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Parkinson Disease: HELP
Articles by Shannon L. Rhodes
Based on 16 articles published since 2010
(Why 16 articles?)
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Between 2010 and 2020, Shannon L. Rhodes wrote the following 16 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Editorial After half a century of research on smoking and PD, where do we go now? 2010

Ritz, Beate / Rhodes, Shannon L. · ·Neurology · Pubmed #20220125.

ABSTRACT: -- No abstract --

2 Clinical Trial Serum metabolomics of slow vs. rapid motor progression Parkinson's disease: a pilot study. 2013

Roede, James R / Uppal, Karan / Park, Youngja / Lee, Kichun / Tran, Vilinh / Walker, Douglas / Strobel, Frederick H / Rhodes, Shannon L / Ritz, Beate / Jones, Dean P. ·Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, Georgia, United States of America. ·PLoS One · Pubmed #24167579.

ABSTRACT: Progression of Parkinson's disease (PD) is highly variable, indicating that differences between slow and rapid progression forms could provide valuable information for improved early detection and management. Unfortunately, this represents a complex problem due to the heterogeneous nature of humans in regards to demographic characteristics, genetics, diet, environmental exposures and health behaviors. In this pilot study, we employed high resolution mass spectrometry-based metabolic profiling to investigate the metabolic signatures of slow versus rapidly progressing PD present in human serum. Archival serum samples from PD patients obtained within 3 years of disease onset were analyzed via dual chromatography-high resolution mass spectrometry, with data extraction by xMSanalyzer and used to predict rapid or slow motor progression of these patients during follow-up. Statistical analyses, such as false discovery rate analysis and partial least squares discriminant analysis, yielded a list of statistically significant metabolic features and further investigation revealed potential biomarkers. In particular, N8-acetyl spermidine was found to be significantly elevated in the rapid progressors compared to both control subjects and slow progressors. Our exploratory data indicate that a fast motor progression disease phenotype can be distinguished early in disease using high resolution mass spectrometry-based metabolic profiling and that altered polyamine metabolism may be a predictive marker of rapidly progressing PD.

3 Article Organophosphate Pesticide Exposures, Nitric Oxide Synthase Gene Variants, and Gene-Pesticide Interactions in a Case-Control Study of Parkinson's Disease, California (USA). 2016

Paul, Kimberly C / Sinsheimer, Janet S / Rhodes, Shannon L / Cockburn, Myles / Bronstein, Jeff / Ritz, Beate. ·Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), Los Angeles, California, USA. ·Environ Health Perspect · Pubmed #26383258.

ABSTRACT: BACKGROUND: Nitric oxide synthase (NOS) genes are candidates for Parkinson's disease (PD) because NOS enzymes produce nitric oxide (NO), a pro-oxidant that can damage neurons. Widely used organophosphate (OP) pesticides can induce oxidative stress and are reported to increase PD risk. Additionally, two single nucleotide polymorphisms (SNPs) from the PON1 (paraoxonase 1) gene influence the ability to metabolize OPs. OBJECTIVE: Here, we investigated contributions of NOS genes and OP pesticides to PD risk, controlling for PON1 status. METHODS: In 357 incident PD cases and 495 population controls, we investigated eight NOS SNPs and interactions with both household and ambient agricultural OP exposures assessed with geographic information system (GIS). RESULTS: In comparing PD in homozygous variant carriers of NOS2A rs1060826 versus homozygous wild-type or heterozygotes, we estimate an adjusted odds ratio (OR) of 1.51 (95% CI: 0.95, 2.41). When considering interactions between NOS1 rs2682826 and OP exposure from household use, the OR for frequent OP use alone was 1.30 (95% CI: 0.72, 2.34) and for the CT+TT genotype alone was 0.89 (95% CI: 0.58, 1.39), and for frequent OP use combined with the CT+TT genotype the OR was 2.84 (95% CI: 1.49, 5.40) (interaction p-value 0.04). Similar results were seen for ambient OP exposure. Interactions between OP exposure and three other NOS1 SNPs and a genetic risk score combining all NOS1 SNPs reached statistical significance. CONCLUSIONS: We found that OP pesticides were more strongly associated with PD among participants with variant genotypes in NOS1, consistent with the importance of oxidative stress-inducing mechanisms. Our data provide evidence for NOS1 modifying PD risk in OP exposed populations. CITATION: Paul KC, Sinsheimer JS, Rhodes SL, Cockburn M, Bronstein J, Ritz B. 2016. Organophosphate pesticide exposures, nitric oxide synthase gene variants, and gene-pesticide interactions in a case-control study of Parkinson's disease, California (USA). Environ Health Perspect 124:570-577; http://dx.doi.org/10.1289/ehp.1408976.

