Caroline M. Tanner

Rotenone, Paraquat, and Parkinson’s Disease

Background Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson’s disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Objectives Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. Methods We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls: one case. Results In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0–2.8] including rotenone (OR = 2.5; 95% CI, 1.3–4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2–3.6), including paraquat (OR = 2.5; 95% CI, 1.4–4.7). Conclusions PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology.

EPIDEMIOLOGY OF PARKINSON'S DISEASE

Additional epidemiologic studies may provide important insights into the etiology of Parkinsons disease. Moreover as the elderly population of Europe and the United States grows, accurate public health planning requires accurate incidence and prevalence estimates. The recent development of a therapy that may slow disease progression (see article by Tetrud elsewhere in this issue) makes early identification and treatment of Parkinsons disease particularly important. Investigations of early markers of Parkinsons disease or markers of disease susceptibility are critical areas of future research, requiring careful collaboration between epidemiologists and laboratory scientists.

Association of olfactory dysfunction with risk for future Parkinson's disease

Although olfactory dysfunction is commonly associated with Parkinsons disease (PD), it is not known whether such dysfunction can predate the onset of clinical PD in a community‐based population. This study examines the association of olfactory dysfunction with future development of PD in Honolulu‐Asia Aging Study cohort members

Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.

Although the causes of Parkinsons disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD–rs6812193 near SCARB2 (, ) and rs11868035 near SREBF1/RAI1 (, )—both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%–7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinsons disease remains to be discovered.

Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease

BACKGROUND The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant. OBJECTIVE To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD. DESIGN, SETTING, AND PARTICIPANTS Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects. MAIN OUTCOME MEASURES Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial. RESULTS The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by alpha-tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with alpha-tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinsons Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinsons Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with alpha-tocopherol. CONCLUSIONS Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.

Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial.

Deprenyl (selegiline) delays the need for levodopa therapy in patients with early Parkinsons disease, but the long‐term benefits of this treatment remain unclear. During 1987 to 1988, 800 patients with early Parkinsons disease were randomized in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial to receive deprenyl, tocopherol, combined treatments, or a placebo and were then placed on active deprenyl (10mg/day). A second, independent randomization was carried out in early 1993 for 368 subjects who by that time had required levodopa and who had consented to continuing the deprenyl treatment (D subjects) or changing to a matching placebo (P subjects) under double‐blind conditions. The first development of wearing off, dyskinesias, or on–off motor fluctuations was the prespecified primary outcome measure. During the average 2‐year follow‐up, there were no differences between the treatment groups with respect to the primary outcome measure (hazard ratio, 0.87; 95% confidence interval, 0.63, 1.19; p = 0.38), withdrawal from the study, death, or adverse events. Although 34% of D subjects developed dyskinesias and only 19% of P subjects did (p = 0.006), only 16% of D subjects developed freezing of gait but 29% of P subjects did (p = 0.0003). Decline in motor performance was less in D subjects than P subjects. Levodopa‐treated Parkinsons disease patients who had been treated with deprenyl for up to 7 years, compared with patients who were changed to a placebo after about 5 years, experienced slower motor decline and were more likely to develop dyskinesias but less likely to develop freezing of gait.

Head injury and Parkinson's disease risk in twins.

Head injury is an inconsistently reported risk factor for Parkinsons disease (PD). Many related variables might confound this association, such as differences in childhood and adolescent lifestyles or genetically determined risk‐taking behaviors. Twin studies circumvent some of these problems, because twins are genetically and environmentally much more similar than typical cases and control subjects.

Environmental factors in the etiology of Parkinson's disease.

Parkinsons disease (PD) has been proposed to result from the interaction of aging and environment in susceptible individuals. Defective metabolism of debrisoquine, inherited as an autosomal recessive, has been associated with this susceptibility. In 35 PD patients and 19 age-matched controls, no significant differences in debrisoquine metabolism were found, although a trend to impaired metabolism was noted in patients with disease onset less than or equal to 40. Foci of PD patients were associated with rural living and well water drinking, or rural living coupled with market gardening or wood pulp mills. In a questionnaire survey, patients with PD onset less than or equal to age 47 were significantly more likely to have lived in rural areas and to have drunk well water than those with onset greater than or equal to age 54 (p less than or equal to 0.01). Because of population mobility in North America, a case-control study designed to test environmental, occupational, dietary and other proposed risk factors for PD was conducted in China, where the population is more stationary and the environment more stable. No significant differences in incidences of head trauma, smoking or childhood measles were found between patients and controls.

Bowel movement frequency in late-life and incidental Lewy bodies

It is not known if constipation is associated with the preclinical phase of Parkinsons disease (PD), often characterized by the presence of incidental Lewy bodies (ILB). Such an association could provide evidence that constipation is an early symptom of PD. The purpose of this report is to examine the association between late‐life bowel movement frequency and ILB. Bowel movement frequency was assessed from 1991 to 1993 in 245 men aged 71 to 93 years in the Honolulu‐Asia Aging Study who later received postmortem examinations. All were without clinical PD and dementia. Brains were examined for ILB in the substantia nigra and locus ceruleus. Among the decedents, 30 men had ILB (12.2%). After age‐adjustment, the percent of brains with ILB declined with increasing bowel movement frequency (P = 0.013). For men with <1, 1, and >1 bowel movement/day, corresponding percents were 24.1, 13.5, and 6.5%. Findings persisted after additional adjustment for time to death, mid‐life pack‐years of smoking and coffee intake, physical activity, and cognitive function. Infrequent bowel movements are associated with ILB. Findings provide evidence that constipation can predate the extrapyramidal signs of PD. Constipation could be one of the earliest markers of the beginning of PD processes.

Occupation and Risk of Parkinsonism: A Multicenter Case-Control Study

BACKGROUND We examined risk of parkinsonism in occupations (agriculture, education, health care, welding, and mining) and toxicant exposures (solvents and pesticides) putatively associated with parkinsonism. OBJECTIVE To investigate occupations, specific job tasks, or exposures and risk of parkinsonism and clinical subtypes. DESIGN Case-control. SETTING Eight movement disorders centers in North America. PARTICIPANTS Inclusion criteria were parkinsonism (>or=2 cardinal signs), diagnosis within 8 years of recruitment (to minimize survival bias), and ability to participate in detailed telephone interviews. Control subjects were primarily nonblood relatives or acquaintances of patients. MAIN OUTCOME MEASURES This multicenter case-control study compared lifelong occupational and job task histories to determine associations with parkinsonism and certain clinical subtypes (postural instability and gait difficulty and age at diagnosis <or=50 years). RESULTS Findings in 519 cases and 511 controls were analyzed. Work in agriculture, education, health care, or welding was not associated with increased risk of parkinsonism. Unexpected increased risks associated with legal, construction and extraction, or religious occupations were not maintained after adjustment for duration. Risk of parkinsonism increased with pesticide use (odds ratio, 1.90; 95% confidence interval, 1.12-3.21), use of any of 8 pesticides mechanistically associated with experimental parkinsonism (2.20; 1.02-4.75), and use of 2,4-dichlorophenoxyacetic acid (2.59; 1.03-6.48). None of the specific occupations, job tasks, or task-related exposures were associated with younger age at diagnosis (<or=50 years). Ever working in business and finance, legal occupations, construction and extraction, or transportation and material moving was associated with postural instability and gait difficulty subtype of parkinsonism. Tobacco use was inversely associated with parkinsonism risk. CONCLUSION The association of disease risk with pesticides support a toxicant-induced cause of parkinsonism.