12 supplementation (0-1000 µg/d). Impaired vitamin B12 status may be a modifiable risk factor for ARHL in older adults. Since vitamin B12 repletion did not improve hearing function in vitamin B12 deficient participants, this suggests that prevention of vitamin B12 deficiency may be important.

This research adds to the growing body of literature that suggests CVD- and

nutrition-related risk factors are associated with hearing loss in older people.

INDEX WORDS:

Vitamin B12, Methylmalonic acid, Intervention, Hearing loss, CVD risk factors, Older adults

HEARING IMPAIRMENT, CARDIOVASCULAR DISEASE RISK FACTORS, METHYLMALONIC ACID, AND VITAMIN B12 STATUS IN OLDER ADULTS

by

SOHYUN PARK B.S., The Kosin University, South Korea, 1998 M.S., The Sookmyung Women’s University, South Korea, 2000

A Dissertation Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree

DOCTOR OF PHILOSOPHY

ATHENS, GEORGIA 2006

© 2006 Sohyun Park All Rights Reserved

HEARING IMPAIRMENT, CARDIOVASCULAR DISEASE RISK FACTORS, METHYLMALONIC ACID, AND VITAMIN B12 STATUS IN OLDER ADULTS

by

SOHYUN PARK

Electronic Version Approved: Maureen Grasso Dean of the Graduate School The University of Georgia May 2006

Major Professor:

Mary Ann Johnson, Ph.D.

Committee:

Mary Ann Johnson, Ph.D. Albert R. De Chicchis, Ph.D. Joan G. Fischer, Ph.D. Arthur Grider, Ph.D. James L. Hargrove, Ph.D.

iv

DEDICATION I would like to dedicate this achievement to my parents, Sungman Park and Malpil Lee, for their unconditional love and immeasurable support. My achievement of this higher degree would not have been possible without them. With this opportunity, I would like to let my parents know how much I love them and appreciate their sacrifice. I would also like to dedicate this accomplishment to my husband Antonio, my family, and my friends, for their love, encouragement, and unfailing support of my advanced education. Their love and support have sustained me during this long journey. Thank you all!

감사의 글 오늘이 있기까지 헌신적인 사랑으로 저에게 모든 것을 베풀어 주신 사랑하는 나의 부모님 (아버지 박성만님 과 어머니 이말필님)께 박사과정의 결실인 이 논문을 받칩니다. 부모님의 헌신적인 사랑, 희생, 그리고 뒷받침 없이는 오늘의 결실이 없다고 해도 과언이 아닙니다. 이 기회를 통해, 부모님께 제가 얼마나 부모님을 사랑하고, 존경하고, 그리고 부모님의 희생에 감사 드리는지를 진심으로 전하고 싶습니다. 사랑, 격려, 그리고 응원을 해준 사랑하는 나의 남편 (안토니오), 가족들, 친구들, 그리고 교수님들에게 이 결실을 받칩니다.

박사과정 기간 동안 사랑으로 나를 격려해 주신 모든 분들께 이 결실을

드리면서 기쁨을 함께 하고자 합니다. 정말 감사 드립니다. 2006년 5월 박 소 현 올림

v

ACKNOWLEDGEMENTS I would like to extend a sincere thank you to my committee members: Dr. Mary Ann Johnson, Dr. Albert R. De Chicchis, Dr. Joan G. Fischer, Dr. Arthur Grider, and Dr. James L. Hargrove for their professional advice and guidance. I would like to give a very special thank you to my major professor, Dr. Mary Ann Johnson, for her steady support, encouragement, and assistance during completion of this dissertation and throughout my graduate school education. I would like to thank the people who collaborated on this project and helped in data collection, analysis, and editing: Dr. Sally P. Stabler, Dr. Kelly Shea-Miller, Dr. Robert J. Nozza, Dr. Robert H. Allen, Dr. Dorothy B. Hausman, Evelyn Dolce, Nikki Hawthorne, Jean Edmonds, Nancy Omdahl, and Tiffany Sellers. I would also like to thank my wonderful fellow graduate students and friends for your friendship, laughter, and willingness to help me throughout my graduate training. Thank you so much.

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TABLE OF CONTENTS Page ACKNOWLEDGEMENTS.............................................................................................................v LIST OF TABLES......................................................................................................................... ix LIST OF FIGURES ....................................................................................................................... xi CHAPTER 1

INTRODUCTION .........................................................................................................1 References .................................................................................................................5

2

LITERATURE REVIEW ..............................................................................................8 Background and Significance....................................................................................8 Purpose ......................................................................................................................9 The Human Auditory System..................................................................................10 Assessment of Auditory Function ...........................................................................15 The Biological Basis of Hearing Loss in Older Adults...........................................18 The Prevalence of Hearing Loss .............................................................................20 Hearing Loss and Quality of Life in Older Adults ..................................................21 Risk Factors for Hearing Loss.................................................................................22 Functions of Vitamin B12 ........................................................................................41 Biomarkers for Vitamin B12 Status .........................................................................43 Defining Vitamin B12 Status....................................................................................44 The Prevalence of Vitamin B12 Deficiency.............................................................45

vii Vitamin B12 and Hearing Loss ................................................................................46 Purpose, Specific Aims, Hypotheses, and General Approach ................................54 Figure 2.1.................................................................................................................11 Figure 2.2.................................................................................................................23 Table 2.1..................................................................................................................47 References ...............................................................................................................56 3

PREVALENCE OF HEARING IMPAIRMENT IN OLDER ADULTS IN THE OLDER AMERICANS ACT NUTRITION PROGRAMS ....................................67 Abstract ...................................................................................................................68 Introduction .............................................................................................................69 Methods ...................................................................................................................70 Results .....................................................................................................................73 Discussion ...............................................................................................................74 References ...............................................................................................................77 Tables ......................................................................................................................80

4

HEARING IMPAIRMENT AND CARDIOVASCULAR DISEASE RISK FACTORS IN OLDER ADULTS ..........................................................................85 Abstract ...................................................................................................................86 Introduction .............................................................................................................87 Materials and Methods ............................................................................................88 Results .....................................................................................................................91 Discussion ...............................................................................................................92 References ...............................................................................................................99

viii Tables ....................................................................................................................102 5

AGE-RELATED HEARING LOSS, METHYLMALONIC ACID, AND VITAMIN B12 STATUS IN OLDER ADULTS .....................................................................108 Abstract .................................................................................................................109 Introduction ...........................................................................................................110 Subjects and Methods............................................................................................112 Results ...................................................................................................................117 Discussion .............................................................................................................119 References .............................................................................................................127 Tables ....................................................................................................................131 Figures ...................................................................................................................139

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CONCLUSIONS........................................................................................................143

APPENDICES .............................................................................................................................147 A

RELATIONSHIP OF THE HEARING HANDICAP INVENTORY FOR THE ELDERLY WITH PURE-TONE AVERAGE IN OLDER ADULTS .............148

B

RELATIONSHIP OF HEARING IMPAIRMENT WITH CARDIOVASCULAR DISEASE RISK FACTORS IN OLDER ADULTS.........................................151

C

RELATIONSHIPS OF AGE-RELATED HEARING LOSS WITH MULTIPLE MEASURES OF VITAMIN B12 STATUS IN OLDER ADULTS ..................180

D

NUTRITION, HEARING AND MEMORY AMONG SENIOR CENTER IN NORTHEAST GEORGIA CONSENT FORM AND TEST BOOK ..............225

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LIST OF TABLES Page Table 2.1: Summary of research linking hearing impairment, vitamin B12, and folate.................47 Table 3.1: Prevalence of hearing impairment by age, gender, and race based on pure-tone average threshold (1, 2, and 4 kHz) ............................................................................80 Table 3.2: Mean air-conduction pure-tone threshold (dB hearing level), standard deviation for the best ear and the worst ear by age, gender, race, and frequency ..................................81 Table 3.3: Association between Hearing Handicap Inventory for the Elderly and pure-tone average threshold in the best ear and the worst ear .....................................................83 Table 3.4: Number of participants self-perceived as being with or without handicap according to pure-tone average categories........................................................................................84 Table 4.1: Characteristics of participants.....................................................................................102 Table 4.2: Correlation between blood lipids and pure-tone average threshold (1, 2, and 4 kHz) in the best ear and the worst ear.....................................................................................103 Table 4.3: Demographics, cardiovascular disease risk factors, and auditory function in the best ear and the worst ear (≤ 25 vs. > 25 dB hearing level) ..............................................104 Table 4.4: Demographics, cardiovascular disease risk factors, and auditory function in the best ear and the worst ear (≤ 40 vs. > 40 dB hearing level) ..............................................106 Table 5.1: Characteristics of participants at baseline...................................................................131 Table 5.2: Correlations of vitamin B12, methylmalonic acid, and total homocysteine with puretone average threshold in the best ear and the worst ear at baseline..........................132

x Table 5.3: Demographics, nutrition and auditory function in the best ear at baseline ................133 Table 5.4: Demographics, nutrition and auditory function in the worst ear at baseline ..............135 Table 5.5: Demographics, nutrition and auditory function in the worst ear at baseline in Caucasians..................................................................................................................137

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LIST OF FIGURES Page Figure 2.1: Human auditory system ..............................................................................................11 Figure 2.2: Working model for hypothesized relationships of nutrition with age-related hearing loss ...........................................................................................................................23 Figure 5.1: Serum methylmalonic acid concentration and poor hearing status in the best ear and the worst ear at baseline...........................................................................................139 Figure 5.2: Serum vitamin B12 concentration and poor hearing status .......................................140 Figure 5.3: Prevalence of vitamin B12 deficiency (defined as serum vitamin B12 < 258 pmol/L, methylmalonic acid > 271 nmol/L, and methylmalonic acid > 2-methylcitric acid) in participants with poor hearing status ......................................................................141 Figure 5.4: Pure-tone average threshold (1, 2, and 4 kHz) before vitamin B12 supplementation and after three months of supplementation..............................................................142

1

CHAPTER 1 INTRODUCTION Hearing impairment is the third most common chronic health condition in older adults (Lethbridge-Cejku and Vickerie, 2005). The human ear has a conductive component (the outer and middle ear) and a sensorineural component (the inner ear and auditory nerve). Frequently, a person’s pure-tone average, the mean of three or four contiguous frequencies, is used to predict the degree of communication impact imposed by hearing loss (Martin and Clark, 2002; Newman and Sandridge, 2004). Higher hearing threshold indicates poorer hearing sensitivity and greater difficulty hearing and understanding speech. Hearing impairment may result from numerous factors including genetics, noise, acoustic trauma, viral or bacterial infections, sensitivity to certain drugs or medications, and aging (Johnson et al., 2004). In the 2003 National Health Interview Survey, 17.6% of people aged 45 to 64 years, 29.7% of people aged 65 to 74 years, and 46.4% of people aged 75 or older reported difficulty in hearing (Lethbridge-Cejku and Vickerie, 2005). The prevalence of hearing impairment increases with advanced age (Gates and Mills, 2005). Men typically have poorer hearing status than women (Torre et al., 2005). Hearing impairment adversely affects the lives of older adults. Even mild hearing loss is associated with impaired quality of life, functional disabilities, and adverse effects on physical, cognitive, emotional, behavioral, and social function (Jerger et al., 1995; Dalton et al., 2003; Bazargan et al., 2001; Gates and Mills, 2005). Despite the high prevalence of hearing loss in older adults, there is limited comprehensive and systematic research concerning the possible interactions among poor diet and hearing loss (Johnson et al., 2004). Several lines of evidence

2 suggest that cardiovascular diseases (CVD) and CVD risk factors may be related to hearing loss. Hearing loss was associated with high intake of saturated fats in humans (Rosen et al., 1970) and with high dietary cholesterol in chinchillas (Sikora et al., 1986). Abnormal blood lipids may enhance the adverse effects of noise on hearing loss (Axelsson and Lindgren, 1985). Auditory dysfunction was associated with hyperlipidemia or hypercholesterolemia in some (Rosen and Olin, 1965; Torre et al., 2005), but not all studies (Jones and Davis, 1999, 2000). Other CVD risk factors, self-reported or quantitatively measured, such as stroke, hypertension, heart disease, coronary heart disease, myocardial infarction, smoking, and diabetes mellitus, also have been associated with hearing loss in some (Gates et al., 1993; Torre et al., 2005; Cruickshanks et al., 1998a, 1998b; Frisina et al., 2006; Uchida et al., 2005), but not all studies (Drettner et al., 1975; Jones and Davis, 1999, 2000; Nondahl et al., 2004). Hearing loss may be related to vascular disease and neural degeneration or disorders (Gate et al., 1993; Seidman et al., 1996), and the vascular and neural systems depend on certain nutrients, such as vitamin B12 or folate, for optimal structure and function (Johnson et al., 2004). Vitamin B12 deficiency is common in older adults (Wolters et al., 2004; Baik and Russell, 1999). The prevalence of vitamin B12 deficiency (5% to 23% in people aged 60 years or older) increases with advanced age, mainly because atrophic gastritis decreases the production of the acid and digestive enzymes needed to cleave protein-bound vitamin B12 from the natural chemical form of vitamin B12 (Baik and Russell, 1999; IOM, 1998; Wolters et al., 2004; Johnson et al., 2003). Risk factors for vitamin B12 deficiency include low animal protein intake, no crystalline vitamin B12 from supplements or fortified foods, malabsorption associated with atrophic gastritis or Helicobacter pylori infection, pancreatic or intestinal pathology, and gastric acid-reducing medications (Baik and Russell, 1999; IOM, 1998, Johnson et al., 2003; Wolters et al., 2004).

3 Several studies suggest that vitamin B12 deficiency may be related to hearing loss. Poor vitamin B12 status was associated with auditory dysfunction in some (Houston et al., 1999; Gok et al., 2004; Shemesh et al., 1993), but not all studies (Berner et al., 2000; Fine et al., 1990; Fine and Hallett, 1980). Tinnitus (ringing in the ears) (Shemesh et al., 1993) and auditory hallucinations (Hector and Burton, 1988) have been recorded as symptoms of vitamin B12 deficiency. However, none of these studies have assessed the relationship of hearing with measures of vitamin B12 status such as methylmalonic acid (MMA) other than serum vitamin B12 and homocysteine (Hcy). MMA and Hcy are sensitive indicators of vitamin B12 status (Wolters et al., 2004; Baik and Russell, 1999). Therefore, the purposes of this dissertation were to evaluate the prevalence of hearing impairment, to examine a possible relationship of hearing impairment with CVD risk factors among a sample of older adults, and to evaluate a possible relationship of age-related hearing loss with poor vitamin B12 status in older adults, using multiple measures of vitamin B12 status and by repletion with a vitamin B12 supplement. Chapter 2 in this dissertation is a review of the literature. The literature review explores the human auditory system, assessment of auditory function, prevalence and biological basis of hearing loss in older adults, the association of hearing loss with CVD, CVD risk factors, and vitamin B12 status as well as functions and diagnosis of vitamin B12. Chapter 3 describes the methods used and the results obtained concerning the prevalence of hearing impairment and the relationship between Hearing Handicap Inventory for the Elderly and pure-tone average thresholds. Chapter 4 describes the methods used and the results obtained concerning the relationships between hearing impairment and CVD risk factors.

4 Chapter 5 describes the methods and the results obtained concerning a possible relationship between age-related hearing loss and poor vitamin B12 status in older adults, using multiple measures of vitamin B12 status and by repletion with a vitamin B12 supplement. Chapter 6 presents a summary of the major findings of this dissertation.

5 References Axelsson A, Lindgren F. Is there a relationship between hypercholesterolaemia and noiseinduced hearing loss? Acta Otolaryngol (Stockh) 1985;100:379-86. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr 1999;19:357-77. Bazargan M, Baker RS, Bazargan SH. Sensory impairments and subjective well-being among aged African American persons. J Gerontol B Psychol Sci Soc Sci 2001;56(5):268-78. Berner B, Ødem L, Parving A. Age-related hearing impairment and B vitamin status. Acta Otolaryngol 2000;120:633-7. Cruickshanks KJ, Wiley TL, Tweed TS, Klein BE, Klein R, Mares-Periman JA, Nondahl DM. Prevalence of hearing loss in older adults in Beaver Dam, Wisconsin. Am J Epidemiol 1998a; 148(9):878-86. Cruickshanks KJ, Klein R, Klein BEK, Wiley TL, Nondahl DM, Tweed TS. Cigarette smoking and hearing loss. JAMA 1998b; 279(21):1715-9. Dalton DS, Cruickshanks KJ, Klein BE, Klein R, Wiley TL, Nondahl DM. The impact of hearing loss on quality of life in older adults. Gerontologist 2003;43(5):661-8. Drettner B, Hedstrand H, Klockhoff I, Svedbery A. Cardiovascular risk factors and hearing loss. Acta Otolaryngol (Stockh) 1975;79:366-71. Fine EJ, Hallett M. Neurophysiological study of subacute combined degeneration. J Neurol Sci 1980;45:331-6. Fine EJ, Soria E, Paroski MW, Petryk D, Thomasula L. The neurophysiological profile of vitamin B12 deficiency. Muscle Nerve 1990;13:158-64. Frisina ST, Mapes F, Kim S, Frisina DR, Frisina RD. Characterization of hearing loss in aged type II diabetics. Hear Res. 2006;211(1-2):103-13. Gates GA, Cobb JL, D’Agostino RB, Wolf PA. The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors. Arch Otolaryngol Head Neck Surg 1993;119:156-61. Gates GA, Mills JH. Presbycusis. Lancet 2005;366:1111-20. Gok U, Halifeoglu I, Canatan C, Yildiz M, Gursu MF, Gur B. Comparative analysis of serum homocysteine, folic acid levels in patients with noise-induced hearing. Auris Nasus Larynx 2004;31:19-22.

6 Hector M, Burton JR. What are the psychiatric manifestations of vitamin B12 deficiency? J Am Geriatr Soc 1988;36:1105-12. Houston DK, Johnson MA, Nozza RJ, et al. Age-related hearing loss, vitamin B-12 and folate in elderly women. Am J Clin Nutr 1999;69:564-71. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington DC; National Academy Press, 1998. Jerger J, Chmiel R, Wilson N, Luchi R. Hearing impairment in older adults: new concepts. J Am Geriatr Soc 1995;43:928-35. Johnson MA, De Chicchis AR, Willott JF, Shea-Miller K, Nozza RJ. Hearing loss and nutrition in older adults. In: Bales CW, Ritchie CS, ed. Handbook of clinical nutrition in aging. Totowa, NJ: Humana Press, 2004:291-307. Johnson MA, Hawthorne N, Brackett W, et al. Hyperhomocysteinemia and vitamin B12 deficiency in elderly using Title IIIc nutrition services. Am J Clin Nutr 2003;77:211-20. Jones NS, Davis A. A prospective case-controlled study of 197 men, 50-60 years old, selected at random from a population at risk from hyperlipidaemia to examine the relationship between hyperlipidaemia and sensorineural hearing loss. Clin Otolaryngol Allied Sci 1999;24(5):449-56. Jones NS, Davis A. A retrospective case-controlled study of 1490 consecutive patients presenting to a neuro-otology clinic to examine the relationship between blood lipid levels and sensorineural hearing loss. Clin Otolaryngol Allied Sci 2000;25(6):511-7. Lethbridge-Cejku M, Vickerie J. Summary health statistics for U.S. adults: National Health Interview Survey, 2003. National Center for Health Statistics. Vital Health Stat 10(225), 2005. Internet: http://www.cdc.gov/nchs/data/series/sr_10/sr10_225.pdf (accessed 17 April 2006). Martin DC, Francis J, Protetch J, Huff FJ. Time dependency of cognitive recovery with cobalamin replacement: report of a pilot study. J Am Geriatr Soc 1992;40(2):168-72. Newman CW, Sandridge SA. Hearing loss is often undiscovered, but screening is easy. Cleve Clin J Med 2004;71(3):225-32. Rosen S, Olin P. Hearing loss and coronary heart disease. Arch Otolaryg 1965;82:236-43. Rosen S, Olin P, Rosen HV. Dietary prevention of hearing loss. Acta Otolaryng 1970;70:242-7. Seidman MD, Khan MJ, Dolan DF, Quirk WS. Age-related differences in cochlear microcirculation and auditory brain stem response. Arch Otolaryngol Head Neck Surg 1996;122:1221-1226.

7 Shemesh Z, Attias J, Ornan M, Shapira N, Shahar A. Vitamin B12 deficiency in patients with chronic tinnitus and noise-induced hearing loss. Am J Otolaryngol 1993;2:94-9. Sikora MA, Morizono T, Ward WD, Paparella MM, Leslie K. Diet-induced hyperlipidemia and auditory dysfunction. Acta Otolaryngol 1986;102:372-81. Torre P 3rd, Cruickshanks KJ, Klein BEK, Klein R, Nondahl DM. The association between cardiovascular disease and cochlear function in older adults. J Speech Lang Hear Res 2005;48:473-81. Uchida Y, Nakashima T, Ando F, Niino N, Shimokata H. Is there a relevant effect of noise and smoking on hearing? A population-based aging study. Int J Audiol 2005;44:86-91. Wolters M, Ströhle A, Hahn A. Cobalamin: a critical vitamin in the elderly. Prev Med 2004;39:1256-66.

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CHAPTER 2 LITERATURE REVIEW Background and Significance The growth rate of the elderly population (over 65 years) has increased rapidly during the last few decades and will continue to increase for the next 50 years in the United States (U.S. Census, 2004). The number of people over 65 years was 36 million in 2003 and is expected to increase to nearly 55 million in 2020 and to 87 million in 2050 (U.S. Census, 2004; Federal Interagency Forum, 2004). About 88% of older adults were aged 65 to 84 years and 12% were aged 85 years and older in 2000 (U.S. Census, 2004). More than 96% of older adults live in the community rather than in long-term care facilities (Federal Interagency Forum, 2004). Human life expectancy also has increased dramatically during the last few decades. Those who are 65 years old today can expect to live more than 18 additional years, and 85-year-olds can expect to live more than six additional years (Federal Interagency Forum, 2004). With increased human longevity, healthy aging and well-being are important issues. As Americans live longer lives, more people will experience hearing loss, and hearing loss adversely affects the lives of older adults. Although hearing loss is common in older adults, healthy diet and lifestyle may delay the onset of hearing loss and diminish the severity of hearing impairment. Many studies have tried to find the possible association between auditory dysfunction and certain nutrients, life styles, or certain diseases. Research indicates that cardiovascular diseases (CVD) and CVD risk factors may contribute to hearing loss. Hearing loss was associated with high intake of saturated fats or cholesterol (Rosen et al., 1970; Sikora et al., 1986). Abnormal

9 blood lipids may enhance the adverse effects of noise on hearing loss, and auditory dysfunction was associated with hyperlipidemia or hypercholesterolemia (Axelsson and Lindgren, 1985; Rosen and Olin, 1965; Torre et al., 2005). Other CVD and CVD risk factors, such as stroke, hypertension, heart disease, coronary heart disease, myocardial infarction, smoking status, and diabetes mellitus, also have been associated with hearing loss (Gates et al., 1993; Torre et al., 2005; Cruickshanks et al., 1998a, 1998b; Frisina et al., 2006; Uchida et al., 2005). Research also has demonstrated that vitamin B12 deficiency may be linked to hearing loss. Poor vitamin B12 status was associated with auditory dysfunction in some studies (Houston et al., 1999; Quaranta et al., 2004; Gok et al., 2004; Shemesh et al., 1993), but not all studies (Berner et al., 2000; Durga et al., 2006). Tinnitus (ringing in the ears) (Shemesh et al., 1993) and auditory hallucinations (Hector and Burton, 1988) have been recorded as symptoms of vitamin B12 deficiency. Purpose The purpose of this literature review is to discuss the general knowledge of the human auditory system, the potential risk factors for hearing loss, and the possible role of CVD, CVD risk factors, and vitamin B12 in auditory function. First, the anatomy and function of the human auditory system, assessments of auditory function, exogenous factors affecting auditory dysfunction, and effects of the aging process on the auditory system will be reviewed. Second, the prevalence of hearing loss and the possible risk factors for hearing loss, such as cardiovascular disease events, cigarette smoking, diabetes, hyperlipidemia, and hypertension, will be reviewed. Third, the prevalence of vitamin B12 deficiency and functions of vitamin B12 will be reviewed.

Fourth, the possible association between auditory dysfunction and poor

vitamin B12 status will be reviewed.

10 The Human Auditory System Anatomy and Function The human auditory system is divided into four components: outer ear, middle ear, inner ear, and auditory nerve and central auditory pathways (Figure 2.1). Outer Ear The outer ear, consisting of the auricle (or pinna), external auditory canal, and tympanic membrane, is the canal by which sounds are initially introduced to the hearing mechanism (Martin and Clark, 2002). The auricle assists in gathering the sound, and the external auditory canal efficiently transfers the acoustic energy. The tympanic membrane, which is located at the end of the auditory canal, vibrates by the acoustic energy. The outer third of the external auditory canal contains hair follicles and cerumen, which help to prevent foreign objects from passing into the inner two-thirds of the external auditory canal. Deformities of the outer ear do not affect the sensorineural mechanism, but do affect the conductive mechanism. Middle Ear The middle ear is an air-filled cavity consisting of bones, windows, ligaments, and muscles (Martin and Clark, 2002). The mastoid is a non-solid bone surrounding the ear and honeycombed with air cells. These cells form the pneumatic mastoid of the temporal bone. Three miniature bones (malleus, incus, and stapes) are called the ossicles. The manubrium (handle) of the malleus is connected to the tympanic membrane, and the head part of the malleus is connected to the incus. The incus is connected to the stapes, which is the smallest bone in the human body. Vibrations of the tympanic membrane are transmitted to this ossicular chain and then to the oval window. The ossicles contribute to the transformation of acoustic energy to mechanical energy.

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Conductive portion

Sensorineural portion

Inner ear Outer ear

Middle ear

Age-related hearing loss

FIGURE 2.1 Human auditory system (Adapted from http://www.sirinet.net/~jgjohnso/earparts. jpg.)

12 There are two windows (oval and round) in the middle ear. The foot-plate of the stapes fits into the oval window. The sound pressure collected by tympanic membrane is concentrated on this oval window, consequently increasing the sound pressure. The promontory is positioned between the oval window and round window. There are two muscles (stapedius and tensor tympani) in the middle ear, and these muscles may protect the inner ear by stiffening the ossicular chain and thereby decreasing sound pressure reaching the inner ear. The stapedius muscle is innervated by a branch of the facial nerve. Upon contraction of the muscle, it is pulled posteriorly and stiffens the ossicle chain and tympanic membrane. The tensor tympani muscle is innervated by the trigeminal (Vth) cranial nerve, and the contraction of tensor tympani muscle moves the malleus, making the tympanic membrane tense. Abnormalities in the middle ear affect the conductive mechanism, but do not affect the sensorineural mechanism. Inner Ear The cochlea is located in the inner ear (Gate and Mills, 2005; Martin and Clark, 2002). The snail shell-like, fluid-filled cochlea (35 mm in length) consists of the scala vestibuli, scala media (cochlear duct), scala tympani, Reissner’s membrane (located between the scala vestibuli and scala media), basilar membrane (located between the scala media and scala tympani), and helicotrema (apex of the cochlea, which localizes low frequency). Energy transformation occurs in the inner ear from mechanical energy into electrochemical energy for transmission to the brain. The spiral ligament supports the scala media and stria vascularis. The stria vascularis, located on the lateral wall of the cochlea, produces the endolymph and provides nutrients and oxygen to the cochlea. The organ of Corti, which is the end organ of hearing system and contains sensory cells, is located on the basilar membrane in the scala media. The organ of Corti

13 contains outer hair cells, inner hair cells, the tunnel of Corti, and the tectorial membrane. Stereocilia (hairs) on the top of outer hair cells are embedded in the tectorial membrane. The direction of stereocilia has an important role. The bending of stereocilia one direction activates the hair cells and bending in the opposite direction inhibits the hair cells. Sound vibrations transmitted from the middle ear to the inner ear cause a disturbance of the fluids within the cochlea, which results in the deflection of the basilar membrane in a wavelike motion. This wavelike motion, referred to as the traveling wave, always moves from the base (detecting high frequency with shorter wavelengths) of the cochlea to the apex (detecting low frequencies with longer wavelengths). When the basilar membrane moves up and down, the hair cells are twisted in an intricate way. The exact mechanism of the organ of Corti is very complicated and is not fully understood. Twisted hair cells cause the cilia of hair cells to bend, which releases a chemical. This in-and-out cycle of the stereocilia of the outer hair cells stimulates auditory neurons, ultimately causing action potential. Fluids The cochlea has two different types of fluids (perilymph and endolymph). The scala vestibuli and scala tympani contain perilymph that is high in sodium and low in potassium. The scala media contains endolymph that is high in potassium and low in sodium. Due to high potassium content in endolymph, a strong positive potential (averaging 80 millivolts) is observed in endolymph when compared to perilymph in the scala tympani.

Perilymph in the scala

vestibuli exhibits positive and small potential (3 milivolts) compared to perilymph in the scala tympani. The remaining part of the cochlea shows negative direct current potential, and all of those potentials change.

14 Hair Cells and Auditory Neuron There are approximately three to five rows of 12,000 to 15,000 outer hair cells and one row of 3,000 inner hair cells on the basilar membrane (Martin and Clark, 2002). In the outer hair cells, the neuron contacts about 10 hair cells. Inner hair cells consist of approximately 25 nerve fibers, and each nerve fiber contacts one hair cell.

The cochlea contains 30,000 afferent

(sensory) neurons and 1,800 efferent neurons. The cell bodies for these neurons are located in the modiolus (central core of the cochlea) (Gate and Mills, 2005; Martin and Clark, 2002). The afferent neurons transmit electrical impulses from the cochlea to the central auditory nerve system, and the efferent axons project from the medial and lateral superior olivary complex in the brainstem to make contact with the hair cells. Auditory Nerve and Central Auditory Pathways The auditory nerves have two different types of fibers (type I and type II). Approximately 90% to 95% are type I fibers, which are big, myelinated, and bipolar neurons that stimulate inner hair cells. About 5% to 10% of fibers are type II fibers, which are small, unmyelinated neurons that supply efferent synapses with the outer hair cells (Gate and Mills, 2005). The nerve fibers course through the modiolus and through the internal auditory canal, which carries the cochlear branch of the auditory nerve (VIIIth cranial) (Martin and Clark, 2002). The auditory nerve fibers synapse at the level of the cochlear nucleus in the caudal portion of the brainstem. From the cochlear nucleus nerve fibers ascend in the central auditory nervous system synapsing with several nuclei along the way, including the superior olivary complex, lateral lemniscus, inferior colliculus, and medial geniculate body. From the medial geniculate body, auditory radiations project to the primary and secondary auditory cortex.

15 Assessment of Auditory Function The human auditory system has a conductive component (the outer ear and the middle ear) and a sensorineural component (the inner ear and the auditory nerve).

During air-

conduction measurements, sound travels through the outer ear, middle ear, inner ear, and neural pathways (Martin and Clark, 2002).

During bone-conduction measurements, sound energy

bypasses the outer ear and the middle ear, with minor exceptions, and reaches the inner ear directly. During a hearing assessment, pure tones of several different frequencies are presented to the listener. Audiometric results plotted on a graph with intensity represented on the Y axis and frequency shown on the X axis. The unit of measurement of sound intensity is the decibel (dB). Hearing threshold is defined as the lowest sound level that an individual can detect 50% of the time when it is presented and is expressed in dB hearing level (HL). Zero dB HL represents the average normal hearing of young adults. The ear exhibits different amounts of sensitivity to various frequencies. Most sensitive frequencies are in the range of 1000 hertz (Hz) to 4000 Hz in humans. Different amounts of pressure are required for 0 dB HL at various frequencies. Hearing thresholds can be determined by pure-tone audiometers, which generate a number of pure tones at various frequencies (from 125 to 8000 Hz). Air-conduction audiometry is used to specify the degree of hearing loss at different frequencies (from 250 to 8000 Hz). However, it cannot specify whether the hearing loss is produced by a defect in the conductive mechanism or the sensorineural mechanism, or both (Martin and Clark, 2002). Bone-conduction audiometry is used to determine the sensorineural activity level. The measurement can be done by placing a bone vibrator on the mastoid (bone behind the ears) or forehead. Various ranges of frequencies can be tested with bone-conduction audiometry.

Depending on the difference between the air-conduction and bone-conduction

16 thresholds (called air-bone gap), the types of hearing loss can be defined (e.g. conductive hearing loss, sensorineural hearing loss, or mixed hearing loss). If the air-bone gap is greater than 10 dB, it indicates a possible pathology in the middle ear. Conductive hearing loss demonstrates an impaired air-conduction threshold and a normal bone-conduction threshold due to damage, disease, or dysfunction of the outer or middle ear. Sensorineural hearing loss is one in which the hearing impairment results from structural damage or alteration to the inner ear (sensory) or auditory nerve dysfunction (neural). Sensorineural hearing loss displays impaired thresholds in both air-conduction and bone-conduction due to damage, disease, or dysfunction of the inner ear. Mixed hearing loss is a combination of conductive and sensorineural hearing loss due to dysfunction of the outer or middle ear and inner ear (Martin and Clark, 2002). Frequently, a person’s pure-tone average (PTA), the mean of three or four contiguous frequencies, is used to predict the degree of communication impact imposed by hearing loss. There are different categories to define hearing loss by the severity of hearing loss. When PTA is 25 dB or less, it is considered normal hearing. PTA from 26 to 40 dB is considered mild hearing loss, and hearing aids are probably considered. PTA from 41 to 55 dB is considered moderate hearing loss, and hearing aids are definitely considered. When PTA is between 56 and 70 dB, it is a moderately severe hearing loss. PTA from 71 to 90 dB is considered severe hearing loss. Lastly, when PTA is greater than 90 dB, it is considered profound hearing loss (Martin and Clark, 2002; Newman and Sandridge, 2004). Higher hearing threshold indicates poorer hearing sensitivity and greater difficulty hearing and understanding speech. The auditory brainstem response (ABR) measures responses from the synchronized activity of the auditory nerve and neural structures within the brainstem using an electrophysiological technique consisting of a series of waveforms. The ABR is used to monitor

17 the auditory system and to evaluate the neurological intactness of the brainstem (Martin and Clark, 2002; Boettcher, 2002). Each wave has different generating sites. Wave I and II are generated from the VIIIth cranial nerve. For the later waves that comprise the ABR, there is not a 1:1 correspondence between the generating site and the wave component. Clear responses are observed from waves I, III, and V. The ABR provides information on wave latency, interwave latency, and wave amplitudes. Hearing thresholds can be estimated by determining the lowest intensity for which wave V can be identified. The ABR is not affected by sleeping condition, and only one ear is tested at a time. The ABR is used to evaluate the neurological intactness of the brainstem and to estimate hearing sensitivity.

Prolonged interwave intervals, wave V

interaural latency difference, abnormal amplitude ratios, and prolonged or disappearance of the waves that comprise the ABR is an abnormal finding. Acoustic immittance measurements are used to identify abnormality in middle ear function, but do not provide information on the hearing levels (Martin and Clark, 2002). Three tests in acoustic immittance measurements are used in determining the presence or absence of normal middle ear function.

These measurements include static acoustic immitance,

tympanometric width, and middle ear pressure. Static acoustic compliance provides information on the compliance of the tympanic membrane as a function of the air pressure in the outer ear canal. Normal compliance values are between 0.3 and 1.6 cm3. A compliance value below the normal range is indicative of a stiffened middle ear system. The compliance value above the normal range is indicative of a hypercompliant middle ear system.

Tympanometric width

provides information about the shape of the tympanogram. The peak in the tympanogram defines middle ear pressure values.

In the normal ear, peak compliance generally occurs

between + 50 and - 150 decaPascals (the unit of measurement) (Martin and Clark, 2002).

18 The acoustic reflex is another component of the acoustic immittance battery. This reflex measures the contraction of the middle ear muscles in response to intense sounds. In individuals with normal hearing, the middle ear reflex will occur at the 85 dB sensation level. The reflex will be absent in individuals with conductive hearing loss or cochlear hearing loss. The Biological Basis of Hearing Loss in Older Adults Age-related hearing loss, known as presbycusis, is a loss of hearing caused by the aging process and is usually a sensorineural hearing disorder (Gates and Mills, 2005; NIDCD, 2006a). Presbycusis is related to deterioration of cochlear hair cells and spiral ganglion cells (Schuknecht and Gacek, 1993) and is one of most common chronic impairments in older adults (Cruickshanks et al., 1998a, 1998b; Gates and Mills, 2005). The progressive loss of hearing sensitivity with advanced age is due largely to disorders of the peripheral auditory system, specifically abnormalities within the cochlea (Jerger et al., 1995; Mosciki et al., 1985). The cochlea is the auditory portion of the inner ear that rests within a bony spiral canal that contains fluid-filled membranous channels (Martin and Clark, 2002).

Although the nature of the impairment

associated with presbycusis is well-documented and some areas in the auditory system that are affected have been identified, the causes of hearing loss remain unknown. It is likely that accumulation of chronic noise exposure and other environmental agents (e.g., toxic substances or drugs) in daily life contribute to hearing loss in some older adults (Brant et al., 1996; Gates et al., 1990). Furthermore, there is a genetic link to the degree to which someone loses hearing with advanced age (Gates et al., 1990; Moscicki et al., 1985). Older adults with presbycusis have difficulty understanding speech (worse with presence of background noise) and high-pitch sounds (e.g., ringing of a telephone or high-pitched women’s voices) (Johnson et al., 2004; Gate and Mills, 2005; Martin and Clark, 2002).

19 Individuals with presbycusis may experience a variety of difficulties such as people’s speech seems mumbled, slurred, unclear and low in volume; high-pitched sounds such as "s" and "th" are difficult to hear and distinguish; conversations are difficult to understand, particularly with background noise; higher pitched women’s voices are more difficult to hear than men’s voices; and some sounds seem annoying or overly loud (Johnson et al., 2004; NIDCD, 2006a). The characteristic of presbycusis is elevated hearing thresholds at high frequencies at the beginning and then progressing to low frequencies with the passage of time (Parham, 1997; Gates and Mills, 2005). Some older adults also experience tinnitus, which is a ringing, roaring and/or hissing sound in one or both ears. Hearing problems can make it very difficult for an older adult to understand and follow health advice from their physician and other health professionals (Johnson et al., 2004; NIDCD, 2006b). Presbycusis can be classified into four categories (Martin and Clark, 2002). First, sensory presbycusis is caused by a loss of sensory cells of hearing such as outer hair cells and supporting cells in the cochlea. Individuals with sensory presbycusis experience greater hearing loss at higher frequencies. Second, neural presbycusis is caused by a loss of neurons in the cochlea, resulting in poor speech recognition. Third, strial presbycusis is caused by atrophy of the stria vascularis in the cochlea, which does not affect speech recognition. Fourth, cochlear conductive presbycusis is caused by impaired mobility of the cochlear divisions, resulting in sensorineural hearing loss.

20 The Prevalence of Hearing Loss Approximately 31 million Americans have hearing impairment (Kochkin, 2005). The prevalence of hearing loss increases greatly with advanced age and is greater in men than in women (Torre et al., 2005; Moscicki et al., 1985; Cruickshanks et al., 1998b). In the 2003 National Health Interview Survey, 6.9 % of people aged 18 to 44 years, 17.6% of people aged 45 to 64 years, 29.7% of people aged 65 to 74 years, and 46.4% of people aged 75 or older had selfreported difficulty in hearing (Lethbridge-Cejku and Vickerie, 2005). In the Framingham Heart Study Cohort, 83.0% had age-related hearing loss in 2,293 participants aged 57 to 89 years (Moscicki et al., 1985). This may be due to a strict definition of hearing loss (defined as hearing thresholds > 20 dB HL in any one of frequencies from 0.5 to 4 kHz) in the study. In the Health, Aging, and Body Composition study, 59.9% had hearing loss (defined as PTA across 0.5, 1, and 2 kHz > 25 dB HL in the worse ear; N = 2,052; aged 73 to 84 years, Helzner et al., 2005). The high prevalence of hearing loss is a worldwide problem among adults. In Israel, the prevalence of hearing loss was 4.5% in adults younger than 35 years and 10.5% over 35 years old in 13,308 men (aged 20 to 68 years) (Sharabi et al., 2002). In an Italian study, 27.2% of older adults (N = 1,332; aged 65 to 96 years) had self-reported hearing loss (Cacciatore et al., 1999). In an Australian study, 86% had hearing loss (defined as PTA across 0.5, 1, 2, and 4 kHz > 25 dB HL in the best ear) in 93 community-dwelling older adults (aged 65 to 99 years) with poor health status (Jee et al., 2005). Of those with hearing loss, 35.5% had mild hearing loss (PTA 26 to 40 dB HL), 33.3% had moderate hearing loss (PTA 41 to 60 dB HL), and 17.2% had severe hearing loss (PTA > 60 dB HL).

21 Hearing Loss and Quality of Life in Older Adults Hearing loss adversely affects the lives of older adults and has enormous costs related to poor quality of life (Johnson et al., 2004). Even mild hearing loss is associated with impaired quality of life and functional disabilities, and adverse effects on physical, cognitive, emotional, behavioral, and social function (Jerger et al., 1995; Dalton et al., 2003; Bazargan et al., 2001; Gates and Mills, 2005) as well as mental and emotional problems such as fear, anger, depression, frustration, embarrassment, anxiety, withdrawal, emotional ability, aloofness, paucity of speech, and confusion or dementia (Mader, 1984; Cacciatore et al., 1999). Hearing loss and activity limitation was examined in participants (N = 8,767) aged 70 years or older from the 1994 National Health Interview Second Supplement on Aging (Campbell et al., 1999). Older adults with impaired hearing were more likely to report activity limitations than those with normal hearing, such as difficulties in walking (30.7% vs. 21.3%, respectively), getting outside (17.3% vs. 12.0%), getting into and out of bed or a chair (15.1% vs. 9.8%), managing medication (7.7% vs. 4.8%), and preparing meals (11.6% vs. 7.6%). Thus, hearing impairment in older adults can lead to frustrating, embarrassing, and even dangerous situations (Johnson et al., 2004; NIDCD, 2006a, 2006b). For example, older adults with impaired hearing cannot hear others trying to alert them when dangers are nearby, such as sirens, horns, and other types of alarms.

22 Risk Factors for Hearing Loss Hearing loss or deafness has been associated with a variety of factors including genetics, noise or trauma, sensitivity to certain drugs or medications, viral or bacterial infections, lifestyles (diets, alcohol drinking, physical activities, and smoking), health status, environment, and aging process (Gates and Mills, 2005; Johnson et al., 2004). Despite the prevalence of high hearing loss among older adults, there has been no comprehensive and systematic research effort directed toward understanding the possible interactions among poor diet, genetic disorders, and agerelated hearing loss. Thus, there is a profound gap in our knowledge concerning the role of these factors in hearing loss in older adults (Johnson et al., 2004). Research on the relationships of age-related hearing loss with nutritional status may lead to identification of risk factors for age-related hearing loss and possibly to prevention and treatment strategies aimed at reducing the prevalence and progression of this devastating disorder. Age-related hearing loss has been related to vascular disease and neural degeneration or disorder (Gate et al., 1993; Seidman et al., 1996). The vascular and neural systems depend on certain nutrients, such as vitamin B12 and folate, for optimal structures and functions (Johnson et al., 2004). The working model for exploring the associations of nutrition and age-related hearing loss is illustrated in Figure 2.2 (Johnson et al., 2004).

23

Advancing Age Genetics

Poor Nutritional Status: • Vitamin D • Calcium • Vitamin B12 • Folate Poor Gastric Function CVD Risk Factors

Age-Related Hearing Loss

Degeneration of: • Vascular System • Nervous System • Skeletal System

FIGURE 2.2 Working model for hypothesized relationships of nutrition with age-related hearing loss (Adapted from Johnson et al., 2004 with permission)

24 Cardiovascular Disease and Hearing Loss Vascular disorders in the cochlea and arteriosclerosis may contribute to sudden deafness, presbycusis, and inherited deafness (Kimura, 1986; Makishima, 1978). Several lines of evidence suggest that hearing impairment may be associated with cardiovascular disease (CVD) (e.g., coronary heart disease, heart attack, and intermittent claudication) and/or CVD risk factors (e.g., diabetes, hypertension, hyperlipidemia, and smoking habit) (Brant et al., 1996; Gates et al., 1993; Cruickshanks et al., 1998b; Pillsbury, 1986; Gates and Mills, 2005; Rosen and Olin, 1965; Torre et al., 2005; Durga et al., 2006). In the Epidemiology of Hearing Loss Study, self-reported histories of CVD, pure-tone air- and bone-conduction audiometry, and distortion product otoacoustic emissions were obtained in 1,501 participants aged 43 to 84 years in the United States (Torre et al., 2005). Cochlear function was measured based on distortion product otoacoustic emissions, and cochlear impairment was defined as < +9 dB distortion product otoacoustic emissions/noise ratio at 2, 3, and 4 kHz.

Self-reported history of myocardial infarction was correlated with cochlear

dysfunction in women, but not in men, after controlling for lifestyle factors (e.g. smoking, diabetes, noise exposure, activity, alcohol, and age). However, other CVD variables (e.g. selfreported stroke, brain hemorrhage, and angina) were not correlated with cochlear dysfunction. In the Framingham cohort study, hearing loss at low frequencies in the worse ear (0.25, 0.5, and 1 kHz) was significantly correlated with documented coronary heart disease (CHD) while hearing impairment at low frequencies in the better ear was significantly correlated with stroke (676 men; Gates et al., 1993). In women (n = 996), hearing loss at low frequencies in the better ear was correlated with CVD, CHD, and intermittent claudication, whereas hearing loss at low frequencies in the worse ear was correlated with CVD and stroke.

25 In a cross-sectional study in the Netherlands, self-reported family history of premature vascular disease (onset < 60 years in first degree family) was significantly associated with PTAlow frequencies (0.5, 1, and 2 kHz), and self-reported vascular diseases were significantly related with PTA-high frequencies (4, 6, and 8 kHz) in 728 older adults (aged 50 to 70 years) (Durga et al., 2006). In contrast, in a cross-sectional analysis of the Health, Aging, and Body Composition study, myocardial infarction or congestive heart failure were not associated with hearing loss (defined as PTA across 0.5, 1, and 2 kHz > 25 dB HL in the worse ear; N = 2,052; aged 73 to 84 years) (Helzner et al., 2005). Cerebrovascular disease significantly increased risk of hearing loss by 56%. Drettner et al. (1975) found no significant relationship between CVD risk factors and sensorineural hearing loss (SNHL) in 1,000 men with a mean age of 50 years. Kent et al. (1986) found no significant correlation between noise-induced hearing loss (NIHL) and CVD in 2,250 air force aircrew population (aged 19 to 57 years). In this study, cardiovascular function was measured by systolic and diastolic blood pressure and clinical diagnoses of CVD. It is not clearly understood whether there is a direct relationship between hearing loss and CVD, or if the association is mediated indirectly (Gates et al., 1993). CVD may decrease blood supply to the cochlea and cause cochlea degeneration and cochlear dysfunction (Torre et al., 2005). Severe spiral ganglion atrophy was observed in patients with arterial and arteriolar sclerosis (N = 40; > 50 years) (Makishima, 1978). Also, a positive correlation was found between the degree of lumen narrowing of the internal auditory artery and the degree of spiral ganglion atrophy in the patients. This study suggested that spiral ganglion atrophy caused by chronic reduction of blood supply due to arteriolar sclerosis might be the primary cause of the

26 hair cell lesion. Additional research is needed to identify the mechanisms and metabolic defects responsible for the auditory dysfunction associated with CVD. Cigarette Smoking Status and Hearing Loss Many studies have examined the possible relationship between auditory dysfunction and cigarette smoking (Barone et al., 1987; Cunningham et al., 1983; Nakanishi et al., 2000; Sharabi et al., 2002; Siegelaub et al., 1974; Nomura et al., 2005a, 2005b; Burr et al., 2005; Ferrite and Santana, 2005; Itoh et al., 2001; Cruickshanks et al., 1998b). Several large population-based studies have shown the possible association between hearing loss and smoking status. In a cross-sectional study [Epidemiology of Hearing Loss Study (EHLS)], self-reported history of cigarette smoking and PTA (0.5, 1, 2, and 4 kHz) were obtained in 3,753 adults (aged 48 to 92 years) (Cruickshanks et al., 1998b). The prevalence of hearing loss (defined as PTA > 25 dB HL in the worse ear) was significantly higher in current smokers than in nonsmokers. After controlling for other factors (age, history of CVD, alcohol consumption, occupational noise exposure, and education), smokers were more likely to have hearing loss than the nonsmokers [odd ratio, 1.69; 95% confidence interval (CI), 1.31-2.17]. Furthermore, a significant association was found between hearing loss and pack-years of smoking; heavy smokers (≥ 40 pack-years) were more likely to have hearing loss than non-heavy smokers (0 pack-years; odd ratio, 1.3; 95% CI, 1.04-1.63). Nondahl et al. (2004) examined a possible relationship between serum cotinine and hearing loss in a nested cross-sectional and case-control study in the EHLS (197 participants with hearing loss and age matched 394 controls; aged 53 to 75 years). Cotinine is a metabolite of nicotine and a biomarker of measuring short-term tobacco exposure (Bramer and Kallungal, 2003).

No significant association of

hearing loss with serum cotinine or self-reported smoking status was found in this study.

27 In a cross-sectional analysis of the Health, Aging, and Body Composition study, current smokers had a significantly higher risk (by 68%) of hearing loss (defined as PTA across 0.5, 1, and 2 kHz > 25 dB HL in the worse ear) than non-smokers in older adults (N = 2,052; aged 73 to 84 years) (Helzner et al., 2005). Additionally, past smoking status was not associated with hearing loss. In a Japanese Longitudinal Study of Aging, air-conduction pure-tone thresholds at octave intervals from 0.5 to 8 kHz and self-reported smoking status were obtained in adults (N = 1,478; aged 40 to 79 years) (Uchida et al., 2005). Smokers had significantly higher hearing thresholds at 4 kHz (but not other test frequencies) than non-smokers in men (but not in women) in the better ear and the worse ear. Itoh et al. (2000) conducted an epidemiological study in Japan, and information on airconduction thresholds and self-reported smoking habits was collected in older adults (n = 496; aged 60 to 80 years) with bilateral hearing loss (hearing threshold > 40 dB HL at 4 kHz) and in the age-matched controls (n = 2,807) without bilateral hearing loss (hearing threshold ≤ 40 dB HL at 4 kHz for both ears). Current smokers had a significantly higher risk for developing hearing loss than non-smokers after controlling for age and gender (odd ratio, 2.29; 95% CI, 1.68-3.12). However, pure-tone thresholds and otoscopic evaluation were not performed in this study. In contrast, in the Baltimore Longitudinal Study of Aging, cigarette smoking was not significantly associated with hearing loss (defined as PTA across 0.5, 1, 2, and 3 kHz ≥ 30 dB HL in either ear) in 531 men and 310 women (Brant et al., 1996). In the Danish Work Environment Cohort Study, information on the self-reported hearing loss and smoking status was obtained in adults (N = 7,221; aged 18 to 59 years) (Burr et al., 2005). Significantly higher risk for hearing loss was found in smokers than non-smokers among

28 women, but not among men. In a five-year follow-up study, participants did not have hearing loss or head injury at baseline (n = 4,766). Five-year incidence of hearing loss was significantly higher in smokers than non-smokers among men, but not among women. However, data for hearing loss was obtained by a self-reported questionnaire, so the prevalence of hearing loss may be underestimated. In a retrospective cross-sectional study conducted in Israel, pure-tone hearing thresholds were measured from 0.25 to 8 kHz in men (N = 13,308; aged 20 to 68 years) (Sharabi et al., 2002). Smoking increased the risk for developing hearing loss by 45% compared to nonsmokers. Current smokers had significantly higher risk for developing conductive hearing loss (odd ratio, 1.85; 95% CI, 1.31-2.27) and SNHL (odd ratio, 2.16; 95% CI, 1.06-3.26) than non-smokers. In contrast, Pyykkö et al. (1988) found no significant relationship between SNHL and smoking status in 199 professional forest workers at 4 kHz. In a cross-sectional study conducted in the Netherlands, hearing thresholds were not independently associated with smoking status in 728 older adults (aged 50 to 70 years) (Durga et al., 2006). A possible association among cigarette smoking, occupational exposure to noise, and hearing loss were examined in several studies. Nakanishi et al. (2000) found that the higher number of cigarettes smoked per day the greater the risk for developing hearing loss at high frequency (≥ 40 dB HL at 4 kHz at least one ear) but not at low frequency (≥ 30 dB HL at 1 kHz at least one ear) in 1,554 male office workers (aged 30 to 59 years) with low noise exposure during five years of follow-up in Japan. In another Japanese study, pure-tone threshold at 4 kHz were measured in 397 metal factory workers [mean age (± SD): 42 ± 11 years] with occupational noise exposure (Nomura et al., 2005a). Participants with hearing loss (≥ 40 dB HL at 4 kHz) were more likely to be past smokers.

