Anabel Chade

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.

Motor-language coupling: direct evidence from early Parkinson’s disease and intracranial cortical recordings

Language and action systems are functionally coupled in the brain as demonstrated by converging evidence using Functional magnetic resonance imaging (fMRI), electroencephalography (EEG), transcranial magnetic stimulation (TMS), and lesion studies. In particular, this coupling has been demonstrated using the action-sentence compatibility effect (ACE) in which motor activity and language interact. The ACE task requires participants to listen to sentences that described actions typically performed with an open hand (e.g., clapping), a closed hand (e.g., hammering), or without any hand action (neutral); and to press a large button with either an open hand position or closed hand position immediately upon comprehending each sentence. The ACE is defined as a longer reaction time (RT) in the action-sentence incompatible conditions than in the compatible conditions. Here we investigated direct motor-language coupling in two novel and uniquely informative ways. First, we measured the behavioural ACE in patients with motor impairment (early Parkinsons disease - EPD), and second, in epileptic patients with direct electrocorticography (ECoG) recordings. In experiment 1, EPD participants with preserved general cognitive repertoire, showed a much diminished ACE relative to non-EPD volunteers. Moreover, a correlation between ACE performance and action-verb processing (kissing and dancing test - KDT) was observed. Direct cortical recordings (ECoG) in motor and language areas (experiment 2) demonstrated simultaneous bidirectional effects: motor preparation affected language processing (N400 at left inferior frontal gyrus and middle/superior temporal gyrus), and language processing affected activity in movement-related areas (motor potential at premotor and M1). Our findings show that the ACE paradigm requires ongoing integration of preserved motor and language coupling (abolished in EPD) and engages motor-temporal cortices in a bidirectional way. In addition, both experiments suggest the presence of a motor-language network which is not restricted to somatotopically defined brain areas. These results open new pathways in the fields of motor diseases, theoretical approaches to language understanding, and models of action-perception coupling.

Solvent exposures and parkinson disease risk in twins

Several case reports have linked solvent exposure to Parkinson disease (PD), but few studies have assessed associations with specific agents using an analytic epidemiologic design. We tested the hypothesis that exposure to specific solvents is associated with PD risk using a discordant twin pair design.

Assessing the non-motor symptoms of Parkinson's disease: MDS-UPDRS and NMS Scale.

Although Parkinsons disease (PD) is characterized by typical motor manifestations, non‐motor symptoms (NMS) are an outstanding part of the disease. At present, several specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society‐Unified Parkinsons Disease Rating Scale (MDS‐UPDRS): Part I – Non‐Motor Aspects of Experiences of Daily Living (nM‐EDL) compared with the Non‐Motor Symptoms Scale (NMSS).

Dietary Fat Intake, Pesticide Use, and Parkinson’s Disease

BACKGROUND Dietary fat intake may modify Parkinsons disease (PD) risk directly or by altering the response to environmental neurotoxicants including pesticides. METHODS We conducted a case-control study of PD nested in the Agricultural Health Study (AHS), a cohort of pesticide applicators and spouses. We evaluated diet and pesticide use before diagnosis in 89 PD cases, confirmed by movement disorder specialists, or a corresponding date in 336 frequency-matched controls. Associations were evaluated using multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS In the AHS, PD was inversely associated with N-3 polyunsaturated fatty acids (PUFAs) (OR 0.4, 95% CI 0.2-0.8 for highest vs. lowest tertile) and the N-3 precursor α-linolenic acid (0.4, 0.2-0.8). In a meta-analysis of nine studies, including the present one, PD was inversely associated with α-linolenic acid (0.81, 0.68-0.96). In the AHS, associations of PD with the pesticides paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 (1.5-12) in individuals with PUFA intake below the median but 1.2 (0.4-3.4) in those with higher intake (p-interaction = 0.10). The OR for rotenone was 5.8 (2.3-15) in those with saturated fat intake above the median but 1.5 (0.5-4.2) in those with lower intake (p-interaction = 0.02). CONCLUSIONS PUFA intake was consistently associated with lower PD risk, and dietary fats modified the association of PD risk with pesticide exposure. If confirmed, these findings suggest that a diet high in PUFAs and low in saturated fats might reduce risk of PD.

Genetic Modification of the Association of Paraquat and Parkinson’s Disease

Paraquat is one of the most widely used herbicides worldwide. It produces a Parkinsons disease (PD) model in rodents through redox cycling and oxidative stress (OS) and is associated with PD risk in humans. Glutathione transferases provide cellular protection against OS and could potentially modulate paraquat toxicity. We investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione S‐transferase M1 (GSTM1) or T1 (GSTT1). Eighty‐seven PD subjects and 343 matched controls were recruited from the Agricultural Health Study, a study of licensed pesticide applicators and spouses in Iowa and North Carolina. PD was confirmed by in‐person examination. Paraquat use and covariates were determined by interview. We genotyped subjects for homozygous deletions of GSTM1 (GSTM1*0) and GSTT1 (GSTT1*0) and tested interaction between paraquat use and genotype using logistic regression. Two hundred and twenty‐three (52%) subjects had GSTM1*0, 95 (22%) had GSTT1*0, and 73 (17%; all men) used paraquat. After adjustment for potential confounders, there was no interaction with GSTM1. In contrast, GSTT1 genotype significantly modified the association between paraquat and PD. In men with functional GSTT1, the odds ratio (OR) for association of PD with paraquat use was 1.5 (95% confidence interval [CI]: 0.6–3.6); in men with GSTT1*0, the OR was 11.1 (95% CI: 3.0–44.6; P interaction: 0.027). Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. GSTT1*0 is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat.

