Prevalence of Parkinson's disease across North America.

Estimates of the prevalence of Parkinson's disease in North America have varied widely and many estimates are based on small numbers of cases and from small regional subpopulations. We sought to estimate the prevalence of Parkinson's disease in North America by combining data from a multi-study sampling strategy in diverse geographic regions and/or data sources. Five separate cohort studies in California (2), Minnesota (1), Hawaii USA (1), and Ontario, Canada (1) estimated the prevalence of PD from health-care records (3), active ascertainment through facilities, large group, and neurology practices (1), and longitudinal follow-up of a population cohort (1). US Medicare program data provided complementary estimates for the corresponding regions. Using our age- and sex-specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged ≥45 years to be 572 per 100,000 (95% confidence interval 537-614) that there were 680,000 individuals in the US aged ≥45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections. Regional variations in prevalence were also observed in both the project results and the Medicare-based calculations with which they were compared. The estimates generated by the Hawaiian study were lower across age categories. These estimates can guide health-care planning but should be considered minimum estimates. Some heterogeneity exists that remains to be understood.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Marinesco bodies and substantia nigra neuron density in Parkinson's disease.

AIM: Marinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study. METHODS: Data on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007. RESULTS: Marinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein ε4 alleles. CONCLUSIONS: While findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes.

Association of DRD2 and DRD3 polymorphisms with Parkinson's disease in a multiethnic consortium.

OBJECTIVE: To examine genetic associations of polymorphisms in the dopamine receptor D2 (DRD2) and D3 (DRD3) genes with risk of Parkinson's disease (PD). METHODS: The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case-control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression. RESULTS: Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR=1.5, 95% CI 1.0-2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African-Americans, showing an inverse association with PD risk (OR=0.10, 95% CI 0.2-0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR=0.4, 95% CI 0.2-0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. CONCLUSIONS: DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.

BACKGROUND AND PURPOSE: In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. METHODS: Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). CONCLUSION: In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.

Association of fibrinogen with Parkinson disease in elderly Japanese-American men: a prospective study.

BACKGROUND: The purpose of this prospective study was to examine whether fibrinogen level is associated with Parkinson disease (PD) for both prevalent and incident cases. METHODS: The Honolulu Asia-Aging Study is a longitudinal study of Japanese-American men based on the Honolulu Heart Study birth cohort. The original cohort consisted of 8,006 participants with selective service records who were living on the island of Oahu, Hawaii, in 1965. For this analysis, baseline was defined as the 1991-1993 examination (n = 3,845) when men were aged 71-93 years old. Multivariate logistic regression and Cox proportional hazards models were used, adjusting for potential confounders. RESULTS: We identified 61 prevalent cases and 61 incident cases of PD during the follow-up. High fibrinogen level (presence in the top quintile) was associated with higher frequency of PD for both prevalent (OR = 2.07, 95% CI = 1.10-3.88, p = 0.024) and incident cases (HR = 3.05, 95% CI = 1.34-6.97, p = 0.008) among men aged 76-93 years, after adjusting for age, smoking, and low-density lipoprotein cholesterol. CONCLUSIONS: These results suggest high fibrinogen level is associated with increased risk of PD among men over 75 years.

Serum estradiol and risk of stroke in elderly men.

OBJECTIVE: To determine if levels of serum estradiol and testosterone can predict stroke in a population-based sample of elderly men. METHODS: Serum 17beta estradiol and testosterone were measured in 2,197 men aged 71 to 93 years who participated in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent stroke, coronary heart disease, and cancer. Participants were followed to the end of 1998 for thromboembolic and hemorrhagic events. RESULTS: During the course of follow-up, 124 men developed a stroke (9.1/1,000 person-years). After age adjustment, men in the top quintile of serum estradiol (> or =125 pmol/L [34.1 pg/mL]) experienced a twofold excess risk of stroke vs men whose estradiol levels were lower (14.8 vs 7.3/1,000 person-years, p < 0.001). Among the lower quintiles, there were little differences in the risk of stroke. Findings were also significant and comparable for bioavailable estradiol and for thromboembolic and hemorrhagic events. After additional adjustment for hypertension, diabetes, adiposity, cholesterol concentrations, atrial fibrillation, and other characteristics, men in the top quintile of serum estradiol continued to have a higher risk of stroke vs those whose estradiol levels were lower (relative hazards = 2.2; 95% CI = 1.5 to 3.4, p < 0.001). Testosterone was not related to the risk of stroke. CONCLUSIONS: High levels of serum estradiol may be associated with an elevated risk of stroke in elderly men.