Hearing loss was associated with smoking and

29 occupational noise exposure. Ferrite and Santana (2005) conducted a cross-sectional study in Brazil, and pure-tone thresholds were obtained in men (N = 535; aged 20 to 55 years) working at a large metal plant. The combination of noise exposure and smoking had a significantly positive association with hearing loss (defined as hearing threshold > 25 dB HL at one of 3, 4, 6, and 8 kHz), but smoking alone did not have a significant effect on hearing loss, which suggests a synergistic effect of smoking and noise exposure on auditory dysfunction. Wild et al. (2005) evaluated a possible association between NIHL and long-term occupational noise exposure (≥ 10 years working at the brick manufacturing plant) in 88 men (mean age, 46.7 years) in a prospective observational cohort study. Smokers had significantly higher hearing thresholds at 3 and 4 kHz than non-smokers, which indicates poorer hearing status among the smokers compared to non-smokers. This study suggested that long-term smoking status may exacerbate NIHL. Limitations of this study were that no control group was included in this study, and the sample size was relatively small. Palmer et al. (2004) found that cigarette smoking was a risk factor for self-reported hearing impairment without occupational noise exposure in participants (N = 12,907; aged 16 to 64 years) in the United Kingdom. This risk for hearing loss further increased with the number of years exposed to noise. In contrast, Starck et al. (1999) found no significant difference on hearing thresholds between smokers and non-smokers (199 forest workers and 171 shipyard workers; aged 21 to 60 years) with occupational noise exposure. In a meta-analysis, 15 observational studies (10 cross-sectional, 4 cohort, and 1 casecontrol) were included to examine whether smoking caused hearing loss (Nomura et al., 2005b). This study found that smoking increased the risk for developing hearing loss. It is not clear whether or not smoking directly causes hearing loss, but smoking cessation may be a useful tactic for retaining auditory function.

30 The mechanisms by which smoking may cause hearing loss are not entirely known. Smoking negatively affects the cochlear artery by elevating carbon monoxide and nicotine levels in the blood. High carbon monoxide and nicotine levels may contract blood vessels or cause vasospasm and thrombotic occlusions (Zelman and Kan, 1973). Smoking may cause hearing loss at high frequencies by impairing the vascular system in the cochlear artery (Nakanishi et al., 2000). Another possible mechanism is that smoking may increase blood viscosity and damage sensory cells (Nakanishi et al., 2000). Male smokers had higher hematocrit, plasma fibrinogen concentration, and plasma viscosity than non-smokers (Rampling, 1999).

Multi-center

longitudinal studies with all age populations and a control group well-matched for all known confounding variables are needed to identify the mechanisms and metabolic defects responsible for the association of auditory dysfunction with smoking status. Diabetes Mellitus and Hearing Loss Several studies have examined the association between hearing loss and diabetes mellitus, but the findings are inconsistent (Frisina et al., 2006; Ishii et al., 1992; Assimakopoulos et al., 2001; Niedzielska and Katska, 1998). In a cross-sectional analysis of the Health, Aging, and Body Composition study, diabetes mellitus was significantly associated with a 42% higher risk of hearing loss (defined as PTA across 0.5, 1, and 2 kHz > 25 dB HL in the worse ear; N = 2,052; aged 73 to 84 years) (Helzner et al., 2005). In a population-based longitudinal study conducted in Beaver Dam, WI (the EHLS and the Beaver Dam Eye Study), PTA (0.5, 1, 2, and 4 kHz) was calculated in older adults with type II diabetes (aged 43 to 84 years, n = 344) and in participants without diabetes (n = 3,029) (Dalton et al., 1998). Participants with type II diabetes had significantly higher hearing thresholds (33.3 vs. 26.9 dB HL, respectively) than those without type II diabetes. A significantly greater

31 prevalence of hearing loss (defined as PTA > 25 dB HL) was found in diabetic participants compared to non-diabetic individuals (59% vs. 44%, respectively), but after controlling for age, this significance disappeared. Subset analyses were conducted after excluding individuals with hearing loss inconsistent with age-related hearing loss. A significant relationship between type II diabetes and age-related hearing loss was found in this subset analyses (odd ratio, 1.41; 95% CI, 1.05-1.88). Additionally, there was a significant association between hearing loss (odd ratio, 2.28; 95% CI, 1.04-5.00) and the presence of complications of diabetes (e.g. nephropathy). However, hemoglobin A1c was not associated with hearing loss.

This population-based

longitudinal study suggested that there is a weak association between hearing loss and type II diabetes. In contrast, in the Framingham cohort study, Gates et al. (1993) found no relationship between hearing thresholds and the presence or absence of diabetes mellitus or glucose intolerance in men and women (N = 1,662). In a cross-sectional study in the Netherlands, hearing thresholds were not independently associated with self-reported diabetes mellitus in older adults (N = 728; aged 50 to 70 years) (Durga et al., 2006). Four different PTAs were measured in 60 older adults with type II diabetes (n = 30; aged 59 to 92 years) and in those without type II diabetes (n = 30; aged 59 to 88 years); PTA-1 (0.5, 1, and 2 kHz), PTA-2 (1, 2, and 4 kHz), PTA-3 (4, 8, and 9 kHz), and PTA-4 (10, 11, 12, and 14 kHz) (Frisina et al., 2006). Participants with type II diabetes had significantly higher hearing thresholds in all four PTAs in both ears than those without type II diabetes, which indicates that diabetic individuals have poorer hearing status than non-diabetic participants. This hearing difference between diabetic and non-diabetic groups was greater at low frequencies than at high frequencies.

32 In a Mexican study, the association between type II diabetes and auditory function was examined using pure-tone audiometry and auditory brainstem response (ABR) in 188 older adults [mean age ± (SD): 50 ± 6 years; 94 diabetic participants and 94 healthy controls] (Díaz de León-Morales et al., 2005). Participants with type II diabetes had significantly higher PTA at high frequencies (2, 4, and 8 kHz) and higher hearing threshold at 8 kHz than the control group. However, the PTAs at low frequencies (0.125, 0.25, and 0.5 kHz) and at middle frequencies (0.5, 1, and 2 kHz) were not different between the groups. The ABR results showed that diabetic participants had significantly prolonged latency of wave V and interwave I-V and III-V latencies compared to the control group. This study indicated that participants with type II diabetes had impaired hearing status and impaired ABR. The possible association between diabetes and NIHL has been evaluated in various studies. In a retrospective study, Ishii et al. (1992) examined men with occupational noise exposure of approximately 30 years (N = 229; aged 55 to 68 years). In this study, NIHL was defined as hearing level ≥ 65 dB HL at 3, 4, or 6 kHz in at least one ear with ± 20 dB thresholds in the contralateral ear.

A significantly higher prevalence of type II diabetes was observed in

men with severe NIHL than in those with non-severe NIHL (16.4% vs. 4.8%, respectively). Nomura et al. (2005a) found that metal factory workers (n = 55; aged 21 to 66 years) with NIHL (defined as hearing level > 40 dB HL at 4 kHz) had significantly higher hemoglobin A1c than those with normal hearing (n = 342) in Japan. Vaughan et al. (2006) conducted a five-year prospective study examining a veteran population (N = 694; aged 25 to 83 years) at the National Center for Rehabilitative Auditory Research at the Veterans Affairs Medical Center in Portland. Diabetic patients aged 60 or younger had higher prevalence of hearing loss at high frequencies (> 8 kHz) than the age-matched control group, but this pattern was not observed in patients older

33 than 60 years. However, one limitation in this study was not including a control population (only the veteran population was used). In a retrospective study, the effect of diabetes on SNHL was examined in 66,036 participants (12,575 diabetic patients and 53,461 age-matched non-diabetic patients) (Kakarlapudi et al., 2003). The database at the Veterans Affairs Maryland Health Care System was used, and this database has a large population of patients receiving care for a single problem. A significantly higher prevalence of SNHL was observed in the diabetic group than in the nondiabetic group (13.1% vs. 10.3%, respectively). However, information on age was not provided in this study. In contrast, self-reported diabetes mellitus was not associated with SNHL in men aged 50 to 60 years (197 patients with SNHL; 237 controls from National Study of Hearing data) (Jones and Davis, 1999). A possible association between idiopathic sudden hearing loss (ISHL) and type II diabetes was evaluated in a Japanese study (Fukui et al., 2004). ISHL is defined as deafness of sudden onset (≤ three days) with unknown origin. Among 148 patients with ISHL, 16.2 % had type II diabetes, and these diabetic patients had more severe hearing loss than non-diabetic patients. One of the limitations of this study was not including a healthy control group such as people without ISHL. In a case-report study, a 44-year-old man had a sudden sensorineural hearing loss (SSNHL) at all test frequencies from 0.5 to 8 kHz (Assimakopoulos et al., 2001). Biochemical tests showed elevated hemoglobin A1c (8.5%), hyperglycemia, and glycosuria. The diagnosis was made as type II diabetes.

Following insulin treatment for four days, rapid hearing

improvement was observed, and after the fourth day of insulin treatment, hearing levels were

34 stabilized. Even though this is only one case study, this study suggested that sudden hearing loss may be a symptom of diabetes mellitus. Few studies have examined the relationship between hearing loss and type I diabetes. Children and adolescents (n = 63; < 18 years) with type I diabetes had hearing loss (> 25 dB HL in any test frequency) at middle and high frequencies (2 to 8 kHz), while the matched nondiabetic group (n = 63) did not have hearing loss (Elamin et al., 2005). In another study, 37 children aged 6 to 18 years with type I diabetes had ABR disturbances, such as elongation of the latency of wave I, III, and V without hearing loss, suggesting a conduction disturbance (Niedzielska and Katska, 1998). In contrast, no significant difference in auditory function was found in children with type I diabetes (n = 51, aged 8 to 21 years) compared to non-diabetic children (n = 13). This may be due to the small sample size (Sieger et al., 1983). The mechanisms by which diabetes mellitus may cause auditory dysfunction are not fully known. Diabetic patients had 10-20 times thicker capillary walls of the stria vascularis in the cochlea than those without diabetes (Jorgensen, 1961). The changes in the vascular system caused by diabetic complications (angiopathy) may impair inner ear and facial nerve function (Jorgensen, 1961). Elevated glucose concentrations may cause auditory dysfunction. Diabetes may increase outer hair cell loss in the mid-portion of the cochlear (Triana et al., 1991). Noninsulin-dependent diabetic rats had significant outer hair cell loss in the cochlea compared to non-diabetic rats, which suggests possible inner ear damage, particularly outer hair cell loss, may be caused by hyperglycemia (Rust et al., 1992). High glucose levels may damage the cochlear nerves by changing the osmolality, blood viscosity, and aggregation of platelets. These may cause microthromboses related to the cochlear nerve (Assimakopoulos et al., 2001). Patients with type II diabetes had higher whole blood viscosity, plasma viscosity, and fibrinogen level

35 than healthy controls, but no difference was found in hematocrit between groups (Rampling, 1999). Several reviewers concluded that there may be an association between diabetes and hearing loss, but it is not clear whether or not diabetes mellitus directly causes hearing loss (Fowler and Jones, 1999; Maia and de Campose, 2005). Multi-center longitudinal studies with all age populations with a control group well-matched for all known confounding variables are needed to identify the mechanisms and metabolic defects responsible for the association of diabetes mellitus with auditory dysfunction. Hyperlipidemia and Hearing Loss Several studies suggested hyperlipidemia or hypercholesterolemia as risk factors for hearing loss. In a Japanese study (607 men and 317 women; aged 40 to 59 years), mean hearing levels in the better ear were measured from 0.125 to 8 kHz in participants with no history of noise exposure or disease associated with hearing loss (Suzuki et al., 2000). Low serum highdensity lipoprotein (HDL) cholesterol concentration was significantly related to hearing loss at 2 and 4 kHz in men. However, total serum cholesterol and total triglyceride concentrations were not significantly associated with hearing loss.

In another Japanese study, air-conduction

thresholds and concentrations of total cholesterol and triglycerides were measured in older adults (n = 496; aged 60 to 80 years) with bilateral hearing loss (hearing threshold > 40 dB HL at 4 kHz) and age-matched controls (n = 2,807) without bilateral hearing loss (hearing threshold ≤ 40 dB HL at 4 kHz for both ears) (Itoh et al., 2001). Conversely, high fasting total cholesterol concentration significantly lowered the risk for hearing loss. Durga et al. (2006) conducted a cross-sectional study in the Netherlands and found that hearing thresholds were not independently associated with hypercholesterolemia (defined as total cholesterol > 6.5 mmol/L,

36 HDL cholesterol < 0.9 mmol/L, or the use of lipid-lowering medication) in older adults (N = 728; aged 50 to 70 years). Hyperlipidemia, noise exposure, and auditory dysfunction were examined in animal and human studies.

Chinchillas (aged 0.5 to 2 years) were fed either a normal diet or a 1%

cholesterol diet for six months (Sikora et al., 1986). In addition to the diet, chinchillas were either exposed to no noise or noise (with intensity levels of either 105 or 114 dB). Without noise exposure, chinchillas fed the 1% cholesterol diet had significantly worse hearing status than those fed the control diet at high frequencies (8, 12, and 16 kHz). Pillsbury (1986) found that with noise exposure, spontaneously hypertensive rats fed an atherogenic diet (high in cholesterols and triglycerides) had worse auditory acuity than hypertensive rats fed a normal diet. Tami et al. (1985) examined the effects of noise exposure and hypercholesterolemia on auditory function measured by ABR in three groups of eight-week-old male rabbits (N = 11; regular diet/noise; 2% cholesterol diet/noise; or regular diet/no noise). Hypercholesterolemia alone had no effect on auditory dysfunction.

In a human study, the synergistic effect of noise and

hypercholesterolemia on hearing loss was shown in 78 men aged 50 years with serum cholesterol level > 7 mmol/L and 75 men aged 50 years with serum cholesterol level < 7 mmol/L (Axelsson and Lindgren, 1985).

Men with high serum cholesterol concentrations and elevated noise

exposure had a greater risk (relative risk, 2.6; CI, not provided) for NIHL than participants with low serum cholesterol concentrations and elevated noise exposure (relative risk, 1.8; CI, not provided). Information on noise exposure was obtained by a self-reported questionnaire. In the condition of low noise exposure, high cholesterol concentrations alone did not increase the risk of NIHL.

In a Japanese study, concentrations of total cholesterol, HDL cholesterol, and

triglycerides and pure-tone threshold at 4 kHz were measured in 397 metal factory workers

37 [mean age (± SD): 42 ± 11 years] with occupational noise exposure (between 85 dB and 95 dB) (Nomura et al., 2005a). These blood lipids (total cholesterol, HDL cholesterol, and triglycerides) were not significantly associated with hearing loss (defined as hearing threshold ≥ 40 dB HL at 4 kHz) in this population. The effects of a high cholesterol diet on hearing loss were examined in participants aged 40 to 59 years (N = 278) in Finland (Rosen et al., 1970). Participants who consumed a diet with high saturated fatty acids for five years had poorer hearing status than those who consumed a diet with more unsaturated fatty acids and less saturated fatty acids for five years, regardless of age, at all test frequencies (0.5, 1, 2, and 4 kHz). In the same study, when participants switched from a diet with high saturated fatty acids to a diet with low saturated fatty acids for three and a half years, their hearing status was improved. When participants changed from a diet with low saturated fatty acids to a diet with high saturated fatty acids, their hearing status worsened (Rosen et al., 1970). In contrast, Jones and Davis (1999) found no significant associations of fasting low-density lipoprotein (LDL) cholesterol, HDL cholesterol, total cholesterol, and triglycerides with SNHL in 197 men (aged 50 to 60 years) with risk factors for ischemic heart disease. The mechanisms by which hyperlipidemia may cause hearing impairment are not fully understood.

Hyperlipidemia may impair auditory function by causing vascular disease,

atherosclerosis, reducing blood and oxygen supply, and agglutination of erythrocytes and platelets in the inner ear (Morizono and Paparella, 1978). Low HDL cholesterol concentration may increase the risk of atherosclerosis-related microcirculatory disorders of the cochlear vascular system and may increase susceptibility to noise in the cochlea (Suzuki et al., 2000).

38 Additional studies with large populations and well-matched control groups for all known confounding variables are needed to identify the mechanisms and metabolic defects responsible for the association of hyperlipidemia with hearing impairment. Hypertension and Hearing Loss The possible connection between hearing loss and hypertension has been examined, but the findings are conflicting.

Few population-based studies have examined whether or not

hypertension has a negative effect on hearing. In the Baltimore Longitudinal Study of Aging, blood pressure and pure-tone thresholds (0.5, 1, 2, and 3 kHz) were measured in 531 men and 310 women (Brant et al., 1996). All participants had PTA (0.5, 1, 2, and 3 kHz) less than 20 dB HL for either ear at baseline, normal otologic history, and no history of noise exposure. The maximum follow-up was 22.8 years in men and 13 years in women in the longitudinal hearing data. Approximately 8.7% of 531 men and 2.3% of 310 women developed hearing loss (defined as PTA across 0.5, 1, 2, and 3 kHz ≥ 30 dB HL in either ear) during the follow-up period. Systolic blood pressure was significantly associated with hearing loss (relative risk, 1.32 for a 20 mmHg rise in systolic blood pressure after controlling for age). Furthermore, high systolic blood pressure had a statistically significant effect on the onset of hearing loss at all ages. In the EHLS, however, hypertension was not significantly correlated with cochlear dysfunction (defined as < +9 dB distortion product otoacoustic emissions/noise ratio at 2, 3, and 4 kHz) in a population based study (N = 1,501; aged 43 to 84 years) (Torre et al., 2005). Hypertension and auditory dysfunction were examined in other human and animal studies. A positive correlation between hypertension (defined as both a systolic blood pressure >160 mmHg and a diastolic blood pressure > 90 mmHg) and hearing loss was found in patients with arteriolar sclerosis as a cause of age-related hearing loss (N = 40; > 50 years) (Makishima, 1978).

39 In a Japanese study, air-conduction thresholds and blood pressures were measured in older adults (n = 496; aged 60 to 80 years) with bilateral hearing loss (hearing threshold > 40 dB HL at 4 kHz) and age-matched controls (n = 2,807) without bilateral hearing loss (hearing threshold ≤ 40 dB at 4 kHz for both ears) (Itoh et al., 2001). Systolic blood pressure and diastolic blood pressure were not significantly associated with hearing loss in this study. Pyykkö et al. (1988) found that SNHL was not significantly correlated with diastolic blood pressure or systolic blood pressure in 199 forest workers. In a cross-sectional study in the Netherlands, Durga et al. (2006) found that hearing thresholds were not independently associated with hypertension (defined as systolic blood pressure ≥ 160 mmHg, diastolic blood pressure ≥ 95 mmHg or the use of antihypertensive medication) in older adults (N = 728; aged 50 to 70 years). Hypertension, noise exposure, and auditory dysfunction were examined in several studies. Tomei et al. (2005) studied whether or not chronic noise exposure could be a risk factor for hypertension and the possible association between hearing impairment and hypertension in 301 pilots [mean age (± SD): 40 ± 8 years]. Blood pressures and hearing thresholds were measured. A significant correlation between degree of hearing loss and flight hours was found. Pilots with audiometric deficits had higher prevalence of basal hypertension than pilots without audiometric deficits. Ishii et al. (1992) conducted a retrospective study in men (N = 229; aged 55 to 68 years) with occupational noise exposure (approximately 30 years).

The authors found that the

prevalence of hypertension (defined as taking high blood pressure medication or diastolic blood pressure ≥ 90 mmHg) was not significantly different between severe NIHL and non-severe NIHL groups. Similar findings were observed in another study (Nomura et al., 2005a). Blood pressures and pure-tone threshold at 4 kHz were measured in 397 metal factory workers [mean age (± SD): 42 ± 11 years] with occupational noise exposure in Japan. Systolic blood pressure

40 and diastolic blood pressure were not associated with hearing loss (defined as hearing threshold ≥ 40 dB HL at 4 kHz). In an animal study, a possible relationship between hearing loss and hypertension was examined in non-hypertensive (n = 32, Wistar Kyoto strain) and spontaneous hypertensive rats (n = 32, SHR strain), which were fed with either an atherogenic diet (high in cholesterols and triglycerides) or a normal diet (Pillsbury, 1986). Rats were assigned to a noise-exposed or a quiet group. Blood pressures were measured at 5, 8 and 13 months of age. Auditory functions were measured by the ABR. With noise exposure, spontaneous hypertensive rats had more significant hearing loss than non-hypertensive rats. Without noise exposure, hypertension and an atherogenic diet did not have significant effect on auditory dysfunction. This study found that atherogenic diet and hypertension had synergistic effect on hearing loss with the condition of noise exposure. Hypotension has been linked to developing SNHL. Participants (n = 20; aged ≤ 50 years) with hypotension (defined as diastolic blood pressure ≤ 60 mmHg and/or systolic blood pressure ≤ 105 mmHg) had SNHL in low frequencies compared to 100 participants with normal blood pressure (Pirodda et al., 1999). The mechanisms of hearing loss caused by hypertension or hypotension are still unclear. One of possible mechanisms is consequent vasoconstriction induced by hypertension. Vasoconstriction of the inner ear blood vessels has negative effects on the blood and oxygen supply to the inner ear. Lack of oxygen and blood supply to the inner ear may cause auditory insensitivity (Pillsbury, 1986; Hillerdal et al., 1987; Tachibana et al., 1984). Another possible mechanism is ionic changes of cellular potentials.

Rarey et al. (1996) found that ionic

alternations of cellular potentials may cause hearing loss in the spontaneously hypertensive rat.

41 Patients with hypertension had higher whole blood and plasma viscosities than those without hypertension, and elevated fibrinogen level was found patients with hypertension (Rampling, 1999).

Additional research is needed to identify the mechanisms and metabolic defects

responsible for the association of hypertension with auditory dysfunction. Functions of Vitamin B12 Poor vitamin B12 status has been associated with neurological problems (IOM, 1998; Baik and Russell, 1999; Miller et al., 2005; Wolters et al., 2004), hematological disorders (IOM, 1998; Baik and Russell, 1999; Miller et al., 2005), and other health-related conditions including poor cognition, dementia, and Alzheimer’s disease (Lewis et al., 2005; Del Parigi et al., 2006), depression (Penninx et al., 2000), hearing loss (Houston et al., 1999; Gok et al., 2004; Shemesh et al., 1993), cancer (Ames and Wakimoto, 2002), and poor bone health (Morris et al., 2005; Dhonukshe-Rutten et al., 2005a, 2005b; Herrmann et al., 2005). Martin et al. (1992) reported that the cognitive dysfunction associated with vitamin B12 deficiency was reversible within one year of onset, but not after one year of onset. Vitamin B12 deficiency is associated with high homocysteine (Hcy), which may be a causal factor in vascular disease and dementia (IOM, 1998; Baik and Russell, 1999; Wolters et al., 2004). High serum or plasma total homocysteine (tHcy) is also associated with dementia and other cognitive disorders (Del Parigi et al., 2006; Seshadri et al., 2002). In the Framingham Study, elevated serum tHcy (> 14 µmol/L) doubled the risk of dementia during a 16-year follow-up period (Seshadri et al., 2002). The attributable population risk for development of dementia was 16% for tHcy and 21% for the APOE-4 allele. Currently, evidence is limited that supplements of vitamin B12 or other Bvitamins directly benefit dementia or cognition, except for established vitamin deficiencies that are corrected in the early stages (Martin et al., 1992; Del Parigi et al., 2006).

42 In the National Health and Nutrition Examination Survey (NHANES) III (737 men and 813 women, aged 55 years and older), participants with osteoporosis had significantly lower serum vitamin B12, higher serum methylmalonic acid (MMA), and elevated serum Hcy than those with normal bone mineral density measured by dual-energy X-ray absorptiometry. However, there was no association between red blood cell (RBC) folate or serum folate and osteoporosis status (Morris et al., 2005). Vitamin B12 is required for two mammalian enzymes (IOM, 1998; Baik and Russell, 1999; Wolters et al., 2004). First, vitamin B12 (methylcobalamin) is a cofactor for methionine synthase that facilitates the methyl transfer from methyltetrahydrofolate to Hcy to form methionine and tetrahydrofolate. Vitamin B12 deficiency is associated with decreased activity of methionine synthase, which leads to increases in Hcy that can be measured in blood (IOM, 1998; Baik and Russell, 1999; Wolters et al., 2004). Elevated serum Hcy is associated with low intake or status of folate, vitamin B6 and B12, as well as other genetic, physiological, and behavioral factors (Jacques et al., 2001; Selhub, 1999; Wolters et al., 2004).

Second, vitamin B12

(adenosylcobalamin) is a cofactor for L-methylmalonyl-CoA mutase that catalyzes the conversion of L-methylmalonyl-CoA to succinyl-CoA. Vitamin B12 deficiency also is associated with decreases in the activity of L-methylmalonyl-CoA mutase, which leads to increases in MMA that can be measured in serum (IOM, 1998; Baik and Russell, 1999; Wolters et al., 2004).

43 Biomarkers for Vitamin B12 Status The most widely used markers of vitamin B12 status are serum or plasma vitamin B12 followed by MMA. Elevated blood concentrations of MMA and Hcy are relatively specific markers for vitamin B12 deficiency. However, a confounding factor in using these metabolites to assess vitamin B12 status is that both are increased when renal function is poor.

Hcy is

influenced by other dietary factors including folate and vitamin B6. MMA can reflect bacterial metabolism of the intestinal microflora (IOM, 1998; Baik and Russell, 1999; Wolters et al., 2004; Sachdev, 2005). Because poor renal function elevates MMA, it has been suggested that other metabolites, such as 2-methylcitrate, be used along with MMA (Allen et al., 1993). When 2-methylcitric acid concentration is greater than MMA concentration, it indicates renal dysfunction as opposed to vitamin B12 deficiency (Stabler et al., 1999). There are three types (I, II, and III) of vitamin B12 binding proteins in plasma, called transcobalamins (TC) (Baik and Russell, 1999). TC II binds to small fraction (7% to 20%) of plasma vitamin B12 and forms a complex, called holotranscoablamin II (holoTC II) (Baik and Russell, 1999). HoloTC II is released into portal circulation and later transported into cells (Baik and Russell, 1999; Herrmann et al., 2003). HoloTC II is a reasonable marker for assessing vitamin B12 status without renal dysfunction (Baik and Russell, 1999; Carmel, 2000; IOM, 1998; Wolters et al., 2004). Higher holoTC II indicates better vitamin B12 status (Herrmann et al., 2003). Megaloblastic anemia is not a reliable sign of vitamin B12 deficiency (Lindenbaum et al., 1988; Stabler, 2001), because megaloblastic anemia does not always appear in people with vitamin B12 deficiency (Camel, 2000).

44 Defining Vitamin B12 Status Generally, serum vitamin B12 < 150 or < 160 pmol/L indicates frank vitamin B12 deficiency (Baik and Russell, 1999; Wolters et al., 2004), but there is no widely accepted biochemical cutoff for marginal or pre-clinical vitamin B12 deficiency or for vitamin B12 adequacy (Allen et al., 1993; Carmel, 2000; Baik and Russell, 1999). Use of both serum vitamin B12 and MMA may improve the differential diagnosis of vitamin B12 deficiency. Information from several sources suggests that marginal status might be defined as a serum vitamin B12 above 160 pmol/L and below 222 to 258 pmol/L (300 to 350 pg/ml) along with serum MMA concentrations > 270 or > 370 nmol/L (+ 2 and + 3 standard deviations (SDs) above the values in young controls) (Moelby et al., 1990; Lindenbaum et al., 1994; Pennypacker et al., 1992; Rasmussen et al., 1996; Stabler et al., 1990, 1997).

The age-adjusted geometric mean

concentration of plasma MMA was 137 nmol/L in NHANES 1999-2000 (Pfeiffer et al., 2005). There are concerns that raising the lower limit of normal serum vitamin B12 will falsely classify many vitamin B12 adequate people as deficient (Carmel, 2000), and others question the use of increased MMA as the only marker for diagnosis of vitamin B12 deficiency (Hvas et al., 2001). Pennypacker et al. (1992) reported that in older adults at geriatric outpatient clinics with serum vitamin B12 < 222 pmol/L and with no previous history of vitamin B12 deficiency, the prevalence of elevated serum MMA (> 3 SDs) was similar among those with serum vitamin B12 of 75 to 148 pmol/L and 148 to 222 pmol/L. In the Framingham elderly population, serum MMA and tHcy concentrations were similarly elevated among those with serum vitamin B12 concentrations of 74 to 147 pmol/L and 148 to 258 pmol/L (Lindenbaum et al., 1994). In contrast, others reported that the prevalence of elevated serum MMA (>270, > 370, or > 376 nmol/L) is quite different among those with serum vitamin B12 in the very low (< 150

45 pmol/L) versus the moderately low ranges (150 to 250 pmol/L).

In older Americans in

NHANES III (N = 1,145; ≥ 65 y, multi-ethnic), their serum MMA was > 370 nmol/L (90th percentile in young adults) in 65.2% of those with serum vitamin B12 ≤ 148 pmol/L and 14.8% of those with serum vitamin B12 > 148 pmol/L (Morris et al., 2002).

Similarly, Carmel et al.

(1999) found that the prevalence of elevated serum MMA (> 370 or > 376 nmol/L) was 55.1%, 12.4%, and 10.8% in those with serum vitamin B12 in the ranges of < 140 pmol/L, 140 to 258 pmol/L, and > 258 pmol/L, respectively in older adults (N = 591; > 60 years, multi-ethnic). Due to high cutoff points for elevated serum MMA concentration (> 370 nmol/L rather than > 270 nmol/L), the prevalence of elevated serum MMA was not strongly related to serum vitamin B12 concentration. Although there is no clear consensus definition of the biochemical cutoffs for poor vitamin B12 status, serum vitamin B12 < 258 pmol/L and serum MMA > 271 nmol/L seems reasonable and has been linked with health problem such as poor cognition (Lewis et al., 2005; Johnson et al., 2003), anemia (Johnson et al., 2003), and depression (Penninx et al., 2000). Additional research is needed to identify the concentrations of serum vitamin B12 and MMA that are linked with specific biochemical, clinical and physiological measures of obvious vitamin B12 deficiency as well as marginal or pre-clinical deficiency. The Prevalence of Vitamin B12 Deficiency Depending on the biochemical criterion that is used, 5% to more than 23% of older adults are deficient in vitamin B12 (Baik and Russell, 1999; Stabler, 2001; Johnson et al., 2003; IOM, 1998; Wolters et al., 2004). Risk factors for deficiency include low animal protein intake, no crystalline vitamin B12 from supplements or fortified foods, malabsorption associated with atrophic gastritis or Helicobacter pylori infection, pancreatic or intestinal pathology, and gastric

46 acid-reducing medications (Baik and Russell, 1999; IOM, 1998, Garcia et al., 2002; Johnson et al., 2003; Rajan et al., 2002a, 2002b; Stabler, 2001; Wolters et al., 2004). The prevalence of vitamin B12 deficiency increases with advanced age, mainly because atrophic gastritis decreases the production of the acid and digestive enzymes needed to cleave protein-bound vitamin B12 from the natural chemical form of vitamin B12 found in meat, poultry, fish and dairy foods (Baik and Russell, 1999; IOM, 1998; Wolters et al., 2004). Loss of intrinsic factor (causing pernicious anemia), gastrectomy, and ileal disease/resection are less common causes of vitamin B12 deficiency. People over 50 years old should consume the Recommended Dietary Allowances for vitamin B12 in the crystalline form (i.e., fortified foods or dietary supplements), which does not require gastric acid or enzymes for initial digestion (USDHHS and USDA, 2005; IOM, 1998). Approximately 10% to 30% of older adults have malabsorption of protein-bound vitamin B12 and about 1% to 2% lack intrinsic factor (the causal factor in pernicious anemia), which is required for active uptake of vitamin B12 in the small intestine (Baik and Russell, 1999; Stabler, 2001). Vitamin B12 and Hearing Loss Poor vitamin B12 status was associated with auditory dysfunction in some (Houston et al., 1999; Quaranta et al., 2004; Gok et al., 2004; Shemesh et al., 1993), but not all studies (Berner et al., 2000; Fine et al., 1990; Fine and Hallett, 1980; Durga et al., 2006) (Table 2.1). Tinnitus (ringing in the ears) (Shemesh et al., 1993) and auditory hallucinations (Hector and Burton, 1988) have been recorded as symptoms of vitamin B12 deficiency. None of these studies, however, has assessed the relationship of hearing with measures of vitamin B12 status such as MMA other than serum vitamin B12 and Hcy. MMA and Hcy are sensitive indicators of vitamin B12 status (Wolters et al., 2004; Baik and Russell, 1999; Savage et al., 1994).

47 TABLE 2.1 Summary of Research Linking Hearing Impairment, Vitamin B12, and Folate Age (years)

N

Serum vitamin B12 (pmol/L) 308 ± 152 [NA]

Serum folate (nmol/L) 25.8 ± 18.7

RBC folate (nmol/L) 522 ± 234

Homocysteine (µmol/L)

55

Type of hearing loss ARHL d

65 ± 4 b (60-71)c

NA e

ARHL was associated with poor vitamin B12 and folate status.

Berner et al., 2000 f

Median: 78 (67-88)

91

ARHL

Median: 237 (79-1160)

NA

Median: 11.1 (7.0-33.7)

ARHL was not associated with vitamin B12 and folate status.

Durga et al., 2006 g

60 ± 6 (50-70)

728

ARHL

Median: 330 (252-382)

12 ± 4

Whole blood, median: 295 (90-737) 691 ± 260

Gok et al., 2004 h

36 ± 4

60

NIHL i

261.7 ± 98.6

11.7 ± 3.9

NA

12.8 ± 3.8

Shemesh et al., 1993 j

39.4 ± 10.5

113

NIHL

NA

NA

NA

NA

43 (16-70)

67

SSNHLl

NA

13.1

NA

9.2

Capaccio et al., 2005a m

53.6 ±11.3

201

SSHL n

NA

21.5

NA

12.7

Capaccio et al., 2005b o

48.5 ±14.9

180

SSHL

NA

21.8

NA

12.4

Houston et al., 1999 a

Cadoni et al., 2004 k

14.4 ± 2.4

Findings

Conversely, hearing loss was associated with low concentration of Hcy and high concentrations of folate, vitamin B12 and B6. NIHL was associated with elevated Hcy and poor folate and vitamin B12 status. NIHL was prevalent participants with vitamin B12 deficiency. SSNHL was associated with elevated Hcy and low folate concentrations. SSHL was associated with elevated Hcy and low folate concentrations. SSHL was associated with elevated Hcy and low folate concentrations.

48 a

Houston DK, Johnson MA, Nozza RJ, et al. Age-related hearing loss, vitamin B-12 and folate in elderly women. Am J Clin Nutr 1999;69:564-71.

b

Mean ± SD.

c

Ranges in parentheses.

d

ARHL, age-related hearing loss.

e

NA, not available.

f

Berner B, Ødem L, Parving A. Age-related hearing impairment and B vitamin status. Acta Otolaryngol 2000;120:633-7.

g

Durga J, Anteunis LJC, Schouten EG, Bots ML, Kok FJ, Verhoef P. Association of folate with hearing in dependent on the 5,10-methylenetetrahydrofolate reductase 677C → T mutation. Neurobiol Aging 2006;27:482-9.

h

Gok U, Halifeoglu I, Canatan C, Yildiz M, Gursu MF, Gur B. Comparative analysis of serum homocysteine, folic acid levels in patients with noise-induced hearing. Auris Nasus Larynx 2004;31:19-22.

i

NIHL, noise-induced hearing loss.

j

Shemesh Z, Attias J, Ornan M, Shapira N, Shahar A. Vitamin B12 deficiency in patients with chronic tinnitus and noise-induced hearing loss. Am J Otolaryngol 1993;2:94-9.

k

Cadoni G, Agostino S, Scipione S, Galli J. Low serum folate levels: A risk factor for sudden sensorineural hearing loss? Acta Otolaryngol 2004;124:608-11.

l

SSNHL, sudden sensorineural hearing loss.

m

Capaccio P, Ottaviani F, Cuccarini V, et al. Methylenetetrahydrofolate reductase gene mutations as risk factors for sudden hearing loss. Am J Otolaryngol 2005a;26(6):383-7.

n

SNHL, sensorieneural hearing loss.

o

Capaccio P, Ottaviani F, Cuccarini V, et al. Sudden hearing loss and MTHFR 677C>T/1298A>C gene polymorphisms. Genet Med 2005b;7(3): 206-8.

49 The influence of vitamin B12 status on auditory function has been examined in several studies and the findings are mixed (Houston et al., 1999; Shemesh et al., 1993; Gok et al., 2004; Berner et al., 2000). The associations of age-related hearing loss with vitamin B12 and folate in 55 women aged 60 to 71 years were examined (Houston et al., 1999).

For the hearing

assessment, PTA in the better ear across 4 frequencies (0.5, 1, 2, and 4 kHz) was used. Women with hearing loss (PTA ≥ 20 dB HL) had significantly lower mean serum vitamin B12 concentration (236 vs. 380 pmol/L, respectively) and significantly lower mean RBC folate concentration (425 vs. 619 nmol/L) than women with normal hearing. In a subgroup of women who did not take a multivitamin containing vitamin B12 and folate, women with impaired hearing had a significantly lower mean serum vitamin B12 concentration (156 vs. 302 pmol/L, respectively), a significantly lower mean RBC folate concentration (288 vs. 502 nmol/L), and a significantly lower mean serum folate concentration (10.5 vs. 19.6 nmol/L) than women with normal hearing. Significant inverse correlations for PTA with serum vitamin B12 concentration (r = -0.58) and with RBC folate concentration (r = -0.37) were found. Berner et al. (2000) found no relationship of age-related hearing loss with vitamin B12 or folate in 35 men and 56 women (aged 67 to 88 years). PTA (from 0.5 to 4 kHz in the right ear) was not significantly correlated with serum vitamin B12, whole blood folic acid, or plasma Hcy. A limitation of Berner et al.’s study was that there was no normal-hearing group, and all participants were hearing-impaired (PTA > 25 dB HL). In a cross-sectional study in the Netherlands, the association between hearing thresholds and fasting plasma Hcy, serum folate, RBC folate, serum vitamin B12, and plasma vitamin B6 were examined in 728 older adults (aged 50 to 70 years) (Durga et al., 2006). Major exclusion criteria for this study were Hcy < 13 µmol/L, vitamin B12 < 200 pmol/L, self-reported kidney or

50 thyroid disease, and taking dietary supplements containing B vitamins. PTA-low frequencies (0.5, 1, and 2 kHz) and PTA-high frequencies (4, 6, and 8 kHz) were not associated with concentrations of Hcy, folate, vitamin B12, and plasma vitamin B6. Contrary to their hypothesis, high concentrations of serum folate and vitamin B12 were significantly associated with higher PTA, which indicates poorer hearing status. The lack of association of vitamin B12 and folate status with auditory function may be due to their exclusion criteria regarding vitamin B12 and Hcy, namely that people with abnormal concentrations were excluded. In Israel, vitamin B12 status in army personnel [N = 113; mean age (± SD): 39.4 ± 10.5 years] with a history of military noise exposure was examined [chronic tinnitus/noise-induced hearing loss (NIHL, n = 57), NIHL alone (n = 29), and normal hearing (n = 27)] (Shemesh et al., 1993).

The prevalence of vitamin B12 deficiency (serum vitamin B12 < 184 pmol/L) was

significantly higher in those with tinnitus/NIHL compared with the other groups.

Twelve

tinnitus participants with vitamin B12 deficiency received vitamin B12 therapy (1 mg/week, parenteral) until their serum vitamin B12 concentrations were above 258 pmol/L in a blood sample taken one month after the last injection.

Subjective improvement in tinnitus was

observed in all 12 patients following vitamin B12 replacement therapy. The tinnitus patients with vitamin B12 deficiency had poorer hearing status than tinnitus patients with normal vitamin B12 status. In a Turkish study of NIHL, fasting blood samples (serum concentrations of vitamin B12, folate, and Hcy) and hearing levels were measured in 28 men with NIHL [mean age (± SD): 37 ± 5 years] and 32 men without NIHL [mean age (± SD): 36 ± 4 years] (Gok et al., 2004). Men with NIHL had significantly higher mean serum Hcy concentration, lower mean serum folate concentration, and lower mean serum vitamin B12 concentration than the control group.

51 The associations of folate, Hcy, and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) with hearing loss have been examined in other studies. Low serum folate and high Hcy concentrations were found in 43 patients (23 women and 20 men; aged 17 to 70 years) with sudden sensorineural hearing loss (SSHL) compared with the control group (n = 24; aged 16 to 62) in Italy (Cadoni et al., 2004). SSHL is a sensorineural hearing loss occurring within ≤ 3 days and hearing thresholds of ≥ 30 dB HL at least three contiguous audiometric frequencies. However, serum vitamin B12 concentrations were not reported in this study. In another Italian study, patients with SSHL [n = 67; mean age (± SD): 53.6 ± 11.3 years] had significantly higher serum Hcy and lower serum folate concentrations than the controls (n = 134). SSHL was significantly associated with MTHFR (at nucleotides 677 and 1298) gene mutations in adults (Capaccio et al., 2005a, 2005b). Low dietary intakes of folate and/or vitamin B12 elevate Hcy concentrations in the blood (Wolters et al., 2004). MTHFR is a folate-related enzyme catalyzing the reduction of 5, 10-methylene-tetrahydrofolic acid to 5-methyltetrahydrofolic acid, followed by methyl transfer from methyltetrahydrofolate to Hcy to form methionine and tetrahydrofolate facilitated by methionine synthase.

Reduced activity of

MTHFR disrupts folate metabolism and leads to elevation of Hcy concentrations. Vitamin B12 is an essential cofactor for methionine synthase, so vitamin B12 deficiency decreases the activity of methionine synthase, which leads to increases in Hcy concentrations (IOM, 1998; Baik and Russell, 1999; Shane, 2000). Hearing thresholds in the right ear were measured before and after treatment in the control group (placebo) and the vitamin B12 treatment group (seven doses of 1 mg/d and one dose of 5 mg/d; intramuscularly) in adults [N = 20; aged 20 to 30 years; hearing threshold within 15 dB HL at all test frequencies (0.25 to 8 kHz) at baseline] (Quaranta et al., 2004). Mean (±

52 SD) vitamin B12 concentrations were 278.5 ± 44.9 pmol/L in the control group and 287.8 ± 50.6 pmol/L in the vitamin B12 treatment group before the treatment, suggesting that their vitamin B12 status was above the level considered deficient (< 258 pmol/L) and was between the 25th and 50th percentile based on NHANES III (Wright et al., 1998). There was no effect of vitamin B12 supplements on hearing thresholds. Temporary threshold shift was measured at 1, 2, 3, and 4 kHz after noise exposure. Vitamin B12 treatment had a protective effect on auditory function against noise exposure at 3 and 4 kHz only, suggesting that enhanced vitamin B12 status may offer some protection against noise exposure. Some investigators have directly or indirectly assessed the effects of vitamin B12 deficiency on the auditory nerves or brainstem (an electrophysiologic response that is generated by the acoustic nerve and auditory structures within the brainstem; Martin and Clark, 2002; Boettcher, 2002). Auditory dysfunction and severe vitamin B12 deficiency in rhesus monkeys was examined over a five-year period (Agamanolis et al., 1976). Although peripheral hearing levels were not monitored, the auditory nerve and other nerves had active lesions associated with vitamin B12 deficiency. The relationship between brainstem auditory evoked responses (BAERs) and vitamin B12 deficiency was examined (N = 7; aged 35 to 72 years) (Krumholz et al., 1981). The diagnosis of vitamin B12 deficiency was based on the degree of clinical neurological involvement (such as sensory loss, motor loss, cortical dysfunction, and optic neuropathy), but serum vitamin B12 concentrations were not reported. Two of seven participants with vitamin B12 deficiency had delayed BAERs without hearing loss. In contrast, in a human study, nine out of 10 men with vitamin B12 deficiency (defined as serum vitamin B12 < 162 pmol/L; aged 43 to 78 years) had normal BAERs, indicating a normal brainstem auditory pathway (Fine et al., 1990). In three case reports, men with vitamin B12 deficiency (serum vitamin B12 concentration < 125

53 pmol/L) had normal BAERs (Fine and Hallett, 1980). The small sample sizes of these human studies and lack of vitamin B12 adequate control groups make it difficult to derive meaningful conclusions about the effect of vitamin B12 deficiency on BAERs. The mechanisms by which poor vitamin B12 status may cause hearing loss are not entirely known. As previously noted, some studies suggest vitamin B12 deficiency may compromise auditory nerve or brainstem (Agamanolis et al., 1976; Krumholz et al., 1981). However, agerelated hearing loss is mostly due to disorders of the peripheral auditory system and, more specifically, abnormalities within the cochlea (Jerger et al., 1995; Mosciki et al., 1985). Nerve cells have small stores of vitamin B12 and may be particularly sensitive to low vitamin B12 status (Herbert, 1994). Poor vitamin B12 status may increase susceptibility to the harmful effects of noise in the cochlea, damage myelin, and cause auditory neuropathy (Shemesh et al., 1993). Elevated blood concentrations of MMA and Hcy are relatively specific markers for vitamin B12 deficiency, but Hcy may also be elevated in poor folate and/or vitamin B6 status (Wolters et al., 2004; Sachdev, 2005). MMA is believed to be a neurotoxin (Kölker et al., 2000; Wajner and Coelho, 1997), and Hcy may be a vasculotoxin (Sachdev, 2005) and a neurotoxin (Bleich et al., 2004). Therefore, poor vitamin B12 and/or folate status might impair the vascular and nervous components of the auditory system through direct and indirect effects. Animal studies, as well as prospective and/or intervention studies in humans, with all age populations and a control group well-matched for all known confounding variables, are needed to demonstrate a causal role for vitamin B12 and to identify the mechanisms and metabolic defects responsible for the association of auditory dysfunction with poor vitamin B12 and folate status. Furthermore, research is needed to examine the possible effect of vitamin B12 supplement on the auditory system.

54 Purpose, Specific Aims, Hypotheses, and General Approach The purpose of this dissertation was to examine the prevalence of hearing impairment among older adults, to evaluate the relationship of hearing impairment with CVD risk factors, and to evaluate the relationship of age-related hearing loss with poor vitamin B12 status, using multiple measures of vitamin B12 status and by repletion with a vitamin B12 supplement. To the accomplish these goals, the research project was designed to assess the relationship of hearing impairment with CVD risk factors, vitamin B12 deficiency, MMA and tHcy elevations, and changes in auditory function through vitamin B12 supplementation. The aims of chapter three is to evaluate the prevalence of hearing impairment and to examine a possible relationship of Hearing Handicap Inventory for the Elderly and PTA in older adults. The aim of chapter four is to evaluate a possible relationship of hearing impairment with CVD risk factors in older adults. The aim of chapter five is to evaluate a possible association of agerelated hearing loss with poor vitamin B12 status in older adults, using multiple measures of vitamin B12 status and following repletion with a vitamin B12 supplement. It was hypothesed that: 1) the prevalence of hearing impairment would be higher than general population; 2) hearing status would be negatively associated with CVD risk factors in older adults; and 3) age-related hearing loss would be associated with several indices of poor vitamin B12 status including low serum vitamin B12, high MMA, and high Hcy, and that vitamin B12 repletion would improve hearing loss in vitamin B12-deficient individuals. The next three chapters will examine the prevalence of hearing impairment, the role of CVD risk factors, and vitamin B12 status with regard to hearing impairment in older adults aged 58 to 97 years.

55 Future studies are needed to determine if changes in auditory structures secondary to poor intakes of nutrients result in functional changes in the auditory system secondary to alterations in nutritional status.

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67

CHAPTER 3 PREVALENCE OF HEARING IMPAIRMENT IN OLDER ADULTS IN THE OLDER AMERICANS ACT NUTRITION PROGRAMS1

1

Park S, Johnson MA, Shea-Miller K, and De Chicchis AR. To be submitted to the Journal of Aging and Health.

68 Abstract Objective: The prevalence of hearing impairment and a possible relationship of Hearing Handicap Inventory for the Elderly (HHIE) with pure-tone average threshold (PTA) were evaluated in older adults receiving nutrition and health services from the Older Americans Act Nutrition Programs. Methods: Air-conduction thresholds were obtained at octave intervals from 0.25 to 8 kHz using a diagnostic audiometer, and PTA was calculated at frequencies 1, 2, and 4 kHz in older adults (N = 147; mean age (± SD): 76 ± 8 years; 82% female; 70% Caucasian; 30% African-American). The HHIE was used to measure the perceived effect of hearing handicap. Results: A high prevalence of hearing impairment (PTA > 25 dB hearing level) was observed in this population (63.3% in the best ear and 74.1% in the worst ear), and this prevalence increased with advanced age. Men had higher prevalence of hearing impairment than women. A moderate correlation was found between HHIE and PTA. Discussion: More attention needs to be paid to the hearing impairment in older adults who receive community-based nutrition and health services.

HHIE may be a reasonable self-

assessment tool to identify older adults who should undergo an audiometric assessment of auditory function as part of their routine health assessments. Keywords: hearing impairment, older adults, prevalence, Older Americans Act Nutrition Program

69 Introduction Approximately 31 million Americans have hearing impairment (Kochkin, 2005). The prevalence of hearing loss increases greatly with advanced age and is typically greater in men than in women (Torre et al., 2005; Moscicki et al., 1985; Cruickshanks et al., 1998). In the 2003 National Health Interview Survey, 6.9 % of people aged 18 to 44 years, 17.6% of people aged 45 to 64 years, 29.7% of people aged 65 to 74 years, and 46.4% of people aged 75 or older had selfreported difficulty in hearing (Lethbridge-Cejku and Vickerie, 2005). Hearing loss adversely affects the lives of older adults.

Even mild hearing loss is

associated with impaired quality of life, functional disabilities, and adverse effects on physical, cognitive, emotional, behavioral, and social function (Jerger et al., 1995; Dalton et al., 2003; Bazargan et al., 2001; Gates and Mills, 2005). Hearing sensitivity can be readily assessed in community and clinical settings by presenting a series of pure tones to an individual’s ears across a range of test frequencies and determining the lowest stimulus level (threshold) that a tone can be detected. Frequently, a person’s pure-tone average (PTA), the mean of three or four contiguous frequencies, is used to predict the degree of communication impact imposed by hearing loss. For example, a PTA between 26 and 40 dB hearing level (HL) is considered mild hearing impairment (Martin and Clark, 2002; Newman and Sandridge, 2004) and would suggest difficulty hearing faint speech. Higher hearing threshold indicates poorer hearing sensitivity and greater difficulty hearing and understanding speech.

The Hearing Handicap Inventory for the Elderly (HHIE) is a self-

assessment tool that intends to identify self-perceived hearing impairment in noninstitutionalized older adults and consists of emotional and social components (Weinstein and Ventry, 1983).

