Abstract
Background: Evidence suggests that nigrostriatal system disorders are associated with PD and adiposity. Whether patterns of adiposity coexist or predate clinical PD is unknown. This report examines the relation between midlife adiposity and the risk of PD.
Methods: Measurement of adiposity occurred from 1965 to 1968 in 7,990 men in the Honolulu Heart Program (aged 45 to 68 years and without PD). Adiposity measures included body mass index (BMI), subscapular skinfold thickness (SSF), and triceps skinfold thickness (TSF). Follow-up for incident PD occurred over a 30-year period.
Results: During the course of follow-up, PD was observed in 137 men. Among the measures of adiposity, age-adjusted incidence of PD increased threefold from 3.7/10,000 person-years in the bottom quartile of TSF (1 to 5 mm) to 11.1/10,000 person-years in the top quartile (11 to 32 mm, p < 0.001). Effects of TSF on PD were independent of cigarette smoking, coffee consumption, physical activity, daily caloric and fat intake, and the other measures of adiposity (p < 0.001). Whereas rates of PD were lowest in the bottom quartile of BMI and SSF vs higher quartiles, associations with PD were weaker than they were for TSF. The effect of TSF on clinical onset before age 65 years was similar to the effect that was observed in later life.
Conclusions: Increased triceps skinfold thickness measured in midlife is associated with an elevated risk of future PD. Whether patterns of adiposity reflect a unique metabolic pathology in individuals at a high risk of PD warrants further study.
The cardinal signs of PD are due in large part to the loss of dopamine-producing neurons in the pars compacta region of the substantia nigra.1 Nerve cell loss in other regions of the brain, including influences on the autonomic nervous system, is also known to occur.1-7⇓⇓⇓⇓⇓⇓ Evidence for an effect of complex nervous system interactions involving autonomic dysfunction on appetite regulation and energy metabolism,8 as well as recent observations that obesity in humans is related to the depletion of striatal dopamine receptor availability,9 suggests that nigrostriatal system disorders are associated with PD and adiposity. Whether these pathologic processes coexist or whether characteristic patterns of adiposity can predate clinical PD and its early motor symptoms is unknown. Such processes could have associations with specific forms of obesity and contribute to the complexity and heterogeneity in body fat among individuals and to its wide variation in response to exercise, diet, and other interventions. The purpose of this report is to examine the association between measures of adiposity observed in middle-adulthood and the future risk of PD based on 30 years of follow-up of a cohort of asymptomatic men enrolled in the Honolulu Heart Program.
Materials and methods.
Study sample.
From 1965 to 1968, the Honolulu Heart Program began following 8,006 men of Japanese ancestry living on the island of Oahu, Hawaii, for the development of cardiovascular disease.10-12⇓⇓ At the time of study enrollment, subjects were aged 45 to 68 years. Initial screening consisted of a baseline physical examination and documentation of cardiac and neurologic conditions to identify prevalent cases of cardiovascular disease. Procedures were in accordance with institutional guidelines and approved by an institutional review committee. Informed consent was obtained from the study participants.
Since the beginning of the Honolulu Heart Program, surviving members participated in repeat examinations and were tracked for morbidity and mortality outcomes through a comprehensive system of surveillance that included a review of all hospital discharges, death certificates, and autopsy records. For this report, follow-up for incident PD began at the time of study inception (1965 through 1968). After excluding 14 men with missing measures of adiposity and two men with prevalent PD, 7,990 remained available for follow-up.
Measurement of adiposity and confounding information.
At the time when follow-up began, body mass index (BMI) was used as a standard measure of overall adiposity (weight in kg/height in m2). Measures of central and peripheral adiposity included subscapular skinfold thickness (SSF) and triceps skinfold thickness (TSF). For both SSF and TSF, skinfold thicknesses were recorded to the nearest millimeter on the left side in the standing position using Lange calipers (Cambridge Instruments). Measurement of SSF was taken 4 cm below the angle of the scapula. For TSF, arms hung vertically with muscles relaxed while measurements were taken over the triceps muscle midway between the axilla and the elbow.
