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Parkinson Disease: HELP
Articles by Cyrus P. Zabetian
Based on 86 articles published since 2009
(Why 86 articles?)
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Between 2009 and 2019, C. Zabetian wrote the following 86 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial The Clinical Profile of GBA-Related Lewy Body Disorders. 2016

Zabetian, Cyrus P. ·Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Department of Neurology, University of Washington School of Medicine, Seattle. ·JAMA Neurol · Pubmed #27723881.

ABSTRACT: -- No abstract --

2 Review Precision Medicine: Clarity for the Complexity of Dementia. 2016

Cholerton, Brenna / Larson, Eric B / Quinn, Joseph F / Zabetian, Cyrus P / Mata, Ignacio F / Keene, C Dirk / Flanagan, Margaret / Crane, Paul K / Grabowski, Thomas J / Montine, Kathleen S / Montine, Thomas J. ·Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington. · Group Health Research Institute, Seattle, Washington. · Department of Neurology, Oregon Health and Science University, Portland, Oregon; Portland Veterans Affairs Medical Center, Portland, Oregon. · Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington; Parkinson's Disease Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington; Department of Neurology, University of Washington, Seattle, Washington. · Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington; Department of Neurology, University of Washington, Seattle, Washington. · Department of Pathology, University of Washington, Seattle, Washington. · Department of Medicine, University of Washington, Seattle, Washington. · Department of Neurology, University of Washington, Seattle, Washington; Department of Radiology, University of Washington, Seattle, Washington. · Department of Pathology, University of Washington, Seattle, Washington. Electronic address: tmontine@uw.edu. ·Am J Pathol · Pubmed #26724389.

ABSTRACT: Three key elements to precision medicine are stratification by risk, detection of pathophysiological processes as early as possible (even before clinical presentation), and alignment of mechanism of action of intervention(s) with an individual's molecular driver(s) of disease. Used for decades in the management of some rare diseases and now gaining broad currency in cancer care, a precision medicine approach is beginning to be adapted to cognitive impairment and dementia. This review focuses on the application of precision medicine to address the clinical and biological complexity of two common neurodegenerative causes of dementia: Alzheimer disease and Parkinson disease.

3 Review The genetics of Parkinson disease. 2010

Bekris, Lynn M / Mata, Ignacio F / Zabetian, Cyrus P. ·Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA. lbekris@u.washington.edu ·J Geriatr Psychiatry Neurol · Pubmed #20938043.

ABSTRACT: Parkinson disease (PD) is the second most common neurodegenerative disorder. In most instances, PD is thought to result from a complex interaction between multiple genetic and environmental factors, though rare monogenic forms of the disease do exist. Mutations in 6 genes (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have conclusively been shown to cause familial parkinsonism. In addition, common variation in 3 genes (MAPT, LRRK2, and SNCA) and loss-of-function mutations in GBA have been well-validated as susceptibility factors for PD. The function of these genes and their contribution to PD pathogenesis remain to be fully elucidated. The prevalence, incidence, clinical manifestations, and genetic components of PD are discussed in this review.

4 Review Association between the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1) S18Y variant and Parkinson's Disease: a HuGE review and meta-analysis. 2009

Ragland, Margaret / Hutter, Carolyn / Zabetian, Cyrus / Edwards, Karen. ·Department of Epidemiology, University of Washington, Center for Genomics and Public Health, Box 354921, 6200 NE 74th Street, Building 29, Suite 250, Seattle, WA 98115, USA. ·Am J Epidemiol · Pubmed #19864305.

ABSTRACT: The ubiquitin carboxyl-terminal esterase L1 gene, UCHL1, located on chromosome 4p14, has been studied as a potential candidate gene for Parkinson's disease risk. The authors conducted a Human Genome Epidemiology review and meta-analysis of published case-control studies of the UCHL1 S18Y variant and Parkinson's disease in Asian and Caucasian samples. The meta-analysis of studies in populations of Asian ancestry showed a statistically significant association between the Y allele and reduced risk of Parkinson's disease under a recessive model (odds ratio (OR) for YY vs. SY + SS = 0.79, 95% confidence interval (CI): 0.67, 0.94; P = 0.006). For a dominant model, the association was not significant in Asian populations (OR for YY + SY vs. SS = 0.88, 95% CI: 0.68, 1.14; P = 0.33). For populations of European ancestry, the meta-analysis showed a significant association between the Y allele and decreased risk of Parkinson's disease under a dominant model (OR = 0.89, 95% CI: 0.81, 0.98; P = 0.02) but not under a recessive model (OR = 0.92, 95% CI: 0.66, 1.30; P = 0.65). Using the Venice criteria, developed by the Human Genome Epidemiology Network Working Group on the assessment of cumulative evidence, the authors concluded that moderate evidence exists for an association between the S18Y variant and Parkinson's disease.