70 The Older Americans Act Nutrition Program (OAANP) is the largest federally funded community-based elderly nutrition program and is designed to address dietary insufficiency and social isolation among older adults (O’Shaughnessy, 2004; Ponza et al., 1996; AoA, 2006). The OAANP provides grants to state agencies on aging to support a variety of health and wellness services, and congregate and home-delivered meals for people 60 years and older. One goal of the OAANP is to provide health promotion and disease management services (O’Shaughnessy, 2004; Ponza et al., 1996; AoA, 2006). Hearing loss may limit a person’s ability to understand verbal information. For example, senior centers often provide health and nutritional information orally, such as through monthly nutrition and health education programs to help older adults improve their eating habits, disease management, and health status. Therefore, older individuals with impaired hearing may experience difficulty in understanding such programs at their senior center. Also, little is known about the prevalence of hearing impairment in this population. The specific aims of this study were to evaluate the prevalence of hearing impairment and to examine a possible relationship of HHIE and PTA in older adults. Methods STUDY POPULATION The questionnaires and all procedures were approved by the Institutional Review Boards on Human Subjects of the Georgia Department of Human Resources, the University of Georgia, and the Athens Community Council on Aging. Participants were recruited from the OAANP at six senior centers in northeast Georgia, USA. Written informed consent was obtained from each participant. Prior to the auditory assessment, two nurse practitioners conducted otoscopic exams of the outer ear and ear canal to detect excessive cerumen, foreign bodies, or other obvious disorders of the ear canal or tympanic membrane that would prevent a safe and reliable

71 evaluation and to identify obvious disorders that might require a medical referral. Following this exam, 18 individuals were excluded and/or declined further participation in the study. Of the originally enrolled 150 participants, one participant dropped out due to a medical condition and two did not complete the hearing assessment. Participants with abnormal middle ear function were included.

Thus, 147 participants (aged 58 to 97 years; 27 men; 120 women; 70%

Caucasian; 30% African-American), who were physically and mentally able to participate in the study, had hearing data from the best ear available for statistical analysis. Hearing levels could not be measured in the left ear of four participants at certain frequencies due to the severity of the hearing impairment, so the right ear was used as the best ear, and the worst ear data were missing in those four participants. As a result, worst ear data was available from 143 participants for statistical analysis. DATA COLLECTION Assessments were performed in the six senior centers (January through April of 2001). Questionnaires were administered by interviewers trained to collect information on demographics, general health, and auditory function. These interviewers read questions to the participants and recorded their responses. A revised version of the University of Georgia Speech and Hearing Clinic history form was completed to assess family history of hearing loss and noise exposure. One licensed audiologist with no knowledge about the health or hearing status of the participants conducted the auditory assessments using portable equipment (Grason-Stadler GSI 38, Madison, WI). The assessment was conducted in a quiet area of each senior center because these older adults were not able to travel to the University of Georgia Speech and Hearing Clinic. Air-conduction thresholds were obtained at octave intervals from 0.25 to 8 kHz by using a

72 diagnostic audiometer meeting specifications in accordance with the American National Standards Institute S3.6 (1996) and by following standard audiometric clinical procedures (Yantis, 1994; American Speech-Language-Hearing Association, 1978). For middle ear function, four tympanometric measures were performed using a Grason-Stadler model GSI-38 tympanometer, including static acoustic admittance, tympanometric width, ear canal volume, and tympanometric peak pressure (Wiley et al., 1996). The HHIE was used to identify social and emotional problems due to hearing impairment (Weinstein et al., 1986; Weinstein and Ventry, 1983). The HHIE contained 25 questions (13 social and 12 emotional) and scored 0, 2, or 4 depending on the answers with a minimum score of 0 and a maximum score of 100 points. Higher scores indicate greater evidence of hearing handicap (Weinstein et al., 1986; Weinstein and Ventry, 1983). DATA ANALYSIS For each participant, the ears were classified as the best ear and the worst ear. The best ear was defined as the ear with the lowest hearing levels at 0.5, 1, 2, 4, and 8 kHz. If these were equal, the right ear was labeled the best ear.

The statistical analyses were performed

independently for the best ear and the worst ear in order not to neglect participants with at least one affected ear. Hearing function was assessed as a modified PTA (1, 2, and 4 kHz) in the best ear and the worst ear. Hearing levels at 0.5 kHz were not included in the PTA, as testing was conducted in a quiet room rather than in a sound-treated audiometric suite. Noise levels were monitored in each facility using a sound level meter, and environmental background noise prohibited reliable measurements at this frequency. Hearing test data were sufficient to permit categorization of participants into normal and impaired hearing based on two cutoffs for poor hearing status of > 25 or > 40 dB HL (Martin and Clark, 2002; Newman and Sandridge, 2004).

73 Hearing status was dichotomized (normal or impaired hearing). The normality of data was checked by skewness and kurtosis. Spearman’s correlation coefficients were used to examine associations between PTA as a continuous variable and HHIE controlling for age, gender, race, family history of hearing loss, and noise exposure. A series of logistic regression analyses were conducted with hearing status as a dependent variable and HHIE, age, gender, race, family history of hearing loss, and noise exposure as independent variables. Some of the differences in categorical variables were tested by use of the chi-square statistic. Data are presented as mean ± standard deviation (SD) or as a percent. Data were analyzed with the Statistical Analysis System (Version 9.1, SAS Institute Inc, Cary, NC). A P value of ≤ 0.05 was considered statistically significant. Results A total of 147 participants were included in this study. The prevalence of hearing impairment based on two cutoffs is shown in Table 3.1. Approximately 63% in the best ear and 74% in the worst ear of this population had hearing impairment (PTA > 25 dB HL). The prevalence of hearing impairment was significantly increased with advanced age. Approximately 41% of participants aged ≤ 69 years, 50% of participants aged 70-79 years, and 90% of participants aged ≥ 80 years had hearing impairment (PTA > 25 dB HL in the best ear). This prevalence was further increased in the worst ear (56% of participants aged ≤ 69 years, 66% of participants aged 70-79 years, and 94% of participants aged ≥ 80 years).

Men had

significantly higher prevalence of hearing impairment than women (85% vs. 58% in the best ear, respectively, P = 0.02 and 92% vs. 71% in the worst ear, P = 0.04) after controlling for age, race, family history of hearing loss, and noise exposure.

Mean air-conduction thresholds for

frequencies from 0.5 to 8 kHz and PTA (1, 2, and 4 kHz) are shown in Table 3.2 by age, gender,

74 and race. PTA in both ears was significantly correlated with HHIE total, emotional, and social scores (Table 3.3).

The prevalence of subjective hearing impairment (HHIE > 16 points;

Weinstein and Ventry, 1983) increased as the severity of hearing impairment became worse (Table 3.4). There was a sharp increase in the percentage of participants with HHIE > 16 when PTA was greater than 40 dB HL. More information on the relationship of HHIE with PTA is shown in Appendix A (Tables A.1–A.3). Discussion This is a first study to our knowledge that assesses the prevalence of hearing impairment and examines an association between HHIE and PTA in the OAANP. The major findings are that the prevalence of hearing impairment appears to be higher in this OAANP sample (> 25 dB HL: 63.3% in the best ear and 74.1% in the worst ear) compared to other adult populations such as the Epidemiology of Hearing Loss Study (N = 3,753; aged 48 to 92 years; 46% in the worst ear PTA > 25 dB HL across 0.5, 1, 2, and 4 kHz) (Cruickshanks et al., 1998). In the Health, Aging, and Body Composition study, 59.9% had hearing loss (defined as PTA across 0.5, 1, and 2 kHz > 25 dB HL in the worse ear; N = 2,052; aged 73 to 84 years) (Helzner et al., 2005). In an Italian study, 27.2% of older adults (N = 1,332; aged 65 to 96 years) had self-reported hearing loss (Cacciatore et al., 1999). This higher prevalence hearing impairment in the present study was perhaps due to the generally poor health and nutritional status of this population, which is why many of these older people seek services at senior centers (O’Shaughnessy, 2004; Ponza et al., 1996). However, it is difficult to compare the prevalence hearing impairment among studies due to different characteristics (e.g., age, gender, and race) of the study populations, variations in cutoffs for defining hearing impairment, and/or the use of self-reported information or audiometric measures of auditory function.

75 There was a moderate correlation between HHIE and PTA (rho = 0.45 to 0.53). These correlations of PTA with emotional and social scales indicate that hearing impairment may have both emotional and social impacts. Based on a considerable increase in the handicap category at PTA > 40 dB HL, 40 dB HL may be a reasonable cutoff to use as a basic for referral for audiometric assessment of auditory function. The present study was a partial replication of the Weinstein and Ventry (1983) study that examined the association of PTA (0.5, 1, and 2 kHz) with HHIE in 100 non-institutionalized older adults [mean age (± SD): 75.7 ± 7.2 years with a range from 65 to 92 years]. Similar to the present study, PTA was significantly correlated with HHIE (total, emotional, and social scores). This result may indicate that HHIE is a reasonable self-assessment tool to identify hearing impairment in older adults and the need for referral for further evaluation. Hearing loss adversely affects the lives of older adults and has enormous costs related to poor quality of life (Johnson et al., 2004). Hearing loss and activity limitation was examined in participants (N = 8,767) aged 70 years or older from the 1994 National Health Interview Second Supplement on Aging (Campbell et al., 1999). Older adults with impaired hearing were more likely to report activity limitations than those with normal hearing, such as difficulties in walking (30.7% vs. 21.3%, respectively), getting outside (17.3% vs. 12.0%), getting into and out of bed or a chair (15.1% vs. 9.8%), managing medication (7.7% vs. 4.8%), and preparing meals (11.6% vs. 7.6%). Thus, hearing impairment in older adults can lead to frustrating, embarrassing, and even dangerous situations (Johnson et al., 2004; NIDCD, 2006a, 2006b). For example, older adults with impaired hearing cannot hear others trying to alert them when dangers are nearby, such as sirens, horns, and other types of alarms.

76 There are a variety of strategies to assist older adults with hearing impairment including hearing aids (Johnson et al., 2004). Hearing aids are probably considered in older adults with a mild hearing loss (PTA from 26 to 40 dB HL) and definitely considered in older adults with PTA > 40 dB HL (Martin and Clark, 2002). Audiologic services (such as hearing aids) should be available to community-residing adults (Lee et al., 2005) and perhaps could be added to the other health promotion programs and services provided in the OAANP at senior centers (Ponza et al., 1996; National Resource Center on Nutrition, Physical Activity, and Aging, 2002). There are a few limitations in the present study, such as a convenient sample with wide age ranges and relatively small sample size.

Nonetheless, hearing impairment was very

prevalent in these participants of the OAANP in northeast Georgia. A moderate correlation between HHIE and PTA may indicate that HHIE is a reasonable self-assessment tool to identify hearing impairment in older adults. More attention may be needed in senior centers to address this high prevalence of hearing loss by providing hearing screenings and referrals, as well as making sure that speakers are amplified appropriately and are aware of the extent of hearing impairment in this population. Also, given the high prevalence of both hearing impairment and nutrition problem, this population may also be useful for examining associations of hearing impairment with cardiovascular disease and nutrition risk factors, as will be discussed in subsequent chapters (4 and 5).

77 References Administration on Aging (2006). Older Americans Act. Retrieved April 7, 2006, from http://www.aoa.gov/about/legbudg/oaa/legbudg_oaa.asp American National Standards (1996). Specifications for audiometers (ANSI S3.6–1996). New York: Acoustical Society of America. American Speech-Language-Hearing Association (1978). Guidelines for manual pure tone threshold audiometry. ASHA, 20, 297-301. Bazargan, M., Baker, R.S., & Bazargan, S.H. (2001). Sensory impairments and subjective wellbeing among aged African American persons. The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 56(5), 268-278. Cacciatore, F., Napoli, C., Abete, P., Marciano, E., Triassi, M., & Rengo, F. (1999) Quality of life determinants and hearing function in an elderly population: Osservatorio Geriatrico Campano Study Group. Gerontology, 45(6), 323-328. Campbell, V.A., Crews, J.E., Moriarty, D.G., Zack, M.M., & Blackman, D.K. (1999). Surveillance for sensory impairment, activity limitation, and health-related quality of life among older adults- United States, 1993–1997 In: CDC Surveillance December 17, 1999. MMWR 1999;48(No. SS-8):131-156. Cruickshanks, K.J., Wiley, T.L., Tweed, T.S., Klein, B.E., Klein, R., Mares-Periman, J.A., & Nondahl, D.M. Prevalence of hearing loss in older adults in Beaver Dam, Wisconsin (1998). American Journal of Epidemiology, 148(9), 878-886. Dalton, D.S., Cruickshanks, K.J., Klein, B.E., Klein, R., Wiley, T.L., & Nondahl, D.M. (2003). The impact of hearing loss on quality of life in older adults. The Gerontologist, 43(5), 661668. Gates, G.A., & Mills, J.H. (2005). Presbycusis. Lancet, 366, 1111-1120. Helzner, E.P., Cauley, J.A., Pratt, S.R., Wisniewski, S.R., Zmuda, J.M., Talbott, E.O., et al. (2005). Race and sex differences in age-related hearing loss: The Health, Aging, and Body Composition Study. Journal of the American Geriatrisc Society, 53, 2119-2127. Jerger, J., Chmiel, R., Wilson, N., & Luchi, R. (1995). Hearing impairment in older adults: new concepts. Journal of the American Geriatrisc Society, 43, 928-935. Johnson, M.A., De Chicchis, A.R., Willott, J.F., Shea-Miller, K., & Nozza, R.J. (2004). Hearing loss and nutrition in older adults. In: Bales CW, Ritchie CS, ed. Handbook of clinical nutrition in aging. Totowa, NJ: Humana Press, 291-307.

78 Kochkin, S. (2005). MarkeTrak VII: Hearing loss population tops 31 million people. The Hearing Review,12(17), 16-29. Lee, D.J., Lam, B.L., Gomez-Marin, O., Sheng, D.D., & Caban, A.J. (2005). Concurrent hearing and visual impairment and morbidity in community-residing adults. Journal of Aging and Health,17(5), 531-546. Lethbridge-Cejku, M., & Vickerie, J. (2005). Summary health statistics for U.S. adults: National Health Interview Survey, 2003. National Center for Health Statistics. Vital Health Stat 10(225). Retrieved April 17, 2006, from http://www.cdc.gov/nchs/data/series/sr_10/sr10_225.pdf Martin, F.N., & Clark, J.G. (2002). Introduction to Audiology. 8th ed. Boston; Allyn and Bacon. Moscicki, E.K., Elkins, E.F., Baum, H.M., & McNamara, P.M. (1985). Hearing loss in the elderly: An epidemiologic study of the Framingham Heart Study Cohort. Ear and Hearing, 6(4), 184-190. National Institute on Deafness and Other Communication Disorders. (2006a). Presbycusis. 2006a. Retrieved April 17, 2006, from http://www.nidcd.nih.gov/health/hearing/presbycusis.asp National Institute on Deafness and Other Communication Disorders. (2006b). Hearing loss and older adults. Retrieved April 17, 2006, from http://www.nidcd.nih.gov/health/hearing/older.asp National Resource Center on Nutrition, Physical Activity, & Aging. (2002). Wellness activities for older Americans. Retrieved April 17, 2006, from http://nutritionandaging.fiu.edu/creative_solutions/wellness_programs.asp Newman, C.W., & Sandridge, S.A. (2004). Hearing loss is often undiscovered, but screening is easy. Cleveland Clinic Journal of Medicine, 71(3), 225-232. Torre, P. 3rd., Cruickshanks, K.J., Klein, B.E.K., Klein, R., & Nondahl, D.M. (2005). The association between cardiovascular disease and cochlear function in older adults. Journal of Speech, Language, Hearing Research, 48,473-481. O’Shaughnessy, C. (2004). CRC Report for Congress. Older Americans Act Nutrition Program. Retrieved April 17, 2006, from http://www.nationalaglawcenter.org/assets/crs/RS21202.pdf Ponza, M., Ohls, J.C., & Millen, B.E. (1996). Serving Elders at Risk. The Older Americans Act Nutrition Programs. National Evaluation of the Elderly Nutrition Program, 1993-1995, Executive Summary. Princeton, NJ: Mathematica Policy Research. Retrieved April 17, 2006, from http://www.aoa.gov/prof/aoaprog/nutrition/program_eval/eval_report.asp

79 Yantis, P.A. (1994). Pure tone air conduction testing. 4th. ed. In: Katz J, editor. Handbook of clinical audiology. Baltimore: Williams & Wilkins; p. 97-108. Weinstein, B.E., Spitzer, J.B., & Ventry, I.M. (1986). Test-retest reliability of the Hearing Handicap Inventory for the Elderly. Ear and Hearing, 7(5), 295-299. Weinstein, B.E., & Ventry, I.M. (1983). Audiometric correlates of the Hearing Handicap Inventory for the elderly. Journal of Speech Hearing Disorders, 48(4), 379-384. Wiley, T.L., Cruickshanks, K.J., Nondahl, D.M., Tweed, T.S., Klein, R., & Klein, B.E.K. (1996). Tympanometric measures in older adults. Journal of American Academy of Audiology, 7, 260-268.

80 TABLE 3.1 Prevalence of Hearing Impairment by Age, Gender, and Race based on Pure-tone Average Threshold (1, 2, and 4 kHz) Hearing Impairment Pure-tone average threshold > 25 dB Pure-tone average threshold > 40 dB hearing level a hearing level b Best ear Worst ear Best ear Worst ear c d N n N n N n N n Age (years) ≤ 69 (%) 70-79 (%) ≥ 80 (%) Pe Gender Female (%) Male (%) Pf Pg Race Caucasian (%) AfricanAmerican (%) Ph Pi

34 56 57

14 28 51

41.2 50.0 89.5 55 dB (moderately severe)

37 45 42 19

36 (97.3%) 40 (88.9%) 28 (66.7%) 8 (42.1%)

1 (2.7%) 5 (11.1%) 14 (33.3%) 11 (57.9%)

Total

143

112

31

a

Hearing Handicap Inventory for the Elderly has total 25 questions (score ranged from 0 to 100).

Higher number indicates worse hearing impairment. b

Number of total participants.

85

CHAPTER 4 HEARING IMPAIRMENT AND CARDIOVASCULAR DISEASE RISK FACTORS IN OLDER ADULTS1

1

Park S, Johnson MA, Shea-Miller K, and De Chicchis AR. Submitted to Acta OtoLaryngologica.

86 ABSTRACT Conclusion-- Pure-tone average threshold (PTA) in the poorest ear was significantly correlated with high-density lipoprotein (HDL) cholesterol, whereas PTA in both ears was significantly correlated with the total cholesterol/HDL cholesterol ratio. Thus, HDL cholesterol may be a modifiable risk factor for hearing loss. Objectives-- Hearing impairment is the third most common chronic health condition in older adults and is associated with impaired quality of life. The purpose of this cross-sectional study was to evaluate the relationship of hearing impairment with cardiovascular disease risk factors in older adults. Method-- PTA was calculated at frequencies 1, 2, and 4 kHz in older adults (N = 146; mean age (± SD): 76 ± 8 years; 82% female; 71% Caucasian; 29% African-American). PTA is the mean of three or four contiguous frequencies and is used to predict the degree of communication impact imposed by hearing loss. Results-- Based on logistic regression models controlled for age, gender, race, family history of hearing loss, and noise exposure, participants with impaired hearing [> 25 dB hearing level (HL)] had significantly lower HDL cholesterol concentrations than those with normal hearing (≤ 25 dB HL; 1.40 vs. 1.59 mmol/L, respectively, P = 0.04) in the worst ear. Participants with impaired hearing (> 40 dB HL) had lower HDL cholesterol than those with PTA ≤ 40 dB HL in the best (1.26 vs. 1.52 mmol/L, respectively, P = 0.008) and the worst ear (1.33 vs. 1.53 mmol/L, respectively, P = 0.02). LDL cholesterol, total cholesterol, and triglycerides were not significantly associated with hearing loss. Keywords: hearing impairment, CVD risk factors, older adults, blood lipids

87 INTRODUCTION Approximately 31 million Americans have hearing impairment (Kochkin, 2005). The human ear has a conductive component (the outer and middle ear) and a sensorineural component (the inner ear and auditory nerve). In air conduction testing sound travels through the outer ear, middle ear, inner ear, and neural pathways (Martin and Clark, 2002).

In bone

conduction testing sound energy bypasses the outer ear and middle ear, with minor exceptions and reaches the inner ear directly.

Pure-tone average threshold (PTA) is determined by

averaging the hearing thresholds at either three or four adjacent octave frequencies and is used to predict the degree of communication impact imposed by hearing loss. For example, a PTA between 26 and 40 dB hearing level (HL) is considered mild hearing impairment (Martin and Clark, 2002) and would suggest difficulty hearing faint speech. Higher hearing thresholds indicate poorer hearing sensitivity and greater difficulty hearing and understanding speech. Hearing impairment may result from numerous factors including genetics, noise, acoustic trauma, viral or bacterial infections, sensitivity to certain drugs or medications, and aging (Johnson et al., 2004). In older adults (65 years and older), hearing impairment is the third most common chronic health condition, exceeded only by arthritis and hypertension (Lethbridge-Cejku and Vickerie, 2005). In the 2003 National Health Interview Survey, 6.9 % of people aged 18 to 44 years, 17.6% of people aged 45 to 64 years, 29.7% of people aged 65 to 74 years, and 46.4% of people aged 75 or older reported difficulty in hearing (Lethbridge-Cejku and Vickerie, 2005). The prevalence of hearing impairment increases with advanced age (Gates and Mills, 2005; Jee et al., 2005). Men typically have poorer hearing status than women (Torre et al., 2005; Moscicki et al., 1985). Hearing impairment adversely affects the lives of older adults. Even mild hearing loss is associated with impaired quality of life, functional disabilities, and adverse effects on

88 physical, cognitive, emotional, behavioral, and social function (Jerger et al., 1995; Dalton et al., 2003; Bazargan et al., 2001; Gates and Mills, 2005). Several lines of evidence suggest that cardiovascular disease (CVD) risk factors may be related to hearing loss. Hearing loss was associated with high intake of saturated fats in humans (Rosen et al., 1970) and with high dietary cholesterol in chinchillas (Sikora et al., 1986). Abnormal blood lipids may enhance the adverse effects of noise on hearing loss (Axelsson and Lindgren,

1985).

Auditory

dysfunction

was

associated

with

hyperlipidemia

or

hypercholesterolemia in some (Rosen and Olin, 1965; Torre et al., 2005), but not all studies (Jones and Davis, 1999, 2000; Durga et al., 2006). Other CVD risk factors, self-reported or quantitatively measured, such as stroke, hypertension, heart disease, coronary heart disease, myocardial infarction, smoking, and diabetes mellitus, also have been associated with hearing loss in some (Gates et al., 1993; Torre et al., 2005; Cruickshanks et al., 1998a; Frisina et al., 2006; Uchida et al., 2005), but not all studies (Drettner et al., 1975; Kent et al., 1986; Jones and Davis, 1999, 2000; Nondahl et al., 2004; Pyykkö et al., 1988). Therefore, the purpose of the present study was to evaluate a possible relationship between hearing impairment and CVD risk factors in older adults. It was hypothesized that hearing status would be negatively associated with CVD risk factors. MATERIALS AND METHODS Subjects The questionnaires and all procedures were approved by the Institutional Review Boards on Human Subjects of the Georgia Department of Human Resources, the University of Georgia, and the Athens Community Council on Aging.

Participants were recruited from Older

Americans Act Nutrition Program at six senior centers in northeast Georgia, USA. Written

89 informed consent was obtained from each participant. Prior to the auditory assessment, two nurse practitioners conducted otoscopic exams of the outer ear and ear canal to detect excessive cerumen, foreign bodies, or other obvious disorders of the ear canal or tympanic membrane that would prevent a safe and reliable evaluation and to identify obvious disorders that might require a medical referral. Following this exam, 18 individuals were excluded and/or declined further participation in the study. Of the originally enrolled 150 participants, one participant dropped out due to a medical condition, two did not complete the hearing assessment, and one had incomplete blood lipid analysis. Participants with abnormal middle ear function were included. Thus, 146 participants (aged 58 to 97 years; 27 men; 119 women; 70.6% Caucasian; 29.4% African-American), who were physically and mentally able to participate in the study, had hearing data from the best ear available for statistical analysis. Hearing levels could not be measured in the left ear of four participants at certain frequencies due to the severity of the hearing impairment, so the right ear was used as the best ear, and the worst ear data were missing in those four participants. As a result, worst ear data was available from 142 participants for statistical analysis. Methods Assessments were performed in the six senior centers (January through April of 2001). Non-fasting blood specimens were collected due to the advanced age and possible frailty of the participants by a licensed phlebotomist.

Blood samples for serum concentrations of HDL

cholesterol, LDL cholesterol, total cholesterol, and triglycerides were collected by standard methods and were analyzed in a local clinical laboratory (SmithKline-Beecham Clinical Laboratories, Atlanta, GA) within one month prior to auditory assessment. Questionnaires were administered by interviewers trained to collect information on demographics, general health, and

90 auditory function. These interviewers read questions to the participants and recorded their responses. A revised version of the University of Georgia Speech and Hearing Clinic history form was completed to assess family history of hearing loss and noise exposure. A self-reported history of health problems and current medications was obtained including variables related to diabetes mellitus, stroke, heart disease, congestive heart failure, hypertension, and use of tobacco products.

Systolic blood pressure and diastolic blood pressure were measured (Critikon

DINAMAPTM Vital Signs Monitor 1846 SX, Tampa, FL). One licensed audiologist with no knowledge about the health or hearing status of the participants conducted the auditory assessments using portable equipment (Grason-Stadler GSI 38, Madison, WI). The assessment was conducted in a quiet area of each senior center because these older adults were not able to travel to the University of Georgia Speech and Hearing Clinic. Air-conduction thresholds were obtained at octave intervals from 0.25 to 8 kHz using a diagnostic audiometer meeting specifications in accordance with the American National Standards Institute S3.6 (1996) and following standard audiometric clinical procedures (Yantis, 1994; American Speech-Language-Hearing Association, 1978). For middle ear function, four tympanometric measures were performed using a Grason-Stadler model GSI-38 tympanometer, including static acoustic admittance, tympanometric width, ear canal volume, and tympanometric peak pressure (Wiley et al., 1996). Statistical analysis For each participant, the ears were classified as the best ear and the worst ear, depending on PTA at 1, 2, and 4 kHz. With the exception of one participant, the ears did not differ by more than 15 dB. The statistical analyses were performed independently for the best ear and the worst ear in order not to neglect participants with at least one affected ear. Hearing function was

91 assessed as a modified PTA (1, 2, and 4 kHz) in the best ear and the worst ear. The participants’ hearing level at 0.5 kHz was not included in the PTA, as testing was conducted in a quiet room rather than in a sound-treated audiometric suite. Noise levels were monitored in each facility using a sound level meter, and environmental background noise prohibited reliable measurements at this frequency. Hearing test data were sufficient to permit categorization of participants into normal and impaired hearing based on two cutoffs for poor hearing status (> 25 and > 40 dB HL). Hearing status was dichotomized (normal or impaired hearing). Normal distributions of data were checked by skewness and kurtosis. Data were log transformed to approximate normal distributions where necessary. Spearman’s correlation coefficients were used to examine association between PTA as a continuous variable and blood lipids and further association with partial correlation controlling for age, gender, race, family history of hearing loss, and noise exposure. A series of logistic regression analyses were conducted with hearing status as a dependent variable and blood lipids, age, gender, race, family history of hearing loss, and noise exposure as independent variables. Data are presented as mean ± standard deviation (SD) or percent. Data were analyzed with the Statistical Analysis System (Version 9.1, SAS Institute Inc, Cary, NC). A P value of ≤ 0.05 was considered statistically significant. RESULTS A total of 146 participants were included in these analyses and their demographic information and blood lipids are shown in Table 4.1. Based on a definition of hearing loss as PTA > 25 dB HL in the best ear, 63.7% of this population had a hearing impairment. PTA in the worst ear was significantly correlated with HDL cholesterol level and total cholesterol/HDL cholesterol ratio, while PTA in the best ear was significantly correlated with the total cholesterol/HDL cholesterol ratio (Table 4.2).

There were no significant correlations of PTA with other blood lipid

92 parameters. The relationship of blood lipid parameters and other factors with PTA using two cutoff limits for poor hearing (> 25 and > 40 dB HL) in the best and the worst ear are shown in Tables 4.3 and 4.4. Based on a series of logistic regression models controlling for age, gender, race, family history of hearing loss, and noise exposure, participants with impaired hearing (PTA > 25 dB HL) in their worst ear had significantly lower mean HDL cholesterol concentrations than individuals with normal hearing (PTA ≤ 25 dB HL) in their worst ear. Participants with hearing impairment (PTA > 40 dB HL) had significantly lower mean HDL cholesterol concentrations than those with PTA ≤ 40 dB HL in the best ear and the worst ear. However, there were no significant differences in concentrations of LDL cholesterol, total cholesterol, and triglycerides between normal hearing and impaired hearing groups. In analyses conducted after excluding participants who were taking a cholesterol lowering medication, the association of low HDL cholesterol with hearing impairment was similar to the results seen for the total sample (Appendix B Tables from B.16 to B.19). Hearing impairment was not significantly associated with self-reported CVD risk factors (e.g. hypertension, diabetes mellitus, use of tobacco products, stroke, heart disease, and congestive heart failure), systolic blood pressure, diastolic blood pressure, or hypertension (defined as systolic blood pressure ≥ 140 mmHg; American Heart Association, 2006a) (Appendix B Tables from B.1 to B.15). Therefore, participants with the poorest hearing (PTA > 40 dB HL) had lower HDL cholesterol concentrations no matter which ear was used to classify them. DISCUSSION Low HDL cholesterol concentration was consistently and significantly related to hearing impairment among older adults of the Older Americans Act Nutrition Program in northeast Georgia. This observation adds to the growing body of evidence that CVD risk factors may be

93 related to hearing impairment in older adults. Also, this association of low HDL cholesterol concentration with hearing impairment occurred in a population with a relatively higher prevalence of hearing impairment than other populations, such as the Epidemiology of Hearing Loss Study (Cruickshanks et al., 1998b). However, hearing impairment was not associated with heart disease, stroke, congestive heart failure, hypertension, diabetes mellitus, or use of tobacco products, perhaps because most of these measures (except blood pressure) were self-reported rather than objectively documented by physician report or medical records. Similarly, the relationship of hearing loss with CVD and non-lipid CVD risk factors in other studies is mixed (Gates et al., 1993; Torre et al., 2005; Jones and Davis., 1999). These findings of blood lipids and hearing loss are consistent with other studies, such as the Framingham cohort study (676 men and 996 women; Gates et al., 1993). In the Framingham study, blood lipids (serum total cholesterol, triglycerides, and HDL) and two PTAs, PTA at low frequencies (0.25, 0.5, and 1 kHz) and PTA at high frequencies (4, 6, and 8 kHz), in the best ear and the worst ear were measured. There was a significant negative relationship between ageadjusted HDL concentration and PTA at low frequency in women in the worst ear. However, similar to the present study, concentrations of total serum cholesterol and triglycerides were not associated with age-related hearing loss. In a Japanese study (607 men and 317 women; aged 40 to 59 years), mean hearing levels in the better ear were measured from 0.125 to 8 kHz in participants with no history of noise exposure or disease associated with hearing loss (Suzuki et al., 2000). Low serum HDL cholesterol concentration was significantly related to hearing loss at 2 and 4 kHz in men. However, similar to the present study, concentrations of total serum cholesterol and triglycerides were not significantly associated with hearing loss. In contrast, a study found no significant associations between hearing loss at any tested frequency (0.25 to 8

94 kHz) and blood lipids (fasting LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides) in 197 men (aged 50 to 60 years) with risk factors for ischemic heart disease (Jones and Davis., 1999). Hyperlipidemia, noise exposure, and auditory dysfunction were examined in animal and human studies.

Chinchillas (aged 0.5 to 2 years) were fed either a normal diet or a 1%

cholesterol diet for six months (Sikora et al., 1986). In addition to the diet, chinchillas were either exposed to no noise or noise (with intensity levels of either 105 or 114 dB). Without noise exposure, chinchillas fed the 1% cholesterol diet had significantly worse hearing status than those fed with the control diet at high frequencies (8, 12, and 16 kHz). The effects of noise exposure and hypercholesterolemia on auditory function measured by auditory brainstem response (ABR) in three groups of eight weeks old male rabbits (N = 11; regular diet/noise; 2% cholesterol diet/noise; or regular diet/no noise) were also examined (Tami et al., 1985). Hypercholesterolemia alone had no effect on auditory dysfunction in this animal model. In a human study, a synergistic effect of noise and hypercholesterolemia on hearing loss was shown in 78 men aged 50 years with serum cholesterol level > 7 mmol/L and 75 men aged 50 years with serum cholesterol level < 7 mmol/L (Axelsson and Lindgren, 1985). Men with high serum cholesterol levels and elevated noise exposure had greater risk (relative risk of 2.6; CI, not provided) for noise-induced hearing loss (NIHL) than participants with low serum cholesterol concentrations and elevated noise exposure (relative risk of 1.8; CI, not provided). Similar to the present study, noise exposure was assessed by self-reported questionnaire. In the condition of low noise exposure, high cholesterol levels alone did not increase the risk of hearing loss (Axelsson and Lindgren, 1985). In contrast, no interaction between HDL cholesterol levels and noise exposure was found in the present study, perhaps because of the advanced age of the

95 participants and/or high proportion of women participants who generally have less noise exposure than men (Now Hear This, 2004; NIHCS, 1990). The effects of a high cholesterol diet on hearing loss were examined in participants aged 40 to 59 years (N = 278) in Finland (Rosen et al., 1970). Participants who consumed a diet with high saturated fatty acids for five years had poorer hearing status than those who consumed a diet with more unsaturated fatty acids and less saturated fatty acids for five years, regardless of age, at all test frequencies (0.5, 1, 2, and 4 kHz). In the same study, when participants switched from a diet with high saturated fatty acids to a diet with low saturated fatty acids for three and half years, their hearing status improved. When participants changed from a diet with low saturated fatty acids to a diet with high saturated fatty acids, their hearing status worsened (Rosen et al., 1970). CVD and related risk factors have been examined in several large studies and the findings are mixed (N = 1,501 to 1,672; Torre et al., 2005; Gates et al., 1993). In the Epidemiology of Hearing Loss Study, self-reported history of CVD, pure-tone air- and bone-conduction audiometry, and distortion product otoacoustic emissions were obtained from 1,501 participants aged 43 to 84 years in the United States (Torre et al., 2005). Cochlear function was measured based on distortion product otoacoustic emissions, and cochlear impairment was defined as < +9 dB distortion product otoacoustic emissions/noise ratio at 2, 3, and 4 kHz. Self-reported history of myocardial infarction was correlated with cochlear dysfunction in women but not in men after controlling for lifestyle factors (e.g. smoking, diabetes, noise exposure, activity, alcohol, and age). However, other CVD variables (e.g. self-reported stroke, brain hemorrhage, angina, and hypertension defined by blood pressure measurement) were not correlated with cochlear dysfunction. In the Framingham cohort study, hearing impairment at low frequencies in the

96 worse ear was significantly correlated with documented coronary heart disease (CHD) while hearing impairment at low frequencies in the better ear was significantly correlated with stroke (676 men; Gates et al., 1993). In women (n = 996), hearing loss at low frequencies in the better ear was correlated with CVD, CHD, and intermittent claudication, whereas hearing loss at low frequencies in the worse ear was correlated with CVD and stroke.

Hypertension was

significantly associated with PTA in men (at high frequency in the worse ear) and in women (at low frequency in the better ear). However, no significant association of diabetes mellitus, and smoking status with hearing impairment was found. In a cross-sectional study in the Netherlands, hearing thresholds were not independently associated with hypercholesterolemia (defined as total cholesterol > 6.5 mmol/L, HDL cholesterol < 0.9 mmol/L, or the use of lipid-lowering medication), self-reported diabetes mellitus, hypertension (defined as systolic blood pressure ≥ 160 mmHg, diastolic blood pressure ≥ 95 mmHg or the use of antihypertensive medication), and smoking status in 728 older adults (aged 50 to 70 years) (Durga et al., 2006). However, selfreported family history of premature vascular disease (onset < 60 years in first degree family) was significantly associated with PTA-low frequencies (0.5, 1, and 2 kHz), and self-reported vascular diseases were significantly related with PTA-high frequencies (4, 6, and 8 kHz) in this study. In contrast, Drettner et al. (1975) found no significant relationship between CVD risk factors and hearing loss except smoking habits in 1,000 men aged 50 years. Without noise exposure, hearing levels in the right ear were significantly poorer in heavy smokers than in nonsmokers (Drettner et al., 1975). The mechanisms by which hyperlipidemia, other CVD risk factors, and CVD may cause hearing impairment are not entirely known. Hyperlipidemia may impair auditory function by causing vascular disease, atherosclerosis, reducing blood and oxygen supply, and agglutination

97 of erythrocytes and platelets in the inner ear (Morizono and Paparella, 1978).

Low HDL

cholesterol concentration may increase the risk of atherosclerosis-related microcirculatory disorders of the cochlear vascular system and may increase susceptibility to noise in the cochlea (Suzuki et al., 2000). CVD may decrease blood supply to the cochlea and cause cochlear degeneration and cochlear dysfunction (Torre et al., 2005). There are some limitations in the present study. Blood lipids were assessed under nonfasting condition. However, non-fasting HDL cholesterol and total cholesterol are similar according to American Heart Association (2006b) and other (Craig et al., 2000). This study was a cross sectional study, so causal relationships between CVD risk factors and hearing impairment cannot be determined. In summary, hearing impairment was prevalent in these participants of the Older Americans Act Nutrition Program in northeast Georgia. HDL cholesterol level was significantly associated with hearing impairment, but the lack of association with other CVD risk factors may be related to the small sample size and/or the self-reported nature of this information. The observation that HDL cholesterol level was significantly associated with hearing impairment suggests that low HDL cholesterol level may be a modifiable risk factor for hearing impairment. Additional research is needed to identify the mechanisms and metabolic defects responsible for the auditory dysfunction associated with CVD and CVD-related risk factors.

98 ACKNOWLEDGMENTS This research was funded by the United States Department of Agriculture National Research Initiative-Competitive Grants Program (GEO-2000-01327), the UGA Agricultural Experiment Station, and the northeast Georgia Area Agency on Aging. We thank Nicole Hawthorne, Jean Edmonds, and Evelyn Dolce for their assistance with data collection for this study and Dr. Dorothy B. Hausman with scientific and editorial advice.

99 References American Heart Association. (2006). What Is High Blood Pressure? Retrieved April 17, 2006, from http://www.americanheart.org/presenter.jhtml?identifier=2112 American National Standards. (1996). Specifications for audiometers (ANSI S3.6–1996). New York: Acoustical Society of America. American Speech-Language-Hearing Association. (1978). Guidelines for Manual Pure Tone Threshold Audiometry. American Speech-Language-Hearing Association, 20,297-301. Axelsson, A., & Lindgren, F. (1985). Is there a relationship between hypercholesterolaemia and noise-induced hearing loss? Acta oto-laryngologica, 100, 379-386. Bazargan, M., Baker, R. S., & Bazargan, S. H. (2001). Sensory impairments and subjective wellbeing among aged African American persons. The journals of gerontology. Series B, Psychological sciences and social sciences, 56(5), 268-78. Cruickshanks, K. J., Klein, R., Klein, B. E. K., Wiley, T. L., Nondahl, D. M., & Tweed, T. S. (1998a). Cigarette smoking and hearing loss. JAMA, 279(21), 1715-1719. Cruickshanks, K. J., Wiley, T. L., Tweed, T.S., Klein, B.E., Klein, R., Mares-Periman, J. A., & Nondahl, D. M. (1998b). Prevalence of hearing loss in older adults in Beaver Dam, Wisconsin. American Journal of Epidemiology, 148(9), 878-886. Dalton, D. S., Cruickshanks, K. J., Klein, B. E., Klein, R., Wiley, T. L., & Nondahl, D. M. (2003). The impact of hearing loss on quality of life in older adults. The Gerontologist, 43(5), 661-668. Drettner, B., Hedstrand, H., Klockhoff, I., & Svedbery, A. (1975). Cardiovascular risk factors and hearing loss. Acta oto-laryngologica, 79, 366-371. Durga, J., Anteunis, L. J. C., Schouten, E. G., Bots, M. L., Kok, F.J., & Verhoef, P. (2006). Association of folate with hearing in dependent on the 5,10-methylenetetrahydrofolate reductase 677C → T mutation. Neurobiology of Aging, 27, 482-489. Frisina, S. T., Mapes, F., Kim, S., Frisina, D. R., & Frisina, R. D. (2006). Characterization of hearing loss in aged type II diabetics. Hearing Research, 211(1-2), 103-113. Gates, G. A., Cobb, J. L., D’Agostino, R. B., & Wolf, P. A. (1993). The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors. Archives of otolaryngology--head & neck surgery, 119, 156-161. Gates, G. A., & Mills, J. H. (2005). Presbycusis. Lancet, 366, 1111-1120.

100 Jee, J., Wang, J. J., Rose, K. A., Lindley, R., Laudau, P., & Mitchell, P. (2005). Vision and hearing impairment in aged care clients. Ophthalmic Epidemiology, 12, 199-205. Jerger, J., Chmiel, R., Wilson, N., & Luchi, R. (1995). Hearing impairment in older adults: new concepts. Journal of the American Geriatrics Society, 43, 928-935. Johnson, M. A., De Chicchis, A. R., Willott, J. F., Shea-Miller, K., & Nozza, R. J. (2004). Hearing loss and nutrition in older adults, In: Bales CW, Ritchie CS, editors. Handbook of clinical nutrition in aging. Totowa, NJ: Humana Press, 291-307. Jones, N. S., & Davis, A. (1999). A prospective case-controlled study of 197 men, 50-60 years old, selected at random from a population at risk from hyperlipidaemia to examine the relationship between hyperlipidaemia and sensorineural hearing loss. Clinical otolaryngology and allied sciences, 24(5), 449-456. Jones, N. S., & Davis, A. (2000). A retrospective case-controlled study of 1490 consecutive patients presenting to a neuro-otology clinic to examine the relationship between blood lipid levels and sensorineural hearing loss. Clinical otolaryngology and allied sciences, 25(6), 511-517. Kent, S. J., von Gierke, H. E., & Tolan, G. D. (1986). Analysis of the potential association between noise-induced hearing loss and cardiovascular disease in USAF aircrew members. Aviation, space, and environmental medicine, 57, 348-361. Kochkin, S. (2005). MarkeTrak VII: Hearing loss population tops 31 million people. The Hearing Review, 12(17), 16-29. Lethbridge-Cejku, M., & Vickerie, J. (2005). Summary health statistics for U.S. adults: National Health Interview Survey, 2003. National Center for Health Statistics. Vital and Health Statistic, 10(225). Martin, F. N., & Clark, J. G. (2002). Introduction to Audiology. 8th ed. Boston: Allyn and Bacon. Morizono, T., & Paparella, M. M. (1978). Hypercholesterolemia and auditory dysfunction. Experimental studies. The Annals of otology, rhinology, and laryngology, 87, 804-814. Moscicki, E. K., Elkins, E. F., Baum, H. M., & McNamara, P. M. (1985). Hearing loss in the elderly: An epidemiologic study of the Framingham Heart Study Cohort. Ear and Hearing, 6(4), 184-190. National Institude of Health Consens Statement. (1990). Noise and hearing loss. Jan 2224;8(1):1-24. Retrieved April 17, 2006, from http://consensus.nih.gov/1990/1990NoiseHearingLoss076html.htm

101 Nondahl, D. M., Cruickshanks, K. J., Dalton, D. S., Schubert, C. R., Klein, B. E. K., Klein, R., & Tweed, T. S. (2004). Serum cotinine level and incident hearing loss. A case-control study. Archives of otolaryngology--head & neck surgery, 130, 1260-1264. Now Hear This. (2004). Hearing loss: The numbers 1.4 million adults in Michigan report having hearing loss. 7(3):1-4. Retrieved April 17, 2006, from: http://oem.msu.edu/news/Hv7n3.pdf Pyykkö, I., Koskimies, K., Starck, J., Pekkarinen, J., & Inaba, R. (1988). Evaluation of factors affecting sensory neural hearing loss. Acta oto-laryngologica. Supplementum, 449, 155-158. Rosen, S., Olin, P., & Rosen, H. V. (1970). Dietary prevention of hearing loss. Acta otolaryngologica, 70, 242-247. Rosen, S., & Olin, P. (1965). Hearing loss and coronary heart disease. Archives of otolaryngology, 82, 236-243. Sikora, M. A., Morizono, T., Ward, W. D., Paparella, M. M., & Leslie, K. (1986). Diet-induced hyperlipidemia and auditory dysfunction. Acta oto-laryngologica, 102, 372-381. Suzuki, K., Kaneko, M., & Murai, K. (2000). Influence of serum lipids on auditory function. The Laryngoscope, 110(10 Pt 1), 1736-1738. Tami, T. A., Fankhauser, C. E., & Mehlum, D. L. (1985). Effects of noise exposure and hypercholesterolemia on auditory function in the New Zealand white rabbit. Archives of otolaryngology-head & neck surgery, 93, 235-239. Torre, P. 3rd., Cruickshanks, K. J., Klein, B. E. K., Klein, R., & Nondahl, D. M. (2005). The association between cardiovascular disease and cochlear function in older adults. Journal of speech, language, and hearing research, 48, 473-481. Uchida, Y., Nakashima, T., Ando, F., Niino, N., & Shimokata, H. (2005). Is there a relevant effect of noise and smoking on hearing? A population-based aging study. International journal of audiology, 44, 86-91. Wiley, T. L., Cruickshanks, K. J., Nondahl, D. M., Tweed, T. S., Klein, R., & Klein, B. E. K. (1996). Tympanometric measures in older adults. Journal of the American Academy of Audiology, 7, 260-268. Yantis, P. A. (1994). Pure tone air conduction testing. 4th. ed. In: Katz J, editor. Handbook of clinical audiology. Baltimore: Williams & Wilkins. 97-108.

102 TABLE 4.1 Characteristics of participants

Age (years) Gender Female (%) Male (%) Race Caucasian (%) African-American (%) Body weight (kg) Body mass index (kg/m2) PTA d in the best ear (dB HL) e PTA in the worst ear (dB HL) PTA > 25 dB HL in the best ear (%) PTA > 25 dB HL in the worst ear (%) PTA > 40 dB HL in the best ear (%) PTA > 40 dB HL in the worst ear (%) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Total cholesterol (mmol/L) Total cholesterol/ HDL cholesterol ratio Triglycerides (mmol/L)

Na 146 146

nb 146

Mean ± SD or % 76 ± 8 (58-97) c

119 27

81.5 18.5

103 43 146 146 146 142 93 106 46 61 143 36 145 146 141 146 146 146

70.6 29.4 78.4 ± 18.0 (40.8-137.9) 29.2 ± 6.1 (15.2-48.3) 34 ± 14 (8-73) 38 ± 15 (10-83) 63.7 74.7 31.5 43.0 9 ± 4 (0-18) 24.7 16 ± 18 (0-83) 1.44 ± 0.42 (0.70-2.86) 3.07 ± 0.89 (1.43-6.71) 5.42 ± 1.10 (3.33-10.01) 4.0 ± 1.3 (2.0-9.0) 1.99 ± 1.16 (0.58-8.78)

146

146 146 146 142 146 142 146 142 143 146 145 146 141 146 146 146

a

Number of total participants.

b

Number of participants with the condition.

c

Range in parentheses.

d

PTA, pure-tone average threshold of 1, 2, and 4 kHz.

e

dB HL, hearing level in decibel.

103 TABLE 4.2 Correlation between blood lipids and pure-tone average threshold (PTA; 1, 2, and 4 kHz) in the best ear and the worst ear

HDL cholesterol

LDL cholesterol

Total cholesterol

Total cholesterol/HDL cholesterol ratio

Triglycerides

a

PTA in the best ear (N = 140) r = -0.14 a

PTA in the worst ear (N = 136) r = -0.18 a

P = 0.10 a r = -0.14 b P = 0.10 b

P = 0.04 a r = -0.18 b P = 0.04 b

r = 0.05 a P = 0.56 a r = 0.04 b

r = 0.006 a P = 0.95 a r = -0.01 b

P = 0.67 b

P = 0.87 b

r = 0.003 a P = 0.97 a

r = -0.04 a P = 0.65 a

r = -0.01 b P = 0.91 b

r = -0.06 b P = 0.50 b

r = 0.19 a

r = 0.18 a

P = 0.03 a r = 0.18 b P = 0.04 b

P = 0.04 a r = 0.17 b P = 0.05 b

r = 0.07 a P = 0.41 a r = 0.07 b P = 0.40 b

r = 0.09 a P = 0.33 a r = 0.09 b P = 0.33 b

Partial Spearman correlation coefficient controlled for age, gender, race, family history of

hearing loss, and noise exposure. b

Partial Spearman correlation coefficient controlled for age, gender, race, family history of

hearing loss, noise exposure, and taking cholesterol lowering medication.

104 TABLE 4.3 Demographics, cardiovascular disease risk factors, and auditory function in the best ear and the worst ear (≤ 25 vs. > 25 dB hearing level)

Nc Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Body weight (kg) Body mass index (kg/m2) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Total cholesterol (mmol/L) Total cholesterol/ HDL cholesterol ratio Triglycerides (mmol/L) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Body weight (kg) Body mass index (kg/m2) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Total cholesterol (mmol/L) Total cholesterol/ HDL cholesterol ratio Triglycerides (mmol/L)

Hearing Normal Impaired (PTAa ≤ 25 dB HLb) (PTA > 25 dB HL) Mean ± SD Mean ± SD nd or % nd or %

P valuee

P valuef

P valueg

146 146 146 146 146 146 146 143 146 145

53 53 53 49 34 53 53 53 10 52

36.3 19 ± 4 72 ± 6 92.5 64.2 82.9 ± 19.7 30.3 ± 6.8 9±3 18.9 11 ± 14

93 93 93 70 69 93 93 90 26 93

63.7 43 ± 11 79 ± 7 75.3 74.2 75.8 ± 16.5 28.5 ± 5.5 9±4 28.0 18 ± 20

271 nmol/L and serum vitamin B12 < 258 pmol/L after three months of intervention), and was thus

116 excluded from statistical analyses; possible reasons for non-response include poor compliance, poor gastric function, and/or poor renal clearance of MMA. Therefore, 80 participants were included in statistical analyses in the best ear at post-treatment. Hearing levels could not be measured in the left ear of four participants at certain frequencies due to the severity of hearing impairment at post-treatment. Additionally, one person was found to be a statistical outlier [defined as a greater than 2 standard deviation (SD) difference in hearing level score between baseline and post-treatment] and was excluded from statistical analyses in the worst ear. As a result, 75 participants were included in statistical analyses in the worst ear at post-treatment. Statistical analysis For each participant, the ears were classified as the best ear and the worst ear, respectively, depending on PTA at 1, 2, and 4 kHz. The statistical analyses were performed independently for the best ear and the worst ear in order not to neglect participants with at least one affected ear. Hearing function was assessed as a modified PTA (1, 2, and 4 kHz) in the best ear and the worst ear. Hearing levels at 0.5 kHz were not included in the PTA, as testing was conducted in a quiet room rather than in a sound-treated audiometric suite. Noise levels were monitored in each facility using a sound level meter, and environmental background noise prohibited reliable measurements at this frequency. Hearing test data were sufficient to permit categorization of participants into normal and impaired hearing based on a cutoff for poor hearing status of > 25 dB HL (Martin and Clark, 2002; Newman and Sandridge, 2004). Hearing status was dichotomized (normal or impaired hearing). The normality of data was checked by skewness and kurtosis. Data were log transformed to approximate normal distributions where necessary. Data are presented as mean ± SD or as a percent. Spearman’s correlation coefficients were used to examine associations between PTA as a continuous variable and serum vitamin B12,

117 MMA, and tHcy (univariate and partial correlations controlling for age, gender, race, creatinine, family history of hearing loss, and noise exposure). A series of logistic regression analyses were conducted with hearing status as a dependent variable and biochemical variables, age, gender, race, family history of hearing loss, and noise exposure as independent variables. Some of the differences in categorical variables were tested by use of the chi-square statistic. For the baseline and post-treatment comparisons within groups, paired t tests were used to compare between the baseline and post-treatment variables within the treatment groups.