4 Article APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. 2014

Mata, Ignacio F / Leverenz, James B / Weintraub, Daniel / Trojanowski, John Q / Hurtig, Howard I / Van Deerlin, Vivianna M / Ritz, Beate / Rausch, Rebecca / Rhodes, Shannon L / Factor, Stewart A / Wood-Siverio, Cathy / Quinn, Joseph F / Chung, Kathryn A / Peterson, Amie L / Espay, Alberto J / Revilla, Fredy J / Devoto, Johnna / Hu, Shu-Ching / Cholerton, Brenna A / Wan, Jia Y / Montine, Thomas J / Edwards, Karen L / Zabetian, Cyrus P. ·Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington3Department of Neurology, University of Washington School of Medicine, Seattle. · Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington3Dep. · Department of Neurology, University of Pennsylvania, Philadelphia7Department of Psychiatry, University of Pennsylvania, Philadelphia8Parkinson's Disease Research, Education, and Clinical Center and Mental Illness Research, Education, and Clinical Center. · Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia10Institute on Aging, University of Pennsylvania, Philadelphia. · Department of Neurology, University of Pennsylvania, Philadelphia. · Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia. · Department of Epidemiology, School of Public Health, University of California, Los Angeles12Department of Environmental Health Sciences, School of Public Health, University of California, Los Angeles13Department of Neurology, University of California, Los. · Department of Neurology, University of California, Los Angeles. · Department of Epidemiology, School of Public Health, University of California, Los Angeles. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia. · Parkinson's Disease Research, Education, and Clinical Center,Portland Veterans Affairs Medical Center, Portland, Oregon16Department of Neurology, Oregon Health and Science University, Portland. · Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio. · Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio18Department of Neurology, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio. · Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington4Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle. · Department of Epidemiology, University of Washington, Seattle20currently with Department of Epidemiology, University of California, Irvine. · Department of Pathology, University of Washington School of Medicine, Seattle. ·JAMA Neurol · Pubmed #25178429.

ABSTRACT: IMPORTANCE: Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature. OBJECTIVE: To determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD. DESIGN, SETTING, AND PARTICIPANTS: We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene. MAIN OUTCOMES AND MEASURES: Nine variables derived from 7 psychometric tests. RESULTS: The APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10(-6); corrected P [Pc] = 6.0 × 10(-5)), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10(-5); Pc = 9 × 10(-5)); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests. CONCLUSIONS AND RELEVANCE: Our data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

5 Article People with Parkinson's disease and normal MMSE score have a broad range of cognitive performance. 2014

Burdick, Daniel J / Cholerton, Brenna / Watson, G S / Siderowf, Andrew / Trojanowski, John Q / Weintraub, Daniel / Ritz, Beate / Rhodes, Shannon L / Rausch, Renecca / Factor, Stewart A / Wood-Siverio, Cathy / Quinn, Joseph F / Chung, Kathryn A / Srivatsal, Sindhu / Edwards, Karen L / Montine, Thomas J / Zabetian, Cyrus P / Leverenz, James B. ·Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA. ·Mov Disord · Pubmed #25073717.

