From the Division of Diabetes Translation, National Center for Chronic Disease without diabetes was examined by use of the 19992002 US National Health and …
American Journal of Epidemiology Advance Access published August 11, 2006
American Journal of Epidemiology Copyright 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in USA
DOI: 101093/aje/kwj281
Original Contribution Peripheral Insensate Neuropathy–A Tall Problem for US Adults?
Yiling J Cheng, Edward W Gregg, Henry S Kahn, Desmond E Williams, Nathalie De Rekeneire, and K M Venkat Narayan
From the Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, US Department of Health and Human Services, Atlanta, GA Received for publication January 11, 2006; accepted for publication April 6, 2006
The relation between height and lower extremity peripheral insensate neuropathy among persons with and without diabetes was examined by use of the 19992002 US National Health and Nutrition Examination Survey with 5,229 subjects aged 40 or more years A monofilament was used to determine whether any of three areas on each foot were insensate Peripheral insensate neuropathy was defined as the presence of one or more insensate areas Its prevalence was nearly twice as
high among persons with diabetes 212 as among those without diabetes 115; p 0001 Men 162 had 17 times the prevalence of peripheral insensate neuropathy as did women 94, but the difference was not significant after adjustment for height Greater height was associated with increased peripheral insensate neuropathy prevalence among persons with and without diabetes p 0001 This association was characterized by a sharp increase in prevalence among persons who were taller than 1755 cm Peripheral insensate neuropathy risk was significantly higher among those taller than 1755 cm adjusted odds ratio 23, 95 confidence interval: 15, 35 The authors conclude that body height is an important correlate of peripheral insensate neuropathy This association largely accounts for the difference in peripheral insensate neuropathy prevalence between men and women Height may help health-care providers to identify persons at high risk of peripheral insensate neuropathy aging; body composition; data collection; diabetes mellitus; peripheral nervous system diseases
Abbreviations: A1c, glycated hemoglobin A1c; CI, confidence interval; NHANES, National Health and Nutrition Examination Survey; SE, standard
error
Peripheral insensate neuropathy is common in the middleaged or older adult US population 1 It is one of the most disabling complications of diabetes because of its high incidence and its potential to lead to lower extremity ulceration, deformation, and amputation 2 Early identification of neuropathy, tight glycemic control among people with diabetes, smoking cessation, and other preventive care are considered key public-health strategies against costly foot complications 36 Factors associated with neuropathy include diabetes mellitus, poor glycemic control, male sex, White race, and older age 1, 7, 8
There is also growing, yet still unappreciated evidence that height may be an important and practical predictor of peripheral insensate neuropathy or lower extremity amputation 79 Height may increase the risk of peripheral insensate neuropathy because of increased axon surface exposure to toxins Most studies that have noted a relation of height with peripheral neuropathy or amputation were conducted among persons with diabetes mellitus 7, 1015, and few population-based studies have been conducted 13 It is unknown whether there is a threshold in the association between height
and risk for peripheral insensate neuropathy in the general population
Reprint requests to Dr Yiling J Cheng, Information Technology Support Contract, Division of Diabetes Translation, Centers for Disease Control and Prevention, 4770 Buford Highway, NE, Mailstop K-10, Atlanta, GA 30341 e-mail: ycc1@cdcgov
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2 Cheng et al
As the first nationally representative epidemiologic survey to include an assessment of peripheral insensate neuropathy based on monofilament testing, the 19992002 US National Health and Nutrition Examination Survey NHANES allowed us to explore the relation between body height and peripheral insensate neuropathy among persons with and without diabetes mellitus, while accounting for various confounders or effect modifiers In particular, it allowed us to examine whether there are threshold effects in the association between height and peripheral insensate neuropathy and whether any association is modified by the effects of factors such as diabetes status, sex, and race/ ethnicity
crimination of sensation by the examinee Impaired sensation was quantified by the total number of insensate areas for both feet range: 06, and peripheral insensate neuropathy was