Occupational and other risk factors for hand-grip strength: the Honolulu-Asia Aging Study.

BACKGROUND: In certain occupations, including farm work, workers are exposed to hazardous substances, some of which are known to be toxic to the nervous system and may adversely affect muscle strength. Measurement of hand-grip strength may be useful for detecting neurotoxic exposure. METHODS: The authors studied 3522 participants of the Honolulu Heart Program and the Honolulu-Asia Aging Study to determine whether occupational exposures to pesticides, solvents, and metals assessed at exam I (1965-68) are associated with hand-grip strength at exam IV (1991-93) and change in hand-grip strength over 25 years. Correlation, analysis of variance and covariance, and linear regression were used to evaluate the associations. RESULTS: At exam IV, participants ranged in age from 71-93 years; mean hand-grip strength was 39.6 kg at exam I and 30.3 kg at exam IV. Over 25 years, the decline in hand-grip strength was an average of 8-9 kg for all exposures. Hand-grip strength was inversely associated with age and glucose but directly associated with cognitive function, BMI, and haemoglobin level. No other exposures were associated with hand-grip strength. CONCLUSION: This study did not provide evidence that occupational exposure to pesticides, solvents, and metals adversely affected hand-grip strength in this population, but confirmed other important associations with hand-grip strength.

Neuropathologic findings in essential tremor.

Pathologic findings, including cerebellar changes and brainstem Lewy bodies, distinguished 10 essential tremor (ET) cases from 12 controls. Numbers of torpedoes (p = 0.009) and Bergmann glia (p = 0.046) were increased in cases. Six cases (60%) had Lewy bodies vs 2 controls (16.7%) (odds ratio 7.5, 95% CI 1.04 to 54.1; p = 0.035). Four of these six had an atypical distribution of brainstem Lewy bodies. ET may be pathologically heterogeneous.

Excessive daytime sleepiness and subsequent development of Parkinson disease.

OBJECTIVE: To determine if excessive daytime sleepiness (EDS) can predate future Parkinson disease (PD). METHODS: EDS was assessed in 3,078 men aged 71 to 93 years in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent PD and dementia. Follow-up for incident PD was based on three repeat neurologic assessments from 1994 to 2001. RESULTS: During the course of follow-up, 43 men developed PD (19.9/10,000 person-years). After age adjustment, there was more than a threefold excess in the risk of PD in men with EDS vs men without EDS (55.3 vs 17.0/10,000 person-years; odds ratio [OR] = 3.3; 95% CI = 1.4 to 7.0; p = 0.004). Additional adjustment for insomnia, cognitive function, depressed mood, midlife cigarette smoking and coffee drinking, and other factors failed to alter the association between EDS and PD (OR = 2.8; 95% CI = 1.1 to 6.4; p = 0.014). Other sleep related features such as insomnia, daytime napping, early morning grogginess, and frequent nocturnal awakening showed little relation with the risk of PD. CONCLUSIONS: Excessive daytime sleepiness may be associated with an increased risk of developing Parkinson disease.

Consumption of milk and calcium in midlife and the future risk of Parkinson disease.