ABSTRACT: Cognitive impairment, including dementia, is common in Parkinson's disease (PD). The Mini-Mental State Examination (MMSE) has been recommended as a screening tool for Parkinson's disease dementia (PDD), with values below 26 indicative of possible dementia. Using a detailed neuropsychological battery, we examined the range of cognitive impairment in PD patients with an MMSE score of 26 or higher. In this multicenter, cross-sectional, observational study, we performed neuropsychological testing in a sample of 788 PD patients with MMSE scores of 26 or higher. Evaluation included tests of global cognition, executive function, language, memory, and visuospatial skills. A consensus panel reviewed results for 342 subjects and assigned a diagnosis of no cognitive impairment, mild cognitive impairment, or dementia. Sixty-seven percent of the 788 subjects performed 1.5 standard deviations below the normative mean on at least one test. On eight of the 15 tests, more than 20% of subjects scored 1.5 standard deviations or more below the normative mean. Greatest impairments were found on Hopkins Verbal Learning and Digit Symbol Coding tests. The sensitivity of the MMSE to detect dementia was 45% in a subset of participants who underwent clinical diagnostic procedures. A remarkably wide range of cognitive impairment can be found in PD patients with a relatively high score on the MMSE, including a level of cognitive impairment consistent with dementia. Given these findings, clinicians must be aware of the limitations of the MMSE in detecting cognitive impairment, including dementia, in PD.

6 Article Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease. 2014

Fitzmaurice, Arthur G / Rhodes, Shannon L / Cockburn, Myles / Ritz, Beate / Bronstein, Jeff M. ·From the Department of Neurology (A.G.F., B.R., J.M.B.), David Geffen School of Medicine at UCLA, Los Angeles · Department of Molecular Toxicology (A.G.F., B.R., J.M.B.), University of California, Los Angeles · Departments of Epidemiology (S.L.R., B.R.) and Environmental Health Sciences (B.R.), UCLA Fielding School of Public Health, Los Angeles · Department of Preventive Medicine (M.C.), Keck School of Medicine of USC, Los Angeles · and Parkinson's Disease Research, Education, and Clinical Center (J.M.B.), Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA. ·Neurology · Pubmed #24491970.

ABSTRACT: OBJECTIVE: The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson disease (PD) risk in an epidemiologic study. METHODS: A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinson's Environment & Genes (PEG) Study. Common variants in the mitochondrial ALDH2 gene were genotyped to assess effect measure modification (statistical interaction) of the pesticide effects by genetic variation. RESULTS: All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides. CONCLUSION: ALDH inhibition appears to be an important mechanism through which environmental toxicants contribute to PD pathogenesis, especially in genetically vulnerable individuals, suggesting several potential interventions to reduce PD occurrence or slow or reverse its progression.

7 Article Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin. 2014

Rhodes, Shannon L / Buchanan, Daniel D / Ahmed, Ismaïl / Taylor, Kent D / Loriot, Marie-Anne / Sinsheimer, Janet S / Bronstein, Jeff M / Elbaz, Alexis / Mellick, George D / Rotter, Jerome I / Ritz, Beate. ·Department of Epidemiology, UCLA Fielding School of Public Health, 650 Charles E. Young Drive S, Los Angeles, CA 90095-1772, USA. Electronic address: shannon.rhodes@ucla.edu. · Cancer and Population Studies Group, Queensland Institute of Medical Research, 300 Herston Rd, Brisbane, QLD 4006, Australia; University of Queensland, School of Medicine, Brisbane, Australia; Princess Alexandra Hospital, Australia. · Centre for Research in Epidemiology and Population Health, Biostatistics team, INSERM U1018, F-94276 le Kremlin Bicêtre, France; Univ Paris-Sud, UMRS 1018, F-94276 le Kremlin Bicêtre, France. · Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 West Carson, Bldg E5, Torrance, CA 90502, USA. · Sorbonne Paris Cité, Université Paris Descartes, INSERM UMR-S 775, France; Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Biochimie, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire, France. · Department of Human Genetics, David Geffen School of Medicine at UCLA, 695 Charles E. Young Drive South, Box 708822, Los Angeles, CA 90095-7088, USA; Department of Biomathematics, David Geffen School of Medicine at UCLA, Box 951766, Room 5303 Life Sciences, Los Angeles, CA 90095-1766, USA; Department of Biostatistics, UCLA Fielding School of Public Health, 650 Charles E. Young Drive S, Los Angeles, CA 90095-1772, USA. · Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA. · Centre for Research in Epidemiology and Population Health, Social and Occupational Determinants of Health, INSERM U1018, F-94807 Villejuif, France; Univ Versailles St-Quentin, UMRS 1018, F-94807, Villejuif France. · Eskitis Institute for Drug Discovery, Griffith University, Nathan 4111, Brisbane, Australia; Department of Neurology, Princess Alexandra Hospital, Brisbane, Australia. · Department of Epidemiology, UCLA Fielding School of Public Health, 650 Charles E. Young Drive S, Los Angeles, CA 90095-1772, USA; Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA; Department of Environmental Health Sciences, UCLA Fielding School of Public Health, 650 Charles E. Young Drive S, Los Angeles, CA 90095-1772, USA. ·Neurobiol Dis · Pubmed #24121126.