defined as one or more insensate area Previous studies have found the presence of one or more insensate areas to be highly predictive of ulcers and amputation and to have moderately high sensitivity 85 percent and specificity 80 percent based on vibration testing and ulcer history 1720
Diabetes and other measurements
MATERIALS AND METHODS
The NHANES is a nationally representative survey of the US civilian noninstitutionalized population conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention 16 Since 1999, NHANES staff have conducted interviews and performed physical examinations on a continuous basis Participants are interviewed in their homes about their health history, health behaviors, and risk factors and subsequently undergo the physical examination at a mobile examination center The procedures to select the sample and conduct the interview and examination have been described elsewhere 16 Informed consent is obtained from all participants, and the protocol has been approved by the institutional review board of the National Center for Health Statistics This report is based on 4 years of NHANES data from 1999 to 2002 Of 6,668
persons aged 40 or more years who answered the diabetes questionnaire during this time, 5,848 878 percent also underwent the health examination, which included anthropometry Of this sample, 619 106 percent did not undergo the peripheral insensate neuropathy examination because they refused or had a physical/health limitation, because of technical problems and errors in measurement, or because of some other unspecified reason; 86 more were excluded from our analysis because they had no height measurement Thus, peripheral insensate neuropathy examination results and height were available for 5,229 subjects aged 40 or more years
Assessment of peripheral insensate neuropathy
Peripheral insensate neuropathy was assessed by testing subjects foot sensation with a standardized 507-gauge 10-g force Semmes-Weinstein nylon monofilament according to a standard protocol 1 Health technicians applied pressure with the monofilament at three sites on the bottom of each of the subjects feet plantar, first metatarsal head; plantar, fifth metatarsal head; and plantar, hallux ie, a total of six sites They applied the monofilament until it buckled and then held it for another second A site was
considered insensate if there were 1 two incorrect responses, 2 two unable to determine responses, or 3 one incorrect and one unable to determine response for a site The sites are tested in a nonsequential order to allow for better dis-
Participants responses to the questionnaires were used to categorize them by their self-reported physician-diagnosed diabetes status, duration of history of diabetes no diabetes; diabetes 7 years; diabetes 7 years, measured high blood pressure yes, no, and age years, race/ethnicity nonHispanic White vs others, education less than high school vs high school education or more, current smoking status yes, no, and current alcohol consumption status none; mild: 1 drink/week; moderate: 17 drinks/week; and heavy: 8 drinks/week Participants height cm and weight kg were measured with a standard protocol, and they were divided into four quartile groups by height 161, 1611679, 1681759, and 176 cm and by weight 67, 67789, 79919, and 92 kg Their body mass index was calculated as weight kg/height m2, and they were divided into three groups on the basis of their body mass index: normal 25, overweight 25299, and obese 30 The glycated hemoglobin A1c A1c percentage
was used to measure participants glycemic control They were divided into two sets of four quartiles on the basis of their A1c percentage levels: 61, 6271, 7283, and 84 percent for those with diabetes and 51, 5152, 5354, and 55 percent for those without diabetes Detailed descriptions about blood collection and processing are provided in the NHANES Laboratory/Medical Technologists Procedures Manual 21 The self-reported average level of physical activity, including work, housework if a homemaker, and going to and attending classes if a student, each day had been divided into three levels: mainly sit, walk a lot, and carry loads or climb often Participants blood pressure was measured according to standard protocol involving three and sometimes four systolic and diastolic blood pressure measurements taken with a mercury sphygmomanometer in the mobile examination center on all eligible individuals 21 We defined high blood pressure as an average systolic blood pressure of 140 or more mmHg or an average diastolic blood pressure of 90 or more mmHg
Statistical analyses
In our primary analyses, we estimated the prevalence of peripheral insensate neuropathy in the overall noninstitutionalized
US population aged 40 or more years and within several subgroups We used SAS, version 91, software SAS Institute, Inc, Cary, North Carolina for data
Body Height and Peripheral Insensate Neuropathy