Difference scores were

calculated for PTA (1, 2, and 4 kHz) to examine changes in this variable from baseline to posttreatment. Data were analyzed with the Statistical Analysis System (Version 9.1, SAS Institute Inc, Cary, NC). A P value of ≤ 0.05 was considered statistically significant. RESULTS A total of 93 participants were included in these analyses and their demographic and biochemical information are shown in Table 5.1. In the entire cohort, no participant had folate deficiency (serum folate < 6.8 nmol/L; Wright et al., 1998).

In the worst ear, PTA was

significantly correlated with serum MMA concentration (Table 5.2). There were no correlations of PTA with serum vitamin B12 and tHcy. The relationships of vitamin B12 and other metabolites with PTA (normal hearing ≤ 25 vs. impaired hearing > 25 dB HL) in the best and the worst ear are shown in Tables 5.3 and 5.4. In the best ear (Table 5.3), participants with impaired hearing had significantly higher mean serum MMA concentrations and non-significantly higher prevalence of low pepsinogen I concentrations (≤ 20 ng/mL; Sepulveda, 2004) than individuals with normal hearing. In the worst ear (Table 5.4), participants with impaired hearing had significantly higher mean serum MMA concentrations, higher prevalence of elevated MMA concentrations (> 271 nmol/L), higher prevalence of vitamin B12 deficiency (as defined by

118 vitamin B12 < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid), higher prevalence of low serum vitamin B12 (< 185 and < 258 pmol/L), and non-significantly lower mean vitamin B12 concentrations than individuals with normal hearing. These associations were strengthened or attenuated depending on the other factors included in the models, such as age, gender, race, creatinine, family history of hearing loss, and noise exposure. There was no association of mean tHcy concentrations, the prevalence of taking dietary supplements, and intakes of synthetic vitamin B12 or folate with PTA in either ear. Mean serum concentrations of vitamin B12 and MMA and the prevalence of vitamin B12 deficiency based on three different cutoffs for poor hearing (> 20, > 25, and > 40 dB HL) in the best and the worst ear are shown in Figures 5.1, 5.2, and 5.3, and similar patterns were observed regardless of cutoff levels for poor hearing. More information is shown in Appendix C (Tables from C.1 to C.16). The mean PTA before and after vitamin B12 supplement is shown in Figure 5.4. Paired t tests showed no significant changes in mean PTA between baseline and post-treatment within groups (placebo, 25, 100, and 1000 µg/d) after three months of supplementation with vitamin B12. The association between age-related hearing loss and vitamin B12 status were examined separately in each ethnicity (Appendix C Tables from C.17 to C.23). In full models (controlling for age, gender, creatinine, family history of hearing loss, and noise exposure) in the worst ear in Caucasians (Table 5.5), those with impaired hearing (PTA > 25 dB HL) had higher mean serum MMA concentration (382 ± 355 vs. 213 ± 74, respectively, P = 0.008), higher prevalence of elevated MMA concentration (> 271 nmol/L; 51.3% vs. 16.7%, P = 0.03), lower mean serum vitamin B12 (282.8 ± 123.0 vs. 354.7 ± 72.9, P = 0.02), and higher prevalence of low serum vitamin B12 concentration (< 285 pmol/L; 43.6% vs. 16.7%, P = 0.04), and there was a trend for mean serum tHcy to be higher (11.3 ± 4.3 vs. 9.6 ± 3.9, P = 0.06). Furthermore, in chi-square

119 analyses, Caucasians with impaired hearing had significantly higher prevalence of vitamin B12 deficiency (vitamin B12 < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid; 30.8% vs. 0.0%, respectively, P = 0.01), and higher prevalence of low serum vitamin B12 (< 185 pmol/L; 20.5% vs. 0.0%, P = 0.05) than those with normal hearing (PTA ≤ 25 dB HL). These relationships were not seen in African-Americans (Appendix C Tables from C.20 to C.23). DISCUSSION The main finding of this study is that impaired hearing in older adults was associated with several indices of poor vitamin B12 status including low serum vitamin B12 and high MMA concentrations. Most of these associations remained when controlled for other factors that might impair hearing or vitamin B12 status such as age, gender, race, family history of hearing loss, noise exposure, and serum creatinine.

Associations of impaired hearing with vitamin B12

deficiency were not as apparent in the best ear, perhaps because of the overall mild degree of hearing loss in this study and/or the relatively small sample size that limited the power to detect these associations. These findings complement emerging evidence that vitamin B12 status, as well as folate status, may be related to hearing loss (Houston et al., 1999; Gok et al., 2004; Shemesh et al., 1993; Cadoni et al., 2004). Other studies have focused on the relationship of hearing loss with blood concentrations of vitamin B12 and related metabolites, the influence of vitamin B12 deficiency on nerve damage and conduction velocities in the auditory brainstem response, interactions of B-vitamin metabolism with noise exposure, and polymorphisms in genes related to B-vitamin metabolism (Agamanolis et al., 1976; Shemesh et al., 1993; Cadoni et al., 2004). Our research team previously reported that low serum vitamin B12 was associated with hearing loss in older Caucasian women (Houston et al., 1999). The present findings extend these findings to another sample of older people that includes men, women, Caucasians and

120 African-Americans, with an overall higher degree of hearing impairment. We did not confirm our previous finding that poor folate status was related to hearing loss in older women (Houston et al., 1999), perhaps because in the present study folate status was better than in our previous study (e.g., serum folate: 43.2 vs. 25.8 nmol/L, respectively). Thus, poor vitamin B12 status may have overshadowed any contributions of folate status to hearing impairment in the present study. In analyses conducted separately for Caucasians (n = 57 to 60) and African-Americans (n = 33), the associations of vitamin B12 status and related metabolites with hearing loss in Caucasians, but not African-Americans, were similar to the results seen for the total sample. The reasons for the difference between Caucasians and African-Americans are not clear, but may be related to the small sample size of African-Americans or to real differences in the metabolism of vitamin B12 and related metabolites between Caucasians and African-Americans (Stabler et al., 1999; Wright et al., 1998). To our knowledge, this is the first study to report an association of elevated serum MMA with hearing loss. MMA accumulates as a result of vitamin B12 deficiency. L-methylmalonylCoA mutase catalyzes the conversion of L-methylmalonyl-CoA to succinyl-CoA and requires vitamin B12 as a cofactor. Therefore, vitamin B12 deficiency is associated with a decrease in the activity of L-methylmalonyl-CoA mutase, which leads to increases in MMA concentration (IOM, 1998; Baik and Russell, 1999; Wolters et al., 2004). Serum MMA concentration may be a particularly sensitive index of hearing problems related to poor vitamin B12 status as it was the only marker of poor vitamin B12 status that was associated with poor hearing in both the best and worst ear. The influence of vitamin B12 status on auditory function has been examined in several studies and the findings are mixed (Houston et al., 1999; Shemesh et al., 1993; Gok et al., 2004;

121 Berner et al., 2000). Berner et al. (2000) found no relationship of vitamin B12 or folate with agerelated hearing loss in 35 men and 56 women (aged 67 to 88 years). PTA (from 0.5 to 4 kHz in the right ear) was not significantly correlated with serum vitamin B12, whole blood folic acid, or plasma Hcy. A limitation of Berner et al.’s study was that there was no normal hearing group, and all participants were hearing impaired (PTA > 25 dB HL). In a cross-sectional study in the Netherlands, the association between hearing thresholds and fasting plasma Hcy, serum folate, RBC folate, serum vitamin B12, and plasma vitamin B6 were examined in 728 older adults (aged 50 to 70 years) (Durga et al., 2006). Major exclusion criteria for this study were Hcy < 13 µmol/L, vitamin B12 < 200 pmol/L, self-reported kidney or thyroid disease, and taking dietary supplements containing B vitamins. PTA-low frequencies (0.5, 1, and 2 kHz) and PTA-high frequencies (4, 6, and 8 kHz) were not associated with concentrations of Hcy, folate, vitamin B12, and plasma vitamin B6. Contrary to their hypothesis, high concentrations of serum folate and vitamin B12 were significantly associated with higher PTA, which indicates poorer hearing status. The lack of association of vitamin B12 and folate status with poor auditory function may be due to their exclusion criteria regarding vitamin B12 and Hcy. In Israel, vitamin B12 status in army personnel [N = 113; mean age (± SD): 39.4 ± 10.5 years] with a history of military noise exposure was examined [chronic tinnitus/noise-induced hearing loss (NIHL, n = 57), NIHL alone (n = 29), and normal hearing (n = 27)] (Shemesh et al., 1993).

The prevalence of vitamin B12 deficiency (serum vitamin B12 < 184 pmol/L) was

significantly higher in those with tinnitus/NIHL compared with the other groups.

Twelve

tinnitus participants with vitamin B12 deficiency received vitamin B12 therapy (1 mg/week, parenteral) until their serum vitamin B12 concentrations were above 258 pmol/L in a blood

122 sample taken one month after the last injection.

Subjective improvement in tinnitus was

observed in all 12 patients following vitamin B12 replacement therapy. Prior to supplementation, the tinnitus patients with vitamin B12 deficiency had poorer hearing status than tinnitus patients with normal vitamin B12. In contrast, there was no association between tinnitus and vitamin B12 status in the present study, perhaps because our population was older (older male and female adults) with less noise exposure compared with the previous study (army personnel). In a Turkish study of NIHL, fasting blood samples (serum concentrations of vitamin B12, folate, and Hcy) and hearing levels were measured in 28 men with NIHL [mean age (± SD): 37 ± 5 years] and 32 men without NIHL [mean age (± SD): 36 ± 4 years] (Gok et al., 2004). Men with NIHL had significantly higher mean serum Hcy concentration, lower mean serum folate concentration, and lower mean serum vitamin B12 concentration than the control group. In contrast, Hcy and folate were not associated with auditory function in the present study, perhaps because of the advanced age and better status of folate and Hcy than in the study by Gok et al. (2004) (e.g., serum folate: 43.2 vs. 11.7 nmol/L; serum Hcy: 10.5 vs. 12.8 µmol/L, respectively). In addition, no interaction of noise exposure with MMA or vitamin B12 was found in the present study, perhaps because of the advanced age of the participants and/or high number of women participants. Women are less likely to have NIHL (Now Hear This, 2004; National Institute of Health Consens Statement, 1990) and have less hearing impairment overall than men (Lethbridge-Cejku and Vickerie, 2005; NAAS, 1999). The associations of folate, Hcy, and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) with hearing loss have been examined in other studies. Low serum folate and high Hcy concentrations were found in 43 patients (23 women and 20 men; aged 17 to 70 years) with sudden sensorineural hearing loss (SSHL) compared with the control group (n = 24;

123 aged 16 to 62 years) in Italy. SSHL is a sensorineural hearing loss occurring within ≤ 3 days and characterized by hearing thresholds of ≥ 30 dB HL in at least 3 contiguous audiometric frequencies (Cadoni et al., 2004). However, serum vitamin B12 concentrations were not reported in this study. In another Italian study, patients with SSHL [n = 67; mean age (± SD): 53.6 ± 11.3 years] had significantly higher serum Hcy and lower serum folate concentrations than the controls (n = 134).

SSHL was significantly associated with MTHFR gene mutations (at

nucleotides 677 and 1298) in adults (Capaccio et al., 2005a, 2005b). Low dietary intakes of folate and/or vitamin B12 elevate Hcy concentrations in the blood (Wolters et al., 2004). MTHFR is a folate-related enzyme catalyzing the reduction of 5, 10-methylene-tetrahydrofolic acid to 5-methyl-tetrahydrofolic acid, followed by methyl transfer from methyltetrahydrofolate to Hcy to form methionine and tetrahydrofolate facilitated by methionine synthase. Reduced activity of MTHFR disrupts folate metabolism and leads to elevation of Hcy concentrations. Vitamin B12 is an essential cofactor for methionine synthase, so vitamin B12 deficiency decreases activity of methionine synthase, which leads to increases in Hcy concentrations (IOM, 1998; Baik and Russell, 1999; Shane, 2000). Hearing thresholds in the right ear were measured before and after treatment with either placebo or vitamin B12 (seven doses of 1 mg/d and one dose of 5 mg/d; intramuscularly) in adults [N = 20; aged 20 to 30 years; hearing thresholds within 15 dB HL at all test frequencies (0.25-8 kHz) at baseline] (Quaranta et al., 2004). Mean (± SD) vitamin B12 concentrations were 278.5 ± 44.9 pmol/L in the control group and 287.8 ± 50.6 pmol/L in the vitamin B12 treatment group before the treatment, suggesting that their vitamin B12 status was above the level considered deficient (< 258 pmol/L) and was between the 25th and 50th percentile based on National Health and Nutrition Examination Survey III (Wright et al., 1998). Similar to the present study, there

124 was no effect of vitamin B12 supplements on hearing thresholds. Temporary threshold shift was measured at 1, 2, 3, and 4 kHz after noise exposure (Quaranta et al., 2004). Vitamin B12 treatment had a protective effect on auditory function against noise exposure at 3 and 4 kHz only, suggesting that enhanced vitamin B12 status may offer some protection against noise exposure. Some investigators have directly or indirectly assessed the effects of vitamin B12 deficiency on the auditory nerves or brainstem response (an electrophysiologic response that is generated by the acoustic nerve and auditory structures within the brainstem; Martin and Clark, 2002; Boettcher, 2002). Auditory dysfunction and severe vitamin B12 deficiency in rhesus monkeys was examined over a five year period (Agamanolis et al., 1976). Although peripheral hearing levels were not monitored, the auditory nerve and other nerves had active lesions associated with vitamin B12 deficiency. The relationship between brainstem auditory evoked responses (BAERs) and vitamin B12 deficiency was examined (N = 7; aged 35 to 72 years) (Krumholz et al., 1981). The diagnosis of vitamin B12 deficiency was based on the degree of clinical neurological involvement (such as sensory loss, motor loss, cortical dysfunction, and optic neuropathy), but serum vitamin B12 concentrations were not reported. Two of seven participants with vitamin B12 deficiency had delayed BAERs without hearing loss. In contrast, in a human study, nine out of 10 men with vitamin B12 deficiency (defined as serum vitamin B12 < 162 pmol/L; aged 43 to 78 years) had normal BAERs, indicating a normal brainstem auditory pathway (Fine et al., 1990). In three case reports, men with vitamin B12 deficiency (serum vitamin B12 concentration < 125 pmol/L) had normal BAERs (Fine and Hallett, 1980). The small sample sizes of these human studies and lack of vitamin B12 adequate control groups make it difficult to derive meaningful conclusions about the effect of vitamin B12 deficiency on BAERs.

125 The mechanisms by which poor vitamin B12 status may cause hearing loss are not entirely known. As previously noted, some studies suggest vitamin B12 deficiency may compromise the auditory nerve or brainstem (Agamanolis et al., 1976; Krumholz et al., 1981). However, agerelated hearing loss is mostly due to disorders of the peripheral auditory system and, more specifically, abnormalities within the cochlea (Jerger et al., 1995; Mosciki et al., 1985). Nerve cells have small stores of vitamin B12 and may be particularly sensitive to low vitamin B12 status (Herbert, 1994). Poor vitamin B12 status may increase susceptibility to the harmful effects of noise in the cochlea, damage myelin, and cause auditory neuropathy (Shemesh et al., 1993). Elevated concentrations of MMA and Hcy are relatively specific markers for vitamin B12 deficiency, but Hcy may also be elevated in poor folate and/or vitamin B6 status (Wolters et al., 2004; Sachdev, 2005). MMA is believed to be a neurotoxin (Kölker et al., 2000; Wajner and Coelho, 1997), and Hcy maybe a vasculotoxin (Sachdev, 2005) and a neurotoxin (Bleich et al., 2004). Therefore, poor vitamin B12 and/or folate status might impair the vascular and nervous components of the auditory system through direct and indirect effects. There are some limitations in the present study. Blood samples were assessed under nonfasting condition. However, fasting status had no effect on serum MMA (Rasmussen, 1989), vitamin B12, and serum folate (Wright et al., 1998). Compared with fasting concentrations, nonfasting plasma Hcy concentration increased after a high protein diet (21.2% of energy) but not after a low protein diet (9.3% of energy) (Verhoef et al., 2005).

Although vitamin B12

supplementation may not improve hearing thresholds, it is also possible that the three months of vitamin B12 supplementation might have been too short to observe significant improvements in auditory function in older adults.

126 In summary, this study suggests that several indices of vitamin B12 status, particularly serum MMA, are associated with auditory dysfunction in older people. Because vitamin B12 repletion did not improve hearing function in vitamin B12 deficient participants, this suggests that prevention of vitamin B12 deficiency is important. Additional research is needed to identify the mechanisms and metabolic defects responsible for the association of vitamin B12 with auditory dysfunction, as well as the auditory benefits associated with treating vitamin B12 deficiency and elevated MMA and tHcy concentrations with vitamin B12 supplementation.

ACKNOWLEDGMENTS This research was funded by the United States Department of Agriculture National Research Initiative-Competitive Grants Program (GEO-2000-01327), the UGA Agricultural Experiment Station, the northeast Georgia Area Agency on Aging, and the NIH National Institute on Aging (AG-09834). We thank Nicole Hawthorne, Jean Edmonds, and Evelyn Dolce for their assistance with data collection for this study and Dr. Dorothy B. Hausman with scientific and editorial advice.

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129 Krumholz A, Weiss H, Goldstein P, Harris K. Evoked responses in vitamin B-12 deficiency. Annals of Neurol 1981;9:407-9. Lethbridge-Cejku M, Vickerie J. Summary health statistics for U.S. adults: National Health Interview Survey, 2003. National Center for Health Statistics. Vital Health Stat 10(225), 2005. Internet: http://www.cdc.gov/nchs/data/series/sr_10/sr10_225.pdf (accessed 17 April 2006). Martin FN, Clark JG. Introduction to Audiology. 8th ed. Boston; Allyn and Bacon, 2002. Moscicki EK, Elkins EF, Baum HM, McNamara PM. Hearing loss in the elderly: An epidemiologic study of the Framingham Heart Study Cohort. Ear Hear 1985;6(4):184-90. National Academy on an Aging Society. Hearing loss: A growing problem that affects quality of life. December. Number 2:1-6, 1999. Internet: http://www.agingsociety.org/agingsociety/pdf/hearing.pdf (assessed 17 April 2006). National Institute on Deafness and Other Communication Disorders. Presbycusis. Internet: http://www.nidcd.nih.gov/health/hearing/presbycusis.asp (assessed 17 April 2006). National Institude of Health Consens Statement. Noise and hearing loss. Jan 22-24;8(1):1-24, 1990. Internet: http://consensus.nih.gov/1990/1990NoiseHearingLoss076html.htm (assessed 17 April 2006). Newman CW, Sandridge SA. Hearing loss is often undiscovered, but screening is easy. Cleve Clin J Med 2004;71(3):225-32. Now Hear This. Hearing loss: The numbers 1.4 million adults in Michigan report having hearing loss. 7(3):1-4. 2004. Internet: http://oem.msu.edu/news/Hv7n3.pdf (assessed 17 April 2006). Quaranta A, Scaringi A, Bartoli R, Margarito MA, Quaranta N. The effects of 'supraphysiological' vitamin B12 administration on temporary threshold shift. Int J Audiol 2004;43(3):162-5. Rajan S, Wallace J, Brodkin K, Beresford S, Allen R, Stabler S. Response of Elevated methylmalonic acid to three dose levels of oral cobalamin in older adults. J Am Geriatr Soc 2002;50:1789-95. Rasmussen K. Studies on methylmalonic acid in humans. I. Concentrations in serum and urinary excretion in normal subjects after feeding and during fasting, and after loading with protein, fat, sugar, isoleucine, and valine. Clin Chem 1989;35(12):2271-6. Sachdev PS. Homocysteine and brain atrophy. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(7):1152-61. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994;96(3):239-46.

130 Sepulveda AR. Gastritis, atrophic. eMedicine. 2004. Internet: http://www.emedicine.com/med/topic851.htm (assessed 17 April 2006). Shane B. Folic acid, vitamin B12, and vitamin B6. In: Stipanuk MH, ed. Biochemical and physiological aspects of human nutrition. Philadelphia, PA: W.B. Saunders Company, 2000:483518. Shemesh Z, Attias J, Ornan M, Shapira N, Shahar A. Vitamin B12 deficiency in patients with chronic tinnitus and noise-induced hearing loss. Am J Otolaryngol 1993;2:94-9. Snow C. Laboratory diagnosis of vitamin B12 and folate deficiency: A guide for the primary care physician. Arch Intern Med 1999;159:1289-98. Stabler S, Allen R, Fried L, et al. Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women. Am J Clin Nutr 1999;70:911-9. Stabler S, Marcell P, Podell E, Allen R, Lindenbaum J. Assay of methylmalonic acid in the serum of patients with cobalamin deficiency using capillary gas chromatography/mass spectrometry. J Clin Invest 1986;77:1606-12. Verhoef P, van Vliet T, Olthof MR, Katan MB. A high-protein diet increases postprandial but not fasting plasma total homocysteine concentrations: a dietary controlled, crossover trial in healthy volunteers. Am J Clin Nutr 2005;82(3):553-8. Yantis PA. Pure tone air conduction testing. 4th. ed. In: Katz J, ed. Handbook of clinical audiology. Baltimore: Williams & Wilkins, 1994: 97-108. Wajner M, Coelho JC. Neurological dysfunction in methylmalonic acidaemia is probably related to the inhibitory effect of methylmalonate on brain energy production. J Inherit Metab Dis 1997;20(6):761-8. Wolters M, Ströhle A, Hahn A. Cobalamin: a critical vitamin in the elderly. Prev Med 2004;39:1256-66. Wright J, Bialostosky K, Gunter E, et al. Blood folate and vitamin B12: United States, 19881994. National Center for Health Statistics. Vital Health Stat. 11(243):1-78, 1998. Internet: http://www.cdc.gov/nchs/data/series/sr_11/sr11_243.pdf (assessed 17 April 2006). Wiley TL, Cruickshanks KJ, Nondahl DM, Tweed TS, Klein R, Klein BEK. Tympanometric measures in older adults. J Am Acad Audiol 1996;7:260-8.

131 TABLE 5.1 Characteristics of participants at baseline

Age (years) Gender Female (%) Male (%) Race Caucasian (%) African-American (%) Hearing level in the best ear (dB) Hearing level in the worst ear (dB) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Number of medications Anemic (%) d Serum vitamin B12 (pmol/L) < 185 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, methylmalonic acid > 271 nmol/L, and methylmalonic acid > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) Serum total homocysteine (µmol/L) Serum folate (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Hemoglobin (g/dL) Mean cell volume (fl) Multivitamin use (%) Synthetic vitamin B12 intake (µg/d) ≥ 2.4 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

Na 93 93

nb 93

Mean ± SD or % 75 ± 7 (58-92) c

77 16

82.8 17.2

93 90 91 93 92 93 92 93 93 93 93

60 33 93 90 91 19 92 93 21 93 10 26 13

64.5 35.5 31 ± 14 (8-73) 34 ± 14 (10-77) 9 ± 4 (0-16) 20.4 15 ± 17 (0-62) 6 ± 3 (0-15) 22.8 339.9 ± 135.8 (76.5-746.3) 10.8 28.0 14.0

93 93 93 93 92 92 92 92 92 92 92 93 93 93 93 93

93 29 93 93 92 9 92 10 92 92 92 30 93 33 93 25

280 ± 251 (104-1972) 31.3 10.5 ± 3.8 (5.1-27.0) 43.2 ± 26.2 (10.0-163.3) 100.9 ± 76.3 (8.6-549.9) 9.8 94.0 ± 40.1 (61.9-406.6) 10.9 4.1 ± 0.3 (3.4-4.9) 13.1 ± 1.3 (9.4-16.8) 89 ± 5 (68-100) 32.3 11.6 ± 62.5 (0.0-600.6) 35.5 178.6 ± 215.6 (0.0-1000.0) 26.9

93

a

Number of total participants.

b

Number of participants with the condition.

c

Range in parentheses.

d

Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males.

132 TABLE 5.2 Correlations of vitamin B12, methylmalonic acid, and total homocysteine with puretone average threshold (1, 2, and 4 kHz) in the best ear and the worst ear at baseline a

Vitamin B12

Pure-tone average threshold in the best ear (N = 91) b r = -0.06

Pure-tone average threshold in the worst ear (N = 88) b R = -0.13

P = 0.58

P = 0.26

r = 0.19

R = 0.27

P = 0.07

P = 0.02

r = -0.02

R = -0.02

P = 0.84

P = 0.83

Methylmalonic acid

Total homocysteine

a

Partial Spearman correlation coefficient, controlled for age, gender, race, creatinine, family

history of hearing loss, and noise exposure. b

Number of total participants.

133 TABLE 5.3 Demographics, nutrition and auditory function in the best ear at baseline Hearing

n

Nc 93

Normal (PTA a ≤ 25 dB HLb) Mean ± SD nd or % 43

Impaired (PTA >25 dB HL) Mean ± SD nd or % 50

Hearing level (dB)

93

43

19 ± 4

50

42 ± 11

Age (years)

93

43

71 ± 6

50

Gender (% of female)

93

41

95.4

Race (% of Caucasian)

93

24

Education (years)

91

Family history of hearing loss (%) Number of years exposed to noise (years) Number of medications

Best ear

P valuee

P valuef

P valueg

78 ± 7

271 nmol/L (%)

≤ 20 ng/mL (%) Serum creatinine (µmol/L)

≥ 2.4 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

134 a

PTA, pure-tone average threshold of 1, 2, and 4 kHz.

b

HL, hearing level.

c

Number of total participants.

d

Number of participants with the condition.

e

Logistic regression model controlled for age and gender.

f

Logistic regression model controlled for age, gender, race, and creatinine.

g

Logistic regression model controlled for age, gender, race, creatinine, family history of hearing

loss, and noise exposure. h

i

Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. MMA, methylmalonic acid.

- Not applicable. There was possibly a quasi-complete separation of data points.

135 TABLE 5.4 Demographics, nutrition and auditory function in the worst ear at baseline Hearing

n

N 90

Normal a b (PTA ≤ 25 dB HL ) Mean ± SD d or % n 33

Impaired (PTA > 25 dB HL) Mean ± SD d or % n 57

Hearing level (dB)

90

33

21 ± 4

57

42 ± 12

Age (years)

90

33

71 ± 5

57

Gender (% of female)

90

31

93.9

Race (% of Caucasian)

90

18

Education (years)

88

Family history of hearing loss (%) Number of years exposed to noise (years) Number of medications

Worst ear

Anemic (%)

P valuee

P valuef

P valueg

77 ± 7

0.0003

0.0002

0.0003

45

79.0

0.05

0.04

0.14

54.6

39

68.4

0.25

0.26

0.38

33

9±3

55

9±4

0.83

0.96

0.97

90

6

18.2

12

21.1

0.66

0.59

0.77

89

32

10 ± 14

57

17 ± 18

0.26

0.24

0.26

90

33

7±3

57

6±3

0.44

0.43

0.37

89

6

18.8

14

24.6

0.85

0.78

0.92

90

33

382.6 ± 125.2

57

314.3 ± 138.8

0.08

0.13

0.14

-

-

0.07

0.09

-

-

c

h

Serum vitamin B12 (pmol/L) < 185 pmol/L (%) < 258 pmol/L (%) j

< 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum MMA (nmol/L)

i

90

0

0.0

10

17.5

0.01

90

5

15.2

21

36.8

0.04 i

90

0

0.0

13

22.8

0.002

90

33

193 ± 70

57

329 ± 306

0.01

0.009

0.005

90

4

12.1

23

40.4

0.05

0.05

0.02

Serum total homocysteine (µmol/L) Serum folate (nmol/L)

90

33

9.8 ± 3.6

57

10.8 ± 3.9

0.81

0.49

0.47

90

33

42.7 ± 24.8

57

42.9 ± 26.9

0.92

0.67

0.80

Serum pepsinogen I (ng/mL)

89

33

106.4 ± 94.5

56

96.9 ± 63.8

0.53

0.60

0.41

89

1

3.0

7

12.5

0.24

0.29

-

89

32

93.9 ± 60.9

57

93.8 ± 23.4

0.69

0.62

0.57

≥ 127 µmol/L (%)

89

3

9.4

7

12.3

0.79

0.79

0.75

Serum albumin (g/L)

89

32

4.1 ± 0.2

57

4.1 ± 0.3

0.63

0.78

0.91

Hemoglobin (g/dL)

89

32

13.1 ± 1.3

57

13.0 ± 1.3

0.99

0.58

0.74

Mean cell volume (fl)

89

32

90 ± 4

57

89 ± 6

0.47

0.35

0.39

Multivitamin use (%)

90

12

36.4

17

29.8

0.87

0.76

0.81

Synthetic B12 intake (µg/d)

90

33

21.9 ± 104.1

57

6.1 ± 11.4

0.62

0.66

0.63

90

11

33.3

21

36.8

0.59

0.97

0.87

90

33

196.3 ± 241.0

57

168.8 ± 203.0

0.48

0.15

0.20

90

10

30.3

14

24.6

0.65

0.30

0.37

> 271 nmol/L (%)

≤ 20 ng/mL (%) Serum creatinine (µmol/L)

≥ 2.4 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

136 a

PTA, pure-tone average threshold of 1, 2, and 4 kHz.

b

HL, hearing level.

c

Number of total participants.

d

Number of participants with the condition.

e

Logistic regression model controlled for age and gender.

f

Logistic regression model controlled for age, gender, race, and creatinine.

g

Logistic regression model controlled for age, gender, race, creatinine, family history of hearing

loss, and noise exposure. h

Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males.

i

Chi-square analyses.

j

MMA, methylmalonic acid.

- Not applicable. There was possibly a quasi-complete separation of data points.

137 TABLE 5.5 Demographics, nutrition and auditory function in the worst ear at baseline in Caucasians Hearing

n

N 57

Normal a b (PTA ≤ 25 dB HL ) Mean ± SD d or % n 18

Impaired (PTA > 25 dB HL) Mean ± SD d or % n 39

Hearing level (dB)

57

18

21 ± 3

39

43 ± 13

Age (years)

57

18

71 ± 5

39

Gender (% of female)

57

17

94.4

Education (years)

55

18

Family history of hearing loss (%)

57

Number of years exposed to noise (years) Number of medications

Worst ear

Anemic (%)

P valuee

P valuef

P valueg

77 ± 8

0.009

0.007

0.007

30

76.9

0.12

0.09

0.17

10 ± 3

37

10 ± 3

0.31

0.32

0.23

4

22.2

10

25.6

0.93

0.85

0.71

57

18

11 ± 15

39

17 ± 18

0.35

0.37

0.34

57

18

7±3

39

6±4

0.59

0.63

0.60

57

2

11.1

7

18.0

0.68

0.38

0.48

57

18

354.7 ± 72.9

39

282.8 ± 123.0

0.02

0.03

0.02

-

-

0.04

0.04

-

-

c

h

Serum vitamin B12 (pmol/L) < 185 pmol/L (%) < 258 pmol/L (%) j

< 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum MMA (nmol/L)

i

57

0

0.0

8

20.5

0.05

57

3

16.7

17

43.6

0.03 i

57

0

0.0

12

30.8

0.01

57

18

213 ± 74

39

382 ± 355

0.03

0.008

0.008

> 271 nmol/L (%)

57

3

16.7

20

51.3

0.06

0.03

0.03

Serum tHcy (µmol/L)

57

18

9.6 ± 3.9

39

11.3 ± 4.3

0.33

0.07

0.06

Serum folate (nmol/L)

57

18

52.9 ± 26.5

39

46.1 ± 30.0

0.32

0.41

0.41

Serum pepsinogen I (ng/mL)

56

18

133.6 ± 116.3

38

98.9 ± 67.1

0.13

0.19

0.19

-

-

≤ 20 ng/mL (%)

i

56

0

0.0

5

13.2

0.16

57

18

100.2 ± 79.2

39

95.9 ± 23.5

0.68

0.29

0.20

≥ 127 µmol/L (%)

57

2

11.1

5

12.8

0.37

0.74

0.82

Serum albumin (g/L)

57

18

4.2 ± 0.2

39

4.1 ± 0.3

0.84

0.82

0.85

Hemoglobin (g/dL)

57

18

13.5 ± 1.4

39

13.3 ± 1.3

0.67

0.41

0.55

Mean cell volume (fl)

57

18

91 ± 3

39

90 ± 6

0.29

0.29

0.30

Multivitamin use (%)

57

9

50.0

13

33.3

0.78

0.65

0.69

Synthetic B12 intake (µg/d)

57

18

5.9 ± 1.6

39

7.4 ± 13.0

0.44

0.48

0.49

57

9

50.0

17

43.6

0.88

0.76

0.81

57

18

302.2 ± 266.6

39

202.1 ± 217.3

0.11

0.07

0.10

57

9

50.0

12

30.8

0.20

0.15

0.19

Serum creatinine (µmol/L)

≥ 2.4 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

138 a

PTA, pure-tone average threshold of 1, 2, and 4 kHz.

b

HL, hearing level.

c

Number of total participants.

d

Number of participants with the condition.

e

Logistic regression model controlled for age and gender.

f

Logistic regression model controlled for age, gender, and creatinine.

g

Logistic regression model controlled for age, gender, creatinine, family history of hearing loss,

and noise exposure. h

Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males.

i

Chi-square analyses.

j

MMA, methylmalonic acid.

- Not applicable. There was possibly a quasi-complete separation of data points.

S e ru m M e th ylm a lo n ic A c id (n m o l/L )

139

550

At or below hearing cutoff

500

Above hearing cutoff (poor hearing)

450 *

400 350

*

*

300 250 200 150 100 50 0 20 dB Best Worst

25 dB Best Worst Hearing Level (decibel)

40 dB Best Worst

FIGURE 5.1 Serum methylmalonic acid concentration (nmol/L) and poor hearing status in the best ear and the worst ear at baseline analyzed using 3 different cutoffs (> 20, > 25, or > 40 dB hearing level). Values are mean ± SEM. For each pair (e.g., ≤ 20 vs. > 20 dB hearing level in the best ear), logistic regression analyses were conducted to determine the relationship of serum methylmalonic acid with hearing levels; models were controlled for age, gender, race, and serum creatinine. Other models for ≤ 25 vs. > 25 dB hearing level are shown in Tables 5.3 and 5.4. * indicates a significant difference within the pair, P ≤ 0.05.

140

500

S eru m V ita m in B 12 (p m o l/L )

450

At or below hearing cutoff Above hearing cutoff (poor hearing)

400 350

*

300 250 200 150 100 50 0 20 dB Best Worst

25 dB Best Worst Hearing Level (decibel)

40 dB Best Worst

FIGURE 5.2 Serum vitamin B12 concentration (pmol/L) and poor hearing status using 3 different cutoffs (> 20, > 25, or > 40 dB hearing level) in the best ear and the worst ear at baseline. Values are mean ± SEM. For each pair (e.g., ≤ 20 vs. > 20 dB hearing level in the best ear), logistic regression analyses were conducted to determine the relationship of serum vitamin B12 with hearing levels; models were controlled for age, gender, race, and serum creatinine. Other models for ≤ 25 vs. > 25 dB hearing level are shown in Tables 5.3 and 5.4. * indicates a significant difference within the pair, P ≤ 0.05.

141

At or below hearing cutoff

P re v a le n c e o f V ita m in B 1 2 D e fic ie n c y (% )

30

Above hearing cutoff (poor hearing) * 22.8 20

* 17.1

17.9

22.7

18.0

11.3 9.3

10

23.3

10.0

3.9 0.0

0.0

0 Best

20 dB Worst

25 dB Best Worst Hearing Level (decibel)

Best

40 dB Worst

FIGURE 5.3 Prevalence (%) of vitamin B12 deficiency (defined as serum vitamin B12 < 258 pmol/L, methylmalonic acid > 271 nmol/L, and methylmalonic acid > 2-methylcitric acid) in participants with poor hearing status using 3 different cutoffs (> 20, > 25, and > 40 dB hearing level) at baseline. Values are mean ± SEM. For each pair (e.g., ≤ 20 vs. > 20 dB hearing level in the best ear), logistic regression analyses were conducted to determine the relationship of prevalence of vitamin B12 deficiency with hearing levels; models were controlled for age, gender, race, and creatinine. Other models for ≤ 25 vs. > 25 dB hearing level are shown in Tables 5.3 and 5.4. * indicates a significant difference within the pair, P ≤ 0.05.

142 A

Best Ear 46 Pure-tone Average Threshold (dB HL)

44 42 40 38 Placebo 36

25 µg/d 100 µg/d 1000 µg/d

34 32 30 28 26 24 22 Baseline

B

Post-treatment

Worst Ear 46

Pure-tone Average Threshold (dB HL)

44 42 40 38 Placebo 36

25 µg/d 100 µg/d 1000 µg/d

34 32 30 28 26 24 22 Baseline

Post-treatment

FIGURE 5.4 Pure-tone average threshold (1, 2, and 4 kHz) before vitamin B12 supplementation (baseline) and after three months of supplementation (post-treatment) with different levels of vitamin B12 (0, 25, 100 and 1000 µg/day) in the best ear (A) and the worst ear (B).

143

CHAPTER 6 CONCLUSIONS The purpose of this dissertation was to: 1) examine the prevalence of hearing impairment among a sample of older adults receiving nutrition services from senior centers in northeast Georgia, 2) evaluate a possible relationship of hearing impairment with CVD and CVD risk factors, and 3) further evaluate a possible relationship of age-related hearing loss with poor vitamin B12 status, using multiple measures of vitamin B12 status and by repletion with a vitamin B12 supplement. Hearing impairment was prevalent among the 147 older adults in this study [pure-tone average threshold (PTA) > 25 dB hearing level; 63% in the best ear and 74% in the worst ear]. Consistent with previous findings, the prevalence of hearing impairment increased with advanced age, and men had poorer hearing status than women. PTA was significantly correlated with self-reported Hearing Handicap Inventory for the Elderly (HHIE) in this population. Participants with impaired hearing scored significantly higher in HHIE than those with normal hearing, which indicates greater evidence of hearing handicap. This result suggests that HHIE may be a reasonable self-assessment tool to identify hearing impairment among older adults. Low HDL cholesterol concentration was consistently and significantly related to hearing impairment. This observation adds to the growing body of evidence that CVD risk factors may be related to hearing impairment in older adults.

Therefore, the observation that HDL

cholesterol concentration was significantly associated with hearing impairment suggests that low HDL cholesterol concentration may be a modifiable risk factor for hearing impairment.

144 However, hearing impairment was not significantly associated with other self-reported CVD risk factors (e.g., hypertension, diabetes mellitus, use of tobacco product, stroke, heart disease, and congestive heart failure), systolic blood pressure, diastolic blood pressure, hypertension, lowdensity lipoprotein cholesterol, total cholesterol, and triglycerides. Additional research is needed to identify whether or not CVD and CVD-related risk factors directly cause hearing loss. Multi-center longitudinal studies with all age populations with a control group well matched for all known confounding variables are needed to identify the mechanisms and metabolic defects responsible for the auditory dysfunction associated with CVD and CVD-related risk factors. Histological studies using experimental animals are necessary to decipher the exact mechanisms. Elevations in MMA concentration (> 271 nmol/L) were prevalent among 93 older adults (31.3%). No participant had folate deficiency (defined as serum folate < 6.8 nmol/L), but 14% of participants had vitamin B12 deficiency (defined as serum vitamin B12 < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid). The findings were that impaired hearing in the worst ear was associated with several indices of poor vitamin B12 status including low serum vitamin B12 and high MMA concentrations. PTA in the worst ear was significantly correlated with serum MMA concentrations, but not with serum concentrations of vitamin B12 and tHcy. Most of these associations remained when controlled for other factors that might impair hearing or vitamin B12 status such as age, gender, race, family history of hearing loss, noise exposure, and serum creatinine concentrations.

The stronger associations of vitamin B12 status with

hearing in Caucasians compared to African-Americans may suggest a real biological difference in the influence of vitamin B12 on hearing loss or may be due to the limited power to detect such an association in the small number of African-Americans in this study (n = 33). These findings

145 complement emerging evidence that vitamin B12 status, as well as folate status may be related to hearing loss. To my knowledge, this is the first study to report an association of elevated MMA with hearing loss. Elevated concentrations of MMA and Hcy are relatively specific markers for vitamin B12 deficiency, but Hcy may also be elevated in poor folate and/or vitamin B6 status. The metabolite MMA appeared to be a sensitive indicator of cellular vitamin B12 deficiency and a better predictor of hearing impairment than measures of serum vitamin B12 or total Hcy. Measurement of serum vitamin B12 concentration alone accounted for little of the variance in auditory function among older adults in this study. This raises the question of whether interventions designed to lower serum MMA and increase vitamin B12 concentrations will prevent or reverse auditory dysfunction in older adults. The current study did not support this possibility. Following three months of supplementation with vitamin B12, those persons with high levels of MMA (> 271 nmol/L) at baseline showed no significant change in the PTA between baseline and post-treatment. Thus, prevention of vitamin B12 deficiency may be important, because vitamin B12 repletion did not improve hearing function in vitamin B12-deficient participants. Prospective and/or intervention studies in humans, with all age populations with a control group well matched for all known confounding variables are needed to demonstrate a causal role for vitamin B12 and to identify the mechanisms and metabolic defects responsible for the association of auditory dysfunction with poor vitamin B12 and folate status. Histological studies using experimental animals are required to understand the exact mechanisms. Investigation of gene defects, such as cblA (MMAA), cblB (MMAB), cblC, cblD, cblE, cblF, cblG (MTR), and cblH, causing vitamin B12-responsive methylmalonic aciduria and/or homocystinuria, and their association with auditory dysfunction are necessary to examine the effects of gene and diet

146 interactions on auditory function. Furthermore, double-blinded randomized clinical trials with long term vitamin B12 supplementation are needed to examine the possible effect of vitamin B12 supplement on the auditory system. Together, these studies suggest that hearing impairment is prevalent in these older adults and that future studies are needed to explore the underlying mechanisms, nutrition-related preventive measures, and the therapeutic effects of optimal nutrition among those with hearing impairment. Research strategies involving animal and human models of hearing impairment, nutrient deficiencies and nutrient excesses, and interaction among nutrition, genetic susceptibility via genes that influence hearing impairment and/or nutrient metabolism and the environment (e.g. noise) may be fruitful.

147

APPENDICES

148

APPENDIX A THE PURPOSE OF APPENDIX A IS TO FURTHER EXAMINE A POSSIBLE RELATIONSHIP OF HEARING HANDICAP INVENTORY FOR THE ELDERLY AND PURE-TONE AVERAGE IN OLDER ADULTS RECEIVING NUTRITION AND HEALTH SERVICES FROM THE OLDER AMERICANS ACT NUTRITION PROGRAMS (TABLES A.1 - A.3). Table A.1 Hearing impairment and Hearing Handicap Inventory for the Elderly based on pure-tone average (PTA; 1, 2, and 4 kHz) a All Participants b

Mean ± SD

Normal (PTA ≤ 25 dB hearing level) nc Mean ± SD

Best ear Social f Emotional g Total h

147 147 147

4.7 ± 8.1 5.4 ± 10.4 10.0 ± 17.7

54 54 54

Worst ear Social Emotional Total

143 143 143

4.4 ± 7.9 5.1 ± 10.0 9.6 ± 17.2

Impaired (PTA > 25 dB hearing level) nc Mean ± SD 93 93 93

P value d

P value e

6.6 ± 9.3 7.6 ± 12.0 14.2 ± 20.3

0.002 0.002 0.002

0.002 0.002 0.002

106 5.6 ± 8.7 106 6.7 ± 11.2 106 12.3 ± 19 PTA > 40 dB hearing level nc Mean ± SD

0.02 0.01 0.009

0.02 0.02 0.01

All Participants Nb Mean ± SD

37 1.1 ± 2.9 37 0.8 ± 2.2 37 1.9 ± 4.8 PTA ≤ 40 dB hearing level nc Mean ± SD

P value d

P value e

Best ear Social Emotional Total

147 147 147

4.7 ± 8.1 5.4 ± 10.4 10.0 ± 17.7

101 101 101

2.2 ± 5.9 2.8 ± 8.9 5.0 ± 14.4

46 46 46

10.1 ± 9.4 11.0 ± 11.4 21.1 ± 19.4

0.0003 0.0002 0.0002

0.001 0.0007 0.0007

Worst ear Social Emotional Total

143 143 143

4.4 ± 7.9 5.1 ± 10.0 9.6 ± 17.2

82 82 82

1.6 ± 4.3 2.2 ± 7.1 3.8 ± 11

61 61 61

8.3 ± 9.8 9.1 ± 12.0 17.4 ± 20.7

0.0002 0.0003 0.0002

0.0004 0.0008 0.0004

N

a

1.3 ± 3.3 1.5 ± 5.2 2.8 ± 8.1

Hearing Handicap Inventory for the Elderly contains total 25 questions. Number of total participants. c Number of participants with the condition. d Logistic regression model adjusted for age, gender, and race. e Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. f Social/Situational score ranged from 0 to 48. Higher number indicates worst hearing impairment. g Emotional score ranged from 0 to 52. Higher number indicates worse hearing impairment. h Score ranged from 0 to 100. Higher number indicates worse hearing impairment. b

149 Table A.2 Means, standard deviations, and range data for the Hearing Handicap Inventory for the Elderly by hearing level category based on pure-tone average threshold (PTA; 1, 2, and 4 kHz) Hearing Handicap Inventory for the Elderly a Emotional c Social/Situational d Total e PTA in dB hearing level Mean ± SD Mean ± SD Mean ± SD Mean ± SD

Hearing level category

Nb

Best ear Normal (0-25 dB)

54

19.5 ± 3.9 (8-25) f

1.5 ± 5.2 (0-28)

1.3 ± 3.3 (0-16)

2.8 ± 8.1 (0-40)

Mild (26-40 dB)

47

34.0 ± 4.1 (27-40)

4.3 ± 11.7 (0-46)

3.2 ± 7.9 (0-34)

7.5 ± 19.1 (0-80)

Moderate (41-55 dB)

34

47.5 ± 4.0 (42-55)

11.2 ± 12.8 (0-48)

8.5 ± 9.0 (0-32)

19.7 ± 21.3 (0-76)

Moderately severe (>55 dB)

12

62.1 ± 4.7 (57-73)

10.3 ± 6.0 (0-24)

14.7 ± 9.5 (4-28)

25.0 ± 12.7 (8-48)

Total

147

34.1 ± 14.2 (8-73)

5.4 ± 10.4 (0-48)

4.7 ± 8.1 (0-38)

10.0 ± 17.7 (0-80)

Worst ear Normal (0-25 dB)

37

21.1 ± 3.5 (10-25)

0.8 ± 2.2 (0-10)

1.1 ± 2.9 (0-12)

1.9 ± 4.8 (0-18)

Mild (26-40 dB)

45

32.8 ± 4.3 (27-40)

3.4 ± 9.2 (0-38)

1.9 ± 5.3 (0-30)

5.4 ± 14.0 (0-68)

Moderate (41-55 dB)

42

47.0 ± 4.8 (42-55)

8.4 ± 13.8 (0-48)

7.0 ± 9.8 (0-34)

15.4 ± 23.2 (0-80)

Moderately severe (>55 dB)

19

65.1 ± 7.9 (57-83)

10.6 ± 6.4 (2-24)

11.1 ± 9.3 (0-38)

21.7 ± 13.1 (6-48)

Total

143

38.2 ± 15.1 (10-83)

5.1 ± 10.0 (0-48)

4.4 ± 7.9 (0-38)

9.6 ± 17.2 (0-80)

a

Hearing Handicap Inventory for the Elderly has total 25 questions. Number of total participants. c Emotional score ranged from 0 to 52. Higher number indicates worse hearing impairment. d Social/Situational score ranged from 0 to 48. Higher number indicates worse hearing impairment. e Score ranged from 0 to 100. Higher number indicates worse hearing impairment. f Range in parentheses. b

150 Table A.3 Hearing Handicap Inventory for the Elderly scores as a function of handicap category and pure-tone average threshold (1, 2, and 4 kHz)

Pure-tone average Best ear 0-25 dB (normal) 26-40 dB (mild) 41-55 dB (moderate) >55 dB (moderately severe) Total Worst ear 0-25 dB (normal) 26-40 dB (mild) 41-55 dB (moderate) >55 dB (moderately severe) Total a

Nb

Hearing Handicap Inventory for the Elderly a 18-42 points > 42 points 0-16 points (Mild to moderate (Significant (No handicap) handicap) handicap)

54 47 34 12 147

51 (94.4%) 41 (87.2%) 19 (55.9%) 3 (25.0%) 114

3 (5.6%) 2 (4.3%) 10 (29.4%) 7 (58.3%) 22

0 (0.0%) 4 (8.5%) 5 (14.7%) 2 (16.7%) 11

37 45 42 19 143

36 (97.3%) 40 (88.9%) 28 (66.7%) 8 (42.1%) 112

1 (2.7%) 3 (6.7%) 8 (19.1%) 9 (47.4%) 21

0 (0.0%) 2 (4.4%) 6 (14.3%) 2 (10.5%) 10

Hearing Handicap Inventory for the Elderly has total 25 questions (score ranged from 0 to 100). Higher number indicates worse hearing impairment. b Number of total participants.