ABSTRACT: Pathologic features of Parkinson's disease (PD) include death of dopaminergic neurons in the substantia nigra, presence of α-synuclein containing Lewy bodies, and iron accumulation in PD-related brain regions. The observed iron accumulation may be contributing to PD etiology but it also may be a byproduct of cell death or cellular dysfunction. To elucidate the possible role of iron accumulation in PD, we investigated genetic variation in 16 genes related to iron homeostasis in three case-control studies from the United States, Australia, and France. After screening 90 haplotype tagging single nucleotide polymorphisms (SNPs) within the genes of interest in the US study population, we investigated the five most promising gene regions in two additional independent case-control studies. For the pooled data set (1289 cases, 1391 controls) we observed a protective association (OR=0.83, 95% CI: 0.71-0.96) between PD and a haplotype composed of the A allele at rs1880669 and the T allele at rs1049296 in transferrin (TF; GeneID: 7018). Additionally, we observed a suggestive protective association (OR=0.87, 95% CI: 0.74-1.02) between PD and a haplotype composed of the G allele at rs10247962 and the A allele at rs4434553 in transferrin receptor 2 (TFR2; GeneID: 7036). We observed no associations in our pooled sample for haplotypes in SLC40A1, CYB561, or HFE. Taken together with previous findings in model systems, our results suggest that TF or a TF-TFR2 complex may have a role in the etiology of PD, possibly through iron misregulation or mitochondrial dysfunction within dopaminergic neurons.

8 Article Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinson׳s disease. 2013

Rhodes, Shannon L / Fitzmaurice, Arthur G / Cockburn, Myles / Bronstein, Jeff M / Sinsheimer, Janet S / Ritz, Beate. ·Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, United States. ·Environ Res · Pubmed #23988235.

ABSTRACT: Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson's disease (PD) pathology, may protect against cytotoxic proteins. Since the ubiquitin-proteasome system (UPS) degrades cytotoxic proteins, dysfunction in the UPS may contribute to PD etiology. Our goal in this study was to screen pesticides for proteasome inhibition and investigate (i) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and (ii) whether genetic variation in candidate genes of the UPS pathway modify those increased risks. We assessed 26S UPS activity in SK-N-MC(u) cells by fluorescence. We recruited idiopathic PD cases (n=360) and population-based controls (n=816) from three counties in California with considerable commercial agriculture. We determined ambient pesticide exposure by our validated GIS-based model utilizing residential and workplace address histories. We limited effect measure modification assessment to Caucasians (287 cases, 453 controls). Eleven of 28 pesticides we screened inhibited 26S UPS activity at 10 µM. Benomyl, cyanazine, dieldrin, endosulfan, metam, propargite, triflumizole, and ziram were associated with increased PD risk. We estimated an odds ratio of 2.14 (95% CI: 1.42, 3.22) for subjects with ambient exposure to any UPS-inhibiting pesticide at both residential and workplace addresses; this association was modified by genetic variation in the s-phase kinase-associated protein 1 gene (SKP1; interaction p-value=0.005). Our results provide evidence that UPS-inhibiting pesticides play a role in the etiology of PD and suggest that genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures.