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TABLE 1 Characteristics of the estimated 1067 million noninstitutionalized US residents aged 40 or more years, by self-reported diabetes status, based on projections from data of the National Health and Nutrition Examination Survey, 19992002
With diabetes mellitus n 683, estimated US 101 million population No or mean SE Without diabetes mellitus n 4,546, estimated US 966 million population No or mean SE
Variables
Height, cm 161 quartile 1 1611679 quartile 2 1681759 quartile 3 176 quartile 4 Weight, kg 67 quartile 1 67789 quartile 2 79919 quartile 3 92 quartile 4 Body mass index, kg/m2 25 normal 25299 overweight 30 obese Age, years mean Sex, men Race/ethnicity, White Education, less than high school Current smoking, yes Alcohol, drinks/week 1 17 8 Physical activity Mainly sit Walk a lot Carry loads or climb often Glycated hemoglobin A1c Lowest quartile Second quartile Third quartile Highest quartile High blood pressure Duration of diabetes mellitus, years 0169 7
Peripheral insensate neuropathy SE, standard error 301 382 185 464 32 536 32 250 20 668 112 06 133 172 174 179 265 211 23 268 19 258 22 263 21 364 23 580 788 1,029 2,016 1,479 173 17 210 07 229 06 388 19 272 11 254 345 83 359 32 502 33 139 18 1,109 2,540 887 254 09 529 09 218 10 584 55 32 850 23 101 20 49 13 2,969 918 574 622 18 231 15 148 08 114 258 308 683 351 257 331 100 179 25 326 22 495 30 613 06 519 24 636 35 348 28 171 21 1,353 1,763 1,418 4,546 2,263 2,549 1,522 886 318 12 378 09 304 12 560 03 469 07 795 15 205 11 203 09 120 176 176 208 182 21 195 22 239 21 384 25 1,222 1,232 1,127 953 262 09 255 09 252 07 232 10 231 158 181 113 302 26 238 26 265 21 195 25 1,337 1,135 1,136 938 249 06 253 07 253 07 246 07
management and manipulation Analyses were conducted with SUDAAN, version 901, software SUDAAN Statistical Software Center, Research Triangle Park, North Carolina to take into account the complex sampling design
and to obtain representative estimates For each of the primary outcomes, we used the largest sample size available to estimate prevalence We computed 95 percent confidence intervals using the critical value for a t distribution with
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FIGURE 1 Age-
and race-adjusted population prevalence of peripheral insensate neuropathy by 2-cm height increments among noninstitutionalized US residents aged 40 or more years, National Health and Nutrition Examination Survey, 19992002
the appropriate number of degrees of freedom for each subgroup, and we used logistic regression to calculate ageand race-adjusted and other multivariate-adjusted prevalence estimators predictive marginals, as well as the odds ratio with 95 percent confidence interval We applied a joinpoint regression model and used the permutation test to determine whether there was a change of linear trend for age- and race-adjusted prevalences of peripheral insensate neuropathy by height 22 The joinpoint and 95 percent confidence interval were calculated by Joinpoint, version 30, freeware 23 We also assessed the significance of interaction terms between height and other variables and tested statistical hypotheses at the 005 level
RESULTS
Persons with diabetes are older than persons without diabetes p 0001 The means of height and weight were 1670 cm standard error SE: 06 and 878 kg SE: 13 for persons with diabetes and 1685 cm SE: 13 and 799 kg SE: 05 for persons without
diabetes Table 1 shows characteristics of the sample by diabetes status weighted to the US population Among the 5,229 persons representing a US population of 107 million 905 percent noninstitutionalized civilians aged 40 or more years, 125 percent had peripheral insensate neuropathy 155 percent among men and 99 percent among women; p 0001 The age- and raceadjusted prevalence of peripheral insensate neuropathy was 212 percent among persons with diabetes and 115 percent among persons without diabetes p 0001 Compared with persons without diabetes, those with diabetes were,
on average, shorter, heavier, and less likely to be nonHispanic White, not to have finished high school, or to smoke or drink Persons with diabetes also had a higher prevalence of high blood pressure than did persons without diabetes The mean duration of diabetes among persons with diabetes was 118 years; the median duration was 7 years with an interquartile range of 215 years Peripheral insensate neuropathy prevalence increased with age and was higher among men than women in all age groups The prevalence of peripheral insensate neuropathy among persons aged 4044 years was 79 percent for men and 30 percent for