151

APPENDIX B THE PURPOSE OF APPENDIX B IS TO FURTHER EXAMINE A POSSIBLE RELATIONSHIP OF HEARING IMPAIRMENT WITH CARDIOVASCULAR DISEASE RISK FACTORS IN OLDER ADULTS AT DIFFERENT FREQUENCIES (PTA, 0.5, 1, 2, 4, AND 8 kHz) IN THE BEST AND THE WORST EAR. TWO DIFFERENT CUTOFFS FOR POOR HEARING (25 AND 40 dB HL) WERE USED (TABLES B.1 - B.11). Table B.1 Characteristics of participants

Age (years) Gender Female (%) Male (%) Race Caucasian (%) African-American (%) Hearing level in the best ear (dB) Hearing level in the worst ear (dB) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) d Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

Number of total participants. Number of participants with the condition. c Range in parentheses. d Hypertension was defined as systolic blood pressure ≥ 140 mmHg. b

Na 146 146

nb 146

Mean ± SD or % 76 ± 8 (58-97) c

119 27

81.5 18.5

146 142 143 146 145 146 146

103 43 146 142 143 36 145 82 89

70.6 29.4 34 ± 14 (8-73) 38 ± 15 (10-83) 9 ± 4 (0-18) 24.7 16 ± 18 (0-83) 56.2 61.0

146 146 146 146 146 146 146 146 146 141 141 146 146 146 146 146 146

146 146 40 17 24 13 29 146 26 141 48 146 78 146 93 146 45

145 ± 23 (89-236) 70 ± 10 (49-103) 27.4 11.6 16.4 8.9 19.9 55 ± 16 (27-110) 18.0 118 ± 34 (55-258) 34.0 208 ± 42 (128-385) 53.4 4.0 ± 1.3 (2-9) 63.7 176 ± 103 (51-777) 31.0

146

152 Table B.2 Demographics, cardiovascular disease risk factors, and auditory function based on pure-tone average threshold (PTA; 1, 2, and 4 kHz) in the best ear and the worst ear (≤ 25 vs. > 25 dB HL)

Na Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years)

Hearing Normal Impaired (PTA ≤ 25 dB HL) (PTA >25 dB HL) Mean ± SD Mean ± SD nb or % nb or %

P value c

P value d

146 146 146 146 146 143 146 145

53 53 53 49 34 53 10 52

36.3 19 ± 4 72 ± 6 92.5 64.2 9±3 18.9 11 ± 14

93 93 93 70 69 90 26 93

63.7 43 ± 11 79 ± 7 75.3 74.2 9±4 28.0 18 ± 20

< 0.0001 0.003 0.23 0.86 0.50 0.10

< 0.0001 0.02 0.33 0.65 0.61 0.11

146 146

27 33

50.9 62.3

55 56

59.1 60.2

0.39 0.66

0.37 0.72

146 146 146

53 53 16

142 ± 19 70 ± 9 30.2

93 93 24

147 ± 25 70 ± 11 25.8

0.50 0.31 0.94

0.42 0.38 0.93

146 146 146

6 12 7

11.3 22.6 13.2

11 12 6

11.8 12.9 6.5

0.41 0.12 0.06

0.38 0.14 0.09

146 146 146 141 141 146 146 146

9 53 8 52 14 53 29 53

17.0 58 ± 19 15.1 114 ± 39 26.9 207 ± 46 54.7 3.8 ± 1.5

20 93 18 89 34 93 49 93

21.5 53 ± 14 19.4 120 ± 31 38.2 209 ± 40 52.7 4.1 ± 1.2

0.69 0.37 0.95 0.99 0.46 0.86 0.94 0.65

0.60 0.18 0.94 0.96 0.38 0.99 0.94 0.53

146

29

54.7

64

68.8

0.28

0.27

146 146

53 18

176 ± 111 34.0

93 27

176 ± 99 29.0

0.97 0.58

0.98 0.53

142 142 142

36 36 36

25.3 21 ± 4 71 ± 6

106 106 106

74.7 44 ± 13 78 ± 8

< 0.0001

< 0.0001

153 Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

142 142 139 142 141

34 21 36 5 35

94.4 58.3 9±3 13.9 10 ± 13

84 78 103 29 106

79.3 73.6 9±4 27.4 17 ± 19

0.02 0.09 0.54 0.23 0.15

0.04 0.20 0.46 0.29 0.18

142 142

20 23

55.6 63.9

60 63

56.6 59.4

0.77 0.89

0.83 0.93

142 142 142

36 36 10

143 ± 18 70 ± 10 27.8

106 106 29

145 ± 24 70 ± 11 27.4

0.83 0.27 0.52

0.96 0.37 0.43

142 142 142

4 7 3

11.1 19.4 8.3

13 16 10

12.3 15.1 9.4

0.53 0.58 0.98

0.57 0.63 0.95

142 142 142 137 137 142 142 142

7 36 4 36 11 36 21 36

19.4 61 ± 18 11.1 120 ± 41 30.6 213 ± 48 58.3 3.7 ± 1.3

20 106 21 101 36 106 56 106

18.9 54 ± 15 19.8 118 ± 31 35.6 208 ± 40 52.8 4.1 ± 1.3

0.77 0.08 0.46 0.17 0.84 0.28 0.56 0.43

0.90 0.04 0.40 0.15 0.83 0.15 0.49 0.41

142

19

52.8

71

67.0

0.33

0.37

142 142

36 10

158 ± 66 27.8

106 35

184 ± 113 33.0

0.46 0.63

0.56 0.75

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. b

154 Table B.3 Demographics, cardiovascular disease risk factors, and auditory function at 1 kHz in the best ear and the worst ear (≤ 25 vs. > 25 dB HL)

Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years)

Na

Hearing Normal Impaired (≤ 25 dB HL) (>25 dB HL) Mean ± SD Mean ± SD nb or % nb or %

P value c

P value d

146 146 146 146 146 143 146 145

82 82 82 69 57 81 17 81

56.2 19 ± 5 73 ± 7 84.2 69.5 10 ± 3 20.7 13 ± 16

64 64 64 50 46 62 19 64

43.8 40 ± 9 80 ± 7 78.1 71.9 9±4 29.7 18 ± 20

< 0.0001 0.17 0.64 0.25 0.32 0.21

< 0.0001 0.53 0.90 0.30 0.35 0.23

146 146

47 51

57.3 62.2

35 38

54.7 59.4

0.35 0.73

0.38 0.78

146 146 146

82 82 22

143 ± 20 70 ± 10 26.8

64 64 18

147 ± 26 69 ± 11 28.1

0.81 0.73 0.49

0.73 0.70 0.56

146 146 146

9 14 7

11.0 17.1 8.5

8 10 6

12.5 15.6 9.4

0.26 0.83 0.53

0.26 0.83 0.48

146 146 146 141 141 146 146 146

18 82 13 79 22 82 41 82

22.0 57 ± 18 15.9 114 ± 36 27.9 207 ± 45 50.0 3.9 ± 1.4

11 64 13 62 26 64 37 64

17.2 53 ± 14 20.3 123 ± 32 41.9 210 ± 39 57.8 4.1 ± 1.3

0.40 0.20 0.40 0.54 0.21 0.81 0.33 0.31

0.50 0.11 0.33 0.56 0.22 0.96 0.35 0.24

146

48

58.5

45

70.3

0.22

0.23

146 146

82 26

176 ± 105 31.7

64 19

177 ± 100 29.7

0.58 0.67

0.59 0.67

145 145 145

62 62 62

42.8 21 ± 4 73 ± 6

83 83 83

57.2 43 ± 12 79 ± 7

< 0.0001

< 0.0001

155 Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

145 145 142 145 144

52 43 62 11 61

83.9 69.4 10 ± 3 17.7 13 ± 15

67 59 80 25 83

80.7 71.1 9±4 30.1 17 ± 20

0.35 0.76 0.35 0.12 0.27

0.73 0.87 0.37 0.14 0.33

145 145

32 40

51.6 64.5

50 49

60.2 59.0

0.67 0.85

0.59 0.83

145 145 145

62 62 14

141 ± 20 69 ± 9 22.6

83 83 26

148 ± 24 70 ± 11 31.3

0.36 0.19 0.10

0.30 0.21 0.10

145 145 145

7 10 6

11.3 16.1 9.7

10 14 7

12.1 16.9 8.4

0.44 0.57 0.86

0.52 0.60 0.85

145 145 145 140 140 145 145 145

15 62 10 60 18 62 35 62

24.2 57 ± 19 16.1 119 ± 37 30.0 212 ± 48 56.5 4.0 ± 1.4

13 83 16 80 30 83 43 83

15.7 54 ± 14 19.3 118 ± 32 37.5 206 ± 37 51.8 4.0 ± 1.3

0.21 0.21 0.44 0.22 0.81 0.20 0.43 0.96

0.29 0.14 0.42 0.17 0.93 0.11 0.36 0.99

145

38

61.3

55

66.3

0.79

0.87

145 145

62 18

171 ± 85 29.0

83 27

181 ± 115 32.5

0.47 0.21

0.55 0.25

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. b

156 Table B.4 Demographics, cardiovascular disease risk factors, and auditory function at 2 kHz in the best ear and the worst ear (≤ 25 vs. > 25 dB HL)

Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years)

Na

Hearing Normal Impaired (≤ 25 dB HL) (>25 dB HL) Mean ± SD Mean ± SD nb or % nb or %

P value c

P value d

146 146 146 146 146 143 146 145

56 56 56 48 37 56 11 55

38.4 19 ± 5 72 ± 6 85.7 66.1 9±4 19.6 13 ± 18

90 90 90 71 66 87 25 90

61.6 45 ± 13 79 ± 7 78.9 73.3 9±3 27.8 17 ± 18

< 0.0001 0.17 0.33 0.92 0.48 0.50

< 0.0001 0.34 0.49 0.92 0.52 0.53

146 146

28 34

50.0 60.7

54 55

60.0 61.1

0.42 0.49

0.38 0.50

146 146 146

56 56 17

141 ± 20 69 ± 10 30.4

90 90 23

148 ± 24 70 ± 11 25.6

0.22 0.19 0.83

0.18 0.23 0.78

146 146 146

6 11 6

10.7 19.6 10.7

11 13 7

12.2 14.4 7.8

0.37 0.54 0.68

0.41 0.53 0.70

146 146 146 141 141 146 146 146

13 56 8 55 17 56 32 56

23.2 59 ± 19 14.3 118 ± 37 30.9 210 ± 44 57.1 3.8 ± 1.4

16 90 18 86 31 90 46 90

17.8 53 ± 14 20.0 118 ± 33 36.1 207 ± 42 51.1 4.1 ± 1.3

0.39 0.04 0.36 0.40 0.98 0.49 0.43 0.29

0.43 0.03 0.35 0.39 0.99 0.39 0.38 0.28

146

31

55.4

62

68.9

0.19

0.19

146 146

56 17

171 ± 109 30.4

90 28

180 ± 99 31.1

0.37 0.64

0.43 0.69

145 145 145

41 41 41

28.3 21 ± 4 71 ± 6

104 104 104

71.7 48 ± 14 78 ± 7

< 0.0001

< 0.0001

157 Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

145 145 142 145 144

37 28 41 7 40

90.2 68.3 9±3 17.1 14 ± 18

82 74 101 29 104

78.9 71.2 9±4 27.9 16 ± 18

0.04 0.86 0.46 0.29 0.99

0.06 0.86 0.62 0.30 0.90

145 145

21 24

51.2 58.5

61 65

58.7 62.5

0.74 0.36

0.62 0.31

145 145 145

41 41 12

141 ± 18 70 ± 10 29.3

104 104 28

147 ± 24 70 ± 11 26.9

0.52 0.73 0.99

0.41 0.84 0.98

145 145 145

4 8 3

9.8 19.5 7.3

13 16 10

12.5 15.4 9.6

0.33 0.76 0.58

0.42 0.67 0.58

145 145 145 140 140 145 145 145

8 41 5 41 11 41 23 41

19.5 61 ± 19 12.2 117 ± 38 26.8 211 ± 45 56.1 3.7 ± 1.3

20 104 21 99 37 104 55 104

19.2 53 ± 14 20.2 119 ± 33 37.4 208 ± 41 52.9 4.1 ± 1.3

0.87 0.02 0.26 0.44 0.59 0.51 0.72 0.16

0.94 0.02 0.27 0.38 0.70 0.37 0.58 0.19

145

22

53.7

71

68.3

0.20

0.19

145 145

41 12

163 ± 66 29.3

104 33

183 ± 114 31.7

0.33 0.35

0.40 0.41

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. b

158 Table B.5 Demographics, cardiovascular disease risk factors, and auditory function at 4 kHz in the best ear and the worst ear (≤ 25 vs. > 25 dB HL)

Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years)

Na

Hearing Normal Impaired (≤ 25 dB HL) (>25 dB HL) Mean ± SD Mean ± SD nb or % nb or %

P value c

P value d

146 146 146 146 146 143 146 145

53 53 53 50 31 52 6 52

36.3 18 ± 6 72 ± 7 94.3 58.5 9±3 11.3 11 ± 14

93 93 93 69 72 91 30 93

63.7 49 ± 13 79 ± 7 74.2 77.4 9±4 32.3 18 ± 20

< 0.0001 0.0009 0.01 0.53 0.02 0.10

< 0.0001 0.004 0.05 0.48 0.03 0.16

146 146

27 32

50.9 60.4

55 57

59.1 61.3

0.27 0.28

0.22 0.29

146 146 146

53 53 17

142 ± 18 70 ± 10 32.1

93 93 23

147 ± 25 70 ± 11 24.7

0.28 0.16 0.79

0.21 0.20 0.97

146 146 146

3 11 5

5.7 20.8 9.4

14 13 8

15.1 14.0 8.6

0.01 0.16 0.46

0.009 0.17 0.55

146 146 146 141 141 146 146 146

13 53 7 52 10 53 27 53

24.5 61 ± 19 13.2 107 ± 29 19.2 199 ± 36 50.9 3.5 ± 1.1

16 93 19 89 38 93 51 93

17.2 52 ± 13 20.4 124 ± 35 42.7 214 ± 45 54.8 4.3 ± 1.3

0.07 0.03 0.96 0.02 0.01 0.05 0.39 0.008

0.13 0.01 0.86 0.03 0.009 0.11 0.43 0.008

146

25

47.2

68

73.1

0.01

0.02

146 146

53 14

162 ± 109 26.4

93 31

184 ± 99 33.3

0.14 0.39

0.18 0.54

142 142 142

34 34 34

23.9 20 ± 5 71 ± 6

108 108 108

76.1 51 ± 14 78 ± 7

< 0.0001

< 0.0001

159 Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

142 142 139 142 141

33 18 33 5 33

97.1 52.9 9±3 14.7 10 ± 13

85 81 106 29 108

78.7 75.0 9±4 26.9 16 ± 19

0.01 0.02 0.83 0.40 0.38

0.02 0.04 0.77 0.47 0.42

142 142

20 21

58.8 61.8

60 65

55.6 60.2

0.50 0.57

0.56 0.58

142 142 142

34 34 11

143 ± 19 71 ± 9 32.4

108 108 28

145 ± 24 70 ± 11 25.9

0.99 0.85 0.95

0.85 0.70 0.89

142 142 142

2 6 4

5.9 17.7 11.8

15 17 9

13.9 15.7 8.3

0.09 0.77 0.20

0.09 0.80 0.21

142 142 142 137 137 142 142 142

6 34 3 33 6 34 16 34

17.7 60 ± 17 8.8 107 ± 32 18.2 197 ± 39 47.1 3.4 ± 1.0

21 108 22 104 41 108 61 108

19.4 54 ± 16 20.4 122 ± 34 39.4 213 ± 43 56.5 4.2 ± 1.4

0.99 0.31 0.36 0.10 0.05 0.08 0.19 0.03

0.95 0.22 0.32 0.11 0.06 0.12 0.23 0.03

142

15

44.1

75

69.4

0.03

0.03

142 142

34 7

157 ± 123 20.6

108 38

184 ± 97 35.2

0.13 0.17

0.15 0.19

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. b

160 Table B.6 Demographics, cardiovascular disease risk factors, and auditory function at 8 kHz in the best ear and the worst ear (≤ 25 vs. > 25 dB HL)

Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years)

Na

Hearing Normal Impaired (≤ 25 dB HL) (>25 dB HL) Mean ± SD Mean ± SD nb or % n or %

100 100 100 100 100 98 100 100

24 24 24 24 8 24 4 24

24.0 14 ± 8 72 ± 8 100.0 33.3 9±3 16.7 10 ± 14

76 76 76 64 53 74 15 76

100 100

16 15

66.7 62.5

100 100 100

24 24 7

100 100 100

P value c

P value d

76.0 47 ± 10 76 ± 7 84.2 69.7 9±4 19.7 14 ± 17

0.02 f 0.06 g 0.002 g 0.80 f 1.0 g 0.33 f

-

44 50

57.9 65.8

0.48 g 0.81 g

-

145 ± 19 73 ± 10 29.2

76 76 24

145 ± 23 69 ± 11 31.6

0.93 f 0.17 f 1.0 g

-

3 1 1

12.5 4.2 4.2

11 14 9

14.5 18.4 11.8

1.0 g 0.11 g 0.44 g

-

100 100 100 97 97 100 100 100

4 24 2 23 4 24 16 24

16.7 63 ± 18 8.3 112 ± 26 17.4 207 ± 31 66.7 3.4 ± 0.9

20 76 16 74 29 76 40 76

26.3 55 ± 17 21.1 119 ± 37 39.2 210 ± 48 52.6 4.1 ± 1.5

0.42 g 0.05 f 0.23 g 0.43 f 0.08 g 0.73 f 0.25 g 0.02 f

-

100

11

45.8

47

61.8

0.24 g

-

100 100

24 5

174 ± 139 20.8

76 25

173 ± 94 32.9

0.85 h 0.32 g

-

85 85 85

18 18 18

21.2 15 ± 7 71 ± 5

67 67 67

78.8 50 ± 10 75 ± 8

0.02 f

-

161 Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

85 85 84 85 85

18 5 18 2 18

100.0 27.8 9±3 11.1 11 ± 13

60 46 66 13 67

89.6 68.7 9±4 19.4 11 ± 16

0.34 g 0.003 g 0.52 f 0.51 g 0.98 f

-

85 85

14 12

77.8 66.7

36 42

53.7 62.7

0.10 g 1.0 g

-

85 85 85

18 18 6

148 ± 15 74 ± 11 33.3

67 67 20

143 ± 21 69 ± 9 29.9

0.39 f 0.06 f 0.78 g

-

85 85 85

3 1 1

16.7 5.6 5.6

7 12 7

10.5 17.9 10.5

0.44 g 0.28 g 1.0 g

-

85 85 85 82 82 85 85 85

3 18 1 18 3 18 10 18

16.7 66 ± 18 5.6 108 ± 27 16.7 204 ± 34 55.6 3.2 ± 0.8

17 67 13 64 21 67 36 67

25.4 55 ± 17 19.4 117 ± 38 32.8 209 ± 49 53.7 4.0 ± 1.4

0.54 g 0.02 f 0.28 g 0.38 f 0.25 g 0.70 f 1.0 g 0.002 f

-

85

6

33.3

42

62.7

0.03 g

-

85 85

18 3

148 ± 57 16.7

67 24

184 ± 116 35.8

0.38 h 0.16 g

-

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. f Independent-sample t test. g Chi-square analyses. h Wilcoxon-Mann-Whitney test. - Not applicable. There was possibly a quasi-complete separation of data points. b

162 Table B.7 Demographics, cardiovascular disease risk factors, and auditory function based on pure-tone average threshold (PTA; 1, 2, and 4 kHz) in the best ear and the worst ear (≤ 40 vs. > 40 dB HL)

Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female)

Na

Hearing PTA ≤ 40 dB HL PTA > 40 dB HL Mean ± SD Mean ± SD nb or % nb or % P value c

P value d

146 146 146 146 146 143 146 145

100 100 100 90 64 98 18 99

68.5 26 ± 8 75 ± 7 90.0 64.0 9±4 18.0 12 ± 16

46 46 46 29 39 45 18 46

31.5 51 ± 8 80 ± 7 63.0 84.8 9±3 39.1 23 ± 21

< 0.0001 0.0001 0.008 0.15 0.07 0.08

< 0.0001 0.003 0.03 0.25 0.07 0.08

146 146

55 61

55.0 61.0

27 28

58.7 60.9

0.35 0.41

0.29 0.42

146 146 146

100 100 28

144 ± 22 70 ± 10 28.0

46 46 12

148 ± 25 70 ± 11 26.1

0.21 0.48 0.73

0.17 0.44 0.86

146 146 146

12 15 9

12.0 15.0 9.0

5 9 4

10.9 19.6 8.7

0.54 0.55 0.51

0.69 0.57 0.61

146 146 146 141 141 146 146 146

22 100 13 97 33 100 57 100

22.0 58 ± 17 13.0 119 ± 36 34.0 212 ± 45 57.0 3.9 ± 1.4

7 46 13 44 15 46 21 46

15.2 48 ± 11 28.3 117 ± 31 34.1 201 ± 35 45.7 4.3 ± 1.2

0.12 0.02 0.29 0.38 0.95 0.15 0.45 0.56

0.22 0.008 0.25 0.31 0.89 0.07 0.39 0.50

146

56

56.0

37

80.4

0.03

0.04

146 146

100 30

172 ± 106 30.0

46 15

185 ± 96 32.6

0.58 0.85

0.61 0.83

142 142 142 142

81 81 81 74

57.0 28 ± 7 74 ± 7 91.4

61 61 61 44

43.0 53 ± 10 79 ± 8 72.1

< 0.0001 0.0005

< 0.0001 0.003

163 Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

142 139 142 141

52 80 12 80

64.2 9±4 14.8 12 ± 16

47 59 22 61

77.1 9±3 36.1 19 ± 19

0.07 0.14 0.01 0.19

0.23 0.17 0.01 0.23

142 142

43 49

53.1 60.5

37 37

60.7 60.7

0.26 0.33

0.23 0.30

142 142 142

81 81 25

143 ± 21 70 ± 11 30.9

61 61 14

148 ± 25 71 ± 10 23.0

0.28 0.27 0.59

0.28 0.30 0.62

142 142 142

10 14 8

12.4 17.3 9.9

7 9 5

11.5 14.8 8.2

0.53 0.64 0.34

0.78 0.55 0.40

142 142 142 137 137 142 142 142

17 81 9 80 25 81 45 81

21.0 59 ± 17 11.1 117 ± 37 31.3 209 ± 44 55.6 3.8 ± 1.3

10 61 16 57 22 61 32 61

16.4 51 ± 13 26.2 119 ± 29 38.6 209 ± 40 52.5 4.3 ± 1.3

0.30 0.04 0.10 0.56 0.70 0.86 0.81 0.17

0.53 0.02 0.09 0.35 0.93 0.45 0.61 0.20

142

44

54.3

46

75.4

0.05

0.08

142 142

81 23

167 ± 101 28.4

61 22

192 ± 106 36.1

0.12 0.40

0.13 0.44

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. b

164 Table B.8 Demographics, cardiovascular disease risk factors, and auditory function at 1 kHz in the best ear and the worst ear (≤ 40 vs. > 40 dB HL)

Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female)

Na

Hearing ≤ 40 dB HL > 40 dB HL Mean ± SD Mean ± SD nb or % nb or %

146 146 146 146 146 143 146 145

123 123 123 101 83 120 27 122

84.0 24 ± 9 75 ± 7 82.1 67.5 9±4 22.0 15 ± 18

23 23 23 18 20 23 9 23

146 146

70 77

56.9 62.6

146 146 146

123 123 32

146 146 146

P value c

P value d

16.0 50 ± 6 81 ± 8 78.3 87.0 10 ± 3 39.1 17 ± 17

0.002 0.65 0.04 0.48 0.31 0.98

0.003 0.76 0.07 0.45 0.31 1.0

12 12

52.2 57.2

0.55 0.73

0.59 0.79

144 ± 22 70 ± 10 26.0

23 23 8

149 ± 28 68 ± 10 34.8

0.51 0.88 0.11

0.56 0.94 0.09

15 21 12

12.2 17.1 9.8

2 3 1

8.7 13.0 4.4

0.97 0.57 0.54

0.85 0.56 0.57

146 146 146 141 141 146 146 146

28 123 21 120 42 123 68 123

22.8 56 ± 17 17.1 118 ± 35 35.0 210 ± 43 55.3 4 ± 1.3

1 23 5 21 6 23 10 23

4.4 49 ± 11 21.7 116 ± 31 28.6 198 ± 36 43.5 4.2 ± 1.3

0.11 0.06 0.62 0.50 0.50 0.13 0.29 0.63

0.12 0.05 0.68 0.39 0.39 0.08 0.22 0.73

146

76

61.8

17

73.9

0.50

0.53

146 146

123 40

176 ± 102 32.5

23 5

178 ± 112 21.7

0.71 0.24

0.67 0.22

145 145 145 145

109 109 109 93

75.2 27 ± 7 75 ± 7 85.3

36 36 36 26

24.8 54 ± 10 80 ± 8 72.2

0.0003 0.06

0.0005 0.29

165 Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

145 142 145 144

71 107 20 108

65.1 9±4 18.4 14 ± 17

31 35 16 36

86.1 9±3 44.4 21 ± 20

0.01 0.31 0.03 0.27

0.05 0.47 0.03 0.29

145 145

63 68

57.8 62.4

19 21

52.8 58.3

0.53 0.87

0.63 0.82

145 145 145

109 109 30

145 ± 22 70 ± 10 27.5

36 36 10

146 ± 26 69 ± 11 27.8

0.91 0.86 0.54

0.90 0.94 0.54

145 145 145

12 17 9

11.0 15.6 8.3

5 7 4

13.9 19.4 11.1

0.23 0.68 0.58

0.37 0.72 0.48

145 145 145 140 140 145 145 145

23 109 16 106 36 109 60 109

21.1 57 ± 16 14.7 119 ± 35 34.0 210 ± 44 55.1 3.9 ± 1.3

5 36 10 34 12 36 18 36

13.9 49 ± 14 27.8 117 ± 31 35.3 204 ± 37 50.0 4.3 ± 1.3

0.53 0.06 0.21 0.43 0.95 0.32 0.76 0.36

0.81 0.03 0.18 0.30 0.85 0.16 0.61 0.37

145

65

59.6

28

77.8

0.21

0.25

145 145

109 32

170 ± 101 29.4

36 13

196 ± 109 36.1

0.39 0.64

0.39 0.66

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. b

166 Table B.9 Demographics, cardiovascular disease risk factors, and auditory function at 2 kHz in the best ear and the worst ear (≤ 40 vs. > 40 dB HL)

Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female)

Na

Hearing ≤ 40 dB HL > 40 dB HL Mean ± SD Mean ± SD nb or % nb or %

146 146 146 146 146 143 146 145

105 105 105 92 68 104 20 104

71.9 26 ± 9 75 ± 8 87.6 64.8 9±4 19.1 13 ± 16

41 41 41 27 35 39 16 41

146 146

61 65

58.1 61.9

146 146 146

105 105 28

146 146 146

P value c

P value d

28.1 57 ± 10 80 ± 7 65.9 85.4 9±4 39.0 22 ± 21

0.0001 0.002 0.01 0.44 0.11 0.16

0.0002 0.03 0.04 0.62 0.12 0.17

21 24

51.2 58.5

0.53 0.74

0.59 0.77

145 ± 22 70 ± 10 26.7

41 41 12

145 ± 25 69 ± 11 29.3

0.95 0.93 0.34

0.99 0.97 0.41

12 16 9

11.4 15.2 8.6

5 8 4

12.2 19.5 9.8

0.37 0.59 0.95

0.46 0.62 0.95

146 146 146 141 141 146 146 146

24 105 14 102 32 105 55 105

22.9 58 ± 17 13.3 116 ± 36 31.4 208 ± 45 52.4 3.8 ± 1.3

5 41 12 39 16 41 23 41

12.2 49 ± 12 29.3 124 ± 30 41.0 208 ± 35 56.1 4.4 ± 1.2

0.07 0.07 0.16 0.33 0.24 0.86 0.29 0.19

0.13 0.03 0.13 0.35 0.26 0.93 0.31 0.15

146

58

55.2

35

85.4

0.005

0.006

146 146

105 33

173 ± 105 31.4

41 12

186 ± 99 29.3

0.60 0.44

0.64 0.40

145 145 145 145

83 83 83 75

57.2 28 ± 8 74 ± 7 90.4

62 62 62 44

42.8 57 ± 11 79 ± 7 71.0

< 0.0001 0.001

< 0.0001 0.01

167 Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

145 142 145 144

55 82 14 82

66.3 9±3 16.9 12 ± 15

47 60 22 62

75.8 9±4 35.5 20 ± 20

0.19 0.30 0.04 0.16

0.48 0.39 0.05 0.18

145 145

44 50

53.0 60.2

38 39

61.3 62.9

0.27 0.32

0.23 0.32

145 145 145

83 83 22

143 ± 22 70 ± 11 26.5

62 62 18

148 ± 24 70 ± 10 29.0

0.28 0.65 0.39

0.25 0.67 0.39

145 145 145

8 14 8

9.6 16.9 9.6

9 10 5

14.5 16.1 8.1

0.08 0.99 0.45

0.11 0.96 0.53

145 145 145 140 140 145 145 145

19 83 10 81 24 83 44 83

22.9 59 ± 17 12.1 116 ± 37 29.6 210 ± 48 53.0 3.8 ± 1.4

9 62 16 59 24 62 34 62

14.5 50 ± 12 25.8 121 ± 29 40.7 207 ± 33 54.9 4.3 ± 1.2

0.06 0.005 0.15 0.89 0.29 0.65 0.56 0.07

0.12 0.002 0.13 0.98 0.34 0.39 0.65 0.06

145

43

51.8

50

80.7

0.002

0.003

145 145

83 24

168 ± 105 28.9

62 21

189 ± 99 33.9

0.06 0.46

0.08 0.49

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. b

168 Table B.10 Demographics, cardiovascular disease risk factors, and auditory function at 4 kHz in the best ear and the worst ear (≤ 40 vs. > 40 dB HL)

Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female)

Na

Hearing ≤ 40 dB HL > 40 dB HL Mean ± SD Mean ± SD nb or % nb or %

P value c

P value d

146 146 146 146 146 143 146 145

86 86 86 80 50 85 14 85

58.9 24 ± 10 74 ± 7 93.0 58.1 9±4 16.3 11 ± 14

60 60 60 39 53 58 22 60

41.1 56 ± 10 80 ± 7 65.0 88.3 9±3 36.7 22 ± 21

< 0.0001 < 0.0001 < 0.0001 0.21 0.12 0.01

< 0.0001 0.0002 0.0001 0.41 0.15 0.02

146 146

47 52

54.7 60.5

35 37

58.3 61.7

0.15 0.13

0.09 0.12

146 146 146

86 86 28

144 ± 22 70 ± 10 32.6

60 60 12

146 ± 24 70 ± 11 20.0

0.27 0.10 0.28

0.14 0.07 0.20

146 146 146

12 15 8

14.0 17.4 9.3

5 9 5

8.3 15.0 8.3

0.79 0.24 0.20

0.70 0.23 0.34

146 146 146 141 141 146 146 146

19 86 10 85 26 86 47 86

22.1 59 ± 17 11.6 116 ± 35 30.6 207 ± 41 54.7 3.8 ± 1.3

10 60 16 56 22 60 31 60

16.7 51 ± 13 26.7 122 ± 33 39.3 211 ± 44 51.7 4.3 ± 1.3

0.20 0.40 0.46 0.71 0.32 0.41 0.72 0.40

0.34 0.13 0.34 0.65 0.20 0.56 0.62 0.26

146

47

54.7

46

76.7

0.14

0.15

146 146

86 24

166 ± 100 27.9

60 21

191 ± 106 35.0

0.67 0.88

0.65 0.83

142 142 142 142

66 66 66 63

46.5 27 ± 9 73 ± 7 95.5

76 76 76 55

53.5 58 ± 11 79 ± 7 72.4

< 0.0001 < 0.0001

< 0.0001 0.0004

169 Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

142 139 142 141

40 65 9 65

60.6 9±4 13.6 10 ± 13

59 74 25 76

77.6 9±4 32.9 19 ± 20

0.01 0.52 0.02 0.009

0.04 0.74 0.04 0.01

142 142

35 40

53.0 60.6

45 46

59.2 60.5

0.24 0.27

0.21 0.29

142 142 142

66 66 22

144 ± 20 70 ± 10 33.3

76 76 17

146 ± 25 70 ± 11 22.4

0.58 0.26 0.39

0.48 0.31 0.44

142 142 142

8 13 6

12.1 19.7 9.1

9 10 7

11.8 13.2 9.2

0.41 0.14 0.34

0.41 0.14 0.61

142 142 142 137 137 142 142 142

14 66 9 65 19 66 37 66

21.2 60 ± 19 13.6 116 ± 36 29.2 208 ± 43 56.1 3.7 ± 1.3

13 76 16 72 28 76 40 76

17.1 52 ± 13 21.1 120 ± 32 38.9 210 ± 42 52.6 4.2 ± 1.3

0.21 0.14 0.76 0.73 0.60 0.94 0.76 0.50

0.41 0.02 0.98 0.61 0.58 0.53 0.67 0.39

142

36

54.6

54

71.1

0.29

0.39

142 142

66 20

169 ± 106 30.3

76 25

185 ± 102 32.9

0.49 0.89

0.48 0.86

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. b

170 Table B.11 Demographics, cardiovascular disease risk factors, and auditory function at 8 kHz in the best ear and the worst ear (≤ 40 vs. > 40 dB HL)

Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female)

Na

Hearing ≤ 40 dB HL > 40 dB HL Mean ± SD Mean ± SD nb or % nb or %

P value c

P value d

100 100 100 100 100 98 100 100

48 48 48 45 23 48 6 48

48.0 24 ± 13 72 ± 8 93.8 47.9 9±4 12.5 12 ± 14

52 52 52 43 38 50 13 52

52.0 53 ± 6 78 ± 6 82.7 73.1 9±4 25.0 14 ± 18

< 0.0001 0.04 0.0006 0.06 0.20 0.87

< 0.0001 0.05 0.001 0.08 0.20 0.99

100 100

28 29

58.3 60.4

32 36

61.5 69.2

0.57 0.12

0.47 0.11

100 100 100

48 48 17

143 ± 20 72 ± 10 35.4

52 52 14

147 ± 24 68 ± 11 26.9

0.84 0.42 0.91

0.93 0.34 0.69

100 100 100

4 6 4

8.3 12.5 8.3

10 9 6

19.2 17.3 11.5

0.04 0.42 0.89

0.05 0.31 0.98

100 100 100 97 97 100 100 100

13 48 6 47 10 48 25 48

27.1 60 ± 18 12.5 108 ± 28 21.3 201 ± 36 52.1 3.5 ± 1.2

11 52 12 50 23 52 31 52

21.2 54 ± 16 23.1 125 ± 39 46.0 217 ± 51 59.6 4.3 ± 1.5

0.20 0.16 0.66 0.04 0.02 0.10 0.47 0.04

0.24 0.14 0.60 0.05 0.02 0.14 0.54 0.05

100

22

45.8

36

69.2

0.02

0.03

100 100

48 13

165 ± 111 27.1

52 17

181 ± 101 32.7

0.76 0.91

0.83 0.99

85 85 85 85

36 36 36 35

42.0 26 ± 12 71 ± 7 97.2

49 49 49 43

58.0 55 ± 6 76 ± 7 87.8

0.0003 0.06

0.0003 0.06

171 Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Hypertension (%) e Self-reported hypertension and/or taking medication for hypertension (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Self-reported diabetes and/or taking medication for diabetes (%) Self-reported stroke (%) Self-reported heart disease (%) Self-reported congestive heart failure (%) Use of tobacco products (%) HDL cholesterol (mg/dL) HDL cholesterol < 40 mg/dL (%) LDL cholesterol (mg/dL) LDL cholesterol ≥ 130 mg/dL (%) Total cholesterol (mg/dL) Total cholesterol ≥ 200 mg/dL (%) Total cholesterol/ HDL cholesterol ratio Total cholesterol/ HDL cholesterol ratio ≥ 3.5 (%) Triglycerides (mg/dL) Triglycerides ≥ 200 mg/dL (%) a

85 85 85 85

15 36 6 36

41.7 8±3 16.7 11 ± 14

36 48 9 49

73.5 10 ± 3 18.4 11 ± 17

0.0005 0.007 0.74 0.65

0.0006 0.006 0.75 0.65

85 85

22 21

61.1 58.3

28 33

57.1 67.4

0.19 0.18

0.19 0.17

85 85 85

36 36 13

144 ± 18 72 ± 9 36.1

49 49 13

144 ± 21 68 ± 10 26.5

0.26 0.28 0.90

0.24 0.28 0.93

85 85 85

4 4 2

11.1 11.1 5.6

6 9 6

12.2 18.4 12.2

0.46 0.26 0.37

0.46 0.30 0.41

85 85 85 82 82 85 85 85

10 36 3 35 6 36 20 36

27.8 64 ± 18 8.3 109 ± 25 17.1 203 ± 32 55.6 3.3 ± 0.9

10 49 11 47 18 49 26 49

20.4 53 ± 16 22.5 120 ± 42 38.3 212 ± 55 53.1 4.3 ± 1.5

0.23 0.01 0.34 0.14 0.02 0.48 0.85 0.01

0.21 0.01 0.40 0.14 0.02 0.42 0.87 0.01

85

15

41.7

33

67.4

0.03

0.02

85 85

36 9

162 ± 119 25.0

49 18

188 ± 96 36.7

0.65 0.96

0.64 0.96

Number of total participants. Number of participants with the condition. c Logistic regression model adjusted for age, gender, and race. d Logistic regression model adjusted for age, gender, race, family history of hearing loss, and noise exposure. e Hypertension was defined as systolic blood pressure ≥ 140 mmHg. f Chi-square analyses. - Not applicable. There was possibly a quasi-complete separation of data points. b

172 A POSSIBLE RELATIONSHIP OF AGE-RELATED HEARING LOSS WITH CARDIOVASCULAR DISEASE RISK FACTORS IN OLDER ADULTS WAS EXAMINED USING TWO DIFFERENT CUTOFFS FOR POOR HEARING (25 AND 40 dB HL). PARTICIPANTS WITH CONDUCTIVE HEARING LOSS AND ASYMMETRICAL HEARING LOSS WERE EXCLUDED IN THIS ANALYSIS (TABLES B.12 – B.15). Table B.12 Characteristics of participants

Age (years) Gender Female (%) Male (%) Race Caucasian (%) African-American (%) PTA d in the best ear (dB HL) e PTA in the worst ear (dB HL) PTA > 25 dB HL in the best ear (%) PTA > 25 dB HL in the worst ear (%) PTA > 40 dB HL in the best ear (%) PTA > 40 dB HL in the worst ear (%) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Total cholesterol (mg/dL) Total cholesterol/ HDL cholesterol ratio Triglycerides (mg/dL) a

Na 96 96

nb 96

Mean ± SD or % 75 ± 7 (58-92) c

79 17

82.3 17.7

64 32 96 93 51 61 22 30 94 18 95 96 93 96 96 96

66.7 33.3 31 ± 14 (8-73) 34 ± 14 (10-77) 53.1 65.6 22.9 32.3 9 ± 4 (0-16) 18.8 14 ± 17 (0-62) 55 ± 16 (27-110) 116 ± 34 (55-258) 204 ± 41 (128-369) 3.9 ± 1.3 (2.2-9.0) 169 ± 103 (51-777)

96

96 93 96 93 96 93 94 96 95 96 93 96 96 96

Number of total participants without conductive hearing loss and asymmetrical hearing loss. Number of participants with the condition. c Range in parentheses. d PTA, pure-tone average threshold of 1, 2, and 4 kHz. e dB HL, hearing level in decibel. b

173 Table B.13 Correlation between blood cholesterols and pure-tone average (1, 2, and 4 kHz) in the best ear and the worst ear a

HDL cholesterol

LDL cholesterol

Total cholesterol

Total cholesterol/HDL cholesterol ratio

Triglycerides

a

PTA b in the best ear (N = 92) r = -0.16

PTA in the worst ear (N = 89) r = -0.23

P = 0.13

P = 0.04

r = 0.04

r = -0.04

P = 0.72

P = 0.75

r = -0.01

r = -0.11

P = 0.90

P = 0.30

r = 0.22

r = 0.20

P = 0.04

P = 0.06

r = 0.12

r = 0.08

P = 0.26

P = 0.47

Partial Spearman correlation coefficient controlled for age, gender, race, family history of hearing loss, and noise exposure. b PTA, pure-tone average threshold of 1, 2, and 4 kHz.

174 Table B.14 Demographics, cardiovascular disease risk factors, and auditory function in the best ear and the worst ear (PTAa ≤ 25 vs. > 25 dB hearing level) Hearing Normal Impaired (PTA ≤ 25 dB HLb) (PTA > 25 dB HL) Mean ± SD Mean ± SD Nc nd or % nd or %

P value e

P value f

Best ear n 96 45 46.9 51 53.1 Hearing level (dB) 96 45 19 ± 4 51 42 ± 11 Age (years) 96 45 71 ± 6 51 78 ± 7 < 0.0001 < 0.0001 Gender (% of female) 96 42 93.3 37 72.6 0.006 0.03 Race (% of Caucasian) 96 27 60.0 37 72.6 0.33 0.35 Education (years) 94 45 9±3 49 9±4 0.79 0.72 Family history of hearing loss (%) 96 8 17.8 10 19.6 1.00 0.84 Number of years exposed to noise 95 44 11 ± 14 51 18 ± 19 0.32 0.31 (years) HDL cholesterol (mg/dL) 96 45 58 ± 18 51 53 ± 14 0.34 0.14 LDL cholesterol (mg/dL) 93 44 113 ± 39 49 118 ± 30 0.89 0.86 Total cholesterol (mg/dL) 96 45 204 ± 45 51 203 ± 37 0.79 0.71 Total cholesterol/ HDL cholesterol 96 45 4.0 ± 1.0 51 4.0 ± 1.0 0.77 0.60 ratio Triglycerides (mg/dL) 96 45 173 ± 114 51 166 ± 93 0.73 0.77 Worst ear n 93 32 34.4 61 65.6 Hearing level (dB) 93 32 21 ± 4 61 41 ± 12 Age (years) 93 32 71 ± 5 61 77 ± 7 0.0002 0.0003 Gender (% of female) 93 30 93.8 48 78.7 0.04 0.10 Race (% of Caucasian) 93 18 56.3 43 70.5 0.23 0.32 Education (years) 91 32 9±3 59 9±4 0.97 0.95 Family history of hearing loss (%) 93 5 15.6 12 19.7 0.66 0.81 Number of years exposed to noise 92 31 10 ± 14 61 16 ± 17 0.34 0.37 (years) HDL cholesterol (mg/dL) 93 32 60 ± 17 61 53 ± 16 0.09 0.03 LDL cholesterol (mg/dL) 90 32 120 ± 42 58 113 ± 29 0.14 0.14 Total cholesterol (mg/dL) 93 32 211 ± 48 61 200 ± 36 0.10 0.07 Total cholesterol/ HDL cholesterol 93 32 4.0 ± 1.0 4.0 ± 1.0 0.68 0.55 ratio Triglycerides (mg/dL) 93 32 155 ± 67 61 180 ± 119 0.50 0.52 a PTA, pure-tone average threshold of 1, 2, and 4 kHz. b dB HL, hearing level in decibel. c Number of total participants without conductive and asymmetrical hearing loss. d Number of participants with the condition. e Logistic regression model controlled for age, gender, and race. f Logistic regression model controlled for age, gender, race, family history of hearing loss, and noise exposure.

175 Table B.15 Demographics, cardiovascular disease risk factors, and auditory function in the best ear and the worst ear (PTAa ≤ 40 vs. > 40 dB hearing level)

Nc

Hearing PTA ≤ 40 dB HLb PTA > 40 dB HL Mean ± SD Mean ± SD nd or % nd or % P value e

P value f

Best ear n 96 74 77.1 22 22.9 Hearing level (dB) 96 74 25 ± 8 22 52 ± 9 Age (years) 96 74 74 ± 7 22 79 ± 7 0.001 0.001 Gender (% of female) 96 67 90.5 12 54.6 0.0004 0.009 Race (% of Caucasian) 96 46 62.2 18 81.8 0.15 0.22 Education (years) 94 73 9±4 21 9±4 0.73 0.90 Family history of hearing loss (%) 96 11 14.9 7 31.8 0.22 0.31 Number of years exposed to noise 95 73 11 ± 14 22 25 ± 22 0.05 0.07 (years) HDL cholesterol (mg/dL) 96 74 57 ± 17 22 49 ± 12 0.24 0.09 LDL cholesterol (mg/dL) 93 72 117 ± 37 21 111 ± 26 0.31 0.33 Total cholesterol (mg/dL) 96 74 207 ± 43 22 191 ± 26 0.13 0.12 Total cholesterol/ HDL cholesterol 96 74 4.0 ± 1.0 22 4.0 ± 1.0 0.73 0.91 ratio Triglycerides (mg/dL) 96 74 170 ± 108 22 167 ± 85 0.86 0.96 Worst ear n 93 63 67.7 30 32.3 Hearing level (dB) 93 63 26 ± 7 30 51 ± 9 Age (years) 93 63 73 ± 6 30 79 ± 8 0.0002 0.0002 Gender (% of female) 93 59 93.4 19 63.3 0.0002 0.001 Race (% of Caucasian) 93 40 63.5 21 70.0 0.71 0.93 Education (years) 91 62 9±3 29 9±4 0.34 0.36 Family history of hearing loss (%) 93 9 14.3 8 26.7 0.11 0.13 Number of years exposed to noise 92 62 11 ± 14 30 19 ± 20 0.37 0.48 (years) HDL cholesterol (mg/dL) 93 63 59 ± 17 30 49 ± 12 0.02 0.007 LDL cholesterol (mg/dL) 90 62 116 ± 38 28 115 ± 25 0.58 0.51 Total cholesterol (mg/dL) 93 63 207 ± 45 30 199 ± 28 0.35 0.26 Total cholesterol/ HDL cholesterol 93 63 4.0 ± 1.0 30 4.0 ± 1.0 0.19 0.12 ratio Triglycerides (mg/dL) 93 63 165 ± 105 30 185 ± 102 0.12 0.09 a PTA, pure-tone average threshold of 1, 2, and 4 kHz. b dB HL, hearing level in decibel. c Number of total participants without conductive and asymmetrical hearing loss. d Number of participants with the condition. e Logistic regression model controlled for age, gender, and race. f Logistic regression model controlled for age, gender, race, family history of hearing loss, and noise exposure.

176 A POSSIBLE RELATIONSHIP OF HEARING IMPAIRMENT WITH CARDIOVASCULAR DISEASE RISK FACTORS IN OLDER ADULTS WAS EXAMINED USING TWO DIFFERENT CUTOFFS FOR POOR HEARING (25 AND 40 dB HL). PARTICIPANTS WHO WERE TAKING A CHOLESTEROL LOWERING MEDICATION WERE EXCLUDED IN THIS ANALYSIS (TABLES B.16 – B.19). Table B.16 Characteristics of participants

Age (years) Gender Female (%) Male (%) Race Caucasian (%) African-American (%) Body weight (kg) Body mass index PTA d in the best ear (dB HL) e PTA in the worst ear (dB HL) PTA > 25 dB HL in the best ear (%) PTA > 25 dB HL in the worst ear (%) PTA > 40 dB HL in the best ear (%) PTA > 40 dB HL in the worst ear (%) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) Total cholesterol (mmol/L) Total cholesterol/ HDL cholesterol ratio Triglycerides (mmol/L) a

Na 115 115

Mean ± SD or % 77 ± 8 (58-97) c

93 22

80.9 19.1

75 40 115 115 115 112 77 88 37 51 112 24 114 115 111 115 115 115

65.2 34.8 77.7 ± 18.2 (40.8-137.9) 29.0 ± 6.2 (15.2-48.3) 35 ± 14 (8-67) 39 ± 15 (10-83) 67.0 78.6 32.2 45.5 9 ± 4 (0-18) 20.9 15 ± 18 (0-83) 1.44 ± 0.43 (0.70-2.86) 3.14 ± 0.83 (1.43-5.59) 5.45 ± 0.98 (3.33-8.48) 4.0 ± 1.3 (2.0-8.1) 1.96 ± 1.22 (0.58-8.78)

115 115 115 115 112 115 112 115 112 112 115 114 115 111 115 115 115

Number of total participants. Number of participants with the condition. c Range in parentheses. d PTA, pure-tone average threshold of 1, 2, and 4 kHz. e dB HL, hearing level in decibel. b

nb 115

177 Table B.17 Correlation between blood cholesterols and pure-tone average (1, 2, and 4 kHz) in the best ear and the worst ear a

HDL cholesterol

LDL cholesterol

Total cholesterol

Total cholesterol/HDL cholesterol ratio

Triglycerides

a

PTA b in the best ear (N = 110) r = -0.20

PTA in the worst ear (N = 107) r = -0.23

P = 0.05

P = 0.02

r = 0.07

r = 0.03

P = 0.48

P = 0.80

r = 0.001

r = -0.04

P = 0.92

P = 0.70

r = 0.23

r = 0.22

P = 0.02

P = 0.03

r = 0.13

r = 0.15

P = 0.18

P = 0.12

Partial Spearman correlation coefficient controlled for age, gender, race, family history of hearing loss, and noise exposure. b PTA, pure-tone average threshold of 1, 2, and 4 kHz.

178 Table B.18 Demographics, cardiovascular disease risk factors, and auditory function in the best ear and the worst ear (PTAa ≤ 25 vs. > 25 dB hearing level) Hearing Normal Impaired (PTA ≤ 25 dB HLb) (PTA > 25 dB HL) Mean ± SD Mean ± SD Nc nd or % nd or % P value e P value f Best ear n 115 38 33.0 77 67.0 Hearing level (dB) 115 38 19 ± 4 77 42 ± 10 Age (years) 115 38 72 ± 6 77 79 ± 7 < 0.0001 < 0.0001 Gender (% of female) 115 34 89.5 59 76.6 0.10 0.21 Race (% of Caucasian) 115 20 52.6 55 71.4 0.05 0.10 Body weight (kg) 115 38 83.3 ± 20.7 77 75.0 ± 16.2 0.28 0.21 Body mass index 115 38 30.4 ± 7.4 77 28.3 ± 5.5 0.83 0.77 Education (years) 112 38 9±4 74 9±4 0.73 0.91 Family history of hearing loss (%) 115 6 15.8 18 23.4 0.98 0.95 Number of years exposed to noise 114 37 10 ± 14 77 18 ± 19 0.19 0.19 (years) HDL cholesterol (mmol/L) 115 38 1.54 ± 0.50 77 1.39 ± 0.38 0.24 0.11 LDL cholesterol (mmol/L) 111 37 3.01 ± 0.93 74 3.21 ± 0.78 0.96 0.97 Total cholesterol (mmol/L) 115 38 5.38 ± 1.12 77 5.48 ± 0.92 0.59 0.57 Total cholesterol/ HDL cholesterol 115 38 3.8 ± 1.4 77 4.2 ± 1.3 0.64 0.44 ratio Triglycerides (mmol/L) 115 38 1.91 ± 1.40 77 1.98 ± 1.13 0.93 0.99 Worst ear n 112 24 21.4 88 78.6 Hearing level (dB) 112 24 21 ± 4 88 44 ± 13 Age (years) 112 24 71 ± 6 88 78 ± 7 0.0001 0.0003 Gender (% of female) 112 22 91.7 70 79.6 0.21 0.29 Race (% of Caucasian) 112 10 41.7 62 70.5 0.01 0.03 Body weight (kg) 112 24 83.6 ± 21.2 88 76.0 ± 17.1 0.69 0.61 Body mass index 112 24 30.5 ± 7.7 88 28.6 ± 5.8 0.81 0.82 Education (years) 109 24 9±3 85 9±4 0.83 0.82 Family history of hearing loss (%) 112 3 12.5 20 22.7 0.80 0.77 Number of years exposed to noise 111 23 10 ± 14 88 16 ± 18 0.54 0.52 (years) HDL cholesterol (mmol/L) 112 24 1.62 ± 0.46 88 1.40 ± 0.41 0.08 0.05 LDL cholesterol (mmol/L) 108 24 3.19 ± 0.92 84 3.13 ± 0.80 0.11 0.09 Total cholesterol (mmol/L) 112 24 5.56 ± 1.13 88 5.44 ± 0.93 0.08 0.06 Total cholesterol/ HDL cholesterol 112 24 3.6 ± 1.1 88 4.2 ± 1.4 0.37 0.33 ratio Triglycerides (mmol/L) 112 24 1.59 ± 0.66 88 2.07 ± 1.33 0.44 0.46 a PTA, pure-tone average threshold of 1, 2, and 4 kHz. b dB HL, hearing level in decibel. c Number of total participants. d Number of participants with the condition. e Logistic regression model controlled for age, gender, and race. f Logistic regression model controlled for age, gender, race, family history of hearing loss, and noise exposure.

179 Table B.19 Demographics, cardiovascular disease risk factors, and auditory function in the best ear and the worst ear (PTAa ≤ 40 vs. > 40 dB hearing level) Hearing PTA ≤ 40 dB HLb PTA > 40 dB HL Mean ± SD Mean ± SD Nc nd or % nd or % P value e P value f Best ear n 115 78 67.8 37 32.2 Hearing level (dB) 115 78 27 ± 9 37 51 ± 7 Age (years) 115 78 75 ± 8 37 81 ± 6 0.0001 0.0004 Gender (% of female) 115 68 87.2 25 67.6 0.02 0.11 Race (% of Caucasian) 115 44 56.4 31 83.8 0.003 0.02 Body weight (kg) 115 78 79.4 ± 18.9 37 74.1 ± 16.3 0.36 0.22 Body mass index 115 78 29.8 ± 6.6 37 27.2 ± 4.9 0.33 0.25 Education (years) 112 76 9±4 36 9±4 0.19 0.27 Family history of hearing loss (%) 115 12 15.4 12 32.4 0.38 0.31 Number of years exposed to noise 114 77 12 ± 16 37 22 ± 19 0.12 0.10 (years) HDL cholesterol (mmol/L) 115 78 1.53 ± 0.46 37 1.26 ± 0.29 0.02 0.004 LDL cholesterol (mmol/L) 111 76 3.12 ± 0.87 35 3.18 ± 0.75 0.58 0.58 Total cholesterol (mmol/L) 115 78 5.48 ± 1.04 37 5.38 ± 0.86 0.23 0.16 Total cholesterol/ HDL cholesterol 115 78 3.8 ± 1.4 37 4.4 ± 1.1 0.31 0.16 ratio Triglycerides (mmol/L) 115 78 1.87 ± 1.26 37 2.15 ± 1.11 0.31 0.24 Worst ear n 112 61 54.5 51 45.5 Hearing level (dB) 112 61 28 ± 7 51 53 ± 11 Age (years) 112 61 74 ± 7 51 81 ± 7 < 0.0001 < 0.0001 Gender (% of female) 112 54 88.5 38 74.5 0.04 0.07 Race (% of Caucasian) 112 33 54.1 39 76.5 0.007 0.03 Body weight (kg) 112 61 81.0 ± 19.2 51 73.7 ± 16.3 0.30 0.22 Body mass index 112 61 30.3 ± 6.8 51 27.6 ± 5.2 0.32 0.29 Education (years) 109 60 9±4 49 8±4 0.08 0.08 Family history of hearing loss (%) 112 8 13.1 15 29.4 0.26 0.24 Number of years exposed to noise 111 60 12 ± 17 51 18 ± 19 0.55 0.50 (years) 0.02 0.009 HDL cholesterol (mmol/L) 112 61 1.56 ± 0.47 51 1.32 ± 0.34 LDL cholesterol (mmol/L) 108 60 3.09 ± 0.92 48 3.21 ± 0.70 0.53 0.36 Total cholesterol (mmol/L) 112 61 5.45 ± 1.09 51 5.48 ± 0.81 0.28 0.14 Total cholesterol/ HDL cholesterol 112 61 3.7 ± 1.3 51 4.4 ± 1.3 0.15 0.14 ratio Triglycerides (mmol/L) 112 61 1.80 ± 1.25 51 2.17 ± 1.19 0.14 0.13 a PTA, pure-tone average threshold of 1, 2, and 4 kHz. b dB HL, hearing level in decibel. c Number of total participants. d Number of participants with the condition. e Logistic regression model controlled for age, gender, and race. f Logistic regression model controlled for age, gender, race, family history of hearing loss, and noise exposure.