9 Article Functional paraoxonase 1 variants modify the risk of Parkinson's disease due to organophosphate exposure. 2013

Lee, Pei-Chen / Rhodes, Shannon L / Sinsheimer, Janet S / Bronstein, Jeff / Ritz, Beate. ·Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles, CA, USA. ·Environ Int · Pubmed #23602893.

ABSTRACT: BACKGROUND: We previously demonstrated that carriers of the "slower metabolizer" MM genotype of paraoxonase (PON1) who were also exposed to ambient organophosphate (OP) pesticides at their residences were at increased risk of developing Parkinson's disease (PD). Here, with a larger sample size, we extend our previous investigation to consider additional sources of ambient exposure and examined two additional functional PON1 variants. METHODS: From 2001 to 2011, we enrolled incident cases of idiopathic PD and population controls living in central California. We genotyped three well-known functional PON1 SNPs: two exonic polymorphisms (PON1L55M and PON1Q192R) and the promoter region variant (PON1C-108T). Ambient exposures to diazinon, chlorpyrifos, and parathion at residential and workplace addresses were assessed using a validated geographic information system-based model incorporating records of agricultural pesticide applications in California. RESULTS: The odds ratio (OR) for Caucasians exposed to OPs at either residential or workplace addresses varied by PON1 genotype; for exposed carriers of the "faster" metabolizer genotypes, ML or LL, we estimated lower odds ratios (range, 1.20-1.39) than for exposed carriers of the "slower" metabolizer genotype MM (range, 1.78-2.45) relative to unexposed carriers of the faster genotypes. We observed similarly increased ORs for exposure across PON1Q192R genotypes, but no differences across PON1C-108T genotypes. The largest ORs were estimated for exposed carriers of both PON1192QQ and PON155MM (OR range, 2.84-3.57). CONCLUSIONS: Several functional PON1 variants may act together to modify PD risk for ambient OP exposures. While either PON1L55M or PON1Q192R may be sufficient to identify increased susceptibility, carriers of both slow metabolizer variants seem most susceptible to OP exposures.

10 Article Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. 2013

Fitzmaurice, Arthur G / Rhodes, Shannon L / Lulla, Aaron / Murphy, Niall P / Lam, Hoa A / O'Donnell, Kelley C / Barnhill, Lisa / Casida, John E / Cockburn, Myles / Sagasti, Alvaro / Stahl, Mark C / Maidment, Nigel T / Ritz, Beate / Bronstein, Jeff M. ·Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095, USA. ·Proc Natl Acad Sci U S A · Pubmed #23267077.

ABSTRACT: Parkinson disease (PD) is a neurodegenerative disorder particularly characterized by the loss of dopaminergic neurons in the substantia nigra. Pesticide exposure has been associated with PD occurrence, and we previously reported that the fungicide benomyl interferes with several cellular processes potentially relevant to PD pathogenesis. Here we propose that benomyl, via its bioactivated thiocarbamate sulfoxide metabolite, inhibits aldehyde dehydrogenase (ALDH), leading to accumulation of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), preferential degeneration of dopaminergic neurons, and development of PD. This hypothesis is supported by multiple lines of evidence. (i) We previously showed in mice the metabolism of benomyl to S-methyl N-butylthiocarbamate sulfoxide, which inhibits ALDH at nanomolar levels. We report here that benomyl exposure in primary mesencephalic neurons (ii) inhibits ALDH and (iii) alters dopamine homeostasis. It induces selective dopaminergic neuronal damage (iv) in vitro in primary mesencephalic cultures and (v) in vivo in a zebrafish system. (vi) In vitro cell loss was attenuated by reducing DOPAL formation. (vii) In our epidemiology study, higher exposure to benomyl was associated with increased PD risk. This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis.