women, and it increased linearly to 222 percent and 126 percent among those aged 6569 years, reaching 455 percent and 329 percent, respectively, among those aged 85 or more years The mean height was 176 cm among men and 161 cm among women The median and interquartile range of body height for men and women were 176 171181 and 162 157166 cm, respectively; 78 percent of men had height greater than 170 cm, while only 10 percent of women had height greater than 170 cm For our analyses of both sexes together, we chose the second quartile of body height as the referent quartile, because it provided the greatest amount of overlap of the height distributions among men and women As shown in figure 1, the age- and race-adjusted prevalence of peripheral insensate neuropathy was fairly constant among men 1755 cm 5 feet, 9 inches or shorter and among women 1715 cm 5 feet, 8 inches or shorter but increased sharply with height The joinpoint regression detected a linear threshold for men of 1755 cm 95 percent confidence interval CI: 1615, 1815; however, it did not find any statistically significant threshold for women, probably
Body Height and Peripheral Insensate Neuropathy
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TABLE 2
Multivariate-adjusted peripheral insensate neuropathy prevalence among noninstitutionalized US residents aged 40 or more years, with and without diabetes, based on data from the National Health and Nutrition Examination Survey, 19992002
With diabetes mellitus Peripheral insensate neuropathy SEy for categorical variable Odds ratio 95 confidence interval Without diabetes mellitus Peripheral insensate neuropathy SE for categorical variable Odds ratio 95 confidence interval
Height, cm 161 quartile 1 1611679 quartile 2 1681759 quartile 3 176 quartile 4 Weight, kg 67 quartile 1 67789 quartile 2 79919 quartile 3 92 quartile 4 Sex Men Women Race/ethnicity White Non-White Education Less than high school High school or more Smoking Yes No Alcohol drinks/week 1 17 8 Physical activity Mainly sit Walk a lot Carry loads or climb often Glycated hemoglobin A1c Low 
est quartile Second quartile Third quartile Highest quartile Duration of diabetes mellitus, years 0169 7 High blood pressure Yes No Age, years b 245 39 248 27 0047 0012 10 10 10 05, 19 Referent 10, 11 109 10 110 08 0063 0006 10 10 11 08, 13 Referent 11, 12 163 26 314 30 10 25 Referent 14, 45 198 51 217 33 236 39 325 44 10 11 13 21
Referent 05, 27 05, 32 09, 52 115 23 115 15 111 11 106 07 10 10 10 09 Referent 06, 18 05, 18 05, 16 257 31 216 23 336 84 10 08 15 Referent 05, 12 06, 42 108 09 110 07 113 11 10 10 11 Referent 08, 13 08, 13 251 19 216 64 242 90 13 10 12 05, 30 Referent 03, 54 116 08 93 12 113 13 13 10 13 09, 18 Referent 09, 19 222 58 251 19 08 10 04, 18 Referent 123 17 107 07 12 10 08, 18 Referent 262 40 238 27 12 10 06, 22 Referent 139 16 102 07 15 10 11, 21 Referent 237 31 265 25 10 12 Referent 07, 21 104 07 141 13 10 15 Referent 11, 19 252 35 241 34 11 10 05, 22 Referent 111 08 108 10 10 10 08, 14 Referent 242 50 193 38 223 33 295 42 10 07 09 14 Referent 03, 16 04, 18 06, 32 76 07 103 11 109 10 156 15 10 14 15 24 Referent 11, 19 11, 20 18, 31 252 56 174 39 228 42 363 65 17 10 15 31 07, 42 Referent 06, 36 11, 88 80 10 93 11 98 12 175 19 08 10 11 22 06, 11 Referent 07, 17 15, 33
Variables included in full models: height, weight, sex, race/ethnicity, education, smoking, alcohol, average level of physical activity, glycated hemoglobin A1c, duration of diabetes, high blood pressure, and age y SE, standard error
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FIGURE 2 Adjusted estimated population prevalence of peripheral insensate
neuropathy among US residents aged 40 or more years, by diabetes status and height quartiles, based on data from the National Health and Nutrition Examination Survey, 19992002 T-shaped bars, 95 confidence intervals; non-DM, persons without diabetes; DM, persons with diabetes
because there were not enough women 170 cm tall or taller in the study sample The threshold of peripheral insensate neuropathy prevalence by height for the entire study population was also 1755 cm 95 percent CI: 163, 177, similar to that for men The age- and race-adjusted prevalence of peripheral insensate neuropathy was 114 percent among men 1755 cm or shorter and 205 percent among men 176 cm or taller p 0001, while the adjusted prevalence of peripheral insensate neuropathy among women was 98 percent among those 1715 cm or shorter and 119 percent among those taller than 1715 cm p 0500 for only 136 women As shown in table 2, we found similar associations between height and peripheral insensate neuropathy across strata of diabetes status Those 176 cm or taller had almost twice the age- and race-adjusted peripheral insensate neuropathy prevalence 191 percent as those between 161 and 168 cm in height 103