180

APPENDIX C THE PURPOSE OF APPENDIX C IS TO FURTHER EXAMINE A POSSIBLE RELATIONSHIP OF HEARING IMPAIRMENT WITH MULTIPLE MEASURES OF VITAMIN B12 STATUS IN OLDER ADULTS USING TWO DIFFERENT CUTOFFS (25 AND 40 dB HL) IN THE BEST AND THE WORST EAR. A POSSIBLE RELATIONSHIP OF AGE-RELATED HEARING LOSS WITH MULTIPLE MEASURES OF VITAMIN B12 STATUS IN OLDER ADULTS USING THREE DIFFERENT CUTOFFS (20, 25, AND 40 dB HL) IN THE BEST AND THE WORST EAR. PARTICIPANTS WITH CONDUCTIVE HEARING LOSS AND ASYMMETRICAL HEARING LOSS WERE EXCLUDED (TABLES C.1 – C.4).

Table C.1 Characteristics of participants at baseline

Age (years) Gender Female (%) Male (%) Race Caucasian (%) African-American (%) Hearing level in the best ear (dB) Hearing level in the worst ear (dB) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score d Overall health e Number of medications Impaired cognition (%) f Anemic (%) g Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%)

Na 93 93

nb 93

Mean ± SD or % 75 ± 7 (58-92) c

77 16

82.8 17.2

60 33 93 90 91 19 92 93 92 93 93 27 21 93 8 10 19 26 13

64.5 35.5 31 ± 14 (8-73) 34 ± 14 (10-77) 9 ± 4 (0-16) 20.4 15 ± 17 (0-62) 30.2 ± 7.0 (20.0-53.8) 5 ± 4 (0-19) 1.6 ± 0.7 (0-3) 6 ± 3 (0-15) 29.0 22.8 339.9 ± 135.8 (76.5-746.3) 8.6 10.8 20.4 28.0 14.0

93

93 90 91 93 92 93 92 93 93 93 92 93 93 93 93 93 93

181 Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic vitamin B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) a

93 93 93 93 93 93 93 93 93 93 92 92 92 92 92 92 92 92 92 92 93 92 93 93 93 93 93 93 93 93

93 29 12 93 51 35 11 93 93 93 92 9 22 92 10 92 92 92 92 92 93 92 30 93 33 30 11 10 93 25

280 ± 251 (104-1972) 31.3 12.9 10.5 ± 3.8 (5.1-27.0) 54.8 37.6 11.8 43.2 ± 26.2 (10.0-163.3) 260 ± 141 (89-968) 184 ± 68 (58-453) 100.9 ± 76.3 (8.6-549.9) 9.8 23.9 94.0 ± 40.1 (61.9-406.6) 10.9 4.1 ± 0.3 (3.4-4.9) 18 ± 9 (8-79) 13.1 ± 1.3 (9.4-16.8) 89 ± 5 (68-100) 114 ± 67 (42-511) 34 ± 20 (10-144) 4.0 ± 2.0 (0.9-9.4) 32.3 11.6 ± 62.5 (0.0-600.6) 35.5 32.3 11.8 10.8 178.6 ± 215.6 (0.0-1000.0) 26.9

Number of total participants. Number of participants with the condition. c Range in parentheses. d NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. e 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. f Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. g Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. b

182 Table C.2 Demographics, nutrition and auditory function in the best ear and the worst ear at baseline (PTA ≤ 25 vs. > 25 dB hearing level)* Hearing Normal ( PTA ≤ 25 dB HL) Mean ± SD b or % n

Impaired (PTA >25 dB HL) Mean ± SD b or % n

P valuec

P valued

P valuee

93 93 93 93 93 91 93 92

43 43 43 41 24 43 9 42

19 ± 4 71 ± 6 95.4 55.8 9±3 20.9 11 ± 14

50 50 50 36 36 48 10 50

42 ± 11 78 ± 7 72.0 72.0 9±4 20.0 18 ± 19

271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%)

a

183 Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%)

92 92 92 92 92 92 92 93

42 3 42 42 42 42 43 43

92.0 ± 53.6 7.1 4.1 ± 0.3 18 ± 11 12.9 ± 1.3 89 ± 6 115 ± 76 33 ± 23

50 7 50 50 50 50 49 50

95.6 ± 24.1 14.0 4.1 ± 0.3 19 ± 7 13.2 ± 1.2 89 ± 5 113 ± 57 34 ± 17

0.73 0.76 0.69 0.51 0.20 0.60 0.93 0.78

0.65 0.76 0.96 0.22 0.37 0.43 0.87 0.69

0.64 0.75 0.99 0.19 0.31 0.44 0.89 0.71

92 93 93 93 93 93 93 93 93

43 14 43 15 13 4 3 43 12

4.0 ± 1.9 32.6 17.3 ± 91.2 34.9 30.2 9.3 7.0 188.9 ± 227.0 27.9

49 16 50 18 17 7 7 50 13

4.0 ± 2.1 32.0 6.6 ± 12.1 36.0 34.0 14.0 14.0 169.8 ± 207.2 26.0

0.87 0.33 0.86 0.84 0.32 0.17 0.12 0.61 0.96

0.99 0.55 0.92 0.77 0.56 0.23 0.17 0.24 0.56

0.98 0.53 0.99 0.79 0.52 0.22 0.17 0.27 0.58

90 90 90 90 90 88 90 89

33 33 33 31 18 33 6 32

21 ± 4 71 ± 5 93.9 54.6 9±3 18.2 10 ± 14

57 57 57 45 39 55 12 57

42 ± 12 77 ± 7 79.0 68.4 9±4 21.1 17 ± 18

0.0003 0.05 0.25 0.83 0.66 0.26

0.0002 0.04 0.26 0.96 0.59 0.24

0.0003 0.14 0.38 0.97 0.77 0.26

90 89 90 90 90 89 90 90 90 90 90 90

33 33 33 33 6 6 33 0 0 3 5 0

31.7 ± 7.7 6±4 1.6 ± 0.7 7±3 18.2 18.8 382.6 ± 125.2 0.0 0.0 9.1 15.2 0.0

57 56 57 57 20 14 57 8 10 16 21 13

29.6 ± 6.5 5±4 1.6 ± 0.8 6±3 35.1 24.6 314.3 ± 138.8 14.0 17.5 28.1 36.8 22.8

0.82 0.38 0.61 0.44 0.35 0.85 0.08 0.02 j 0.01 j 0.05 0.04 0.002 j

0.78 0.48 0.42 0.43 0.27 0.78 0.13 0.08 0.07 -

0.79 0.47 0.50 0.37 0.13 0.92 0.14 0.10 0.09 -

90

33

193 ± 70

57

329 ± 306

0.01

0.009

0.005

90 90

4 1

12.1 3.0

23 10

40.4 17.5

0.05 0.36

0.05 0.24

0.02 0.22

184 Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

90

33

9.8 ± 3.6

57

10.8 ± 3.9

0.81

0.49

0.47

90 90 90 90 90 90 89 89 89 89 89 89 89 89 89 89 90

15 11 4 33 33 33 33 1 9 32 3 32 32 32 32 33 33

45.5 33.3 12.1 42.7 ± 24.8 258 ± 167 174 ± 72 106.4 ± 94.5 3.0 27.3 93.9 ± 60.9 9.4 4.1 ± 0.2 19 ± 13 13.1 ± 1.3 90 ± 4 119 ± 86 33 ± 25

34 23 6 57 57 57 56 7 12 57 7 57 57 57 57 56 57

59.7 40.4 10.5 42.9 ± 26.9 262 ± 128 191 ± 67 96.9 ± 63.8 12.5 21.4 93.8 ± 23.4 12.3 4.1 ± 0.3 18 ± 7 13.0 ± 1.3 89 ± 6 112 ± 54 34 ± 16

0.50 0.81 0.34 0.92 0.45 0.98 0.53 0.24 0.42 0.69 0.79 0.63 0.98 0.99 0.47 0.75 0.59

0.37 0.99 0.54 0.67 0.69 0.90 0.60 0.29 0.49 0.62 0.79 0.78 0.54 0.58 0.35 0.79 0.40

0.36 0.92 0.71 0.80 0.79 0.87 0.41 0.67 0.57 0.75 0.91 0.47 0.74 0.39 0.81 0.45

89 90 90 90 90 90 90 90 90

33 12 33 11 11 4 3 33 10

4.1 ± 1.9 36.4 21.9 ± 104.1 33.3 33.3 12.1 9.1 196.3 ± 241.0 30.3

56 17 57 21 18 7 7 57 14

3.9 ± 2.1 29.8 6.1 ± 11.4 36.8 31.6 12.3 12.3 168.8 ± 203.0 24.6

0.72 0.87 0.62 0.59 0.74 0.69 0.48 0.48 0.65

0.60 0.76 0.66 0.97 0.88 0.79 0.61 0.15 0.30

0.63 0.81 0.63 0.87 0.97 0.84 0.68 0.20 0.37

* PTA, pure-tone average threshold of 1, 2, and 4 kHz. a Number of total participants. b Number of participants with the condition. c Logistic regression model adjusted for age and gender. d Logistic regression model adjusted for age, gender, race, and creatinine. e Logistic regression model adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. f NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. g 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. h Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. i Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. j Chi-square analyses. - Not applicable. There was possibly a quasi-complete separation of data points.

185 Table C.3 Demographics, nutrition and auditory function in the best ear and the worst ear at baseline (PTA ≤ 40 vs. > 40 dB hearing level)* Hearing PTA ≤ 40 dB HL PTA > 40 dB HL Mean ± SD Mean ± SD b b or % or % n n

P valuec

P valued

P valuee

93 93 93 93 93 91 93 92

71 71 71 65 42 70 12 70

93 92 93 93 93 92 93 93 93 93 93 93

N Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L)

a

25 ± 8 73 ± 7 91.6 59.2 9±4 16.9 12 ± 14

22 22 22 12 18 21 7 22

52 ± 9 79 ± 7 54.6 81.8 9±4 31.8 25 ± 22

0.001 0.0003 0.10 0.66 0.17 0.09

0.002 0.0008 0.09 0.75 0.28 0.09

0.001 0.0009 0.18 0.90 0.35 0.11

71 70 71 71 18 17 71 5 6 13 19 8

30.7 ± 7.2 5±4 1.6 ± 0.8 6±3 25.4 24.3 345.7 ± 133.0 7.0 8.5 18.3 26.8 11.3

22 22 22 22 9 4 22 3 4 6 7 5

28.5 ± 6.3 5±4 1.5 ± 0.7 6±3 40.9 18.2 321.4 ± 146.0 13.6 18.2 27.3 31.8 22.7

0.74 0.92 0.47 0.76 0.45 0.08 0.88 0.89 0.83 0.53 0.96 0.24

0.57 0.95 0.31 0.80 0.20 0.18 0.76 0.77 0.86 0.61 0.92 0.37

0.63 0.95 0.48 0.87 0.15 0.15 0.60 0.76 0.92 0.77 0.82 0.56

93

71

234 ± 109

22

428 ± 454

0.17

0.23

0.29

93 93 93

17 7 71

23.9 9.9 10.2 ± 3.6

12 5 22

54.6 22.7 11.2 ± 4.4

0.13 0.53 0.50

0.18 0.31 0.66

0.20 0.29 0.74

93 93 93 93 93 93 92 92 92 92

37 26 8 71 71 71 70 6 17 70

52.1 36.6 11.3 42.5 ± 23.5 254 ± 138 182 ± 68 100.1 ± 75.3 8.6 24.3 92.6 ± 44.4

14 9 3 22 22 22 22 3 5 22

63.6 40.9 13.6 45.4 ± 34.1 278 ± 149 189 ± 72 103.6 ± 81.2 13.6 22.7 98.4 ± 21.4

0.76 0.29 0.37 0.56 0.42 0.37 0.52 0.57 0.90 0.71

0.92 0.56 0.47 0.99 0.33 0.24 0.52 0.61 0.99 0.58

0.76 0.48 0.67 0.69 0.19 0.21 0.29 0.50 0.73 0.57

186 ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L)

92 92 92 92 92 92 93

7 70 70 70 70 71 71

10.0 4.1 ± 0.3 18 ± 10 13.0 ± 1.3 90 ± 5 113 ± 67 34 ± 20

3 22 22 22 22 21 22

13.6 4.1 ± 0.2 19 ± 7 13.4 ± 1.2 89 ± 6 119 ± 67 33 ± 18

0.25 0.74 0.83 0.21 0.33 0.79 0.23

0.22 0.35 0.60 0.42 0.16 0.95 0.15

0.18 0.30 0.70 0.35 0.21 0.92 0.16

92 93 93 93 93 93 93 93 93

71 24 71 24 22 7 6 71 18

3.9 ± 2.1 33.8 12.7 ± 71.3 33.8 31.0 9.9 8.5 174.2 ± 216.8 25.4

21 6 22 9 8 4 4 22 7

4.3 ± 1.7 27.3 7.8 ± 13.1 40.9 36.4 18.2 18.2 193.0 ± 216.1 31.8

0.16 0.90 0.76 0.80 0.66 0.06 0.05 0.64 0.51

0.27 0.76 0.68 0.72 0.94 0.10 0.10 0.81 0.96

0.37 0.79 0.69 0.99 0.73 0.11 0.10 0.97 0.71

90 90 90 90 90 88 90 89

60 60 60 57 36 59 10 59

26 ± 7 73 ± 6 95.0 60.0 9±3 16.7 12 ± 14

30 31 30 19 21 29 8 30

51 ± 9 79 ± 8 63.3 70.0 9±4 26.7 19 ± 19

0.0002 0.0002 0.47 0.61 0.16 0.68

0.0002 0.0003 0.47 0.41 0.17 0.66

0.0002 0.001 0.70 0.41 0.19 0.75

90 89 90 90 90 89 90 90 90 90 90 90

60 60 60 60 13 13 60 2 3 10 15 6

31.0 ± 7.3 6±4 1.6 ± 0.8 6±3 21.7 22.0 348.9 ± 127.5 3.3 5.0 16.7 25.0 10.0

30 29 30 30 13 7 30 6 7 9 11 7

29.3 ± 6.3 5±4 1.5 ± 0.7 6±3 43.3 23.3 320.1 ± 155.6 20.0 23.3 30.0 36.7 23.3

0.60 0.34 0.59 0.75 0.13 0.38 0.86 0.13 0.12 0.24 0.50 0.13

0.45 0.37 0.50 0.74 0.09 0.52 0.99 0.14 0.14 0.28 0.59 0.17

0.52 0.42 0.57 0.82 0.05 0.47 0.81 0.17 0.20 0.35 0.68 0.25

90

60

223 ± 91

30

390 ± 403

0.12

0.10

0.10

90 90 90

13 5 60

21.7 8.3 10.0 ± 3.3

14 6 30

46.7 20.0 11.3 ± 4.6

0.10 0.78 0.81

0.10 0.72 0.92

0.07 0.75 0.74

187 > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

90 90 90 90 90 90 89 89 89 89 89 89 89 89 89 89 90

30 21 6 60 60 60 59 3 12 59 5 59 59 59 59 60 60

50.0 35.0 10.0 41.6 ± 23.8 251 ± 139 182 ± 68 104.3 ± 77.1 5.1 20.3 91.5 ± 47.4 8.7 4.1 ± 0.3 18 ± 10 13.1 ± 1.4 89 ± 5 114 ± 71 33 ± 21

19 13 4 30 30 30 30 5 9 30 5 30 30 30 30 29 30

63.3 43.3 13.3 45.2 ± 30.4 279 ± 150 191 ± 72 92.9 ± 75.2 16.7 30.0 98.4 ± 22.5 16.7 4.0 ± 0.3 19 ± 6 13.1 ± 1.2 89 ± 6 115 ± 60 36 ± 19

0.87 0.47 0.59 0.17 0.42 0.23 0.08 0.08 0.23 0.98 0.68 0.53 0.79 0.56 0.44 0.80 0.45

0.97 0.57 0.70 0.22 0.37 0.13 0.07 0.09 0.18 0.91 0.66 0.37 0.60 0.38 0.35 0.76 0.36

0.97 0.47 0.75 0.10 0.30 0.11 0.04 0.07 0.14 0.90 0.57 0.32 0.62 0.49 0.39 0.84 0.30

89 90 90 90 90 90 90 90 90

60 20 60 19 17 5 4 60 16

4.1 ± 2.1 33.3 13.8 ± 77.4 31.7 28.3 8.3 6.7 177.3 ± 216.8 26.7

29 9 30 13 12 6 6 30 8

3.8 ± 1.7 30.0 8.1 ± 12.6 43.3 40.0 20.0 20.0 182.0 ± 220.4 26.7

0.56 0.42 0.76 0.23 0.09 0.02 0.02 0.79 0.78

0.49 0.55 0.73 0.34 0.12 0.02 0.02 0.94 0.99

0.33 0.56 0.93 0.24 0.09 0.03 0.02 0.98 0.95

* PTA, pure-tone average threshold of 1, 2, and 4 kHz. a Number of total participants. b Number of participants with the condition. c Logistic regression model adjusted for age and gender. d Logistic regression model adjusted for age, gender, race, and creatinine. e Logistic regression model adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. f NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. g 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. h Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. i Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males.

188 Table C.4 Demographics, nutrition and auditory function in the best ear and the worst ear at baseline (PTA ≤ 20 vs. > 20 dB hearing level)* Hearing Normal (PTA ≤ 20 dB HL) Mean ± SD b or % n

Impaired (PTA > 20 dB HL) Mean ± SD b or % n

P valuec

P valued

P valuee

93 93 93 93 93 91 93 92

26 26 26 24 15 26 5 26

17 ± 3 70 ± 5 92.3 57.7 9±3 19.2 13 ± 14

67 67 67 53 45 65 14 66

37 ± 13 77 ± 7 79.1 67.2 9±4 20.9 16 ± 18

0.0002 0.13 0.60 0.79 0.87 0.91

0.0002 0.08 0.41 0.94 0.87 0.84

0.0001 0.09 0.33 0.76 0.93 086

93 92 93 93 93 92 93 93 93 93 93 93

26 26 26 26 7 6 26 0 0 3 4 1

31.0 ± 6.9 6±4 1.5 ± 0.7 6±4 26.9 23.1 400.8 ± 137.4 0.0 0.0 11.5 15.4 3.9

67 66 67 67 20 15 67 8 10 16 22 12

29.9 ± 7.0 5±3 1.6 ± 0.8 6±3 29.9 22.7 316.3 ± 128.5 11.9 14.9 23.9 32.8 17.9

0.57 0.22 0.42 0.67 0.45 0.28 0.03 0.10 j 0.06 j 0.23 0.09 0.16

0.79 0.24 0.81 0.61 0.48 0.58 0.05 0.29 0.14 0.19

0.81 0.23 0.89 0.57 0.33 0.64 0.06 0.26 0.12 0.17

93

26

202 ± 76

67

310 ± 287

0.30

0.09

0.12

93 93 93

5 1 26

19.2 3.9 9.8 ± 3.7

24 11 67

35.8 16.4 10.7 ± 3.8

0.77 0.67 0.76

0.54 0.29 0.15

0.75 0.30 0.16

93 93 93 93 93 93 92 92 92

13 9 3 26 26 26 25 0 5

50.0 34.6 11.5 41.1 ± 26.2 257 ± 186 183 ± 82 116.4 ± 103.4 0.0 20.0

38 26 8 67 67 67 67 9 17

56.7 38.8 11.9 44.0 ± 26.4 260 ± 120 184 ± 63 95.2 ± 63.4 13.4 25.4

0.99 0.68 0.54 0.62 0.79 0.31 0.15 0.11 j 0.67

0.53 0.78 0.69 0.49 0.50 0.80 0.41 0.99

0.61 0.73 0.73 0.50 0.63 0.67 0.55 0.84

N Best ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%)

a

189 Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%)

92 92 92 92 92 92 92 93

26 3 26 26 26 26 26 26

98.6 ± 66.7 11.5 4.1 ± 0.3 19 ± 14 13.0 ± 1.6 89 ± 6 120 ± 91 35 ± 28

66 7 66 66 66 66 66 67

92.2 ± 23.1 10.6 4.1 ± 0.3 18 ± 7 13.1 ± 1.2 89 ± 5 112 ± 54 33 ± 16

0.19 0.51 0.13 0.93 0.32 0.99 0.64 0.88

0.17 0.52 0.12 0.23 0.67 0.85 0.79 0.44

0.19 0.54 0.10 0.27 0.79 0.87 0.78 0.42

92 93 93 93 93 93 93 93 93

26 10 26 10 9 3 2 26 7

3.9 ± 1.6 38.5 26.5 ± 117.2 38.5 34.6 11.5 7.7 175.3 ± 195.6 26.9

66 20 67 23 21 8 8 67 18

4.0 ± 2.1 29.9 5.6 ± 10.9 34.3 31.3 11.9 11.9 179.9 ± 224.2 26.9

0.64 0.94 0.53 0.83 0.83 0.60 0.34 0.97 0.88

0.84 0.70 0.59 0.57 0.92 0.60 0.38 0.71 0.85

0.84 0.75 0.59 0.59 0.96 0.56 0.34 0.72 0.85

90 90 90 90 90 88 90 89

14 14 14 14 9 14 2 14

18 ± 3 69 ± 4 100.0 64.3 11 ± 3 14.3 10 ± 15

76 76 76 62 48 74 16 75

37 ± 13 76 ± 7 81.6 63.2 9±4 21.1 15 ± 17

-

-

90 89 90 90 90 89 90 90 90 90 90 90

14 14 14 14 2 3 14 0 0 2 3 0

31.2 ± 7.7 4±3 1.7 ± 0.6 5±3 14.3 21.4 388.3 ± 127.0 0.0 0.0 14.3 21.4 0.0

76 75 76 76 24 17 76 8 10 17 23 13

30.3 ± 6.9 5±4 1.6 ± 0.8 6±3 31.6 22.7 330.3 ± 138.0 10.5 13.2 22.4 30.3 17.1

0.65 k 0.25 k 0.46 k 0.27 0.34 j 1.0 j

-

-

90

14

187 ± 73

76

296 ± 272

0.003

-

-

90 90

1 1

7.1 7.1

26 10

34.2 13.2

0.06 j 1.0

-

-

9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

90

14

9.4 ± 4.6

76

10.6 ± 3.6

0.05

l

-

-

90 90 90 90 90 90 89 89 89 89 89 89 89 89 89 89 90

5 4 2 14 14 14 14 0 3 14 2 14 14 14 14 14 14

35.7 28.6 14.3 43.7 ± 28.6 262 ± 231 180 ± 96 136.3 ± 132.8 0.0 21.4 102.9 ± 89.3 14.3 4.2 ± 0.3 21 ± 18 13.1 ± 1.6 89 ± 4 119 ± 115 35 ± 35

44 30 8 76 76 76 75 8 18 75 8 75 75 75 75 75 76

57.9 39.5 10.5 42.6 ± 25.7 260 ± 122 186 ± 64 93.7 ± 59.3 10.7 24.0 92.2 ± 23.4 10.7 4.1 ± 0.3 18 ± 6 13.1 ± 1.3 89 ± 6 113 ± 56 34 ± 16

0.13 j 0.44 j 0.65 j

-

-

89 90 90 90 90 90 90 90 90

14 7 14 6 6 1 1 14 5

4.0 ± 1.3 50.0 45.5 ± 159.8 42.9 42.9 7.1 7.1 199.2 ± 216.8 35.7

75 22 76 26 23 10 9 76 19

4.0 ± 2.1 29.0 5.7 ± 10.6 34.2 30.3 13.2 11.8 175.1 ± 218.0 25.0

-

-

l

0.99 l 0.15 l 0.13 l 0.40 0.35 j 1.0 j l

0.15 0.65 j

k

0.38 l 0.45 k 0.98 l 0.95 l 0.22 l 0.16 0.98 k 0.13 j l

0.89 0.56 j 0.37 j 1.0 j 1.0 j

k

0.76 0.51 j

* PTA, pure-tone average threshold of 1, 2, and 4 kHz. a Number of total participants. b Number of participants with the condition. c Logistic regression model adjusted for age and gender. d Logistic regression model adjusted for age, gender, race, and creatinine. e Logistic regression model adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. f NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. g 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. h Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. i Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. j Chi-square analyses. k Independent-sample t test. l Wilcoxon-Mann-Whitney test. - Not applicable. There was possibly a quasi-complete separation of data points.

191 A POSSIBLE RELATIONSHIP OF HEARING IMPAIRMENT WITH MULTIPLE MEASURES OF VITAMIN B12 STATUS WAS EXAMINED IN OLDER ADULTS. PARTICIPANTS WITH CONDUCTIVE HEARING LOSS, ASYMMETRICAL HEARING LOSS, AND HIGH VITAMIN B12 CONCENTRATIONS WERE INCLUDED (TABLES C.5 - C.8). Table C.5 Characteristics of participants at baseline

Age (years) Gender Female (%) Male (%) Race Caucasian (%) African-American (%) Hearing level in the best ear (dB) Hearing level in the worst ear (dB) Family history of hearing loss (%) Education (years) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score d Overall health e Number of medications Impaired cognition (%) f Anemic (%) g Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%)

Na 147 147

nb 147

Mean ± SD or % 76 ± 8 (58-97) c

120 27

81.6 18.4

147 143 147 144 146 147 146 147 147 147 146 147 147 147 147 147 147

103 44 147 143 37 144 146 147 146 147 147 39 31 147 11 15 26 38 17

70.1 29.9 34 ± 14 (8-73) 38 ± 15 (10-83) 25.2 9 ± 4 (0-18) 15 ± 18 (0-83) 29.3 ± 6.4 (15.2-53.8) 5±3 1.7 ± 0.8 (0-3) 6 ± 4 (0-15) 26.5 21.2 364.1 ± 161.2 (74.3-992.6) 7.5 10.2 17.7 25.9 11.6

147 147 147 147 147 147 147 147 147 147 145 145

147 43 18 147 87 52 19 147 147 147 145 13

270 ± 213 (85-1972) 29.3 12.2 10.6 ± 4.2 (5.1-39.5) 59.2 35.4 12.9 45.6 ± 26.6 (8.8-163.3) 258 ± 129 (89-968) 187 ± 66 (58-453) 100.0 ± 70.9 (8.6-549.9) 9.0

147

192 ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic vitamin B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) a

145 146 146 146 146 146 146 146 147 146 147 147 147 147 147 147 147 147

33 146 17 146 146 146 146 146 147 146 59 147 66 63 29 24 147 55

22.8 95.5 ± 42.5 (53.0-406.4) 11.6 4.1 ± 0.3 (3.4-4.9) 19 ± 8 (8-79) 13.2 ± 1.3 (9.4-17.3) 91 ± 5 (68-107) 117 ± 60 (42-511) 34 ± 21 (9-157) 4.0 ± 2.0 (0.9-9.6) 40.1 13.3 ± 54.8 (0.0-600.6) 44.9 42.9 19.7 16.3 224.7 ± 241.9 (0.0-1200.0) 37.4

Number of total participants. Number of participants with the condition. c Range in parentheses. d NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. e 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. f Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. g Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. b

193 Table C.6 Correlations of vitamin B12, methylmalonic acid, and total homocysteine with pure-tone average (1, 2, and 4 kHz) in the best ear and the worst ear at baseline a

Vitamin B12

Methylmalonic acid

Total homocysteine

a

Pure-tone average threshold in the best ear (N=145) b r = 0.10

Pure-tone average threshold in the worst ear (N=141) b r = 0.07

P = 0.25

P = 0.43

r = -0.03

r = 0.02

P = 0.75

P = 0.78

r = -0.08

r = -0.08

P = 0.37

P = 0.36

Partial Spearman correlation coefficient from multivariable linear regression analysis; adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. b Number of total participants.

194 Table C.7 Demographics, nutrition and auditory function in the best ear and the worst ear at baseline (PTA ≤ 25 vs. > 25 dB hearing level)* Hearing Normal (PTA ≤ 25 dB HL) Mean ± SD b or % n

Impaired (PTA >25 dB HL) Mean ± SD b or % n

P valuec

P valued

P valuee

147 147 147 147 147 144 147 146

54 54 54 50 34 54 11 53

19 ± 4 72 ± 6 92.6 63.0 9±3 20.4 11 ± 14

93 93 93 70 69 90 26 93

43 ± 11 79 ± 7 75.3 74.2 9±4 28.0 18 ± 20

271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%)

a

195 Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposure to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%)

146 146 146 146 146 146 146 147

53 4 53 53 53 53 54 54

91.1 ± 49.1 7.6 4.1 ± 0.3 18 ± 10 13.1 ± 1.4 90 ± 5 116 ± 70 33 ± 21

93 13 93 93 93 93 92 93

98.0 ± 38.4 14.0 4.1 ± 0.3 19 ± 7 13.3 ± 1.3 91 ± 5 117 ± 54 35 ± 21

0.68 0.89 0.22 0.44 0.35 0.55 0.61 0.48

0.67 0.88 0.30 0.18 0.61 0.77 0.57 0.51

0.64 0.87 0.30 0.13 0.46 0.68 0.59 0.46

146 147 147 147 147 147 147 147 147

54 19 54 21 19 7 5 54 17

3.9 ± 1.8 35.2 19.7 ± 87.5 38.9 35.2 13.0 9.3 197.4 ± 222.4 31.5

92 40 93 45 44 22 19 93 38

4.1 ± 2.1 43.0 9.6 ± 18.0 48.4 47.3 23.7 20.4 240.5 ± 252.3 40.9

0.34 0.18 0.51 0.44 0.16 0.18 0.09 0.55 0.40

0.42 0.36 0.46 0.79 0.34 0.26 0.14 0.96 0.72

0.39 0.32 0.52 0.63 0.24 0.23 0.13 0.77 0.57

143 143 143 143 143 140 143 142

37 37 37 35 21 37 6 36

21 ± 4 71 ± 6 94.6 56.8 9±3 16.2 10 ± 13

106 106 106 84 78 103 29 106

44 ± 13 78 ± 8 79.3 73.6 9±4 27.4 17 ± 19

13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

143

37

9.9 ± 3.4

106

10.8 ± 4.5

0.88

0.71

0.77

143 143 143 143 143 143 141 141 141 142 142 142 142 142 142 142 143

18 12 4 37 37 37 36 1 9 36 3 36 36 36 36 37 37

48.7 32.4 10.8 42.8 ± 24.4 249 ± 159 175 ± 69 104.5 ± 90.6 2.8 25.0 92.3 ± 57.7 8.3 4.1 ± 0.2 18 ± 12 13.1 ± 1.3 90 ± 4 117 ± 82 33 ± 24

66 38 13 106 106 106 105 11 23 106 13 106 106 106 106 105 106

62.3 35.9 12.3 46.3 ± 27.4 261 ± 119 192 ± 66 97.5 ± 63.1 10.5 21.9 96.2 ± 37.0 12.3 4.1 ± 0.3 19 ± 7 13.2 ± 1.4 91 ± 6 116 ± 52 35 ± 20

0.87 0.70 0.35 0.84 0.50 0.85 0.42 0.23 0.62 0.54 0.74 0.49 0.73 0.73 0.52 0.91 0.99

0.65 0.97 0.64 0.76 0.86 0.89 0.49 0.26 0.76 0.52 0.78 0.65 0.30 0.65 0.84 0.92 0.86

0.64 0.91 0.82 0.91 0.89 0.97 0.31 0.99 0.49 0.77 0.74 0.22 0.83 0.74 0.99 0.98

142 143 143 143 143 143 143 143 143

37 13 37 12 12 4 3 37 11

4.0 ± 1.8 35.1 19.7 ± 98.3 32.4 32.4 10.8 8.1 190.6 ± 237.5 29.7

105 44 106 53 50 25 21 106 43

4.0 ± 2.1 41.5 11.5 ± 29.0 50.0 47.2 23.6 19.8 240.0 ± 245.0 40.6

0.76 0.29 0.74 0.11 0.13 0.15 0.13 0.55 0.40

0.87 0.69 0.82 0.34 0.40 0.23 0.22 0.79 0.93

0.75 0.65 0.72 0.27 0.32 0.24 0.26 0.94 0.78

* PTA, pure-tone average threshold of 1, 2, and 4 kHz. a Number of total participants. b Number of participants with the condition. c Logistic regression model adjusted for age and gender. d Logistic regression model adjusted for age, gender, race, and creatinine. e Logistic regression model adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. f NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. g 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. h Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. i Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. - Not applicable. There was possibly a quasi-complete separation of data points.

197 Table C.8 Demographics, nutrition and auditory function in the best ear and the worst ear at baseline (PTA ≤ 40 vs. > 40 dB hearing level)* Hearing PTA ≤ 40 dB HL PTA >40 dB HL Mean ± SD Mean ± SD b b or % or % n n

P valuec

P valued

P valuee

147 147 147 147 147 144 147 146

101 101 101 91 64 99 19 100

26 ± 8 75 ± 7 90.1 63.4 9±4 18.8 12 ± 15

46 46 46 29 39 45 18 46

51 ± 8 80 ± 7 63.0 84.8 9±3 39.1 23 ± 21

376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L)

a

198 ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposure to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L)

146 146 146 146 146 146 147

9 100 100 100 100 101 101

9.0 4.1 ± 0.3 18 ± 9 13.1 ± 1.3 90 ± 5 116 ± 61 34 ± 18

8 46 46 46 46 45 46

17.4 4.1 ± 0.3 19 ± 7 13.5 ± 1.4 91 ± 5 118 ± 58 36 ± 26

0.99 0.78 0.65 0.18 0.97 0.63 0.18

0.94 0.35 0.34 0.49 0.56 0.24 0.10

0.96 0.32 0.31 0.46 0.57 0.23 0.10

146 147 147 147 147 147 147 147 147

101 38 101 41 39 15 13 101 33

4.0 ± 2.1 37.6 15.0 ± 65.7 40.6 38.6 14.9 12.9 205.3 ± 236.7 32.7

45 21 46 25 24 14 11 46 22

4.1 ± 1.9 45.7 9.6 ± 12.1 54.4 52.2 30.4 23.9 267.2 ± 250.2 47.8

0.37 0.24 0.83 0.20 0.15 0.03 0.08 0.17 0.11

0.64 0.54 0.64 0.60 0.43 0.07 0.20 0.62 0.35

0.72 0.63 0.71 0.42 0.29 0.07 0.23 0.53 0.26

143 143 143 143 143 140 143 142

82 82 82 75 52 81 13 81

28 ± 7 74 ± 7 91.5 63.4 9±4 15.9 12 ± 16

61 61 61 44 47 59 22 61

53 ± 10 79 ± 8 72.1 77.1 9±3 36.1 19 ± 19

13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

143 143 143 143 143 143 141 141 141 142 142 142 142 142 142 142 143

47 30 8 82 82 82 80 5 18 81 7 81 81 81 81 82 82

57.3 36.6 9.8 43.8 ± 25.9 249 ± 129 185 ± 64 101.0 ± 73.1 6.3 22.5 91.8 ± 42.2 8.6 4.2 ± 0.3 18 ± 9 13.1 ± 1.4 90 ± 5 116 ± 66 33 ± 19

37 20 9 61 61 61 61 7 14 61 9 61 61 61 61 60 61

60.7 32.8 14.8 47.5 ± 27.7 270 ± 131 192 ± 71 97.0 ± 68.3 11.5 23.0 99.7 ± 44.0 14.8 4.1 ± 0.3 19 ± 7 13.3 ± 1.4 91 ± 5 117 ± 54 36 ± 24

0.20 0.12 0.79 0.23 0.48 0.16 0.57 0.29 0.83 0.54 0.96 0.60 0.70 0.51 0.58 0.83 0.87

0.26 0.19 0.94 0.44 0.42 0.07 0.52 0.28 0.96 0.56 0.97 0.33 0.64 0.92 0.89 0.67 0.99

0.33 0.22 0.72 0.14 0.28 0.06 0.33 0.17 0.72 0.63 0.92 0.27 0.65 0.94 0.82 0.79 0.97

142 143 143 143 143 143 143 143 143

82 28 82 30 28 10 8 82 25

4.1 ± 2.1 34.2 14.9 ± 71.4 36.6 34.2 12.2 9.8 188.8 ± 214.3 30.5

60 29 61 35 34 19 16 61 29

4.0 ± 1.9 47.5 11.9 ± 20.4 57.4 55.7 31.2 26.2 278.8 ± 270.7 47.5

0.98 0.03 0.94 0.23 0.01 0.01 0.01 0.05 0.06

0.72 0.10 0.99 0.10 0.04 0.02 0.03 0.18 0.18

0.66 0.10 0.88 0.05 0.02 0.03 0.05 0.13 0.12

* PTA, pure-tone average threshold of 1, 2, and 4 kHz. a Number of total participants. b Number of participants with the condition. c Logistic regression model adjusted for age and gender. d Logistic regression model adjusted for age, gender, race, and creatinine. e Logistic regression model adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. f NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. g 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. h Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. i Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males.

200 A POSSIBLE RELATIONSHIP OF HEARING IMPAIRMENT WITH MULTIPLE MEASURES OF VITAMIN B12 STATUS WAS EXAMINED IN OLDER ADULTS. PARTICIPANTS WITH CONDUCTIVE HEARING LOSS AND ASYMMETRICAL HEARING LOSS WERE INCLUDED. PARTICIPANTS WITH HIGH VITAMIN B12 CONCENTRATIONS (> 95 TH PERCENTILE) WERE EXCLUDED (TABLES C.9 - C.12). Table C.9 Characteristics of participants at baseline (Participants with high vitamin B12 concentrations were excluded.)

Age (years) Gender Female (%) Male (%) Race Caucasian (%) African-American (%) Hearing level in the best ear (dB) Hearing level in the worst ear (dB) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score d Overall health e Number of medications Impaired cognition (%) f Anemic (%) g Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L)

Na 141 141

nb 141

Mean ± SD or % 76 ± 8 (58-97) c

115 26

81.6 18.4

141 137 139 141 140 141 140 141 141 141 140 141 141 141 141 141 141

97 44 141 137 139 36 140 141 140 141 141 38 30 141 11 15 26 38 17

68.8 31.2 34 ± 14 (8-73) 38 ± 15 (10-83) 9 ± 4 (0-18) 25.5 16 ± 18 (0-83) 29.2 ± 6.4 (15.2-53.8) 5 ± 3 (0-19) 1.7 ± 0.8 6 ± 3 (0-15) 27.0 21.4 346.6 ± 138.0 (74.3-746.3) 7.8 10.6 18.4 27.0 12.1

141 141 141 141 141 141 141 141 141 141

141 41 17 141 83 51 19 141 141 141

270 ± 216 (85-1972) 29.1 12.1 10.7 ± 4.3 (5.1-39.5) 58.9 36.2 13.5 44.5 ± 25.7 (8.8-163.3) 256 ± 130 (89-968) 187 ± 68 (58-453)

141

201 Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic vitamin B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) a

139 139 139 140 140 140 140 140 140 140 141 140 141 141 141 141 141 141 141 141

139 13 32 140 17 140 140 140 140 140 141 140 56 141 61 58 26 21 141 52

98.7 ± 70.8 (8.6-549.9) 9.4 23.0 95.5 ± 43.4 (53.0-406.6) 12.1 4.1 ± 0.3 (3.4-4.9) 18 ± 8 (8-79) 13.2 ± 1.3 (9.4-17.3) 91 ± 5 (68-107) 115 ± 61 (42-511) 35 ± 21 (9-157) 4.0 ± 1.9 (0.9-9.4) 39.7 10.8 ± 51.1 (0.0-600.6) 43.3 41.1 18.4 14.9 214.8 ± 230.0 (0.0-1028.6) 36.9

Number of total participants. Number of participants with the condition. c Range in parentheses. d NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. e 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. f Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. g Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. b

202 Table C.10 Correlations of vitamin B12, methylmalonic acid, and total homocysteine with pure-tone average (1, 2, and 4 kHz) in the best ear and the worst ear at baseline a (Participants with high vitamin B12 concentrations were excluded.)

Vitamin B12

Methylmalonic acid

Total homocysteine

a

Pure-tone average threshold in the best ear (N=139) b r = 0.15

Pure-tone average threshold in the worst ear (N=135) b r = 0.12

P = 0.08

P = 0.18

r = -0.03

r = 0.03

P = 0.77

P = 0.74

r = -0.10

r = -0.09

P = 0.25

P = 0.28

Partial Spearman correlation coefficient from multivariable linear regression analysis; adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. b Number of total participants.

203 Table C.11 Demographics, nutrition and auditory function in the best ear and the worst ear at baseline (PTA ≤ 25 vs. > 25 dB hearing level; Participants with high vitamin B12 concentrations were excluded.)* Hearing Normal (PTA ≤ 25 dB HL) Mean ± SD b or % n

Impaired (PTA >25 dB HL) Mean ± SD b or % n

P valuec

P valued

P valuee

141 141 141 141 141 139 141 140

51 51 51 48 31 51 11 50

19 ± 4 72 ± 6 94.2 60.8 9±3 21.6 11 ± 14

90 90 90 67 66 88 25 90

43 ± 11 79 ± 7 74.4 73.3 9±4 27.8 19 ± 20

271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%)

a

204 Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%)

140 140 140 140 140 140 140 141

50 4 50 50 50 50 51 51

90.5 ± 50.5 8.0 4.1 ± 0.3 17 ± 11 13.1 ± 1.4 90 ± 5 114 ± 71 33 ± 21

90 13 90 90 90 90 89 90

98.3 ± 38.9 14.4 4.1 ± 0.3 19 ± 7 13.3 ± 1.3 91 ± 5 116 ± 54 36 ± 21

0.74 0.95 0.23 0.27 0.41 0.39 0.83 0.79

0.73 0.96 0.33 0.07 0.74 0.59 0.81 0.85

0.71 0.99 0.32 0.06 0.58 0.55 0.77 0.80

140 141 141 141 141 141 141 141 141

51 17 51 18 16 5 3 51 15

3.9 ± 1.8 33.3 15.2 ± 83.8 35.3 31.4 9.8 5.9 188.5 ± 222.4 29.4

89 39 90 43 42 21 18 90 37

4.0 ± 2.0 43.3 8.3 ± 11.8 47.8 46.7 23.3 20.0 229.7 ± 234.2 41.1

0.51 0.12 0.93 0.23 0.06 0.05 0.02 0.55 0.28

0.59 0.27 0.99 0.49 0.16 0.08 0.03 0.98 0.58

0.60 0.24 0.94 0.42 0.12 0.08 0.03 0.89 0.49

137 137 137 137 137 135 137 136

37 37 37 35 21 37 6 36

21 ± 4 71 ± 6 94.6 56.8 9±3 16.2 10 ± 13

100 100 100 79 72 98 28 100

45 ± 13 78 ± 8 79.0 72.0 9±4 28.0 17 ± 19

13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

137

37

9.9 ± 3.4

100

10.9 ± 4.6

0.94

0.66

0.68

137 137 137 137 137 137 135 135 135 136 136 136 136 136 136 135 137

18 12 4 37 37 37 36 1 9 36 3 36 36 36 36 37 37

48.7 32.4 10.8 42.8 ± 24.4 249 ± 159 175 ± 69 104.5 ± 90.6 2.8 25.0 92.3 ± 57.7 8.3 4.1 ± 0.2 18 ± 12 13.1 ± 1.3 90 ± 4 117 ± 82 33 ± 24

62 37 13 100 100 100 99 11 22 100 13 100 100 100 100 98 100

62.0 37.0 13.0 44.8 ± 26.2 259 ± 120 192 ± 68 95.6 ± 62.2 11.1 22.2 96.3 ± 38.0 13.0 4.1 ± 0.3 18 ± 7 13.2 ± 1.4 91 ± 6 114 ± 52 35 ± 20

0.90 0.70 0.40 0.93 0.45 0.81 0.40 0.20 0.57 0.51 0.81 0.54 0.86 0.69 0.54 0.76 0.99

0.67 0.97 0.71 0.63 0.80 0.89 0.49 0.25 0.70 0.50 0.84 0.69 0.38 0.71 0.84 0.80 0.85

0.66 0.93 0.94 0.94 0.80 0.95 0.29 0.93 0.47 0.86 0.78 0.31 0.92 0.75 0.84 0.98

135 137 137 137 137 137 137 137 137

37 13 37 12 12 4 3 37 11

4.0 ± 1.8 35.1 19.7 ± 98.3 32.4 32.4 10.8 8.1 190.6 ± 237.5 29.7

98 41 100 48 45 22 18 100 40

3.9 ± 2.0 41.0 7.8 ± 11.3 48.0 45.0 22.0 18.0 226.9 ± 229.4 40.0

0.87 0.35 0.62 0.16 0.20 0.19 0.17 0.75 0.48

0.96 0.75 0.69 0.43 0.50 0.27 0.26 0.60 0.99

0.86 0.71 0.59 0.36 0.43 0.30 0.33 0.77 0.83

* PTA, pure-tone average threshold of 1, 2, and 4 kHz. a Number of total participants. b Number of participants with the condition. c Logistic regression model adjusted for age and gender. d Logistic regression model adjusted for age, gender, race, and creatinine. e Logistic regression model adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. f NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. g 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. h Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. i Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. - Not applicable. There was possibly a quasi-complete separation of data points.

206 Table C.12 Demographics, nutrition and auditory function in the best ear and the worst ear at baseline (PTA ≤ 40 vs. > 40 dB hearing level; Participants with high vitamin B12 concentrations were excluded.)* Hearing PTA ≤ 40 dB HL PTA >40 dB HL Mean ± SD Mean ± SD b b or % or % n n

P valuec

P valued

P valuee

141 141 141 141 141 139 141 140

95 95 95 86 58 94 18 94

26 ± 8 74 ± 7 90.5 61.1 9±4 19.0 13 ± 16

46 46 46 29 39 45 18 46

51 ± 8 80 ± 7 63.0 84.8 9±3 39.1 23 ± 21

376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L)

a

207 ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L)

140 140 140 140 140 140 141

9 94 94 94 94 95 95

9.6 4.1 ± 0.3 18 ± 9 13.1 ± 1.3 90 ± 5 114 ± 62 34 ± 18

8 46 46 46 46 45 46

17.4 4.1 ± 0.3 19 ± 7 13.5 ± 1.4 91 ± 5 118 ± 58 36 ± 26

0.88 0.84 0.90 0.11 0.99 0.85 0.14

0.89 0.36 0.64 0.36 0.53 0.40 0.06

0.92 0.34 0.53 0.34 0.51 0.35 0.06

140 141 141 141 141 141 141 141 141

95 35 95 36 34 12 10 95 30

3.9 ± 2.0 36.8 11.3 ± 61.7 37.9 35.8 12.6 10.5 189.4 ± 216.5 31.6

45 21 46 25 24 14 11 46 22

4.1 ± 1.9 45.7 9.6 ± 12.1 54.4 52.2 30.4 23.9 267.2 ± 250.2 47.8

0.17 0.22 0.67 0.12 0.08 0.01 0.03 0.08 0.09

0.30 0.57 0.50 0.46 0.29 0.02 0.08 0.42 0.38

0.37 0.66 0.62 0.36 0.23 0.03 0.11 0.34 0.30

137 137 137 137 137 135 137 136

78 78 78 72 48 77 13 77

27 ± 7 73 ± 7 92.3 61.5 9±3 16.7 13 ± 16

59 59 59 42 45 58 21 59

53 ± 10 79 ± 8 71.2 76.3 9±4 35.6 19 ±19

13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

137 137 137 137 137 137 135 135 135 136 136 136 136 136 136 136 137

44 29 8 78 78 78 76 5 17 77 7 77 77 77 77 78 78

56.4 37.2 10.3 42.1 ± 24.0 246 ± 130 184 ± 65 99.7 ± 72.5 5.7 22.4 91.5 ± 43.2 9.1 4.1 ± 0.3 18 ± 10 13.1 ± 1.4 90 ± 5 114 ± 66 33 ± 19

36 20 9 59 59 59 59 7 14 59 9 59 59 59 59 58 59

61.0 33.9 15.3 47.2 ± 27.7 270 ± 133 192 ± 72 95.7 ± 68.8 11.9 23.7 100.1 ± 44.6 15.3 4.1 ± 0.3 19 ± 7 13.3 ± 1.4 91 ± 5 117 ± 54 37 ± 24

0.24 0.10 0.75 0.15 0.58 0.21 0.58 0.30 0.87 0.57 0.86 0.73 0.96 0.65 0.44 0.98 0.98

0.33 0.15 0.99 0.30 0.56 0.10 0.54 0.30 0.92 0.59 0.85 0.42 0.99 0.89 0.74 0.86 0.86

0.37 0.18 0.80 0.10 0.39 0.08 0.36 0.19 0.70 0.67 0.85 0.35 0.94 0.89 0.72 0.93 0.84

136 137 137 137 137 137 137 137 137

78 26 78 26 24 8 6 78 23

4.0 ± 2.0 33.3 11.9 ± 68.0 33.3 30.8 10.3 7.7 179.9 ± 213.7 29.5

58 28 59 34 33 18 15 59 28

3.9 ± 1.9 47.5 9.9 ± 11.8 57.6 55.9 30.5 25.4 266.2 ± 245.9 47.5

0.96 0.03 0.70 0.009 0.003 0.004 0.005 0.06 0.05

0.74 0.10 0.59 0.04 0.01 0.009 0.01 0.21 0.18

0.66 0.10 0.85 0.03 0.009 0.01 0.02 0.14 0.13

* PTA, pure-tone average threshold of 1, 2, and 4 kHz. a Number of total participants. b Number of participants with the condition. c Logistic regression model adjusted for age and gender. d Logistic regression model adjusted for age, gender, race, and creatinine. e Logistic regression model adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. f NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. g 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. h Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. i Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males.

209 A POSSIBLE RELATIONSHIP OF HEARING IMPAIRMENT WITH MULTIPLE MEASURES OF VITAMIN B12 STATUS WAS EXAMINED IN OLDER ADULTS. PARTICIPANTS WITH ASYMMETRICAL HEARING LOSS WERE INCLUDED. PARTICIPANTS WITH CONDUCTIVE HEARING LOSS AND HIGH VITAMIN B12 CONCENTRATIONS (> 95 TH PERCENTILE) WERE EXCLUDED (TABLES C.13 - C.16). Table C.13 Characteristics of participants at baseline (Participants with high vitamin B12 concentrations and conductive hearing loss were excluded.)