11 Article Common variation in the LRRK2 gene is a risk factor for Parkinson's disease. 2012

Mata, Ignacio F / Checkoway, Harvey / Hutter, Carolyn M / Samii, Ali / Roberts, John W / Kim, Hojoong M / Agarwal, Pinky / Alvarez, Victoria / Ribacoba, Renee / Pastor, Pau / Lorenzo-Betancor, Oswaldo / Infante, Jon / Sierra, María / Gómez-Garre, Pilar / Mir, Pablo / Ritz, Beate / Rhodes, Shannon L / Colcher, Amy / Van Deerlin, Vivianna / Chung, Kathryn A / Quinn, Joseph F / Yearout, Dora / Martinez, Erica / Farin, Federico M / Wan, Jia Y / Edwards, Karen L / Zabetian, Cyrus P. ·Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA. nachofm@u.washington.edu ·Mov Disord · Pubmed #23115130.

ABSTRACT: BACKGROUND: Common variants in the LRRK2 gene influence the risk of Parkinson's disease (PD) in Asians, but whether the same is true in European-derived populations is less clear. METHODS: We genotyped 66 LRRK2 tagging single-nucleotide polymorphisms (SNPs) in 575 PD patients and 689 controls from the northwestern United States (tier 1). PD-associated SNPs (P < .05) were then genotyped in an independent sample of 3617 cases and 2512 controls from the United States and Spain (tier 2). Logistic regression was used to model additive SNP genotype effects adjusted for age and sex among white individuals. RESULTS: Two regions showed independent association with PD in tier 1, and SNPs in both regions were successfully replicated in tier 2 (rs10878226, combined odds ratio [OR], 1.20; 95% confidence interval [CI], 1.08-1.33; P = 6.3 × 10(-4); rs11176013, OR, 0.89; CI, 0.83-0.95; P = 4.6 × 10(-4)). CONCLUSIONS: Our data suggest that common variation within LRRK2 conveys susceptibility for PD in individuals of European ancestry.

12 Article α-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease. 2012

Ritz, Beate / Rhodes, Shannon L / Bordelon, Yvette / Bronstein, Jeff. ·Department of Epidemiology, University of California Los Angeles, Los Angeles, California, United States of America. britz@ucla.edu ·PLoS One · Pubmed #22615757.

ABSTRACT: Currently, there are no reported genetic predictors of motor symptom progression in Parkinson's disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson's patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson's Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57-10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96-2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.

13 Article Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. 2011

Hamza, Taye H / Chen, Honglei / Hill-Burns, Erin M / Rhodes, Shannon L / Montimurro, Jennifer / Kay, Denise M / Tenesa, Albert / Kusel, Victoria I / Sheehan, Patricia / Eaaswarkhanth, Muthukrishnan / Yearout, Dora / Samii, Ali / Roberts, John W / Agarwal, Pinky / Bordelon, Yvette / Park, Yikyung / Wang, Liyong / Gao, Jianjun / Vance, Jeffery M / Kendler, Kenneth S / Bacanu, Silviu-Alin / Scott, William K / Ritz, Beate / Nutt, John / Factor, Stewart A / Zabetian, Cyrus P / Payami, Haydeh. ·New York State Department of Health Wadsworth Center, Albany, New York, USA. ·PLoS Genet · Pubmed #21876681.

ABSTRACT: Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P(2df) = 10(-6), GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10(-7)) but not in light coffee-drinkers. The a priori Replication hypothesis that "Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers" was confirmed: OR(Replication) = 0.59, P(Replication) = 10(-3); OR(Pooled) = 0.51, P(Pooled) = 7×10(-8). Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10(-3)), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10(-13)). Imputation revealed a block of SNPs that achieved P(2df)<5×10(-8) in GWAIS, and OR = 0.41, P = 3×10(-8) in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

14 Article Replication of GWAS associations for GAK and MAPT in Parkinson's disease. 2011

Rhodes, Shannon L / Sinsheimer, Janet S / Bordelon, Yvette / Bronstein, Jeff M / Ritz, Beate. ·Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA 90095-1772, USA. shannon.rhodes@ucla.edu ·Ann Hum Genet · Pubmed #21058943.