OBJECTIVE: To examine the relation between milk and calcium intake in midlife and the risk of Parkinson disease (PD). METHODS: Findings are based on dietary intake observed from 1965 to 1968 in 7,504 men ages 45 to 68 in the Honolulu Heart Program. Men were followed for 30 years for incident PD. RESULTS: In the course of follow-up, 128 developed PD (7.1/10,000 person-years). Age-adjusted incidence of PD increased with milk intake from 6.9/10,000 person-years in men who consumed no milk to 14.9/10,000 person-years in men who consumed >16 oz/day (p = 0.017). After further adjustment for dietary and other factors, there was a 2.3-fold excess of PD (95% CI 1.3 to 4.1) in the highest intake group (>16 oz/day) vs those who consumed no milk. The effect of milk consumption on PD was also independent of the intake of calcium. Calcium from dairy and nondairy sources had no apparent relation with the risk of PD. CONCLUSIONS: Findings suggest that milk intake is associated with an increased risk of Parkinson disease. Whether observed effects are mediated through nutrients other than calcium or through neurotoxic contaminants warrants further study.

Memory complaints in nondemented men predict future pathologic diagnosis of Alzheimer disease.

The validity of memory complaints as a predictor of Alzheimer disease (AD) was assessed in 237 Japanese-American men autopsied at ages 74 to 97 years. These men were free of dementia at the time memory complaints were assessed 1 to 11 years earlier. Memory complaints were found to predict the neuropathologic diagnosis of AD after adjusting for age, time to death, education, depression, and cognitive functioning.

Quantification of regional glial fibrillary acidic protein levels in Alzheimer's disease.

OBJECTIVES: Our objectives were to quantify glial fibrillary acidic protein (GFAP) in brains of Alzheimer's disease (AD) cases, and non-AD controls to determine the regions with the most severe gliosis in AD. MATERIAL AND METHODS: In a case control design, we used an enzyme-linked immunosorbent assay (ELISA) to quantify GFAP in frozen brain from four areas of neocortex in 10 AD cases, 10 age-matched controls, and 10 younger controls from the Honolulu-Asia Aging Study autopsy archive. RESULTS: Median age at death was 83.5 years for cases and age-matched controls, and 77 years for younger controls. For the AD cases compared with the age-matched controls, levels of GFAP in occipital (P=0.01), parietal (P=0.028), and temporal lobes (P=0.004) (but not frontal) were significantly higher in the cases. The median GFAP excess in AD cases compared with age matched controls was highest in the temporal lobe. CONCLUSIONS: Regional quantification of GFAP reveals that the glial response is most prominent in the temporal lobe in AD.

Midlife adiposity and the future risk of Parkinson's disease.

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.

Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study.

OBJECTIVE: To investigate the relationship between cerebral amyloid angiopathy (CAA), dementia, and cognitive function in an autopsy sample of 211 Japanese-American men from the population-based Honolulu-Asia Aging Study. METHODS: Starting in 1991, participants were assessed with the Cognitive Abilities Screening Instrument (CASI) and diagnosed with dementia (including subtype) based on published criteria. At autopsy, neuropathologists blinded to clinical data examined brains for neurofibrillary tangles (NFT), neuritic plaques (NP), and a number of vascular pathologies, including CAA. CAA was detected by immunostaining for betaA4 amyloid in parenchymal vessels in the neocortex and semiquantitatively rated. Linear regression models were used to examine the association of CASI score, dementia subtype, and CAA controlling for age at death, time between CASI administration and death, education, NP and NFT counts, infarcts, hemorrhage, and APOE genotype. RESULTS: A total of 44.1% of subjects had CAA in at least one neocortical area. The presence of CAA was associated with higher mean NFT and NP counts and having at least one APOE-epsilon4 allele. The interaction between CAA and AD on the adjusted mean CASI score was significant; compared with nondemented men without CAA, the CASI score was 16.6% lower in men with AD and no CAA and 45.9% lower in men with AD plus CAA. CONCLUSIONS: CAA may contribute to the clinical presentation of dementia by interacting with other neuronal pathologies, leading to more severe cognitive impairment in men with both CAA and AD compared with men with only AD or CAA.