Age (years) Gender Female (%) Male (%) Race Caucasian (%) African-American (%) Hearing level in the best ear (dB) Hearing level in the worst ear (dB) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score d Overall health e Number of medications Impaired cognition (%) f Anemic (%) g Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L)

Na 104 104

nb 104

Mean ± SD or % 74 ± 7 (58-92) c

84 20

80.8 19.2

104 101 102 104 103 104 103 104 104 104 103 104 104 104 104 104 104

71 33 104 101 102 24 103 104 103 104 104 28 22 104 9 11 21 29 15

68.3 31.7 32 ± 14 (8-73) 35 ± 14 (10-77) 9 ± 4 (0-16) 23.1 16 ± 17 (0-62) 29.7 ± 7.0 (15.2-53.8) 5 ± 4 (0-19) 1.6 ± 0.7 (0-3) 6 ± 3 (0-15) 26.9 21.4 336.3 ± 132.5 (76.5-746.3) 8.7 10.6 20.2 27.9 14.4

104 104 104 104 104 104 104 104 104 104

104 32 14 104 56 37 11 104 104 104

276 ± 240 (104-1972) 30.8 13.5 10.3 ± 3.6 (5.1-27.0) 53.9 35.6 10.6 42.8 ± 25.4 (10.0-163.3) 252 ± 136 (89-968) 182 ± 66 (58-453)

104

210 Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic vitamin B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) a

102 102 102 103 103 103 103 103 103 103 104 103 104 104 104 104 104 104 104 104

102 10 24 103 11 103 103 103 103 103 104 103 35 104 38 35 14 13 104 29

100.5 ± 73.9 (8.6-549.9) 9.8 23.5 93.3 ± 38.9 (61.9-406.6) 10.7 4.1 ± 0.3 (3.4-4.9) 18 ± 9 (8-79) 13.2 ± 1.4 (9.4-17.3) 90 ± 6 (68-101) 114 ± 63 (42-511) 33 ± 19 (10-144) 4.0 ± 1.9 (0.9-9.4) 33.7 11.2 ± 59.2 (0.0-600.6) 36.5 33.7 13.5 12.5 183.5 ± 214.4 (0.0-1000.0) 27.9

Number of total participants. Number of participants with the condition. c Range in parentheses. d NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. e 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. f Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. g Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. b

211 Table C.14 Correlations of vitamin B12, methylmalonic acid, and total homocysteine with pure-tone average (1, 2, and 4 kHz) in the best ear and the worst ear at baseline a (Participants with high vitamin B12 concentrations and conductive hearing loss were excluded.)

Vitamin B12

Methylmalonic acid

Total homocysteine

a

Pure-tone average threshold in the best ear (N=102) b r = 0.009

Pure-tone average threshold in the worst ear (N=99) b r = -0.04

P = 0.93

P = 0.70

r = 0.12

r = 0.09

P = 0.88

P = 0.38

r = -0.07

r = -0.09

P = 0.47

P = 0.37

Partial Spearman correlation coefficient from multivariable linear regression analysis; adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. b Number of total participants.

212 Table C.15 Demographics, nutrition and auditory function in the best ear and the worst ear at baseline (PTA ≤ 25 vs. > 25 dB hearing level; Participants with high vitamin B12 concentrations and conductive hearing loss were excluded.)* Hearing Normal Impaired (PTA ≤ 25 dB HL) (PTA >25 dB HL) Mean ± SD Mean ± SD b b or % or % n n

P valuec

P valued

P valuee

104 104 104 104 104 102 104 103

48 48 48 45 29 48 11 47

19 ± 4 71 ± 6 93.8 60.4 9±3 22.9 12 ± 14

56 56 56 39 42 54 13 56

42 ± 11 77 ± 8 69.6 75.0 9±4 23.2 19 ± 19

271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%)

a

213 ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%)

102 103 103 103 103 103 103 103 104

10 47 4 47 47 47 47 48 48

21.7 91.5 ± 51.8 8.5 4.1 ± 0.3 17 ± 11 13.0 ± 1.4 90 ± 5 114 ± 73 33 ± 22

14 56 7 56 56 56 56 55 56

25.0 94.9 ± 23.7 12.5 4.1 ± 0.3 18 ± 7 13.3 ± 1.4 90 ± 6 113 ± 55 34 ± 16

0.75 0.61 0.68 0.69 0.52 0.32 0.94 0.98 0.95

0.64 0.56 0.69 0.93 0.17 0.58 0.78 0.95 0.80

0.59 0.53 0.73 0.94 0.14 0.46 0.76 0.92 0.85

103 104 104 104 104 104 104 104 104

48 15 48 16 14 4 3 48 13

4.0 ± 1.8 31.3 15.7 ± 86.4 33.3 29.3 8.3 6.3 181.8 ± 221.3 27.1

55 20 56 22 21 10 10 56 16

4.0 ± 2.0 35.7 7.4 ± 12.3 39.3 37.5 17.9 17.9 184.9 ± 210.2 28.6

0.61 0.19 0.90 0.52 0.18 0.06 0.04 0.95 0.76

0.73 0.35 0.98 0.86 0.35 0.08 0.06 0.56 0.84

0.68 0.34 0.86 0.87 0.33 0.07 0.05 0.61 0.85

101 101 101 101 101 99 101 100

35 35 35 33 20 35 6 34

21 ± 4 70 ± 5 94.3 57.1 9±3 17.1 10 ± 13

66 66 66 50 48 64 17 66

43 ± 12 76 ± 8 75.8 72.7 9±4 25.8 18 ± 18

0.0003 0.01 0.13 0.65 0.44 0.17

0.008 0.01 0.15 0.82 0.42 0.17

0.0003 0.05 0.28 0.80 0.51 0.19

101 100 101 101 101 100 101 101 101 101 101 101

35 35 35 35 7 6 35 1 1 4 6 1

31.0 ± 8.1 6±4 1.6 ± 0.7 6±3 20.0 17.7 371.2 ± 131.8 2.9 2.9 11.4 17.1 2.9

66 65 66 66 20 15 66 8 10 17 23 14

29.4 ± 6.3 5±4 1.6 ± 0.8 5±3 30.3 22.7 316.7 ± 131.9 12.1 15.2 25.8 34.9 21.2

0.84 0.39 0.81 0.43 0.64 0.78 0.14 0.34 0.20 0.13 0.10 0.04

0.61 0.54 0.89 0.49 0.50 0.79 0.31 0.46 0.28 0.20 0.20 0.07

0.65 0.47 0.99 0.41 0.24 0.98 0.36 0.51 0.34 0.26 0.22 0.10

101

35

202 ± 80

66

314 ± 288

0.06

0.08

0.07

101

5

14.3

25

37.9

0.11

0.12

0.07

214 > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

101 101

2 35

5.7 9.9 ± 3.5

11 66

16.7 10.5 ± 3.7

0.61 0.79

0.52 0.91

0.51 0.96

101 101 101 101 101 101 99 99 99 100 100 100 100 100 100 100 101

16 12 4 35 35 35 34 1 9 34 3 34 34 34 34 35 35

45.7 34.3 11.4 42.0 ± 24.3 253 ± 163 176 ± 71 106.3 ± 93.0 2.9 26.5 92.6 ± 59.3 8.8 4.1 ± 0.2 18 ± 12 13.2 ± 1.3 90 ± 4 117 ± 84 33 ± 25

38 24 6 66 66 66 65 8 14 66 8 66 66 66 66 65 66

57.6 36.4 9.1 42.6 ± 25.8 252 ± 124 186 ± 65 96.7 ± 61.8 12.3 21.5 93.5 ± 24.1 12.1 4.1 ± 0.3 18 ± 6 13.2 ± 1.4 90 ± 6 112 ± 51 33 ± 15

0.83 0.47 0.25 0.94 0.28 0.67 0.41 0.18 0.44 0.61 0.66 0.92 0.90 0.98 0.95 0.96 0.65

0.64 0.62 0.44 0.76 0.47 0.62 0.46 0.23 0.55 0.56 0.70 0.70 0.61 0.51 0.65 0.91 0.47

0.68 0.53 0.64 0.94 0.55 0.68 0.31 0.72 0.53 0.67 0.60 0.52 0.71 0.69 0.91 0.56

100 101 101 101 101 101 101 101 101

35 12 35 11 11 4 3 35 10

4.1 ± 1.8 34.3 20.7 ± 101.1 31.4 31.4 11.4 8.6 187.6 ± 236.8 28.6

65 22 66 26 23 10 10 66 18

3.9 ± 2.0 33.3 6.6 ± 11.5 39.4 34.9 15.2 15.2 181.9 ± 205.0 27.3

0.99 0.55 0.61 0.35 0.44 0.42 0.27 0.86 0.99

0.86 0.92 0.68 0.69 0.81 0.52 0.38 0.34 0.54

0.94 0.90 0.62 0.63 0.75 0.56 0.43 0.42 0.65

* PTA, pure-tone average threshold of 1, 2, and 4 kHz. a Number of total participants. b Number of participants with the condition. c Logistic regression model adjusted for age and gender. d Logistic regression model adjusted for age, gender, race, and creatinine. e Logistic regression model adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. f NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. g 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. h Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. i Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. - Not applicable. There was possibly a quasi-complete separation of data points.

215 Table C.16 Demographics, nutrition and auditory function in the best ear and the worst ear at baseline (PTA ≤ 40 vs. > 40 dB hearing level; Participants with high vitamin B12 level and conductive hearing loss were excluded.)* Hearing PTA ≤ 40 dB HL PTA > 40 dB HL Mean ± SD Mean ± SD b b or % or % n n

P valuec

P valued

P valuee

104 104 104 104 104 102 104 103

77 77 77 70 48 76 14 76

25 ± 8 73 ± 7 90.9 62.3 9±4 18.2 12 ± 14

27 27 27 14 23 26 10 27

52 ± 8 78 ± 8 51.9 85.2 9±4 37.0 26 ± 21

0.003 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%) Serum total homocysteine (µmol/L) > 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%)

a

216 Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) Worst ear n Hearing level (dB) Age (years) Gender (% of female) Race (% of Caucasian) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Body mass index (kg/m2) Nutritional Health Score f Overall health g Number of medications Impaired cognition (%) h Anemic (%) i Serum vitamin B12 (pmol/L) < 148 pmol/L (%) < 185 pmol/L (%) < 221 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum methylmalonic acid (nmol/L) > 271 nmol/L (%) > 376 nmol/L (%)

103 103 103 103 103 103 103 104

76 8 76 76 76 76 77 77

92.0 ± 43.5 10.5 4.1 ± 0.3 18 ± 10 13.1 ± 1.3 90 ± 5 113 ± 65 34 ± 20

27 3 27 27 27 27 26 27

96.9 ± 21.6 11.1 4.1 ± 0.3 18 ± 6 13.6 ± 1.5 90 ± 7 115 ± 61 31 ± 16

0.39 0.07 0.95 0.97 0.26 0.88 0.88 0.15

0.31 0.06 0.48 0.51 0.49 0.44 0.96 0.14

0.31 0.05 0.41 0.65 0.34 0.44 0.90 0.12

103 104 104 104 104 104 104 104 104

77 26 77 26 24 8 7 77 20

3.9 ± 2.0 33.8 12.2 ± 68.5 33.8 31.2 10.4 9.1 175.6 ± 216.5 26.0

26 9 27 12 11 6 6 27 9

4.2 ± 1.7 33.3 8.5 ± 12.9 44.4 40.7 22.2 22.2 206.0 ± 210.6 33.3

0.14 0.55 0.78 0.48 0.37 0.04 0.04 0.42 0.48

0.25 0.99 0.64 0.98 0.82 0.08 0.08 0.95 0.99

0.32 0.86 0.66 0.88 0.66 0.10 0.09 0.88 0.77

101 101 101 101 101 99 101 100

65 65 65 61 41 64 12 64

26 ± 7 72 ± 6 93.9 63.1 10 ± 3 18.5 12 ± 14

36 36 36 22 27 35 11 36

52 ± 9 77 ± 8 61.1 75.0 9±4 30.6 20 ± 20

0.0004 9.0 µmol/L (%) > 11.0 µmol/L (%) > 13.9 µmol/L (%) Serum folate (nmol/L) Cystathionine (nmol/L) 2-methylcitric acid (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) ≤ 50 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Blood urea nitrogen (mmol/L) Hemoglobin (g/dL) Mean cell volume (fl) S-adenosyl-methionine (nmol/L) S-adenosyl-homocysteine (nmol/L) SAM/SAH ratio Multivitamin use (%) Synthetic B12 intake (µg/d) ≥ 2.4 µg/d (%) ≥ 6 µg/d (%) ≥ 12 µg/d (%) ≥ 25 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%)

101

65

10.0 ± 3.2

36

10.9 ± 4.3

0.54

0.79

0.71

101 101 101 101 101 101 99 99 99 100 100 100 100 100 100 100 101

32 22 6 65 65 65 63 4 13 64 6 64 64 64 64 65 65

49.2 33.9 9.2 41.0 ± 23.1 247 ± 135 182 ± 66 104.1 ± 75.6 6.4 20.6 91.2 ± 46.4 9.4 4.1 ± 0.3 18 ± 10 13.1 ± 1.4 90 ± 5 114 ± 69 33 ± 20

22 14 4 36 36 36 36 5 10 36 5 36 36 36 36 35 36

61.1 38.9 11.1 44.9 ± 28.7 262 ± 144 185 ± 69 92.9 ± 70.6 13.9 27.8 96.7 ± 22.4 13.9 4.1 ± 0.3 18 ± 6 13.3 ± 1.4 90 ± 6 114 ± 56 34 ± 17

0.74 0.44 0.54 0.17 0.23 0.16 0.09 0.17 0.42 0.63 0.23 0.55 0.98 0.49 0.81 0.72 0.69

0.96 0.71 0.86 0.25 0.28 0.11 0.10 0.20 0.36 0.58 0.22 0.36 0.60 0.28 0.94 0.60 0.47

0.93 0.66 0.96 0.14 0.24 0.09 0.06 0.17 0.29 0.61 0.21 0.34 0.62 0.37 0.95 0.65 0.44

100 101 101 101 101 101 101 101 101

65 21 65 20 18 5 4 65 17

4.0 ± 2.0 32.3 12.8 ± 74.4 30.8 27.7 7.7 6.2 173.0 ± 213.0 26.2

35 13 36 17 16 9 9 36 11

3.9 ± 1.7 36.1 9.1 ± 12.7 47.2 44.4 25.0 25.0 203.5 ± 221.2 30.6

0.89 0.18 0.75 0.09 0.03 0.005 0.004 0.37 0.50

0.74 0.32 0.68 0.18 0.07 0.008 0.006 0.67 0.78

0.63 0.35 0.78 0.14 0.05 0.008 0.007 0.59 0.66

* PTA, pure-tone average threshold of 1, 2, and 4 kHz. a Number of total participants. b Number of participants with the condition. c Logistic regression model adjusted for age and gender. d Logistic regression model adjusted for age, gender, race, and creatinine. e Logistic regression model adjusted for age, gender, race, creatinine, family history of hearing loss, and noise exposure. f NHS: Nutritional Screening Initiative Questionnaire. Higher number indicates greater nutritional risk. g 0 = poor, 1 = fair, 2 = good, and 3 = excellent. Higher number indicates better health status. h Impaired cognition defined as ≥ 9 on Orientation Memory Concentration test. i Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males.

218 A POSSIBLE RELATIONSHIP OF AGE-RELATED HEARING LOSS WITH MULTIPLE MEASURES OF VITAMIN B12 STATUS WAS EXAMINED IN CAUCASIANS (TABLES C.17 – C.19). Table C.17 Characteristics of participants at baseline in Caucasians

Age (years) Gender Female (%) Male (%) Hearing level in the best ear (dB) Hearing level in the worst ear (dB) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Number of medications Anemic (%) d Serum vitamin B12 (pmol/L) < 185 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum MMA (nmol/L) > 271 nmol/L (%) Serum tHcy (µmol/L) Serum folate (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Hemoglobin (g/dL) Mean cell volume (fl) Multivitamin use (%) Synthetic vitamin B12 intake (µg/d) ≥ 2.4 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) a

Na 60 60

nb 60

Mean ± SD or % 75 ± 7 (58-92) c

60 57 58 60 60 60 60 60 60 60 60

48 12 60 57 58 15 60 60 10 60 8 20 12

80.0 20.0 34 ± 15 (15-73) 36 ± 15 (17-77) 10 ± 3 (0-16) 25.0 16 ± 18 (0-62) 6 ± 3 (0-13) 16.7 308.1 ± 113.1 (76.5-559.6) 13.3 33.3 20.0

60 60 60 60 59 59 60 60 60 60 60 60 60 60 60 60

60 25 60 60 59 6 60 7 60 60 60 23 60 27 60 22

328.0 ± 298.7 (138-1972) 41.7 10.8 ± 4.1 (5.1-27.0) 48.6 ± 28.9 (13.6-163.3) 110.3 ± 86.1 (8.6-549.9) 10.2 97.2 ± 46.7 (61.9-406.6) 11.7 4.2 ± 0.3 (3.6-4.9) 13.3 ± 1.3 (9.4-16.8) 90 ± 6 (68-100) 38.3 6.7 ± 11.3 (0.0-50.4) 45.0 230.6 ± 234.0 (0.0-1000.0) 36.7

Number of total participants. Number of participants with the condition. c Range in parentheses. d Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. b

219 Table C.18 Correlations of vitamin B12, methylmalonic acid, and total homocysteine with pure-tone average threshold (1, 2, and 4 kHz) in the best ear and the worst ear at baseline in Caucasians a

Vitamin B12

Methylmalonic acid

Total homocysteine

a

Pure-tone average threshold in the best ear (N = 60) b r = -0.10

Pure-tone average threshold in the worst ear (N = 57) b r = -0.20

P = 0.48

P = 0.15

r = 0.15

r = 0.23

P = 0.28

P = 0.10

r = -0.06

r = -0.06

P = 0.66

P = 0.69

Partial Spearman correlation coefficient, controlled for age, race, creatinine, family history of hearing loss, and noise exposure. b Number of total participants.

220 Table C.19 Demographics, nutrition and auditory function in the best ear at baseline in Caucasians Hearing

Best ear Nc 60 60 60 60 58 60 60

Normal (PTA a ≤ 25 dB HLb) Mean ± SD nd or % 24 24 20 ± 3 24 72 ± 6 23 95.8 24 10 ± 3 6 25.0 24 14 ± 16

Impaired (PTA >25 dB HL) Mean ± SD nd or % 36 36 43 ± 12 36 77 ± 8 25 69.4 34 10 ± 4 9 25.0 36 18 ± 19

P valuee

P valuef

P valueg

n Hearing level (dB) Age (years) 0.01 0.01 Gender (% of female) 0.03 0.03 Education (years) 0.36 0.37 Family history of hearing loss (%) 0.61 0.56 Number of years exposed to noise 0.63 0.60 (years) Number of medications 60 24 7±3 36 6±4 0.28 0.30 h Anemic (%) 60 5 20.8 5 13.9 0.22 0.32 Serum vitamin B12 (pmol/L) 60 24 321.2 ± 92.7 36 299.5 ± 125.4 0.43 0.50 < 185 pmol/L (%) 60 1 4.2 7 19.4 0.20 0.21 < 258 pmol/L (%) 60 7 29.2 13 36.1 0.45 0.51 < 258 pmol/L, MMA > 271 60 4 16.7 8 22.2 0.68 0.70 nmol/L, and MMA > 2-methylcitric acid (%) Serum MMA (nmol/L) 60 24 244 ± 99 36 384 ± 369 0.28 0.15 > 271 nmol/L (%) 60 8 33.3 17 47.2 0.86 0.64 Serum tHcy (µmol/L) 60 24 9.8 ± 3.5 36 11.4 ± 4.5 0.52 0.17 Serum folate (nmol/L) 60 24 48.4 ± 24.8 36 48.8 ± 31.7 0.89 0.77 Serum pepsinogen I (ng/mL) 59 23 126.0 ± 104.8 36 100.3 ± 71.6 0.09 0.13 i ≤ 20 ng/mL (%) 59 0 0.0 6 16.7 0.07 Serum creatinine (µmol/L) 60 24 98.0 ± 68.8 36 96.7 ± 23.8 0.59 0.56 ≥ 127 µmol/L (%) 60 2 8.3 5 13.9 0.54 0.99 Serum albumin (g/L) 60 24 4.2 ± 0.3 36 4.1 ± 0.3 0.84 0.83 Hemoglobin (g/dL) 60 24 13.2 ± 1.5 36 13.4 ± 1.1 0.52 0.70 Mean cell volume (fl) 60 24 90 ± 6 36 90 ± 6 0.60 0.60 Multivitamin use (%) 60 10 41.7 13 36.1 0.57 0.67 Synthetic B12 intake (µg/d) 60 24 5.0 ± 6.8 36 7.8 ± 13.5 0.17 0.19 ≥ 2.4 µg/d (%) 60 12 50.0 15 41.7 0.68 0.58 Synthetic folate intake (µg/d) 60 24 271.0 ± 245.3 36 203.6 ± 225.7 0.32 0.24 ≥ 400 µg/d (%) 60 10 41.7 12 33.3 0.63 0.54 a PTA, pure-tone average threshold of 1, 2, and 4 kHz. b HL, hearing level. c Number of total participants. d Number of participants with the condition. e Logistic regression model controlled for age and gender. f Logistic regression model controlled for age, gender, and creatinine. g Logistic regression model controlled for age, gender, creatinine, family history of hearing loss, and noise exposure. h Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. i Chi-square analyses. - Not applicable. There was possibly a quasi-complete separation of data points.

0.009 0.03 0.41 0.61 0.66 0.31 0.34 0.38 0.15 0.45 0.56

0.14 0.61 0.14 0.93 0.13 0.58 0.99 0.81 0.82 0.56 0.66 0.19 0.51 0.19 0.47

221 A POSSIBLE RELATIONSHIP OF AGE-RELATED HEARING LOSS WITH MULTIPLE MEASURES OF VITAMIN B12 STATUS WAS EXAMINED IN AFRICAN-AMERICANS (TABLES C.20 – C.23). Table C.20 Characteristics of participants at baseline in African-Americans

Age (years) Gender Female (%) Male (%) Hearing level in the best ear (dB) Hearing level in the worst ear (dB) Education (years) Family history of hearing loss (%) Number of years exposed to noise (years) Number of medications Anemic (%) d Serum vitamin B12 (pmol/L) < 185 pmol/L (%) < 258 pmol/L (%) < 258 pmol/L, MMA > 271 nmol/L, and MMA > 2-methylcitric acid (%) Serum MMA (nmol/L) > 271 nmol/L (%) Serum tHcy (µmol/L) Serum folate (nmol/L) Serum pepsinogen I (ng/mL) ≤ 20 ng/mL (%) Serum creatinine (µmol/L) ≥ 127 µmol/L (%) Serum albumin (g/L) Hemoglobin (g/dL) Mean cell volume (fl) Multivitamin use (%) Synthetic vitamin B12 intake (µg/d) ≥ 2.4 µg/d (%) Synthetic folate intake (µg/d) ≥ 400 µg/d (%) a

Na 33 33

nb 33

Mean ± SD or % 74 ± 8 (65-90) c

33 33 33 33 32 33 32 33 33 33 33

29 4 33 33 33 4 32 33 11 33 2 6 1

87.9 12.1 27 ± 11 (8-50) 30 ± 11 (10-53) 8 ± 4 (0-14) 12.1 12 ± 15 (0-57) 5 ± 3 (0-15) 34.4 397.7 ± 155.2 (139-746.3) 6.1 18.2 3.0

33 33 33 33 33 33 32 33 32 32 32 33 33 33 33 33

33 4 33 33 33 3 32 3 32 32 32 7 33 6 33 3

192.9 ± 65.1 (104.0-366.0) 12.1 9.9 ± 2.9 (6.1-16.1) 33.3 ± 16.7 (10.0-79.1) 84.1 ± 51.7 (11.5-212.2) 9.1 87.8 ± 22.7 (61.9-141.4) 9.1 4.0 ± 0.3 (3.4-4.5) 12.6 ± 1.1 (9.9-16.1) 88 ± 5 (74-96) 21.2 20.4 ± 104.3 (0.0-600.6) 18.2 84.2 ± 135.6 (0.0-520.0) 9.1

Number of total participants. Number of participants with the condition. c Range in parentheses. d Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. b

222 Table C.21 Correlations of vitamin B12, methylmalonic acid, and total homocysteine with pure-tone average threshold (1, 2, and 4 kHz) in the best ear and the worst ear at baseline in African-Americans a

Vitamin B12

Methylmalonic acid

Total homocysteine

a

Pure-tone average threshold in the best ear (N = 31) b r = -0.10

Pure-tone average threshold in the worst ear (N = 31) b r = 0.11

P = 0.64

P = 0.58

r = 0.22

r = 0.22

P = 0.27

P = 0.28

r = 0.02

r = -0.03

P = 0.90

P = 0.89

Partial Spearman correlation coefficient, controlled for age, race, creatinine, family history of hearing loss, and noise exposure in African-American. b Number of total participants.

223 Table C.22 Demographics, nutrition and auditory function in the best ear at baseline in African-Americans Hearing

Best ear Nc 33 33 33 33 33 33 32

Normal (PTA a ≤ 25 dB HLb) Mean ± SD nd or % 19 19 19 ± 4 19 70 ± 5 18 94.7 19 9±3 3 15.8 18 7 ± 11

Impaired (PTA >25 dB HL) Mean ± SD nd or % 14 14 37 ± 4 14 80 ± 7 11 78.6 14 6±4 1 7.1 14 19 ± 18

P valuee

P valuef

P valueg

n Hearing level (dB) Age (years) 0.003 0.004 Gender (% of female) 0.04 0.06 Education (years) 0.70 0.67 Family history of hearing loss (%) 0.31 0.21 Number of years exposed to noise 0.07 0.06 (years) Number of medications 33 19 6±4 14 5±2 0.46 0.33 Anemic (%) h 32 5 27.8 6 42.9 0.43 0.44 Serum vitamin B12 (pmol/L) 33 19 437.1 ± 151.6 14 344.2 ± 148.8 0.41 0.39 < 185 pmol/L (%) 33 0 0.0 2 14.3 0.17i < 258 pmol/L (%) 33 2 10.5 4 28.6 0.59 0.59 i < 258 pmol/L, MMA > 271 33 0 0.0 1 7.1 0.42 nmol/L, and MMA > 2-methylcitric acid (%) Serum MMA (nmol/L) 33 19 166 ± 54 14 230 ± 62 0.16 0.19 > 271 nmol/L (%) 33 1 5.3 3 21.4 0.61 0.57 Serum tHcy (µmol/L) 33 19 9.8 ± 3.0 14 10.0 ± 2.9 0.20 0.08 Serum folate (nmol/L) 33 19 31.6 ± 19.3 14 35.7 ± 12.7 0.13 0.09 Serum pepsinogen I (ng/mL) 33 19 76.5 ± 40.2 14 94.5 ± 64.4 0.55 0.65 ≤ 20 ng/mL (%) 33 1 5.3 2 14.3 0.76 0.75 Serum creatinine (µmol/L) 32 18 84.0 ± 20.2 14 92.8 ± 25.4 0.81 0.28 ≥ 127 µmol/L (%) 33 1 5.3 2 14.3 0.15 0.11 Serum albumin (g/L) 32 18 4.1 ± 0.2 14 3.9 ± 0.3 0.79 0.87 Hemoglobin (g/dL) 32 18 12.6 ± 1.0 14 12.7 ± 1.4 0.41 0.42 Mean cell volume (fl) 32 18 88 ± 5 14 87 ± 5 0.54 0.60 Multivitamin use (%) 33 4 21.1 3 21.4 0.86 0.81 Synthetic B12 intake (µg/d) 33 19 32.9 ± 137.5 14 3.5 ± 6.9 0.87 0.87 ≥ 2.4 µg/d (%) 33 3 15.8 3 21.4 0.67 0.61 Synthetic folate intake (µg/d) 33 19 85.1 ± 151.7 14 83.0 ± 115.8 0.89 0.82 ≥ 400 µg/d (%) 33 2 10.5 1 7.1 0.87 0.90 a PTA, pure-tone average threshold of 1, 2, and 4 kHz. b HL, hearing level. c Number of total participants. d Number of participants with the condition. e Logistic regression model controlled for age and gender. f Logistic regression model controlled for age, gender, and creatinine. g Logistic regression model controlled for age, gender, creatinine, family history of hearing loss, and noise exposure. h Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. i Chi-square analyses. - Not applicable. There was possibly a quasi-complete separation of data points.

0.01 0.21 1.0 0.14 0.05 0.39 0.20 0.43 0.21 -

0.66 0.09 0.23 0.32 0.51 0.84 0.92 0.35 0.82 0.32 0.73 0.93

224 Table C.23 Demographics, nutrition and auditory function in the worst ear at baseline in African-Americans

Worst ear

c

N 33 33 33 33 33 33 32

Hearing Normal Impaired a b (PTA > 25 dB HL) (PTA ≤ 25 dB HL ) Mean ± SD Mean ± SD d d or % or % n n 15 18 15 21 ± 5 18 38 ± 8 15 70 ± 6 18 78 ± 7 14 93.3 15 83.3 15 9±3 18 6±4 2 13.3 2 11.1 14 9 ± 12 18 15 ± 17

P valuee

P valuef

P valueg

n Hearing level (dB) Age (years) 0.01 0.01 Gender (% of female) 0.24 0.25 Education (years) 0.25 0.32 Family history of hearing loss (%) 0.38 0.12 Number of years exposed to noise 0.55 0.33 (years) Number of medications 33 15 6±4 18 5±3 0.36 0.45 Anemic (%) h 32 4 28.6 7 38.9 0.62 0.61 Serum vitamin B12 (pmol/L) 33 15 416.0 ± 164.8 18 382.4 ± 149.8 0.77 0.90 < 185 pmol/L (%) 33 0 0.0 2 11.1 0.49i < 258 pmol/L (%) 33 2 13.3 4 22.2 0.97 0.98 i < 258 pmol/L, MMA > 271 33 0 0.0 1 5.6 1.0 nmol/L, and MMA > 2-methylcitric acid (%) Serum MMA (nmol/L) 33 15 169 ± 57 18 213 ± 66 0.49 0.54 > 271 nmol/L (%) 33 1 6.7 3 16.7 0.89 0.95 Serum tHcy (µmol/L) 33 15 10.1 ± 3.3 18 9.6 ± 2.7 0.23 0.18 Serum folate (nmol/L) 33 15 30.4 ± 16.1 18 35.8 ± 17.3 0.52 0.65 Serum pepsinogen I (ng/mL) 33 15 73.7 ± 43.1 18 92.8 ± 57.7 0.36 0.31 ≤ 20 ng/mL (%) 33 1 6.7 2 11.1 0.95 0.90 Serum creatinine (µmol/L) 32 14 85.9 ± 22.6 18 89.4 ± 23.3 0.77 0.85 ≥ 127 µmol/L (%) 33 1 6.7 2 11.1 0.52 0.21 Serum albumin (g/L) 32 14 4.2 ± 0.3 18 4.0 ± 0.3 0.86 0.82 Hemoglobin (g/dL) 32 14 12.6 ± 1.1 18 12.6 ± 1.2 0.98 0.97 Mean cell volume (fl) 32 14 88 ± 5 18 88 ± 5 0.93 0.99 Multivitamin use (%) 33 3 20.0 4 22.2 0.85 0.95 Synthetic B12 intake (µg/d) 33 15 41.1± 154.8 18 3.2 ± 6.2 0.70 0.70 ≥ 2.4 µg/d (%) 33 2 13.3 4 22.2 0.51 0.58 Synthetic folate intake (µg/d) 33 15 69.3 ± 121.3 18 96.6 ± 148.8 0.48 0.57 ≥ 400 µg/d (%) 33 1 6.7 2 11.1 0.50 0.54 a PTA, pure-tone average threshold of 1, 2, and 4 kHz. b HL, hearing level. c Number of total participants. d Number of participants with the condition. e Logistic regression model controlled for age and gender. f Logistic regression model controlled for age, gender, and creatinine. g Logistic regression model controlled for age, gender, creatinine, family history of hearing loss, and noise exposure. h Anemic defined as hemoglobin ≤ 12 g/dL for females, ≤ 13 g/dL for males. i Chi-square analyses. - Not applicable. There was possibly a quasi-complete separation of data points.

0.01 0.41 0.22 0.12 0.27 0.87 0.18 0.98 0.76 -

0.70 0.26 0.68 0.49 0.86 0.19 0.95 0.19 0.89 0.92 0.46 0.61 0.60 0.28

225

APPENDIX D NUTRITION, HEARING AND MEMORY AMONG SENIOR CENTER IN NORTHEAST GEORGIA CONSENT FORM AND TEST BOOK

NUTRITION, HEARING, AND MEMORY AMONG SENIOR CENTERS IN NORTHEAST GEORGIA 2001

226

FORM B NUTRITION, HEARING, AND MEMORY STUDY CONSENT FORM I,_______________________________agree to participate in the research titled "NUTRITION, HEARING, AND MEMORY" conducted by Drs. Mary Ann Johnson, Albert DeChicchis, and L. Stephen Miller in the Departments of Foods and Nutrition, Communication Sciences and Disorders, and Psychology at the University of Georgia. I understand that I do not have to take part if I do not want to. I can stop taking part without giving any reason, and without penalty. I can ask to have all of the information about me returned to me, removed from the research records, or destroyed. My decision to participate will not affect the services that I receive at the Senior Center. The reason for this study is to learn more about nutrition and health, and to determine if taking a vitamin B-12 supplement will help me hear better and improve my memory. If I volunteer to take part in this study, I will be asked to do the following things: 1) Answer questions about my food, nutrition, and health. 2) Have my hearing tested. 3) Have my memory and thinking tested with a computer based test. 4) A medical technologist will take 4 7-10 ml tubes of blood to measure my blood sugar, cholesterol, vitamins and minerals. My blood sample will be destroyed within 10 years. 5) Have my blood pressure taken. 6) I will take a vitamin B-12 supplement (up to 1,000 mcg/day) or a placebo (a pill without vitamin B-12) for 4 months to see if it helps me hear and think better. 7) After 4 months, all of the questions and tests related to health, food, nutrition, hearing, and memory, and the blood tests will be repeated. 8) If my tests show that I have depression, I will be notified and referred for treatment. 9) Someone from the study may call me to clarify my information.

227

If I am found to have vitamin B-12 deficiency, my physician and I will be notified. I will give vitamin B-12 (1,000 mcg/day as a tablet) as part of this study. If my doctor treats me with vitamin B-12 (pill or shots) I can still continue in this study, and will not need to take the vitamin B-12 supplement provided by this study. I will receive $25 after completing all the test the first time, and another $25 after taking vitamin B-12 (or the placebo) for 4 months and repeating the tests a second time. My blood will not be tested for HIV-AIDS. I understand that these questions and blood tests are not for diagnostic purposes. If I have questions about my test results I should see a physician. The benefits for me are that the study may help me understand and improve my health. No risk is expected but I may experience some discomfort or stress when my hearing is tested (because of the ear plugs), when my blood is drawn or when the researchers ask me questions about my health, memory and nutrition. The risks of drawing blood from my arm include the unlikely possibilities of a small bruise or localized infection, bleeding, and fainting. These risks will be reduced in the following ways: my blood will be drawn only by a qualified and experienced person who will follow standard sterile techniques, who will observe me after the needle is withdrawn, and who will apply pressure to the blood draw-site. In the event that I have any health problems associated with the blood draws, my insurance or I will be responsible for any related medical expenses. No information about me, or provided by me during the research, will be shared with others without my written permission, except if it is necessary to protect my welfare (for example, if I need physician care) or if required by law. I will be assigned an identifying number and this number will be used on all of forms I fill out. If I have any further questions about the study, now or during the course of the project I can call Mrs. Nikki Hawthorne 706-542-4838 or Dr. Mary Ann Johnson 706-542-2292. I give my permission for you to release my blood analysis information to my health care providers. Circle one: YES / NO. Initial _____.

228

I give my permission for you to release my hearing results to my health care providers. Circle one: YES / NO. Initial _____. I give my permission for you to release my memory test results to my primary physician. Circle one: YES / NO. Initial _____. I will allow the staff to take my picture, videotape or record me while participating in the study. I can verbally refuse at anytime and my wishes will be upheld. My pictures will only be used to promote this nutrition, hearing, and memory study. Circle one: YES / NO. Initial _____. I understand that I am agreeing by my signature on this form to take part in this project and understand that I will receive a signed copy of this consent form for my records.

__________________________________________________________________ Project Coordinator Date Signature of Participant Date __________________________________________________________________ Phone Number Address Questions or problems regarding your rights as a participant should be addressed to Ms. Julia Alexander; Institutional Review Board; Office of V.P. for Research; The University of Georgia; 604A Graduate Studies Research Center; Athens, GA 30602-7411; Telephone 706-542-6514. revised 00/13/12 UGA project number:H1998-10501-4 DHR project number: 000904

229

FORM D NUTRITION, HEARING, AND MEMORY STUDY CONSENT FORM I,_______________________________agree to participate in a continuation to the research titled "NUTRITION, HEARING, AND MEMORY" conducted by Drs. Mary Ann Johnson, Albert DeChicchis, and L. Stephen Miller in the Departments of Foods and Nutrition, Communication Sciences and Disorders, and Psychology at the University of Georgia. I understand that I do not have to take part if I do not want to. I can stop taking part without giving any reason, and without penalty. I can ask to have all of the information about me returned to me, removed from the research records, or destroyed. My decision to participate will not affect the services that I receive at the Senior Center. The reason for this continuation to this study is to learn more about nutrition and health, and to determine if taking a vitamin B-12 supplement will help improve my memory. If I volunteer to take part in this study, I will be asked to do the following things: 10) 11) 12) 13) 14) 15) 16)

Answer questions about my food, nutrition, and health. Have my memory and thinking tested with a computer based test. A medical technologist will take 2 7-10 ml tubes of blood to measure my vitamin B-12 status. My blood sample will be destroyed within 10 years. Have my blood pressure taken. I will take a vitamin B-12 supplement (up to 1,000 mcg/day) or a placebo (a pill without vitamin B-12) for 6 months to see if it helps me think better. If my tests show that I have depression, I will be notified and referred for treatment. Someone from the study may call me to clarify my information.

I will receive $25 after completing all of the testing. My blood will not be tested for HIV-AIDS. I understand that these questions and blood tests are not for diagnostic purposes. If I have questions about my

230

test results I should see a physician. The benefits for me are that the study may help me understand and improve my health. No risk is expected but I may experience some discomfort or stress when my blood is drawn or when the researchers ask me questions about my health, memory and nutrition. The risks of drawing blood from my arm include the unlikely possibilities of a small bruise or localized infection, bleeding, and fainting. These risks will be reduced in the following ways: my blood will be drawn only by a qualified and experienced person who will follow standard sterile techniques, who will observe me after the needle is withdrawn, and who will apply pressure to the blood draw-site. In the event that I have any health problems associated with the blood draws, my insurance or I will be responsible for any related medical expenses. No information about me, or provided by me during the research, will be shared with others without my written permission, except if it is necessary to protect my welfare (for example, if I need physician care) or if required by law. I will be assigned an identifying number and this number will be used on all forms I fill out. If I have any further questions about the study, now or during the course of the project I can call Mrs. Nikki Hawthorne 706-542-4838 or Dr. Mary Ann Johnson 706-542-2292. I give my permission for you to release my blood analysis information to my health care providers. Circle one: YES / NO. Initial _____. I give my permission for you to release my memory test results to my primary physician. Circle one: YES / NO. Initial _____. I will allow the staff to take my picture, videotape or record me while participating in the study. I can verbally refuse at anytime and my wishes will be upheld. My pictures will only be used to promote this nutrition, hearing, and memory study. Circle one: YES / NO. Initial _____.

231

I understand that I am agreeing by my signature on this form to take part in this project and understand that I will receive a signed copy of this consent form for my records.

_____________________________________________________________ Project Coordinator Date Signature of Participant Date _____________________________________________________________ Phone Number Address Questions or problems regarding your rights as a participant should be addressed to Dr. Chris Joseph; Institutional Review Board; Office of V.P. for Research; The University of Georgia; 604A Graduate Studies Research Center; Athens, GA 30602-7411; Telephone 706-542-6514. UGA project number:H1998-10501-4 DHR project number: 000904 5/16/01

232

Department of Foods and Nutrition University of Georgia 390 Dawson Hall Athens, GA 30602 Date: __________ Dear __________________________: We are so pleased that you are participating in our study "Vitamin B-12 Deficiency in Elderly Nutrition Programs." We look forward to seeing you again in four months to repeat the hearing tests, memory tests, blood tests, and nutrition questions. As a service to our participants we are sending you a copy of your blood work and nutritional status report. These tests are not for diagnostic purposes. If you have any questions about your results, you should call your physician. Your physician will also receive a copy of your blood work, hearing tests, and memory tests. If you have any questions, please contact me at 706-542-4838. Sincerely, Nikki Hawthorne, MS, RD, LD. Research Coordinator Enc.

233

Department of Foods and Nutrition University of Georgia 390 Dawson Hall Athens, GA 30602 Date: __________ Dear __________________________: We are so pleased that you are participating in our study "Vitamin B-12 Deficiency in Elderly Nutrition Programs." We look forward to seeing you again in four months to repeat the hearing tests, memory tests, blood tests, and nutrition questions. As a service to our participants, we are sending you a copy of your blood work and nutritional status report. These tests are not for diagnostic purposes. However, the methylmalonic acid test of your blood indicates that you might be deficient in vitamin B-12. As part of this study, we are giving you a daily supplement of vitamin B-12 (1 milligram) which should improve your vitamin B-12 status if taken daily. Your physician will also receive a copy of your blood work, hearing tests, and memory tests. Your physician may decide to give you vitamin B-12 which will not in any way interfere with this study. If you have any questions about your results, please call your physician and please follow your physicians' advice. If you have any questions, please contact me at 706-542-4838. Sincerely, Nikki Hawthorne, MS, RD, LD. Research Coordinator Enc.

234

Department of Foods and Nutrition University of Georgia 390 Dawson Hall Athens, GA 30602 Date: _______ Dear Physician: Your patient, _______________________, has recently enrolled in the research study titled "Vitamin B-12 Deficiency in Elderly Nutrition Programs" with the Department of Foods and Nutrition at the University of Georgia. As a service to our participants, we are providing their physicians with copies of blood work, nutrition status report, hearing tests, and memory tests. Any critical values have been reported previously to your office. We do not provide a diagnosis based on the results of their blood work. However, based on the serum methylmalonic acid, it is possible that this patient is vitamin B-12 deficient (> 271 nmol/L indicates possible vitamin B-12 deficiency). Your patient's serum methylmalonic acid is _________nmol/L. These analyses were performed by Dr. Sally P. Stabler, MD, Co-Director of Hematology, University of Colorado Health Sciences Center, Denver, CO. As part of this research study, we have given your patient an oral supplement of vitamin B-12 (1 mg) to be taken daily. Oral vitamin B-12 has been shown to reverse vitamin B-12 deficiency (see enclosure). Your follow-up and treatment of possible vitamin B-12 deficiency in this patient is welcome and will not in any way interfere with this ongoing study. If you have any questions, please contact me at 706-542-2292. Sincerely, Mary Ann Johnson, Ph.D. Professor of Foods and Nutrition & Faculty of Gerontology Enc.

235

Department of Foods and Nutrition University of Georgia 390 Dawson Hall Athens, GA 30602 Date: _______ Dear Physician: Your patient, _______________________, has recently enrolled in the research study titled "Vitamin B-12 Deficiency in Elderly Nutrition Programs" with the Department of Foods and Nutrition at the University of Georgia. As a service to our participants, we are providing their physicians with copies of blood work, nutrition status report, hearing tests, and memory tests. Any critical values have been previously reported to your office. We do not provide a diagnosis based on the results of their blood work. If you have any questions, please contact me at 706-542-2292. Sincerely,

Mary Ann Johnson, Ph.D. Professor of Foods and Nutrition & Faculty of Gerontology Enc.

236

Department of Foods and Nutrition University of Georgia 390 Dawson Hall Athens, GA 30602-3622 June 2, 2001 Dear __________________________: We would like to congratulate and thank you for participating in our study "Vitamin B-12 Deficiency in Elderly Nutrition Programs." More than 220 people had their ears examined and 150 people enrolled in the study and are taking a supplement. As a service to our participants we are sending you a copy of your nutritional status report and two copies of your blood work. The extra copy can be given to your physician. These tests are not for diagnostic purposes. If you have any questions about your results, you should contact your physician. Please continue to take your vitamins. We plan to continue the study. It is possible you might qualify and be given more supplements, so please continue to take your remaining vitamins. We will let you know what supplement you were taking and issue the results of the study in the year 2002. Again, we thank you for participating and look forward to seeing you at the senior center soon. If you have any questions please feel free to contact us at 706-542-4838. Sincerely, Nikki Hawthorne, MS, RD, LD. Enc.

237

October 23, 2001 Dear Physician: Your patient, _______________________, has enrolled in the research study titled "Vitamin B12 Deficiency in Elderly Nutrition Programs" with the Department of Foods and Nutrition at the University of Georgia. As a service to our participants, we are providing their physicians with copies of blood work. Any critical values have been previously reported to your office. We do not provide a diagnosis based on the results of their blood work. We gave your patient vitamin B-12 supplements (1000mcg) for 3 months, but their methylmalonic acid is still indicating a vitamin B-12 deficiency (> 271 nmol/L indicates possible vitamin B-12 deficiency). Your patient's methylmalonic acid is _________nmol/L. These analyses were performed by Dr. Sally P. Stabler, MD, Hematologist at the University of Colorado. We are encouraging them to continue taking the supplements however, your treatment of possible vitamin B-12 deficiency in this patient is welcome and will not in any way interfere with this ongoing study. If you have any questions, please feel free to contact me at 706-542-2292. Sincerely, Mary Ann Johnson, Ph.D. Professor of Foods and Nutrition & Faculty of Gerontology Enc.

238 Vitamin B-12 Study Checklist ID:______________ Questionnaire

PRE TEST Date Initials Completed

POST TEST Date Initials Completed

Consent Form Blood Drawn General Information Sun Exposure Blood Pressure (Gave Blood Pressure Form to participant) Orientation/ Memory Test Nutritional Screening Initiative MNA Nutrition Questions Illnesses Medications Supplements: Explained & Date Started Supplements: Stopped Nutritional Status Report Sent to Individual Hearing History Questionnaire (HHQ) Hearing Handicap Inventory for adults (HHIA) Noise Exposure History Hearing Evaluation Cognition/computer -prompted test Geriatric Depression Scale Irritability and Agitation questions

(E) ONLY

Flagged-Explain

239 7 Flagged Notes: _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________ _____________________________________________________________________________________

240 Revised 00/09/13 ID: ______ _______

GENERAL INFORMATION

(1-3)

______

1. Today’s date: ___ / ____ / ____

Month/Day/Year

(10-15)

__ (16)

__ __ . __ (17-20)

2. This information was obtained from: 0 _____ Client 1 _____ Senior center staff person 2 _____ Family member of client 3 _____ Caregiver for client 4 _____ Other: ________________ 3. How long has the client been using the services of the senior center? ___ ___.___ years Code as years (xx.x years)

_ _ _ _ _ _ _ _ 4. Date of birth: ___ / ____ / ____

Month/Day/Year

(21-28)

__ __ __

5. Current age: __________ years

Example: age 75 is 075

(29-31)

__

6. Gender:

______ Male (0)

______ Female (1)

7. Ethnicity:

______ Caucasian (0) ______ Asian (3)

______ Black (1) ______ Other (4)

(32)

__ (33)

__ __

8. Years completed in school?

______ Hispanic (2)

______ Years

(34-35)

__

9. Do you take a multiple-vitamin/mineral supplement? ______ No (0) ____ Yes (1)

(36)

__

10. Do you take any other nutritional supplements that contain vitamins or minerals?

(37)

_____ No (0)

_____ Yes (1)

* Health Care Provider ______________________________________________________ Address___________________________________________________________________ __________________________________________________________________________ Phone____________________________________________________________________ * Care giver/ Next of Kin (1) ___________________________________ Phone______________________________ Address____________________________________________________________________ (2) ___________________________________ Phone______________________________ Address____________________________________________________________________

241 __ __ 38-39

11. How many hours ago did you last eat? _________ (code number of hours ago).

__ 40

12. Fasting status (coded by medical technologist). 0 1

__ 41

13. How would you rate your overall health at the present time -- excellent, good, fair, or poor? 3 2 1 0 9

__ 42

Better About the same Worse Not answered

15. How much do your health troubles stand in the way of your doing things you want to -- not at all, a little (some), or a great deal? 2 1 0 9

__ __ 44-45

Excellent Good Fair Poor Not answered

14. Is your health now better, about the same, or worse than it was five years ago? 2 1 0 9

__ 43

Not fasted, food in the last 4 hours Fasted, food not eaten in the past 4 hours

Not at all A little (some) A great deal Not answered

16. County of residence 00= Madison 01= Morgan 02= Walton

__ 46

03= Jackson 04= Newton 05= Barrow

00-12 06= Greene 09= Elbert 07= Clark 10= Oconee 08= Oglethorpe 11= Jasper

12=Franklin

18. Did you participate in our vitamin supplement study during spring and summer 1999? (ASK ONLY IN GREENE AND MORGAN COUNTY) 1= YES 0= NO

242 SUN EXPOSURE __ 47

19. How many minutes of sun exposure do you get each week? __ (0) < 9 minutes/week __ (1) 10-30 minutes/week __ (2) 30-59 minutes/week __ (3) 60-89 minutes/week __ (4) 90-119 minutes/week __ (5) 120 (2 hours) or more minutes/week __ (8) do not know __ (9) missing

__ 48

20. How often do you use sunscreen when you go outside? __ (0) Rarely/Never __ (1) Sometimes __ (2) Always __ (8) Not applicable; does not go outside __ (9) Missing

__ 49

21. If you use sunscreen, what level do you use? __ (0) Don't know __ (1) SPF 4 or less __ (2) SPF 6 or 8 __ (3) SPF 10 __ (4) SPF 15 __ (5) SPF 30 and up __ (8) Doesn't use __ (9) Missing BLOOD PRESSURE

(NOTE: RECORD RESULTS ON "BLOOD PRESSURE FORM" AND GIVE TO PARTICIPANT) __ __ __ 50-52

__ __ __ 53-55

22. Blood Pressure Systolic (mmHg) __ (0) < 120 Optimal __ (1) < 130 Normal __ (2) 130-139 High-normal __ (3) 140-159 Mild Hypertension (Stage 1) __ (4) 160-179 Moderate Hypertension (Stage 2) __ (5) > 180 Severe Hypertension (Stage 3) __ (999) Missing Diastolic (mmHg) __ (0) < 80 Optimal __ (1) < 85 Normal __ (2) 85-95 High-normal __ (3) 90-99 Mild Hypertension (Stage 1) __ (4) 100-109 Moderate Hypertension (Stage 2) __ (5) > 110 Severe Hypertension (Stage 3)

243 ORIENTATION-MEMORY-CONCENTRATION TEST Read all questions to the participant. Tell them that some of the questions may be easy and some may be hard -- just do the best you can. Resp # of Max. Weight Total onse Errors Errors Factor 1) What is the year now? 1 4 2) What month is it now?

1

3

1

3

2

2

2

2

5

2

Please repeat this phrase after me: JOHN BROWN, 42 MARKET STREET, CHICAGO No score for this -- it is a memory phrase for Item # 6. Allow the person up to three trials for learning (repeating) the phrase. If the subject has not learned the phrase after three trials, record the value of “0” as the total score for Item #6, and proceed to Item #3. 3) Without looking at your watch or a clock, tell me about what time is it? Note: score is correct if within one hour of actual time. 4) Count backwards from 20 to 1. 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 5) Say the months of the year in reverse order. DEC, NOV, OCT, SEPT, AUG, JULY, JUNE, MAY, APR, MAR, FEB, JAN 6) Please repeat the name and address I asked you to remember. Count the number of items (5) in memory phrase recalled incorrectly. An answer of either Market or Market Street is acceptable. John / Brown / 42 / Market Street / Chicago (10-11) TOTAL SCORE Interpretation of corrected scores:

20

Normal or minimal impairment Moderate impairment Severe impairment

Source: Katzman, R., Brown, T., Fuld, P., Peck, A., Schechter, R., Schimmel, H. Validation of a short orientationmemory-concentration test of cognitive impairment. American Journal of Psychiatry 140: 734-739, 1983.