Protective glove use and hygiene habits modify the associations of specific pesticides with Parkinson's disease

Pesticides have been associated with Parkinsons disease (PD), and protective gloves and workplace hygiene can reduce pesticide exposure. We assessed whether use of gloves and workplace hygiene modified associations between pesticides and PD. The Farming and Movement Evaluation (FAME) study is a nested case-control study within the Agricultural Health Study. Use of protective gloves, other PPE, and hygiene practices were determined by questionnaire (69 cases and 237 controls were included). We considered interactions of gloves and hygiene with ever-use of pesticides for all pesticides with ≥5 exposed and unexposed cases and controls in each glove-use stratum (paraquat, permethrin, rotenone, and trifluralin). 61% of respondents consistently used protective gloves and 87% consistently used ≥2 hygiene practices. Protective glove use modified the associations of paraquat and permethrin with PD: neither pesticide was associated with PD among protective glove users, while both pesticides were associated with PD among non-users (paraquat OR 3.9 [95% CI 1.3, 11.7], interaction p=0.15; permethrin OR 4.3 [95% CI 1.2, 15.6] interaction p=0.05). Rotenone was associated with PD regardless of glove use. Trifluralin was associated with PD among participants who used <2 hygiene practices (OR 5.5 [95% CI 1.1, 27.1]) but was not associated with PD among participants who used 2 or more practices (interaction p=0.02). Although sample size was limited in the FAME study, protective glove use and hygiene practices appeared to be important modifiers of the association between pesticides and PD and may reduce risk of PD associated with certain pesticides.

The relationship between executive functions and fluid intelligence in Parkinson's disease

Background We recently demonstrated that decline in fluid intelligence is a substantial contributor to frontal deficits. For some classical ‘executive’ tasks, such as the Wisconsin Card Sorting Test (WCST) and Verbal Fluency, frontal deficits were entirely explained by fluid intelligence. However, on a second set of frontal tasks, deficits remained even after statistically controlling for this factor. These tasks included tests of theory of mind and multitasking. As frontal dysfunction is the most frequent cognitive deficit observed in early Parkinsons disease (PD), the present study aimed to determine the role of fluid intelligence in such deficits. Method We assessed patients with PD (n=32) and control subjects (n=22) with the aforementioned frontal tests and with a test of fluid intelligence. Group performance was compared and fluid intelligence was introduced as a covariate to determine its role in frontal deficits shown by PD patients. Results In line with our previous results, scores on the WCST and Verbal Fluency were closely linked to fluid intelligence. Significant patient–control differences were eliminated or at least substantially reduced once fluid intelligence was introduced as a covariate. However, for tasks of theory of mind and multitasking, deficits remained even after fluid intelligence was statistically controlled. Conclusions The present results suggest that clinical assessment of neuropsychological deficits in PD should include tests of fluid intelligence, together with one or more specific tasks that allow for the assessment of residual frontal deficits associated with theory of mind and multitasking.

Relationship between the MDS-UPDRS domains and the health-related quality of life of Parkinson's disease patients.

The Movement Disorder Society sponsored version of the Unified Parkinsons Disease Rating Scale (MDS‐UPDRS) is a comprehensive instrument for assessing Parkinsons disease (PD). The present study was aimed at determining the relationships between MDS‐UPDRS components and health‐related quality of life (HRQoL) evaluations in PD patients.

Reliability and validity of two self-administered questionnaires for screening restless legs syndrome in population-based studies

BACKGROUND A reliable and valid questionnaire for screening restless legs syndrome (RLS) is essential for determining accurate estimates of disease frequency. In a 2002 NIH-sponsored workshop, experts suggested three mandatory questions for identifying RLS in epidemiologic studies. We evaluated the reliability and validity of this RLS-NIH questionnaire in a community-based sample and concurrently developed and evaluated the utility of an expanded screening questionnaire, the RLS-EXP. METHODS The study was conducted at Kaiser Permanente of Northern California and the Stanford University Sleep Clinic. We evaluated test-retest reliability in a random sample of subjects with prior physician-assigned RLS (n=87), subjects with conditions frequently misclassified as RLS (n=31), and healthy subjects (n=9). Validity of both instruments was evaluated in a random sample of 32 subjects, and in-person examination by two RLS specialists was used as the gold standard. RESULTS For the first three RLS-NIH questions, the kappa statistic for test-retest reliability ranged from 0.5 to 1.0, and sensitivity and specificity was 86% and 45%, respectively. For the subset of five questions on RLS-EXP that encompassed cardinal features for diagnosing RLS, kappas were 0.4-0.8, and sensitivity and specificity were 81% and 73%, respectively. CONCLUSIONS Sensitivity of RLS-NIH is good; however, the specificity of the instrument is poor when examined in a sample that over-represents subjects with conditions that are commonly misclassified as RLS. Specificity can be improved by including separate questions on cardinal features, as used in the RLS-EXP, and by including a few questions that identify RLS mimics, thereby reducing false positives.