Other confounding information observed at the time of study enrollment and known to be related to PD included age, pack-years of cigarette smoking, and intake of coffee.13,14⇓ Data on the intake of caloric and dietary fat were also collected. Information on coffee consumption and daily caloric and fat intake was obtained by a dietitian based on 24-hour dietary recall methods and validated against 7-day diet records in a subset of the original cohort.15 Assessment of physical activity was also made through the measurement of a physical activity index to quantify overall metabolic output during a typical 24-hour period.16-19⇓⇓⇓ Low levels of the physical activity index have been shown to be associated with an increased risk of coronary heart disease and stroke.16-19⇓⇓⇓
PD case finding and diagnosis.
For this report, 30 years of follow-up data were available on incident PD after collection of information on adiposity (1965 through 1968). Before 1991, cases of PD were identified through a review of all hospital records of study participants for new and preexisting diagnoses of PD, an ongoing review of all Hawaii death certificates, and a review of medical records at the offices of local neurologists for all cohort members suspected to have PD.
After 1991, study participants were screened for PD at examinations that occurred from 1991 to 1993. During this time, all subjects were questioned about a diagnosis of PD and the use of PD medications by a structured interview. Study participants received further screening by a technician trained to recognize the clinical signs of parkinsonism (including gait disturbance, tremor, and bradykinesia). Those with a history or sign of parkinsonism were referred to a study neurologist who administered standardized questions about symptoms and the onset of parkinsonism, previous diagnoses, and medication use, followed by a comprehensive and standardized neurologic examination. A diagnosis of PD was made by the study neurologists according to published criteria without access to the risk factor data examined in this report.20 These required that the subject have the following: 1) parkinsonism (e.g., bradykinesia or resting tremor combined with rigidity or postural reflex impairment); 2) a progressive disorder; 3) any two of a marked response to levodopa, asymmetry of signs, asymmetry at onset, or initial onset tremor; and 4) absence of any etiology known to cause similar features. Cases of parkinsonism related to progressive supranuclear palsy, multisystem atrophy, cerebrovascular disease, drug-induced parkinsonism, postencephalitic parkinsonism, or post-traumatic parkinsonism were not included among the cases of PD. During repeat examinations that were given from 1994 to 1996 and from 1996 to 1998, subjects were again asked about a diagnosis of PD and the use of PD medications. Medical records were further reviewed by the study neurologists who applied the same published criteria used earlier in making a diagnosis of PD.20 Further description of the diagnosis of PD is described elsewhere.13,21⇓
Statistical methods.
Crude and age-adjusted incidence rates of PD in person-years were estimated according to ranges of BMI, SSF, and TSF based on the 30 years of follow-up in the 7,990 men who were examined from 1965 through 1968.22 Age-adjusted risk factors across approximate quartiles of each adiposity measure were also derived.22 To test for an independent effect of BMI, SSF, and TSF on the risk of PD, proportional hazards regression models were examined.23 Adjustments were made for age, pack-years of cigarette smoking, coffee consumption, daily caloric and fat intake, and the other measures of adiposity. While BMI, SSF, and TSF were modeled as continuous risk factors, relative risks of PD (and 95% CI) were also estimated comparing the risk of PD between men in each of the top three quartiles of an adiposity measure to those in the bottom quartile. All reported p values were based on two-sided tests of significance.
Results.
The average age at study enrollment (1965 through 1968) of the 7,990 men was 54 years (range, 45 to 68). During the 30 years of follow-up, 137 developed PD. The average age at the time of diagnosis was 73 years (range, 54 to 89) and the average time to a diagnosis was 19 years (range, 2 to 30).
Incidence of PD by quartile of BMI, SSF, and TSF is shown in table 1. For each adiposity measure, age-adjusted incidence of PD was lowest in the first quartile as compared to quartiles that were higher. Differences in the risk of PD across the top three quartiles of BMI and SSF were not apparent. In contrast, the age-adjusted incidence of PD rose consistently from 3.7/10,000 person-years in men in the bottom quartile of TSF (1 to 5 mm) to a threefold excess (11.1/10,000 person-years) in those in the top quartile (11 to 32 mm, p < 0.001).