244 NUTRITIONAL HEALTH: Nutritional Screening Initiative Questionnaire ID: _________ No=0 Yes= ____ NH1. I have an illness or condition that made me change the kind and/or (10) amount of food I eat.............................................................................Yes / No

(2)

____ NH2. I eat fewer than 2 meals per day............................................................Yes / No

(3)

(11)

____ NH3. I eat few fruits or vegetables, or milk products.....................................Yes / No

(2)

(12)

____ NH4. I have 3 or more drinks of beer, liquor or wine almost every day..........Yes / No

(2)

(13)

____ NH5. I have tooth or mouth problems that make it hard for me to eat ...........Yes / No

(2)

(14)

____ NH6. I don’t’ always have enough money to buy the food I need....................Yes / No

(4)

(15)

____ NH7. I eat alone most of the time...................................................................Yes / No

(1)

(16)

____ NH8. I take 3 or more different prescribed or over-the-counter drugs a day....Yes / No

(1)

(17)

____ NH9. Without wanting to, I have lost or gained 10 pounds in the last (18) 6 months...............................................................................................Yes / No

(2)

____ NH10. I am not always physically able to shop, cook, and/or feed myself..........Yes/No

(2)

(19)

Your Nutritional Score is: __________. If it’s: (20-21)

0-2

Good. Recheck your nutritional score in 6 months.

3-5 You are at moderate nutritional risk. See what can be done to improve your eating habits and lifestyle. Your office on aging, senior nutrition program, senior citizens center or health department can help. Recheck your nutritional score in 3 months. 6 or more. You are at high nutritional risk. Bring this checklist the next time you see your doctor, dietitian or other qualified health or social service professional. Talk with them about any problems you may have. Ask for help to improve

245 MINI-NUTRITIONAL ASSESSMENT

Name: Age: 04

First name:

Sex:

ID# ____________ (1-3) Date:

** enter decimal points

(4-5)

TSF.

Triceps skin fold (mm): __ __.__

Kneeht.

Knee Height (cm):

(6-9)

__ __.__ (10-13)

I. ANTHROPOMETRIC ASSESSMENT ____ MNA1. BMI (weight/(height)2 in kg/m2); weight = ____ lbs. / 2.205 = __ __ __ . __kg (14) 0 = BMI < 19 height = ____ in. * .0254 = __ __ __ . __ meters 1 = 19 < BMI < 21 BMI = __ __ . __ 2 = 21 < BMI < 23 3 = BMI > 23

(15-19)kg (20-24)m

_____ MNA2. Mid arm circumference (MAC in cm.): __ __ . __ cm. (29) 0.0 = MAC < 21 0.5 = 21 < MAC < 22 1.0 = MAC > 22

(30-33)cm

_____ MNA3. Calf circumference (CC in cm.): __ __ . __cm. (34) 0 = CC < 31 1 = CC > 31

(35-38)cm

(25-28) BMI

_____ MNA4. Weight loss during last 3 months: _________ lbs. / 2.205 = __ __ __ . __ kg (40-44)kg (39) 0 = weight loss > 3 kg 1 = does not know 2 = weight loss between 1 and 3 kg 3 = no weight loss _____ MNA12A. How many servings of milk, yogurt, or cheese does the individual consume? (45)

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

_____ MNA12D. How many servings of meat, fish, or poultry does the individual consume? (46)

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

246 NUTRITION QUESTIONS __ 47

__ __ 48-49

1. Have you ever received home delivered meals? 0 = Yes 1 = No 2. If you receive home delivered meals, for how long have you been receiving them? __ __ years Code as whole years (xx years)

__ 50

3. How many times a week do you eat at the senior center? 0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week

__

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

4. How many servings of green vegetables do you eat?

51

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week __

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

5. How many servings of orange or yellow vegetable do you eat?

52

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week __

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

6. How many servings of citrus fruit or citrus juice do you eat ( e.g., orange, grapefruit)?

53

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week __

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

7. How many servings of other non-citrus fruit or juice do you consume?

54

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week __

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

8. How many servings of liver (eg., beef, chicken,pork) do you consume?

55

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

247 FOODS FORTIFIED WITH B-VITAMINS We would like to know if you eat any of the following foods that may be fortified with B-vitamins Code daily intake of vit. B12 from each source.

8. Breakfast cereals, such as, Just Right w/ fruits & nuts, Product 19, Nutri-Grain, Total, Special K

0 = No 1 = Yes

If yes, what BRAND(s) do you usually eat?

If yes, how often do you eat breakfast cereal?

9. Breakfast or energy bars, such as, NutriGrain, power bar,

0 = No 1 = Yes

If yes, what BRAND(s) do you usually eat?

If yes, how often do you eat breakfast bars?

10. Liquid meal replacements, such as, carnation, ensure plus

0 = No 1 = Yes

If yes, what BRAND(s) do you usually drink?

If yes, how often do you drink ensure, or boost etc.?

Other

0 = No 1 = Yes

If yes, what BRAND(s) do you usually eat?

If yes, how often do you eat this food?

Other

0 = No 1 = Yes

If yes, what BRAND(s) do you usually eat?

If yes, how often do you eat this food and in what quantity?

Code daily intake of folate from each source.

Code daily intake of vit. B6 from each source.

248

Are You at Risk for Osteoporosis? Complete the following questionnaire to find out your risk for developing osteoporosis. Question 1. Are you a postmenopausal women? 2. If you are a postmenopausal woman, did you have an early (before 50 years old) menopause or surgically induced menopause? 3. If you are a postmenopausal women, are you taking Hormone Replacement Therapy such as Raloxifene, Draloxifene, Premarin, Prempo? 4. Do you have a small, thin frame? 5. Has anyone in your family (father, mother, sister, brother) ever had a fracture or broken bone after age 50? 6. Have you had a fall within the past 1 year? 7. Have you had a fracture or broken bone after age 50? 8. Do you eat at least 2 servings of dairy products such as milk, yogurt, or cheese everyday? 9. Do you eat salmon at least twice a week? 10. Do you eat calcium-rich green vegetables such as mustard, turnip, or collard greens everyday? 11. Do you drink calcium-fortified juice everyday? 12. Do you eat calcium-fortified cereals (such as Total, Kellogg’s K) everyday? 13. Do you take a calcium and vitamin D supplement everyday? 14. Have you been taking excessive thyroid medication or high or prolonged doses of cortisone-like drugs for asthma, arthritis, or cancer? 15. Do you currently or did you ever smoke cigarettes, pipes, cigars or chew tobacco on a daily basis? 16. Do you exercise at least 30 minutes everyday?

Yes

No

(NOTE: COPY THIS INFORMATION FROM PREVIOUS QUESTIONS) 17. Age : _____ years old 18. Gender : Male Female (please circle) 19. Ethnicity : White Black Hispanic Asian 20. County : ______________ 21. Height : ______ feet ______ inches OR ______ cm 22. Weight : _____ pounds OR _______ kg Is height and weight measured or self-reported?

Others (please circle)

The more times you answer in the shaded boxes, the greater your risk for developing osteoporosis. See your physician.

249 MEDICATIONS AND ILLNESSES NAME/ID: _______________ Obtain information from reliable source. This information was provided by: client, caretaker, other___? YES NO DON’T Space (1) (0) KNOW Total number of PRESCRIPTION medications 10-11 Total number of NON -PRESCRIPTION medications, 12-13 not counting vitamins and minerals Multiple vitamin mineral supplement? 0 = no, 1 = yes 14 Number of other nutritional supplements? 15 16-17 Total number of illnesses - fill in when finished below. 1) Anemia in the past year 18 2) Alzheimer’s: Kind________________; Dx date________________ 19 3) Other dementias: Kind_______________; Dx date ______________ 20 4) Cancer: Kind_____________; Dx date__________; Status________ 21 5) Circulatory problems in the past year 22 6) Congestive heart failure in the past year 23 7) Constipation in the past year 24 8) Diabetes: Kind_________________; Dx date ________________ 25 9) Diarrhea in the past year 26 10) Glaucoma in the past year 27 11) Hearing problems in the past year 28 12) Heart disease in the past year 29 13) Hypertension in the past year 30 14) Legally blind in the past year 31 15) Liver disease in the past year 32 16) Mental illness: Kind________________; Dx date_______________ 33 17) Osteoporosis in the past year 34 18) Hip fracture in the past year 35 19) Have you every had a pace maker 36 20) Parkinson’s disease: Dx date____________________ 37 21) Renal disease in the past year 38 22) Respiratory disease in the past year 39 23) Seizures: 1st date_____________; last date______________ 40 24) Skin rashes, bed sores in the past year 41 25) Stroke: Number______; Dates_____________________________ 42 26) Thyroid problems: Kind_____________; Dx date______________ 43 27) Visual disturbances in the past year 44 28) Cataracts in the past year 45 29) Have you used any type of tobacco in the past year 46 30) Have you every had stomach surgery 47 31) Emergency room visit in the past year 48 32) Other 49 33) Arthritis in the past year 50 34) Pneumonia in the past year 51 35) Dizziness in the past year 52 36) Gout in the past year 53 37) 54

250 MEDICATIONS (NOTE: ASK EVERY MEDICATION QUESTION THEN RECORD MEDS ON THE NEXT FORM) 1) Are you currently taking aspirin?

1 = Yes 0 = No 1 = Yes 0 = No 1 = Yes 0 = No 1 = Yes 0 = No

10

2)

Are you currently taking ibuprofen such as Advil, Motrin, Nuprin?

3)

Are you currently taking Aleve?

4)

Are you currently taking Acetaminophen such as Tylenol or similar medication?

5)

Are you currently taking antacids or medications for heartburn or indigestion such as maalox, mylanta, alka aid (alka-seltzer) gaviscon, propulsid, zantac, pepcid, axid, cyotec, tums, tagamet, proton pump inhibitors such as prevacid, prevapac,prilosec, or other medication? CIRCLE ALL THAT APPLY Are you currently taking laxatives such as milk of magnesia, fiber tablets, metamucil or other laxative medication? CIRCLE ALL THAT APPLY

1 = Yes 0 = No

14

1 = Yes 0 = No

15

Are you currently taking a cough suppressant such as humibid, robitussin, entrex or other medication? Are you currently taking allergy, sinus, or cold medication such as chlorpheniramine, relief, allerfed, seldane, sudafed, sine aid, Tylenol allergy sinus, contac, tylenol cold formulas, methypred dose, claritin, phenylprop, guaif, bromfed, tavist-d, actifed, benadryl, equate allergy sinus or other medication? Are you currently using nasal spray for allergy or sinus, such as aerobid, flonase, beconase, Nasalcrom or other medication?

1 = Yes 0 = No 1 = Yes 0 = No

16

1 = Yes 0 = No

18

Are you currently taking a non-steroidal anti-inflammatory drug (NSAID) such as voltaren, diclofenac, naprosyn, naproxyn, sulindac, lodine, relafen, daypro, oruvail or similar medication? Are you currently taking a pain medication such as ultram, darvocet-N-100, fiorinal or similar medication? Are you currently taking an arthritis medication such as prednisone, rheumatrex methotrexate, orasone, deltasone or other medication?

1 = Yes 0 = No

19

1 = Yes 0 = No 1 = Yes 0 = No

20

13)

Are you currently taking antibiotics such as zithromax, amoxicillin or other antibiotic medication?

1 = Yes 0 = No

22

14)

Are you currently taking a sleeping aid such as Tylenol PM or other medication?

1 = Yes 0 = No

23

6)

7) 8)

9)

10)

11) 12)

11 12 13

17

21

251

15)

16)

17)

41)

MEDICATIONS Are you currently taking migraine medication such as mepergan fortis, imitrex, ercaf, Forbal-S or other migraine medication? # 16 and #18 - important for cognitive tests - so probe carefully Are you currently taking anti-anxiety medication such as Alprazolam (xanax), Buspirone (Buspar), Chlordiaxepoxide (Librium), Clonazepam (klonopin), Clorazepate (tranxene), Diazepam (Valium), Hydroxyzine (Vistaril), Lorazepam (Ativan), Oxazepam (Serax), Propanolol (Inderal) or other anti-anxiety medication? Circle all that apply Are you currently taking anti-depressant medication such as Amitriptyline (Elavil), Citalopram (Celexa), Clomipramine (Anafranil), Desipramine (Norpramin), Doxepin (Sinequan), Fluoxetine (Prozac), Fluvoxamine (Luvox), Imipramine (Tofranil), Maprotiline (Ludiomil), Nortriptyline (Pamelor), Paroxetine (Paxil), Sertraline (zoloft), Trazadone (Desyrel), Venlafaxine (Effexor) or other anti-depressant medication? Circle all that apply #41 & 42 - important for cognitive tests - so probe carefully Are you currently taking any drugs to help or enhance your thinking such as Chlorpromazine (Thorazine), Thioridazine (Mellaril), Fluphenazine (Prolixin), Trifluoperazine (Stelazine), Haloperidol (Haldol), Thiothixene (Navane), Loxapine (Loxitane), Molindone (Moban), Clozapine (Clozaril), Risperidone (Risperdal), Quetiapine (Seroquel), Olanzapine (Zyprexa) or other neuroleptic medications? Circle all that apply

1 = Yes 0 = No

24

1 = Yes 0 = No

25

1 = Yes 0 = No

26

1 = Yes 0 = No

27

42)

Are you currently taking any drugs to help or enhance your memory such as Tacrine (Cognex) or Donepezil hydrochloride (Aricept)? Circle all that apply

1 = Yes 0 = No

28

43)

List any other medications currently taken:

29

45)

Are you currently receiving Vitamin B-12 injections/shots? Last Vitamin B-12 shot (date) : ______________ How often? _______________(example: once a year, twice a year, every other month, once a month) 762 (NOTE: IF YES, THEY NEED TO HAVE HAD A SHOT 6 MONTHS AGO OR LATER AND AGREE NOT TO RECEIVE A SHOT FOR THE NEXT FOUR MONTHS TO PARTICIPATE IN THIS STUDY) Total number of prescription medications (total of prescription meds) Total number of non-prescription medications (total of nonprescription meds)

1 = Yes 0 = No 1 = Yes 0 = No

30

31-32 33-34

252 RESIDENT MEDICATION RECORDS: Include prescription, non-prescription, and vitamins/minerals ID _________ DOCUMENTATION (Check all that apply) Medication

Dosage

Schedule

Route of Administration

*How Long have you been taking medication

Bottle only

Cardex Record

Signature Administration Record

253

For how long? Vitamin A Vitamin C Vitamin D Vitamin E Thiamin (B1) Riboflavin (B2) Niacin or Niacinamide or Vit. B3 Pyridoxine or Vitamin B6 Folic acid or Folate Vitamin B-12 Biotin Pantothenic Acid Vitamin K Calcium Iron Phosphorus Iodine Magnesium Zinc Copper Potassium Manganese Chromium Molybdenum Chloride Nickel Silicon Vanadium Boron Fluoride Selenium Other

________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

mg

mg

mg

mg

mg

mg

mg

mg

mg

mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

__________

__________

__________

__________

__________

TOTAL

254

For how long? Vitamin A Vitamin C Vitamin D Vitamin E Thiamin (B1) Riboflavin (B2) Niacin or Niacinamide or Vit. B3 Pyridoxine or Vitamin B6 Folic acid or Folate Vitamin B-12 Biotin Pantothenic Acid Vitamin K Calcium Iron Phosphorus Iodine Magnesium Zinc Copper Potassium Manganese Chromium Molybdenum Chloride Nickel Silicon Vanadium Boron Fluoride Selenium Other

SUPP # __ __ # pills per D, W, M

SUPP # __ __ # pills per D, W, M

SUPP # __ __ # pills per D, W, M

SUPP # __ __ # pills per D, W, M

SUPP # __ __ # pills per D, W, M

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

mg

mg

mg

mg

mg

mg

mg

mg

mg

mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

TOTAL

255 HEARING HANDICAP INVENTORY FOR ADULTS (HHIA) Date: ______ ID: ______ The purpose of these questions is to identify any problems your hearing loss may be causing you. Please do not skip any questions. Even if you feel you do not have a hearing loss, please answer all of the questions. For each question, circle one response: No, Sometimes, or Yes.

S1 E2* S3 E4 E5* S6 S7

E8* S9* E10 S11* E12 S13

E14* S15* E16 E17 E18 S19 E20* S 21*

Does a hearing problem cause you to use the phone less often than you would like? Does a hearing problem cause you to feel embarrassed when meeting new people? Does a hearing problem cause you to avoid groups of people? Does a hearing problem make you irritable? Does a hearing problem cause you to feel frustrated when talking to members of your family? Does a hearing problem cause you difficulty when attending a party? Does a hearing problem cause you difficulty hearing/understanding coworkers, clients, or customers? Do you feel handicapped by a hearing problem? Does a hearing problem cause you difficulty when visiting friends, relatives, or neighbors? Does a hearing problem cause you to feel frustrated when talking to coworkers, clients, or customers? Does a hearing problem cause you difficulty in the movies or theater? Does a hearing problem cause you to be nervous? Does a hearing problem cause you to visit friends, relatives, or neighbors less often than you would like? Does a hearing problem cause you to have arguments with family members? Does a hearing problem cause you difficulty when listening to the TV or radio? Does a hearing problem cause you to go shopping less often than you would like? Does any problem or difficulty with your hearing upset you at all? Does a hearing problem cause you to want to be by yourself? Does a hearing problem cause you to talk to family members less often than you would like? Do you feel that any difficulty with your hearing limits or hampers your personal or social life? Does a hearing problem cause you difficulty when

Line Space Line # 4-5 10

0 2 No Sometimes

4 Yes

No Sometimes

Yes

11

No Sometimes

Yes

12

No Sometimes No Sometimes

Yes Yes

13 14

No Sometimes

Yes

15

No Sometimes

Yes

16

No Sometimes No Sometimes

Yes Yes

17 18

No Sometimes

Yes

19

No Sometimes

Yes

20

No Sometimes No Sometimes

Yes Yes

21 22

No Sometimes

Yes

23

No Sometimes

Yes

24

No Sometimes

Yes

25

No Sometimes

Yes

26

No Sometimes

Yes

27

No Sometimes

Yes

28

No Sometimes

Yes

29

No Sometimes

Yes

30

256 in a restaurant with relatives or friends? E 22 Does a hearing problem cause you to feel No Sometimes Yes 31 depressed? S 23 Does a hearing problem cause you to listen to TV or No Sometimes Yes 32 radio less often than you would like? E 24 Does a hearing problem cause you to feel No Sometimes Yes 33 uncomfortable when talking to friends? E 25 Does a hearing problem cause you to feel left out No Sometimes Yes 34 when you are with a group of people? E 26 Does a hearing problem cause you to feel “stupid” No Sometimes Yes 35 or “dumb”? S 27 Do you have difficulty hearing when someone No Sometimes Yes 36 speaks in a whisper? S 28 Does a hearing problem cause you to attend No Sometimes Yes 37 religious services less often than you would like? * Items comprising the HHIA-S. From: Newman, C.W., Weinstein, B.E., Jacobson, G.P., and Hug, G.A. Test-retest reliability of the Hearing Handicap Inventory for Adults, Ear and Hearing, 1991;12(5): 355-357.

257 NOISE EXPOSURE HISTORY We need to know about noise exposure in your past, even as a child. An example of a loud noise is a noise that makes it hard to talk or hear another person, or makes your ears ring after exposure. NOISE AT YOUR WORK Date Date How often did you use 1. Have you had any of these jobs? Started Ended hearing protection? Never Sometimes Always A. Cannery No Yes 19____ _____ 1 2 3 B. Construction No Yes 19____ _____ 1 2 3 C. Factory: _______________ No Yes 19____ _____ 1 2 3 (type of factory) D. Farming No Yes 19____ _____ 1 2 3 E. Logging, Lumber industry No Yes 19____ _____ 1 2 3 F. Loud music (performing) No Yes 19____ _____ 1 2 3 G. Mining No Yes 19____ _____ 1 2 3 H. Police, Fire, Dept. No Yes 19____ _____ 1 2 3 I. Printing No Yes 19____ _____ 1 2 3 J. Transportation (truck, boat, plane...) No Yes 19____ _____ 1 2 3 K. Any other types of noisy jobs No Yes 19____ _____ 1 2 3 Describe_____________________ NOISE DURING MILITARY SERVICE How often did you use 2. Were you exposed to noise during military Date Date hearing protection? service (including basic training and reserves)? Started Ended Never Sometimes Always A. Artillery No Yes 19___ ______ 1 2 3 B. Explosion No Yes 19___ ______ 1 2 3 C. Planes, helicopters No Yes 19___ ______ 1 2 3 D. Small arms No Yes 19___ ______ 1 2 3 E. Tanks, other heavy equipment No Yes 19___ ______ 1 2 3 F. Other types of noise: No Yes 19___ ______ 1 2 3 Describe_____________________ NOISE DURING RECREATION How often did you use 3. Have you been exposed to noise during Date Date hearing protection? recreational or leisure-time activities? Started Ended Never Sometimes Always A. Gunfire No Yes 19____ _____ 1 2 3 B. Loud Engines (boat, auto, plane, No Yes 19____ _____ 1 2 3 motorcycle, skimobile) C. Loud Music No Yes 19____ _____ 1 2 3 D. Power Tools No Yes 19____ _____ 1 2 3 E. Other types of noise: No Yes 19____ _____ 1 2 3 Describe_____________________ Have you ever undergone any accidental exposure to sudden intense noise? No Yes

1 2 Type of noise_________________________ Your age then________________________ Adapted fom Meikle, Griest & Press (1986)

Which ear or side? LEFT ear 1 BOTH ears Right ear 2 Not sure

3 4

258

Geriatric Depression Scale (GDS) Short form Choose the best answer for how you felt over the past week. Please answer the following questions “YES” or “NO there are no right or wrong answers, only what best applies to you.

1)

Are you basically satisfied with your life?

1 Yes

0 *NO

2)

Have you dropped many of your activities and interests?

*YES

No

11

3)

Do you feel that your life is empty?

*YES

No

12

4)

Do you often get bored?

*YES

No

13

5)

Are you in good spirits most of the time?

Yes

6)

Are you afraid that something bad is going to happen to you?

*YES

7)

Do you feel happy most of the time?

Yes

8)

Do you often feel helpless?

9)

Do you prefer to stay at home, rather than going out and doing new

*NO

Space 10

14

No

15

*NO

16

*YES

No

17

*YES

No

18

No

19

*NO

20

No

21

*NO

22

things? 10)

Do you feel you have more problems with memory than most people?

*YES

11)

Do you think it is wonderful to be alive now?

Yes

12)

Do you feel pretty worthless the way you are now?

*YES

13)

Do you feel full of energy?

Yes

14)

Do you feel that your situation is hopeless?

*YES

No

22

15)

Do you think that most people are better off than you are?

*YES

No

23

* = 1 point. If * score is 10 or greater, or if (Nos. 1,5,7,11,13) were answered with * then the participant may be depressed. Proceed with referral plan.

259

In the last few weeks have you found things to be easily disturbing or annoying (e.g., have other people, objects or situations been getting on your nerves or causing you frustration?) 1

2

3

4

5

6

Not at all

7 all of the time

In the last few weeks have you felt restless or experienced difficulty with activities such as sleeping, following instructions, keeping your mind on what you are doing? 1 Not at all

2

3

4

5

6

7 all of the time

260

NUTRITION AND DEPRESSION STATUS REPORT NAME: _______________________________ COUNTY: ___________________________

NUTRITION SCREENING INITIATIVE - 10 ITEM QUESTIONNAIRE: This questionnaire screens for nutritional problems. _____ 0-2 _____ 3-5 _____ 6 or more.

Good Moderate nutritional risk High nutritional risk; recommend nutrition consult

BODY MASS INDEX (KG/M2) - INDEX OF WEIGHT FOR HEIGHT: This is an index of underweight, normal weight, overweight and obesity. _____ Greater than 30 Obese; recommend nutrition consult _____ 25-29 Overweight; At risk for nutrition problems; recommend nutrition consult _____ 21-24.9 Normal Range _____ Less than 19.9; At risk for nutrition problems; recommend nutrition consult

WEIGHT LOSS (> 3 KG or 7 POUNDS IN PREVIOUS 3 MONTHS): ______ Unintentional weight loss is an indicator of low food intake or illness. However, some people need to lose weight if they are overweight and their weight is contributing to health problems. _____ No weight loss Good _____ Weight loss > 7 lb At risk for nutrition problems; recommend nutrition consult PLEASE FEEL FREE TO CONTACT NIKKI HAWTHORNETO MAKE AN APPOINTMENT FOR A NUTRITIONAL CONSULT: 706-542-4838

GERIATRIC DEPRESSION SCALE- 15 ITEM QUESTIONNAIRE:___________ This questionnaire measures depression. _____ 9 or less; probably not depressed _____ 10 or more; at risk for depression - contact senior center director

261

POST TEST GENERAL INFORMATION

ID: ____________ (1-3)

______

1. Today’s date: ___ / ____ / ____

Month/Day/Year

(10-15)

__ (16)

__ __ . __ (17-20)

2. This information was obtained from: 0 _____ Client 1 _____ Senior center staff person 2 _____ Family member of client 3 _____ Caregiver for client 4 _____ Other: ________________ 3. How long has the client been using the services of the senior center? ___ ___.___ years Code as years (xx.x years)

_ _ _ _ _ _ _ _ 4. Date of birth: ___ / ____ / ____

Month/Day/Year

(21-28)

__ __ __

5. Current age: __________ years

Example: age 75 is 075

(29-31)

__

6. Gender:

______ Male (0)

______ Female (1)

7. Ethnicity:

______ Caucasian (0) ______ Asian (3)

______ Black (1) ______ Other (4)

(32)

__ (33)

__ __

8. Years completed in school?

______ Hispanic (2)

______ Years

(34-35)

__

9. Do you take a multiple-vitamin/mineral supplement? ______ No (0) ____ Yes (1)

(36)

__

10. Do you take any other nutritional supplements that contain vitamins or minerals?

(37)

_____ No (0)

_____ Yes (1)

* Health Care Provider ______________________________________________________ Address___________________________________________________________________ __________________________________________________________________________ Phone____________________________________________________________________ * Care giver/ Next of Kin (1) ___________________________________ Phone______________________________ Address____________________________________________________________________ ___________________________________________________________________________ (2) ___________________________________ Phone_______________________________ Address_____________________________________________________________________

262 __ __

11. How many hours ago did you last eat?

(code number of hours ago).

38-39 __ 40

12. Fasting status (coded by medical technologist). 0 1

__ 41

13. How would you rate your overall health at the present time -- excellent, good, fair, or poor? 3 2 1 0 9

__ 42

14.

Better About the same Worse Not answered

15. How much do your health troubles stand in the way of your doing things you want to -- not at all, a little (some), or a great deal? 2 1 0 9

__ __ 44-45

Excellent Good Fair Poor Not answered

Is your health now better, about the same, or worse than it was five years ago? 2 1 0 9

__ 43

Not fasted, food in the last 4 hours Fasted, food not eaten in the past 4 hours

Not at all A little (some) A great deal Not answered

16. County of residence 00= Madison 01= Morgan 02= Walton

__ 46

03= Jackson 04= Newton 05= Barrow

00-12 06= Greene 09= Elbert 12=Franklin 07= Clark 10= Oconee 08= Oglethorpe 11= Jasper

18. Did you participate in our vitamin supplement study during spring and summer 1999? (ASK ONLY IN GREENE AND MORGAN COUNTY) 1= YES

0= NO

263

BLOOD PRESSURE (NOTE: RECORD RESULTS ON "BLOOD PRESSURE FORM" AND GIVE TO PARTICIPANT)

__ __ __ 50-52

22. Blood Pressure Systolic (mmHg) __ (0) < 120 Optimal __ (1) < 130 Normal __ (2) 130-139 High-normal __ (3) 140-159 Mild Hypertension (Stage 1) __ (4) 160-179 Moderate Hypertension (Stage 2) __ (5) > 180 Severe Hypertension (Stage 3) __ (999) Missing

Diastolic (mmHg) __ __ __ 53-55

__ (0) < 80 Optimal __ (1) < 85 Normal __ (2) 85-95 High-normal __ (3) 90-99 Mild Hypertension (Stage 1) __ (4) 100-109 Moderate Hypertension (Stage 2) __ (5) > 110 Severe Hypertension (Stage 3) __ (999) Missing

264 ORIENTATION-MEMORY-CONCENTRATION TEST Read all questions to the participant. Tell them that some of the questions may be easy and some may be hard -- just do the best you can. Response

# of Errors

Max. Errors

Weight Factor

1) What is the year now?

1

4

2) What month is it now?

1

3

1

3

2

2

2

2

5

2

Total

Please repeat this phrase after me: JOHN BROWN, 42 MARKET STREET, CHICAGO No score for this -- it is a memory phrase for Item # 6. Allow the person up to three trials for learning (repeating) the phrase. If the subject has not learned the phrase after three trials, record the value of “0” as the total score for Item #6, and proceed to Item #3. 3) Without looking at your watch or a clock, tell me about what time is it? Note: score is correct if within one hour of actual time. 4) Count backwards from 20 to 1. 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 5) Say the months of the year in reverse order. DEC, NOV, OCT, SEPT, AUG, JULY, JUNE, MAY, APR, MAR, FEB, JAN 6) Please repeat the name and address I asked you to remember. Count the number of items (5) in memory phrase recalled incorrectly. An answer of either Market or Market Street is acceptable. John / Brown / 42 / Market Street / Chicago (10-11) TOTAL SCORE Interpretation of corrected scores:

20

Normal or minimal impairment Moderate impairment Severe impairment

Source: Katzman, R., Brown, T., Fuld, P., Peck, A., Schechter, R., Schimmel, H. Validation of a short orientation-memory-concentration test of cognitive impairment. American Journal of Psychiatry 140: 734-739, 1983.

265

MINI-NUTRITIONAL ASSESSMENT ID# ____________ (1-3)

Name: Age: 04

First name:

Sex:

Date:

** enter decimal points

(4-5)

TSF.

Triceps skin fold (mm):

__ __.__ (6-9)

Kneeht.

Knee Height (cm):

__ __.__ (10-13)

I. ANTHROPOMETRIC ASSESSMENT ____ MNA1. BMI (weight/(height)2 in kg/m2); weight = ___ lbs. / 2.205 = __ __ __ . __kg (14) 0 = BMI < 19 height = ____ in. * .0254 = __ __ __ . __ meters BMI = __ __ . __ 1 = 19 < BMI < 21 2 = 21 < BMI < 23 3 = BMI > 23

(15-19)kg (20-24)m

_____ MNA2. Mid arm circumference (MAC in cm.): __ __ . __ cm. (29) 0.0 = MAC < 21 0.5 = 21 < MAC < 22 1.0 = MAC > 22

(30-33)cm

_____ MNA3. Calf circumference (CC in cm.): __ __ . __cm. (34) 0 = CC < 31 1 = CC > 31

(35-38)cm

(25-28) BMI

_____ MNA4. Weight loss during last 3 months: _________ lbs. / 2.205 = __ __ __ . __ kg (40-44)kg (39) 0 = weight loss > 3 kg 1 = does not know 2 = weight loss between 1 and 3 kg 3 = no weight loss _____ MNA12A. How many servings of milk, yogurt, or cheese does the individual consume? (45)

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

_____ MNA12D. How many servings of meat, fish, or poultry does the individual consume? (46)

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

266 NUTRITION QUESTIONS __ 47

__ __ 48-49

1. Have you ever received home delivered meals? 0 = Yes 1 = No 2. If you receive home delivered meals, for how long have you been receiving them? __ __ years Code as whole years (xx years)

__ 50

3. How many times a week do you eat at the senior center? 0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week

__

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

4. How many servings of green vegetables do you eat?

51

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week __

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

5. How many servings of orange or yellow vegetable do you eat?

52

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week __

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

6. How many servings of citrus fruit or citrus juice do you eat ( e.g., orange, grapefruit)?

53

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week __

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

7. How many servings of other non-citrus fruit or juice do you consume?

54

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week __

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

8. How many servings of liver (eg., beef, chicken,pork) do you consume?

55

0 ____ Less than one per week 1 ____ 1 per week 2 ____ 2 per week

3 ____ 3 per week 4 ____ 4 per week 5 ____ 5 per week

6 ____ 6 per week 7 ____ At least one per day 8 ____ 2 or more per day 9 ____ Missing/don’t know

267 FOODS FORTIFIED WITH B-VITAMINS We would like to know if you eat any of the following foods that may be fortified with B-vitamins Code daily intake of vit. B12 from each source. 8. Breakfast cereals, such as, Just Right w/ fruits & nuts, Product 19, NutriGrain, Total, Special K

0 = No 1 = Yes

If yes, what BRAND(s) do you usually eat?

If yes, how often do you eat breakfast cereal?

9. Breakfast or energy bars, such as, Nutri-Grain, power bar,

0 = No 1 = Yes

If yes, what BRAND(s) do you usually eat?

If yes, how often do you eat breakfast bars?

10. Liquid meal replacements, such as, carnation, ensure plus

0 = No 1 = Yes

If yes, what BRAND(s) do you usually drink?

If yes, how often do you drink ensure, or boost etc.?

Other

0 = No 1 = Yes

If yes, what BRAND(s) do you usually eat?

If yes, how often do you eat this food?

Other

0 = No 1 = Yes

If yes, what BRAND(s) do you usually eat?

If yes, how often do you eat this food and in what quantity?

Code daily intake of folate from each source.

Code daily intake of vit. B6 from each source.

268 MEDICATIONS AND ILLNESSES NAME/ID: _______________ Obtain information from reliable source. This information was provided by: client, caretaker, other___? YES NO DON’T Space (1) (0) KNOW Total number of PRESCRIPTION medications 10-11 Total number of NON -PRESCRIPTION medications, 12-13 not counting vitamins and minerals Multiple vitamin mineral supplement? 0 = no, 1 = yes 14 Number of other nutritional supplements? 15 16-17 Total number of illnesses - fill in when finished below. 1) Anemia in the past year 18 2) Alzheimer’s: Kind________________; Dx date_____________ 19 3) Other dementias: Kind__________________; Dx date __________ 20 4) Cancer: Kind_____________; Dx date____________; Status_____ 21 5) Circulatory problems in the past year 22 6) Congestive heart failure in the past year 23 7) Constipation in the past year 24 8) Diabetes: Kind_________________; Dx date ________________ 25 9) Diarrhea in the past year 26 10) Glaucoma in the past year 27 11) Hearing problems in the past year 28 12) Heart disease in the past year 29 13) Hypertension in the past year 30 14) Legally blind in the past year 31 15) Liver disease in the past year 32 16) Mental illness: Kind___________________; Dx date___________ 33 17) Osteoporosis in the past year 34 18) Hip fracture in the past year 35 19) Have you every had a pace maker 36 20) Parkinson’s disease: Dx date____________________ 37 21) Renal disease in the past year 38 22) Respiratory disease in the past year 39 23) Seizures: 1st date_____________; last date______________ 40 24) Skin rashes, bed sores in the past year 41 25) Stroke: Number______; Dates_____________________________ 42 26) Thyroid problems: Kind____________; Dx date______________ 43 27) Visual disturbances in the past year 44 28) Cataracts in the past year 45 29) Have you used any type of tobacco in the past year 46 30) Have you every had stomach surgery 47 31) Emergency room visit in the past year 48 32) Other 49 33) Arthritis in the past year 50 34) Pneumonia in the past year 51 35) Dizziness in the past year 52 36) Gout in the past year 53 37) 54

269

MEDICATIONS (NOTE: ASK EVERY MEDICATION QUESTION THEN RECORD MEDS ON THE NEXT FORM) 1)

Are you currently taking aspirin?

1 = Yes 0 = No Are you currently taking ibuprofen such as Advil, Motrin, Nuprin? 1 = Yes 0 = No Are you currently taking Aleve? 1 = Yes 0 = No Are you currently taking Acetaminophen such as Tylenol or 1 = Yes similar medication? 0 = No

10

Are you currently taking antacids or medications for heartburn or indigestion such as maalox, mylanta, alka aid (alka-seltzer) gaviscon, propulsid, zantac, pepcid, axid, cyotec, tums, tagamet, proton pump inhibitors such as prevacid, prevapac,prilosec, or other medication? CIRCLE ALL THAT APPLY Are you currently taking laxatives such as milk of magnesia, fiber tablets, metamucil or other laxative medication? CIRCLE ALL THAT APPLY

1 = Yes 0 = No

14

1 = Yes 0 = No

15

Are you currently taking a cough suppressant such as humibid, robitussin, entrex or other medication? Are you currently taking allergy, sinus, or cold medication such as chlorpheniramine, relief, allerfed, seldane, sudafed, sine aid, Tylenol allergy sinus, contac, tylenol cold formulas, methypred dose, claritin, phenylprop, guaif, bromfed, tavist-d, actifed, benadryl, equate allergy sinus or other medication? Are you currently using nasal spray for allergy or sinus, such as aerobid, flonase, beconase, Nasalcrom or other medication?

1 = Yes 0 = No 1 = Yes 0 = No

16

1 = Yes 0 = No

18

Are you currently taking a non-steroidal anti-inflammatory drug (NSAID) such as voltaren, diclofenac, naprosyn, naproxyn, sulindac, lodine, relafen, daypro, oruvail or similar medication? Are you currently taking a pain medication such as ultram, darvocet-N-100, fiorinal or similar medication? Are you currently taking an arthritis medication such as prednisone, rheumatrex methotrexate, orasone, deltasone or other medication?

1 = Yes 0 = No

19

1 = Yes 0 = No 1 = Yes 0 = No

20

13)

Are you currently taking antibiotics such as zithromax, amoxicillin or other antibiotic medication?

1 = Yes 0 = No

22

14)

Are you currently taking a sleeping aid such as Tylenol PM or other medication?

1 = Yes 0 = No

23

2) 3) 4)

5)

6)

7) 8)

9)

10)

11) 12)

11 12 13

17

21

270

MEDICATIONS 15)

Are you currently taking migraine medication such as mepergan fortis, imitrex, ercaf, Forbal-S or other migraine medication? # 16 and #18 - important for cognitive tests - so probe carefully Are you currently taking anti-anxiety medication such as Alprazolam (xanax), Buspirone (Buspar), Chlordiaxepoxide (Librium), Clonazepam (klonopin), Clorazepate (tranxene), Diazepam (Valium), Hydroxyzine (Vistaril), Lorazepam (Ativan), Oxazepam (Serax), Propanolol (Inderal) or other anti-anxiety medication? Circle all that apply Are you currently taking anti-depressant medication such as Amitriptyline (Elavil), Citalopram (Celexa), Clomipramine (Anafranil), Desipramine (Norpramin), Doxepin (Sinequan), Fluoxetine (Prozac), Fluvoxamine (Luvox), Imipramine (Tofranil), Maprotiline (Ludiomil), Nortriptyline (Pamelor), Paroxetine (Paxil), Sertraline (zoloft), Trazadone (Desyrel), Venlafaxine (Effexor) or other anti-depressant medication? Circle all that apply #41 & 42 - important for cognitive tests - so probe carefully Are you currently taking any drugs to help or enhance your thinking such as Chlorpromazine (Thorazine), Thioridazine (Mellaril), Fluphenazine (Prolixin), Trifluoperazine (Stelazine), Haloperidol (Haldol), Thiothixene (Navane), Loxapine (Loxitane), Molindone (Moban), Clozapine (Clozaril), Risperidone (Risperdal), Quetiapine (Seroquel), Olanzapine (Zyprexa) or other neuroleptic medications? Circle all that apply

1 = Yes 0 = No

24

1 = Yes 0 = No

25

1 = Yes 0 = No

26

1 = Yes 0 = No

27

42)

Are you currently taking any drugs to help or enhance your memory such as Tacrine (Cognex) or Donepezil hydrochloride (Aricept)? Circle all that apply

1 = Yes 0 = No

28

43)

List any other medications currently taken:

29

45)

Are you currently receiving Vitamin B-12 injections/shots? Last Vitamin B-12 shot (date) : ______________ How often? _______________(example: once a year, twice a year, every other month, once a month) 762 (NOTE: IF YES, THEY NEED TO HAVE HAD A SHOT 6 MONTHS AGO OR LATER AND AGREE NOT TO RECEIVE A SHOT FOR THE NEXT FOUR MONTHS TO PARTICIPATE IN THIS STUDY) Total number of prescription medications (total of prescription meds) Total number of non-prescription medications (total of nonprescription meds)

1 = Yes 0 = No 1 = Yes 0 = No

16)

17)

41)

30

31-32 33-34

271

RESIDENT MEDICATION RECORDS: Include prescription, non-prescription, and vitamins/minerals ID _________ DOCUMENTATION (Check all that apply) Medication

Dosage

Schedule

Route of Administration

*How Long have you been taking medication

Bottle only

Cardex Record

Signature Administration Record

272

For how long? Vitamin A Vitamin C Vitamin D Vitamin E Thiamin (B1) Riboflavin (B2) Niacin or Niacinamide or Vit. B3 Pyridoxine or Vitamin B6 Folic acid or Folate Vitamin B-12 Biotin Pantothenic Acid Vitamin K Calcium Iron Phosphorus Iodine Magnesium Zinc Copper Potassium Manganese Chromium Molybdenum Chloride Nickel Silicon Vanadium Boron Fluoride Selenium Other

________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

_____mo/yrs

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

mg

mg

mg

mg

mg

mg

mg

mg

mg

mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

TOTAL

273

For how long? Vitamin A Vitamin C Vitamin D Vitamin E Thiamin (B1) Riboflavin (B2) Niacin or Niacinamide or Vit. B3 Pyridoxine or Vitamin B6 Folic acid or Folate Vitamin B-12 Biotin Pantothenic Acid Vitamin K Calcium Iron Phosphorus Iodine Magnesium Zinc Copper Potassium Manganese Chromium Molybdenum Chloride Nickel Silicon Vanadium Boron Fluoride Selenium Other

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

__________ SUPP # __ __ # pills per D, W, M

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

WRITE IN AMOUNT /PILL & CIRCLE UNIT _____mo/yrs

_____mo/yrs

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

IU RE mg IU mg IU mg mg

mg

mg

mg

mg

mg

mg

mg

mg

mg

mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mg mcg mg mg mcg mg mcg mg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

mcg mg mg mg mcg mg mg mg mg mg mcg mcg mg mcg mg mcg mcg mg mcg mg mcg

TOTAL

274

HEARING HANDICAP INVENTORY FOR ADULTS (HHIA) Date: ______

ID: ______

The purpose of these questions is to identify any problems your hearing loss may be causing you. Please do not skip any questions. Even if you feel you do not have a hearing loss, please answer all of the questions. For each question, circle one response: No, Sometimes, or Yes.

S1 E2* S3 E4 E5* S6 S7

E8* S9* E10 S11* E12 S13

E14* S15* E16 E17

Does a hearing problem cause you to use the phone less often than you would like? Does a hearing problem cause you to feel embarrassed when meeting new people? Does a hearing problem cause you to avoid groups of people? Does a hearing problem make you irritable? Does a hearing problem cause you to feel frustrated when talking to members of your family? Does a hearing problem cause you difficulty when attending a party? Does a hearing problem cause you difficulty hearing/understanding coworkers, clients, or customers? Do you feel handicapped by a hearing problem? Does a hearing problem cause you difficulty when visiting friends, relatives, or neighbors? Does a hearing problem cause you to feel frustrated when talking to coworkers, clients, or customers? Does a hearing problem cause you difficulty in the movies or theater? Does a hearing problem cause you to be nervous? Does a hearing problem cause you to visit friends, relatives, or neighbors less often than you would like? Does a hearing problem cause you to have arguments with family members? Does a hearing problem cause you difficulty when listening to the TV or radio? Does a hearing problem cause you to go shopping less often than you would like? Does any problem or difficulty with your hearing upset you at all?

Line Space Line # 4-5 10

0 2 No Sometimes

4 Yes

No Sometimes

Yes

11

No Sometimes

Yes

12

No Sometimes No Sometimes

Yes Yes

13 14

No Sometimes

Yes

15

No Sometimes

Yes

16

No Sometimes No Sometimes

Yes Yes

17 18

No Sometimes

Yes

19

No Sometimes

Yes

20

No Sometimes No Sometimes

Yes Yes

21 22

No Sometimes

Yes

23

No Sometimes

Yes

24

No Sometimes

Yes

25

No Sometimes

Yes

26

275

E18

Does a hearing problem cause you to want to be by No Sometimes Yes 27 yourself? S19 Does a hearing problem cause you to talk to family No Sometimes Yes 28 members less often than you would like? E20* Do you feel that any difficulty with your hearing No Sometimes Yes 29 limits or hampers your personal or social life? S 21* Does a hearing problem cause you difficulty when No Sometimes Yes 30 in a restaurant with relatives or friends? E 22 Does a hearing problem cause you to feel No Sometimes Yes 31 depressed? S 23 Does a hearing problem cause you to listen to TV or No Sometimes Yes 32 radio less often than you would like? E 24 Does a hearing problem cause you to feel No Sometimes Yes 33 uncomfortable when talking to friends? E 25 Does a hearing problem cause you to feel left out No Sometimes Yes 34 when you are with a group of people? E 26 Does a hearing problem cause you to feel “stupid” No Sometimes Yes 35 or “dumb”? S 27 Do you have difficulty hearing when someone No Sometimes Yes 36 speaks in a whisper? S 28 Does a hearing problem cause you to attend No Sometimes Yes 37 religious services less often than you would like? * Items comprising the HHIA-S. From: Newman, C.W., Weinstein, B.E., Jacobson, G.P., and Hug, G.A. Test-retest reliability of the Hearing Handicap Inventory for Adults, Ear and Hearing, 1991;12(5): 355-357

276

Geriatric Depression Scale (GDS) Short form Choose the best answer for how you felt over the past week. Please answer the following questions “YES” or “NO there are no right or wrong answers, only what best applies to you.

1)

Are you basically satisfied with your life?

1 Yes

2)

Have you dropped many of your activities and interests?

*YES

No

11

3)

Do you feel that your life is empty?

*YES

No

12

4)

Do you often get bored?

*YES

No

13

5)

Are you in good spirits most of the time?

6)

Are you afraid that something bad is going to happen to you?

*YES

7)

Do you feel happy most of the time?

Yes

8)

Do you often feel helpless?

9)

Do you prefer to stay at home, rather than going out and doing new

Yes

0 *NO

*NO

Space 10

14

No

15

*NO

16

*YES

No

17

*YES

No

18

No

19

*NO

20

No

21

*NO

22

things? 10)

Do you feel you have more problems with memory than most people?

*YES

11)

Do you think it is wonderful to be alive now?

Yes

12)

Do you feel pretty worthless the way you are now?

*YES

13)

Do you feel full of energy?

Yes

14)

Do you feel that your situation is hopeless?

*YES

No

22

15)

Do you think that most people are better off than you are?

*YES

No

23

* = 1 point. If * score is 10 or greater, or if (Nos. 1,5,7,11,13) were answered with * then the participant may be depressed. Proceed with referral plan.

277

In the last few weeks have you found things to be easily disturbing or annoying (e.g., have other people, objects or situations been getting on your nerves or causing you frustration?) 1

2

3

4

5

6

Not at all

7 all of the time

In the last few weeks have you felt restless or experienced difficulty with activities such as sleeping, following instructions, keeping your mind on what you are doing? 1 Not at all

2

3

4

5

6

7 all of the time

278

NUTRITION AND DEPRESSION STATUS REPORT NAME: _______________________________ COUNTY: ___________________________ DATE:____________________ NUTRITION SCREENING INITIATIVE - 10 ITEM QUESTIONNAIRE: This questionnaire screens for nutritional problems. _____ 0-2 _____ 3-5 _____ 6 or more.

Good Moderate nutritional risk High nutritional risk; recommend nutrition consult

BODY MASS INDEX (KG/M2) - INDEX OF WEIGHT FOR HEIGHT: This is an index of underweight, normal weight, overweight and obesity. _____ Greater than 30 Obese; recommend nutrition consult _____ 25-29 Overweight; At risk for nutrition problems; recommend nutrition consult _____ 21-24.9 Normal Range _____ Less than 19.9; At risk for nutrition problems; recommend nutrition consult WEIGHT LOSS (> 3 KG or 7 POUNDS IN PREVIOUS 3 MONTHS): __________ Unintentional weight loss is an indicator of low food intake or illness. However, some people need to lose weight if they are overweight and their weight is contributing to health problems. _____ No weight loss Good _____ Weight loss > 7 lb At risk for nutrition problems; recommend nutrition consult PLEASE FEEL FREE TO CONTACT NIKKI HAWTHORNETO MAKE AN APPOINTMENT FOR A NUTRITIONAL CONSULT: 706-542-4838 GERIATRIC DEPRESSION SCALE- 15 ITEM QUESTIONNAIRE:___________ This questionnaire measures depression. _____ 9 or less; probably not depressed _____ 10 or more; at risk for depression - contact senior center director

279

PRE TEST Hearing History Questionnaire (HHQ) Please fill out this form as completely as possible, even if you do not have a hearing problem. I.

IDENTIFICATION

ID/Name:____________________________________ Date:____________________ Date of Birth:__________ Age:___ Telephone #:_______________ II. A.

HISTORY INFORMATION Communication Do you feel you have a hearing loss? Explain: _________________________________________________________________ _________________________________________________________________ If yes: Describe any changes in your hearing since it began: __________________________________________________________________ __________________________________________________________________ Describe any variations in the nature or severity of your problem: __________________________________________________________________ __________________________________________________________________ State your opinion of the cause of your problem: __________________________________________________________________ __________________________________________________________________

B. Family Do any of the following family members have a hearing loss? If yes, please indicate at what age their hearing loss began and the cause. Mother YES NO______________________________________ Father YES NO _____________________________________ Brother YES NO______________________________________ Sister YES NO______________________________________ Grandparent YES NO______________________________________ C. Previous Evaluations and Treatment List any individual or agency who has evaluated your hearing. Include dates and a description of the results: __________________________________________________________________ Have you ever worn a hearing aid? ___________When? ________________ If yes, indicate: Make ________ Model ___________ Ear _______________ D. Medical List any physicians who have provided medical care related to your hearing: __________________________________________________________________ Have you ever experienced any of the following: If yes, explain:

280 Ear Pain Ear Discharge Fullness or pressure in ears Ear, Nose or Throat surgery Dizziness

YES YES YES YES YES

NO NO NO NO NO

__________________________________ __________________________________ __________________________________ __________________________________ __________________________________

Have you ever had any major surgeries? ___________________________________________ If yes, were you given any specific medications at that time? (Please list, especially antibiotics) ______________________________________________________________ ____ Have you ever had chemotherapy? _________________________________________________________________ E. Tinnitus Do you have ringing or noises (tinnitus) in your ears?

YES

NO

If yes, about how long have you been aware of having tinnitus? (1) _____ Less than a year (4) _____ 6 to 10 years (2) _____ 1 to 2 years (5) _____ 11 to 20 years (3) _____ 3 to 5 years (6) _____ 20 or more years Which one of the statements below best describes your current tinnitus? (1) _____ Tinnitus usually lasts a few minutes at most (2) _____ Tinnitus usually lasts up to several hours (3) _____ Tinnitus usually lasts up to several days (4) _____ Tinnitus is always there If your tinnitus is not present all of the time, how much of the time does it seem to be present? (1) _____ Less than half the time (2) _____ Half the time or more Does your tinnitus interfere with your... (1) SLEEP (2) HEARING (3) DAY TO DAY LIVING

YES YES YES

NO NO NO

III. ADDITIONAL COMMENTS _________________________________________________________________________________ _________________________________________________________________________________ _________________________________________________________________________________

_

281

POST TEST Hearing History Questionnaire (HHQ)

E.

Tinnitus Do you have ringing or noises (tinnitus) in your ears?

YES

NO

If yes, about how long have you been aware of having tinnitus? (1) _____ Less than a year (4) _____ 6 to 10 years (2) _____ 1 to 2 years (5) _____ 11 to 20 years (3) _____ 3 to 5 years (6) _____ 20 or more years Which one of the statements below best describes your current tinnitus? (1) _____ Tinnitus usually lasts a few minutes at most (2) _____ Tinnitus usually lasts up to several hours (3) _____ Tinnitus usually lasts up to several days (4) _____ Tinnitus is always there If your tinnitus is not present all of the time, how much of the time does it seem to be present? (1) _____ Less than half the time (2) _____ Half the time or more Does your tinnitus interfere with your... (1) SLEEP (2) HEARING (3) DAY TO DAY LIVING

YES YES YES

NO NO NO

III. ADDITIONAL COMMENTS ______________________________________________________________________________ ______________________________________________________________________________ ______________________________________________________________________________

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