Joint effect of the APOE gene and midlife systolic blood pressure on late-life cognitive impairment: the Honolulu-Asia aging study.

BACKGROUND AND PURPOSE: The aim of this study was to explore the joint effect of the APOE epsilon4 allele and midlife systolic blood pressure (SBP) on the risk for poor cognitive function in late life. METHODS: The study includes 3605 surviving members of the cohort of the Japanese-American men followed prospectively over 26 years (1965-1991) as a part of the Honolulu Heart Program. In 1965 men were aged 45 to 68 years and were living in the island of Oahu, Hawaii. For this study the sample was divided into 4 categories: normal SBP (<160 mm Hg)/No epsilon4, as the reference category; normal SBP/epsilon4; high SBP/no epsilon4; high SBP/epsilon4. The relative risk (RR) of late-life intermediate and poor cognitive function relative to good function was measured by the Cognitive Abilities Screening Instrument (CASI) test. RESULTS: After adjusting for age, education, smoking, alcohol use, and body mass index, the RR for poor cognitive function (CASI <74) compared with good cognitive function (CASI >/=82) in never-treated subjects was 1.3 (95% CI 0.9 to 1.9) for the normal SBP/epsilon4 category, 2.6 (0.7 to 10.0) for the high SBP/no epsilon4, and 13.0 (1.9 to 83.8) for the high SBP/epsilon4. Adjustment for diabetes, prevalent stroke, coronary disease, and ankle-brachial index reduced the RR of poor cognition by 25.5% (RR 13.0 to 10.8) in those with both risk factors. In the treated group, the RR was 1.9 (0.7 to 4.5) for those with both risk factors. CONCLUSIONS: The results suggest that midlife high SBP has a stronger adverse effect on cognitive function in persons with higher genetic susceptibility, but this effect may be modified by antihypertensive treatment.

Resident interpretation of emergency CT scans in the evaluation of acute appendicitis.

PURPOSE: Radiology resident interpretation of computed tomographic (CT) scans at academic institutions often guides management of cases of suspected acute appendicitis in the emergency department. The purpose of this study was to compare resident and faculty interpretation of CT scans obtained for acute appendicitis. MATERIALS AND METHODS: From December 16, 1999, to July 13, 2000, CT was performed in 103 consecutive patients between the hours of 9:00 PM and 8:00 AM who were suspected of having acute appendicitis. The authors compared the residents' preliminary written interpretations with both the final reports written by the faculty and the surgical findings. The faculty interpreting the CT scans were aware of resident interpretations but were not aware that a study was being conducted. RESULTS: The final faculty interpretation and the preliminary resident interpretation were identical in 96 of the 103 patients (93%; 95% confidence interval: 87.8%, 97.2%). In only one patient was a scan originally interpreted as negative interpreted as positive by the faculty member. Clinically, the patient did not have acute appendicitis, and surgery was not perforrmed. CONCLUSION: In the diagnosis of acute appendicitis, image interpretations made by adequately trained radiology residents can be expected to closely match those of the radiology faculty, and the practice of after-hours interpretation of such studies by radiology residents is safe.

Cholesterol and neuropathologic markers of AD: a population-based autopsy study.