Table 1Incidence of PD by quartile of BMI, SSF, and TSF measured at the time of study inception (1965–1968)
Associations between potential factors that could confound the relation between an adiposity measure and the risk of PD are described in table 2. Mean ages and age-adjusted covariates that were measured at the time of study enrollment are provided across the quartiles of BMI. Comparisons across quartiles of SSF and TSF were similar.
Table 2Average age and age-adjusted covariates according to quartile of BMI measured at the time of study inception (1965–1968)
Among the factors, age, pack-years of cigarette smoking, the percent of men who were current smokers, and the physical activity index declined with increasing BMI (p < 0.05). The percent of men who were past smokers increased with BMI (p < 0.001). There was no clear relation between the daily intake of coffee, calories, and fat across the ranges of BMI. As expected, there was a positive association between BMI and the other adiposity measures (p < 0.001).
After adjusting for the possible confounding effect of these other factors, only the association between TSF and PD remained significant. Table 3 provides the results of this latter finding. After adjustment for age, pack-years of smoking, coffee consumption, physical activity, and daily caloric and fat intake (column A), the relative risk of PD increased from 1.5 to 2.5 for men in the second to top quartile of TSF as compared to those in the first quartile. As a continuous risk factor, the rise in PD incidence with increasing TSF was significant (p < 0.001).
Table 3Estimated risk factor–adjusted relative risk of PD in men in the top three quartiles of TSF as compared to men in the 1st quartile
To help determine if the effect of TSF on the risk of PD could be independently attributed to the peripheral location of body fat, additional adjustments were made for BMI and SSF (markers of overall and central adiposity). As seen in column B of table 3, findings suggest that the effect of TSF on PD is independent of the other adiposity measures. The increase in the observed relative risks (column B) as compared with when the effects of BMI and SSF were ignored (column A) is largely due to a small excess of PD in men with an elevated TSF who also had low levels of BMI and SSF. Tests for interaction effects between the adiposity measures on the risk of PD, however, were not significant.
The figure (top panel) further describes the association between TSF and the age-adjusted incidence of early and late PD onset (<65 and ≥65 years of age). Overall, early onset of PD occurred in 19 men (2.3/10,000 person-years), whereas late onset occurred in 118 men (10.7/10,000 person-years). Although the number of early onset cases is small, risk comparisons among the quartiles of TSF were not appreciably different from those made for the later-onset cases. The association between TSF and PD was also not significantly related to the time elapsed from the measurement of TSF to the diagnosis of PD (see the figure, bottom panel). In the first 15 years of follow-up, 42 men were diagnosed with PD (3.7/10,000 person-years), whereas 95 cases were diagnosed in the second 15 years of follow-up (11.9/10,000 person-years). As with early- and late-onset PD, effects of TSF on the risk of PD were similar for diagnoses that occurred during each 15 years of follow-up. Similar findings were also observed within other periods of follow-up.
Figure. Age-adjusted incidence of early and late PD onset (<65 and ≥65 years of age) and the incidence of PD in the first and second 15 years of follow-up according to quartile of triceps skinfold thickness (TSF) measured at the time of study inception (1965 through 1968). p Values represent a test for trend based on modeling TSF as a continuous variable.
Discussion.
Although loss in body fat is common in patients with clinical PD,24,25⇓ reported findings have been limited to cross-sectional and case-control studies with uncertain recall and timing of anthropometric histories. Rarely are different adiposity measures (BMI, SSF, and TSF) available for the assessment of their effects on future disease. We are not aware of another study that has been able to prospectively examine the association between midlife adiposity and the future risk of PD. A major strength of the current report also includes the measurement of adiposity following a standardized protocol well before the development of PD. Because subjects did not have PD when follow-up began, effects of medication for PD on patterns of adiposity are also absent.