percent Among persons with diabetes, duration of diabetes was a strong predictor of peripheral insensate neuropathy risk, while among persons without diabetes, heavy weight, non-White race, and not having finished high school were each associated with higher risk for peripheral insensate neuropathy In a separated multivariate logistic model without height and weight, the odds ratios of peripheral insensate neuropathy among persons with diabetes were 10 referent, 12 95 percent CI: 06, 23, and 15 95 percent CI: 08, 29 for normal, overweight, and obese persons, respectively, while the odds ratios of peripheral insensate neuropathy among persons
without diabetes were 10 referent, 14 95 percent CI: 11, 19, and 18 95 percent CI: 13, 15 by the same three body mass index groups Adjusted total prevalences by height or adjusted prevalences by height and diabetes status adjusted for height, weight, age, sex, race/ethnicity, education, smoking, alcohol consumption, average level of physical activity each day, diabetes and duration of diabetes, and blood pressure status are displayed in figure 2 For the entire population, peripheral insensate neuropathy risk was significantly higher among
persons 176 cm or taller odds ratio 23, 95 percent CI: 15, 35 than among persons 1611679 cm Adjusted peripheral insensate neuropathy prevalence rates were higher among persons with diabetes than among those without diabetes odds ratio 18, 95 percent CI: 13, 25 from another multivariate logistic model Among persons with diabetes, the likelihood of peripheral insensate neuropathy was increased among persons who were either taller than 1755 cm or had been diagnosed with diabetes for at least 7 years We found no statistically significant interactions between subjects height and any of the other potential risk factors we examined, including weight, age, sex, race/ethnicity, educational level, smoking status, alcohol consumption status, A1c percentage, and diabetes status and duration In addition, among persons with diabetes, p values of the interaction terms of height and diabetes duration, as well as height and A1c percentage, were 0428 and 0450, respectively
Body Height and Peripheral Insensate Neuropathy
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When we compared the characteristics of potential study subjects who were excluded from analysis because of missing peripheral insensate neuropathy or height data with those
of the study subjects with peripheral insensate neuropathy and height data, we found that those who were excluded were, on average, older 60 vs 57 years, had a higher prevalence of diabetes 145 percent vs 94 percent, had a higher mean A1c level 58 vs 56 percent, and were less likely to be male 413 percent vs 474 percent or non-Hispanic White 638 percent vs 780 percent
DISCUSSION
In this nationally representative study, we confirmed earlier findings that peripheral insensate neuropathy is common and that it is associated with diabetes, age, and male sex We also found that being tall was a similarly important risk factor and that this association between height and peripheral insensate neuropathy prevalence probably explains the difference in prevalence between men and women Our analysis of both sexes together found that the age- and race-adjusted peripheral insensate neuropathy prevalence among persons in the highest quartile of height was 23 times higher than that among those in the second quartile the quartile of height distribution that included adequate numbers of both men and women Of note, this association was stronger than the association between A1c percentage levels and
peripheral insensate neuropathy prevalence among persons with diabetes Our findings suggest that height, particularly when considered in combination with current recommendations for screening among persons with diabetes, may help to identify persons at relatively high risk for peripheral insensate neuropathy We estimated that 656 percent of noninstitutionalized US adults aged 40 or more years about 66 million people were at high risk for peripheral insensate neuropathy because they were taller than 1755 cm or had diagnosed diabetes for more than 7 years These findings may be useful in the development of risk-stratification algorithms to focus peripheral insensate neuropathy screening on persons at high risk for the condition The pathogenesis of the relation between height and the prevalence of peripheral insensate neuropathy remains unclear It seems unlikely that increased stature has a generalized adverse effect on peripheral nerve function since sensorineural hearing loss, another form of peripheral deficit, by contrast, is associated with reduced stature 24 Instead, the association of height with peripheral insensate neuropathy may be specific to long nerves of the body
Increased nerve length is associated with greater axon surface area, and any localized injury to an axon may impair the overall conduction properties of the nerve Therefore, persons with longer nerves and thus a larger total axon surface area may be at greater risk for neurologic impairment when exposed to otherwise equivalent hazards eg, constant concentration of advanced glycation end products Greater leg length might also be associated with a prolonged time requirement for the complete regeneration of any injured nerve 25; this would tend to increase the duration of pe-