OBJECTIVE: To examine the association of plasma cholesterol (total and high-density [HDL] and low-density lipoprotein) levels with neuritic plaques (NP) and neurofibrillary tangles (NFT) in a population-based autopsy series of 218 Japanese American men followed as a part of the Honolulu-Asia Aging Study. METHODS: Cholesterol levels were measured in late life (average age at death 84.6 years) in all subjects (n = 218) and in midlife (20 years before late life) in a subsample (n = 89); for the analyses, levels were categorized into quintiles, with the lowest quintile serving as the reference. Tissue from four areas of neocortex and two areas of hippocampus was prepared with Bielschowsky silver-stained sections and evaluated by one of three neuropathologists who were blinded to clinical information. Diffuse and neuritic plaques and NFT were counted in field areas standardized to 1 mm(2). Fields were selected from areas with the highest numbers of lesions, and the field with the highest count was taken to represent the brain area. RESULTS: After adjusting for age at death, education, APOE allele, dementia, neuropathologic infarction, and blood pressure, a strong linear association was found for increasing late-life HDL cholesterol (HDL-C) levels and an increasing number of neocortical NP (5th versus 1st quintile: count ratio [95% CI] 2.30 [1.05 to 5.06]) and hippocampal (2.63 [1.25 to 5.50]) and neocortical (4.20 [1.73 to 10.16]) NFT. Trends were similar for the midlife HDL-C levels. CONCLUSIONS: The constituents of HDL-C may play a role in the formation of AD pathology, and these processes are reflected in peripheral measures.

Ankle-brachial blood pressure in elderly men and the risk of stroke: the Honolulu Heart Program.

Although low ankle/brachial blood pressure index (ABI) is a marker of generalized atherosclerosis in the elderly, it has not been identified as a risk factor for stroke. The purpose of this report is to examine the relation between ABI and stroke in elderly men. ABI was measured from 1991 to 1993 in 2767 men aged 71 to 93 years in the Honolulu Heart Program without a history of stroke and coronary heart disease. Subjects were followed for 3 to 6 years for fatal and nonfatal thromboembolic and hemorrhagic stroke. During follow-up, there were 91 strokes. There was an age-adjusted 2-fold excess in men with an ABI < 0.9 (6.0%) versus men with an ABI > or = 0.9 (2.9%, P < 0.01). Thromboembolic events occurred in 4.6% of men with an ABI < 0.9 and in 2.0% in those with an ABI > or = 0.9 (P < 0.01). Hemorrhagic stroke was also more frequent in men with a low ABI (< 0.9) versus a higher ABI (1.9 vs. 0.8%, respectively). After adjusting for other factors, the risk of total and thromboembolic strokes increased with declining ABI (P = 0.019 and P = 0.004, respectively). The relation between ABI and stroke was similar and statistically significant in the presence and absence of diabetes and hypertension (P < 0.05). Findings suggest that ABI is inversely related to the incidence of stroke. Simple measurement of ABI in an outpatient setting could be an important tool for assessing the risk of stroke in the elderly.

Frequency of bowel movements and the future risk of Parkinson's disease.

BACKGROUND: Constipation is frequent in PD, although its onset in relation to clinical PD has not been well described. Demonstration that constipation can precede clinical PD could provide important clues to understanding disease progression and etiology. The purpose of this report is to examine the association between the frequency of bowel movements and the future risk of PD. METHODS: Information on the frequency of bowel movements was collected from 1971 to 1974 in 6790 men aged 51 to 75 years without PD in the Honolulu Heart Program. Follow-up for incident PD occurred over a 24-year period. RESULTS: Ninety-six men developed PD an average of 12 years into follow-up. Age-adjusted incidence declined consistently from 18.9/10,000 person-years in men with <1 bowel movement/day to 3.8/10,000 person-years in those with >2/day (p = 0.005). After adjustment for age, pack-years of cigarette smoking, coffee consumption, laxative use, jogging, and the intake of fruits, vegetables, and grains, men with <1 bowel movement/day had a 2.7-fold excess risk of PD versus men with 1/day (95% CI: 1.3, 5.5; p = 0.007). The risk of PD in men with <1 bowel movement/day increased to a 4.1-fold excess when compared with men with 2/day (95% CI: 1.7, 9.6; p = 0.001) and to a 4.5-fold excess versus men with >2/day (95% CI: 1.2, 16.9; p = 0.025). CONCLUSIONS: Findings indicate that infrequent bowel movements are associated with an elevated risk of future PD. Further study is needed to determine whether constipation is part of early PD processes or is a marker of susceptibility or environmental factors that may cause PD.