These findings suggest that adiposity in middle-adulthood is related to an increased risk of PD in later life. Although PD risk was consistently less in men in the bottom vs higher quartiles of each adiposity measure, associations were strongest for TSF. Here, risk of PD increased consistently with increasing TSF levels after accounting for other risk factors effects, including the simultaneous control for BMI and SSF. In addition, associations were similar for early and late onset of PD and for diagnoses made 15 years beyond the time of adiposity measurement.
The relation between TSF and PD also seemed to persist for repeated measurements that were made from 1991 through 1993, although statistical testing may be limited because of reductions in available follow-up. During the later examination, measurements of BMI, SSF, and TSF were available in 3,512 surviving members of the original cohort aged 71 to 93 years without PD. Among this group, TSF tended to increase from baseline (1965 through 1968) values by an average of 2.2 ± 4.0 mm, whereas SSF and BMI declined modestly (−0.3 ± 6.7 mm and −0.5 ± 2.6 kg/m2). Although changes in body composition are expected to occur with age, each baseline measure was positively and strongly predictive of the later (1991 through 1993) measure (p < 0.001).
In the remaining years of follow-up, 27 men developed PD (20.3/10,000 person-years). Age-adjusted incidence of PD for men in the top quartile of TSF (12.5 to 34 mm) was 34.3/10,000 person-years vs 16.4/10,000 person-years in those who were leaner (2 to 12 mm). The incidence of PD continued to rise significantly with increasing TSF after adjustment for age, BMI, and SSF (p = 0.013). Relations between the other adiposity measures and PD were positive but not significant. In addition, after controlling for TSF at the time of study enrollment (1965 through 1968), risk of PD rose with increasing TSF as the cohort aged, also independent of the other adiposity measures (p = 0.048).
Explanations for the observed findings in the Honolulu Heart Program are unclear, particularly for the long-term preclinical effects of adiposity on cases of PD that were diagnosed well after the time of study enrollment. Excesses in adiposity could have been the consequence of physical inactivity induced by bradykinesia and undiagnosed early PD, reflecting an insidious pathogenic process with a long latency period of more than 15 years in many instances. Such a long latency period is in contrast to the estimated 3- to 6-year preclinical period based on neuroimaging and neuropathology studies in PD.26,27⇓ Although further explanation is needed, the long interval between recorded measures of adiposity and the diagnosis of PD in our study may provide some insights into the pathogenesis of PD and related histologic changes that begin as early as 25 years of age.28 Whether the mechanisms associated with the long-term preclinical effects observed in the current report are different from those that result in weight loss in patients with clinical PD is unknown.24,25⇓ In the current report, physical activity also had no effect on the risk of PD, nor did it modify the observed relation between PD and the measures of adiposity.
Adipose tissue is also known as an important site of estrogen metabolism.29,30⇓ In light of the suggestion that endogenous estrogen in women may have a neuroprotective effect against PD,31 it might be expected that the risk of PD could be reduced in those who are obese. The neuroprotective effect of estrogen, however, has not been clearly established. Others have found no such effect and further hypothesize that estrogen may be antidopaminergic.32 Even in the presence of a protective effect of estrogen, estrogen levels resulting from excesses in adiposity in men may fail to reach critical levels to allow for the appearance of an inverse relation between body fat and PD. Long-term exposure to estrogen concentrations that are normally seen in premenopausal women may also be required. Estrogen metabolism may further vary according to the location of adipose tissue,30 particularly between peripheral (TSF) and central (SSF) body fat. Whether findings from the Honolulu Heart Program can also apply to women warrants further study.
