Samuel M. Goldman

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.

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.

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.

Smoking and Parkinson’s disease in twins

ObjectiveTo test the hypothesis that cigarette smoking protects against the development of PD. BackgroundSmoking has been inversely associated with PD in many studies, but whether this reflects a biologic effect on the underlying disease process or merely confounding or selection bias remains uncertain. MethodsThe authors compared smoking histories in male twin pairs identified from the National Academy of Sciences–National Research Council World War II Veteran Twins Cohort. The amount of cigarettes smoked (in pack-years) was collected until the time of PD onset in the affected twin or until the time of death for the unaffected twin, whichever came first. Differences in pack-years smoked until PD onset and until 10 and 20 years before onset were compared using paired t-tests. Comparisons were made overall and stratified by zygosity and concordance for PD. To assess the role of shared environment, correlation for smoking behaviors was compared between pairs concordant and discordant for PD. ResultsDetailed smoking histories were available for 113 twin pairs in which at least one twin had PD (discordant pairs: 43 monozygotic [MZ], 50 dizygotic [DZ]; concordant pairs: 10 MZ, 10 DZ). Within-pair correlation for ever smoking was high in MZ pairs (phi = 0.47, p = 0.001) but not in DZ pairs (phi = 0.007, p = 0.96). In 33 discordant MZ pairs and 39 discordant DZ pairs in which at least one twin had smoked, the twins without PD smoked more than their brothers smoked (32.5 vs 22.7 pack-years, p = 0.026). This was more marked in the MZ pairs (37.1 vs 25.3 pack-years, p = 0.077) than in the DZ pairs (28.6 vs 20.5 pack-years, p = 0.17). A similar relationship was seen when smoking dose was calculated only until 10 years before PD onset, suggesting that the lower dose of smoking in the twin with PD was not the result of early, undiagnosed disease. ConclusionWithin twin pairs, risk of PD is inversely correlated with the dose (in pack-years) of cigarette smoking. This effect is most pronounced in MZ twins, despite the high correlation for smoking. Because MZ twins are genetically identical and are similar behaviorally, this difference is unlikely to result from either genetic factors or environmental confounders. These results are compatible with a true biologic protective effect of cigarette smoking.

Environmental Toxins and Parkinson's Disease

Parkinsons disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life and is characterized by motor impairment, autonomic dysfunction, and, in many, psychological and cognitive changes. Recent advances have helped delineate pathogenetic mechanisms, yet the cause of PD in most individuals is unknown. Although at least 15 genes and genetic loci have been associated with PD, identified genetic causes are responsible for only a few percent of cases. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, solvents, metals, and other pollutants, and many of these compounds recapitulate PD pathology in animal models. This review summarizes the environmental toxicology of PD, highlighting the consistency of observations across cellular, animal, and human studies of PD pathogenesis.

Essential tremor in twins: An assessment of genetic vs environmental determinants of etiology

Objective: To determine the relative contribution of genetics and environment to essential tremor using a twin study method. Methods: Twins with postural or kinetic tremor were identified by movement disorders specialists during the conduct of a study investigating PD in members of the National Academy of Sciences and National Research Council World War II Veteran Twins Registry. The diagnosis of essential tremor was made by consensus using established diagnostic criteria. Results: A total of 196 twins had postural or kinetic tremor on examination. Of these, 137 had PD or had a twin with PD and were excluded from this study. Thirty-three others were excluded because of incomplete data for their twin. Sixteen twin pairs were identified in which at least one twin had essential tremor. Pairwise concordance in monozygotic twins was approximately two times that in dizygotic twins (0.60 monozygotic, 0.27 dizygotic). Conclusion: This pattern is consistent with a genetic cause of essential tremor. Because monozygotic concordance is not 100%, environmental factors may also play a role in the cause of the disease.

Traumatic brain injury in later life increases risk for Parkinson disease

Traumatic brain injury (TBI) is thought to be a risk factor for Parkinson disease (PD), but results are conflicting. Many studies do not account for confounding or reverse causation. We sought to address these concerns by quantifying risk of PD after TBI compared to non‐TBI trauma (NTT; defined as fractures).

Clinical Correlations With Lewy Body Pathology in LRRK2-Related Parkinson Disease

IMPORTANCE Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD. OBSERVATIONS We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.

Epidemiology of movement disorders

This article reviews recent studies of the epidemiology of movement disorders, including Parkinsons disease, essential tremor, Huntingtons disease, tardive dyskinesia, tic disorders, and dystonias.