ripheral insensate neuropathy, thus increasing the prevalence of peripheral insensate neuropathy in the population Alternatively, the association of height with peripheral insensate neuropathy might be related to the increased hydrostatic pressure experienced in the feet of tall persons when they stand up Peripheral insensate neuropathy would occur more often if aging or prolonged diabetes is linked to a loss of compensatory responses to large pressure changes in small blood vessels Yet another alternative explanation could be related to greater skin thickness or other protective characteristics on the soles of
tall people This would be consistent with our finding that peripheral insensate neuropathy prevalence is related to weight among nondiabetic persons even after adjustment for height and other covariates table 2 In addition, Harris et al 26 showed that height was not associated with extremity symptomatic neuropathy Sorensen et al 7 demonstrated that only 117 percent of persons with lower extremity insensate neuropathy defined by vibration perception threshold had lower foot painful neuropathy In this latter study, height was related to insensate neuropathy but not related to painful neuropathy These data suggest that sensate neuropathy may be different from insensate neuropathy and perhaps less associated with structural nerve damage There were limitations to our study First, because NHANES does not collect information from people in nursing homes or other similar institutions, our subjects were not representative of the entire older US population Second, duration of diabetes as measured in this study did not reflect the true duration of the disease but the time since diagnosis, and actual diabetes onset might precede its diagnosis by several years 27 Third, there were not enough
women taller than 170 cm to reliably determine the peripheral insensate neuropathy prevalence among them Fourth, because this was a cross-sectional study, we could not determine whether the association between modifiable risk factors and the risk of peripheral insensate neuropathy was a cause-effect association This may explain why we did not find smoking to be associated with an increased risk of peripheral insensate neuropathy as the authors of a previous study did 8 Fifth, although persons with significant calluses had been excluded from the study, NHANES did not have detailed information about calluses Finally, we used monofilament testing to determine the peripheral insensate neuropathy status of study subjects when electrophysiologic, nerve conduction, or skin biopsy studies could have produced more accurate diagnostic data; however, in epidemiologic studies, monofilament testing is still an improvement over the use of symptom questionnaires in terms of sensitivity, specificity, and capacity to predict adverse outcomes 1719, 28 In conclusion, we found that body height is a risk factor of peripheral insensate neuropathy, that the difference in height between men and women may
explain much of the difference in peripheral insensate neuropathy prevalence between them, and that peripheral insensate neuropathy prevalence increases sharply with height at a height threshold of around 1755 cm Height may help health-care providers identify persons who require more intensive neuropathic
8 Cheng et al
screening because of their higher risk for peripheral insensate neuropathy
ACKNOWLEDGMENTS
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency Conflict of interest: none declared
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Care 1999;22:598602 20 Abbott CA, Carrington AL, Ashe H, et al The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort Diabet Med 2002;19:37784 21 NHANES laboratory/medical technologists procedures manual Hyattsville, MD: National Center for Health Statistics, 2005 22 Kim HJ, Fay MP, Feuer EJ, et al Permutation tests for joinpoint regression with applications to cancer rates Stat Med 2000;19:33551 23 Statistical Research and Applications Branch, Division of Cancer Control and Population Sciences, National Cancer Institute Joinpoint freeware, version 30 Bethesda, MD: National Cancer Institute, 2005 24 Barrenas ML, Jonsson B, Tuvemo T, et al High risk of sensorineural hearing loss in men born small for gestational age with and without obesity or height catch-up growth: a prospective longitudinal register study on birth size in 245,000 Swedish conscripts J Clin Endocrinol Metab 2005; 90:44526 25 Polydefkis M, Hauer P, Sheth S, et al The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy Brain 2004;127:160615 26 Harris
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