ABSTRACT: In the investigation of disease aetiology, the genome-wide association study (GWAS) provides a hypothesis-free investigation of the broader human genome and, as with all scientific investigations, replication is essential to validate any findings. To date, six GWAS have been performed to investigate the influence of common genetic variation in Parkinson's disease (PD) and only two associations have been replicated: alpha synuclein (SNCA) and microtubule-associated protein tau (MAPT), both PD candidate genes before GWAS. In our population-based study, we genotyped four of the top single-nucleotide polymorphisms (SNPs) from a previous study. By using the identical analytic method and genetic model in our independent sample, we provide evidence for replication of rs1724425 near MAPT (OR = 0.74, P= 0.0163) and rs1564282 in cyclin G-associated kinase (GAK; OR = 1.61, P= 0.0151); rs3775478 of multimerin 1 (MMRN1) (P= 0.30) and rs356229 of SNCA (P= 0.14) did not replicate in our study population. While MAPT has been considered a PD candidate gene and has been observed in association with PD in other GWAS, GAK is a new candidate for investigation in future studies.

15 Article α-Synuclein gene may interact with environmental factors in increasing risk of Parkinson's disease. 2010

Gatto, Nicole M / Rhodes, Shannon L / Manthripragada, Angelika D / Bronstein, Jeff / Cockburn, Myles / Farrer, Matt / Ritz, Beate. ·Departmen of Epidemiology, University of California Los Angeles, Los Angeles, CA, USA. ·Neuroepidemiology · Pubmed #20664293.

ABSTRACT: BACKGROUND: Although of great interest and suggested in prior reports, possible α-synuclein (SNCA) gene-environment interactions have not been well investigated in humans. METHODS: We used a population-based approach to examine whether the risk of Parkinson's disease (PD) depended on the combined presence of SNCA variations and two important environmental factors, pesticide exposures and smoking. RESULTS/CONCLUSIONS: Similar to recent meta- and pooled analyses, our data suggest a lower PD risk in subjects who were either homozygous or heterozygous for the SNCA REP1 259 genotype, and a higher risk in subjects who were either homozygous or heterozygous for the REP1 263 genotype, especially among subjects with an age of onset ≤68 years. More importantly, while analyses of interactions were limited by small cell sizes, risk due to SNCA variations seemed to vary with pesticide exposure and smoking, especially in younger onset cases, suggesting an age-of-onset effect.

16 Article L-type calcium channel blockers and Parkinson disease in Denmark. 2010

Ritz, Beate / Rhodes, Shannon L / Qian, Lei / Schernhammer, Eva / Olsen, Jørgen H / Friis, Søren. ·Department of Epidemiology, University of California at Los Angeles School of Public Health, Los Angeles, CA, USA. britz@ucla.edu ·Ann Neurol · Pubmed #20437557.

ABSTRACT: OBJECTIVE: This study was undertaken to investigate L-type calcium channel blockers of the dihydropyridine class for association with Parkinson disease (PD), because some of these drugs traverse the blood-brain barrier, are potentially neuroprotective, and have previously been evaluated for impact on PD risk. METHODS: We identified 1,931 patients with a first-time diagnosis for PD between 2001 and 2006 as reported in the Danish national hospital/outpatient database and density matched them by birth year and sex to 9,651 controls from the population register. The index date for cases and their corresponding controls was advanced to the date of first recorded prescription for anti-Parkinson drugs, if prior to first PD diagnosis in the hospital records. Prescriptions were determined from the national pharmacy database. In our primary analyses, we excluded all calcium channel blocker prescriptions 2 years before index date/PD diagnosis. RESULTS: Employing logistic regression analysis adjusting for age, sex, diagnosis of chronic pulmonary obstructive disorder, and Charlson comorbidity score, we found that subjects prescribed dihydropyridines (excludes amlodipine) between 1995 and 2 years prior to the index date were less likely to develop PD (odds ratio, 0.73; 95% confidence interval, 0.54-0.97); this 27% risk reduction did not differ with length or intensity of use. Risk estimates were close to null for the peripherally acting drug amlodipine and for other antihypertensive medications. INTERPRETATION: Our data suggest a potential neuroprotective role for centrally acting L-type calcium channel blockers of the dihydropyridine class in PD that should be further investigated in studies that can distinguish between types of L-type channel blockers.