In addition, extensions to other population segments is also unknown, although the rate of PD described in the current report is in general agreement with rates that have been observed in Europe and the United States.21,33⇓ Nevertheless, men in the Honolulu Heart Program are unique. For example, early childhood experiences were often difficult. Study participants were either immigrants or the progeny of immigrants from Japan who migrated to Hawaii as contract laborers to serve in the sugar and pineapple industries. As a possible consequence of these experiences at an important time of physical development, subjects tended to be smaller than men of similar age in the United States.34
There also exists the possibility that mortality from other causes could have resulted in a poor estimate of the true effect of adiposity on PD, although such an effect is likely to be small. The best description of the true association between TSF and PD might actually appear in the left side of the top panel of the figure (for PD cases diagnosed <65 years). In this instance, competing risks occur too infrequently in this long-lived sample to account for the pattern of association that was observed between TSF and PD. Even within the first 15 years of follow-up, the effect of early mortality from other causes is likely to be modest. Early mortality in the top or bottom quartiles of TSF also does not explain the findings observed in this report. After adjustment for age and the other risk factors, including BMI and SSF, excluding men in the top and bottom quartiles of TSF failed to alter the observed association between TSF and PD (p = 0.0291 and p = 0.007 when men in the top and bottom quartiles were excluded). Duplicate analyses for BMI and SSF also failed to alter the observed associations that these body composition measures have with PD.
Although corroborating data are limited, a recent animal study suggests that the association between adiposity and PD could be due to an increased susceptibility to environmental factors that lead to PD. In transgenic mice with genetically determined obesity, increased vulnerability to the neurotoxicants methamphetamine and kainic acid was associated with a greater decrease in levels of striatal dopamine and tyrosine hydroxylase and to elevated levels of glial fibrillary acidic protein, a sensitive indicator of neuronal damage.35 Body fat may also act as a reservoir for lipid-soluble neurotoxins that selectively damage dopamine-producing neurons in the substantia nigra. Regional differences in fatty tissue turnover and neurotoxin release from these regions may also explain the stronger association of peripheral body adiposity (TSF) to PD as compared to overall (BMI) and central (SSF) adiposity.
Obesity could also be directly linked with derangements in dopaminergic systems that increase the risk of PD. Recently, obesity in humans has been associated with a decrease in dopamine receptor availability in a study using [c-11] raclopride to measure D2 dopamine receptors with PET.9 Increases in appetite and weight have also been associated with drugs that block dopamine D2 receptors,36,37⇓ whereas treatment with levodopa is often associated with weight loss and appetite suppression.38 It is possible that decreased D2 receptors in obese individuals could lead to compensatory increases in dopamine turnover, consequent increases in oxidative metabolites, and eventually, to an increase in oxidative stress and neuronal death.
High caloric and fat intake, including the intake of dietary cholesterol, has also been observed in patients with PD,39,40⇓ although an association between these dietary items (including iron and animal fat) and the future risk of PD was not observed in the Honolulu sample. There also exists the possibility that such effects were not apparent because of the underreporting of dietary intake in subjects who were overweight.41,42⇓ Such underreporting in the current study, however, does not seem to explain the relation that was observed between adiposity and PD because excesses in PD were also observed in the leaner men in the second quartile of each body composition measure as compared to the first quartile (see table 1).
Although clinical implications are difficult to address based on findings from the current report, identifying patterns of adiposity that predate clinical PD could suggest that subtle PD processes have the potential for being recognized before the emergence of motor symptomatology. Combining information on adiposity with other factors, such as a positive family history or early signs of developing movement abnormalities, could have some uses for identifying high-risk individuals for future PD. In light of the evidence that pathologic processes in PD may include effects on adiposity,8,9,36-40⇓⇓⇓⇓⇓⇓ further studies of susceptibility and environmental factors that may increase the risk of PD in individuals with characteristic patterns of adiposity appear to be warranted.
Acknowledgments
Supported by a grant from the United States Department of the Army (DAMD17-98-1-8621), by the NIH (National Institute on Aging Contract N01-AG-4-2149 and grant 1-R01-AG17155-01A1, National Heart, Lung, and Blood Institute Contract N01-HC-05102, and a National Institute of Neurological Disorders and Stroke grant 1-R01-NS41265-01), and by Department of Veterans Affairs medical research funds.
Footnotes
-
The information contained in this article does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred.
- Received April 15, 2002.
- Accepted June 27, 2002.
References
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