5 Review Cognitive impairment and dementia in patients with Parkinson disease. 2009

Leverenz, James B / Quinn, Joseph F / Zabetian, Cyrus / Zhang, Jing / Montine, Kathleen S / Montine, Thomas J. ·Mental Illness Research, Education, and Clinical Centers of Veterans Administration, Department of Neurology, Oregon Health & Sciences University, Portland, OR, USA. ·Curr Top Med Chem · Pubmed #19754405.

ABSTRACT: Parkinson disease (PD) is an already prevalent neurodegenerative disease that is poised to at least double over the next 25 years. Although best known for its characteristic movement disorder, PD is now appreciated commonly to cause cognitive impairment, including dementia, and behavioral changes. Dementia in patients with PD is consequential and has been associated with reduced quality of life, shortened survival, and increased caregiver distress. Here we review clinical presentation and progression, pathological bases, identification of genetic risk factors, development of small molecule biomarkers, and emerging treatments for cognitive impairment in patients with PD.

6 Article Stool Immune Profiles Evince Gastrointestinal Inflammation in Parkinson's Disease. 2018

Houser, Madelyn C / Chang, Jianjun / Factor, Stewart A / Molho, Eric S / Zabetian, Cyrus P / Hill-Burns, Erin M / Payami, Haydeh / Hertzberg, Vicki S / Tansey, Malú G. ·Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. · Department of Neurology, Albany Medical College, Albany, New York, USA. · Veterans Affairs Puget Sound Health Care System and Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA. · Department of Neurology, University of Alabama at Birmingham, Birminham, Alabama, USA. · HudsonAlpha Institute for Biotechnology, Huntsville, Alabama. · Center for Nursing Data Science, Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, Georgia, USA. ·Mov Disord · Pubmed #29572994.

ABSTRACT: BACKGROUND: Gastrointestinal symptoms are common in Parkinson's disease and frequently precede the development of motor impairments. Intestinal inflammation has been proposed as a driver of disease pathology, and evaluation of inflammatory mediators in stool could possibly identify valuable early-stage biomarkers. We measured immune- and angiogenesis-related proteins in human stool to examine inflammatory profiles associated with Parkinson's disease. METHODS: Stool samples and subjects' self-reported metadata were obtained from 156 individuals with Parkinson's disease and 110 without, including spouse and nonhousehold controls. Metadata were probed for disease-associated differences, and levels of 37 immune and angiogenesis factors in stool homogenates were measured by multiplexed immunoassay and compared across experimental groups. RESULTS: Parkinson's disease patients reported greater incidence of intestinal disease and digestive problems than controls. Direct comparison of levels of stool analytes in patients and controls revealed elevated vascular endothelial growth factor receptor 1, interleukin-1α, and CXCL8 in patients' stool. Paired comparison of patients and spouses suggested higher levels of multiple factors in patients, but this was complicated by sex differences. Sex, body mass index, a history of smoking, and use of probiotics were found to strongly influence levels of stool analytes. Multivariate analysis accounting for these and other potential confounders confirmed elevated levels of interleukin-1α and CXCL8 and also revealed increased interleukin-1β and C-reactive protein in stool in Parkinson's disease. These differences were not dependent on subject age or disease duration. CONCLUSIONS: Levels of stool immune factors indicate that intestinal inflammation is present in patients with Parkinson's disease. © 2018 International Parkinson and Movement Disorder Society.

7 Article Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease. 2018

Cholerton, Brenna / Johnson, Catherine O / Fish, Brian / Quinn, Joseph F / Chung, Kathryn A / Peterson-Hiller, Amie L / Rosenthal, Liana S / Dawson, Ted M / Albert, Marilyn S / Hu, Shu-Ching / Mata, Ignacio F / Leverenz, James B / Poston, Kathleen L / Montine, Thomas J / Zabetian, Cyrus P / Edwards, Karen L. ·Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA. Electronic address: bchol@stanford.edu. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. · Portland Veterans Affairs Health Care System, Portland, OR, USA; Department of Neurology, Oregon Health and Science University, Portland, OR, USA. · Neurodegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Neurodegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA; Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. · Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. · Department of Neurology and Neurological Sciences, Stanford School of Medicine, Palo Alto, CA, USA. · Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA. · Department of Epidemiology, University of California, Irvine, School of Medicine, Irvine, CA, USA. ·Parkinsonism Relat Disord · Pubmed #29478836.

ABSTRACT: INTRODUCTION: Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease. METHODS: Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD. RESULTS: Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males. CONCLUSIONS: This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD.

8 Article The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study. 2018

Liu, Shu-Ying / Wile, Daryl J / Fu, Jessie Fanglu / Valerio, Jason / Shahinfard, Elham / McCormick, Siobhan / Mabrouk, Rostom / Vafai, Nasim / McKenzie, Jess / Neilson, Nicole / Perez-Soriano, Alexandra / Arena, Julieta E / Cherkasova, Mariya / Chan, Piu / Zhang, Jing / Zabetian, Cyrus P / Aasly, Jan O / Wszolek, Zbigniew K / McKeown, Martin J / Adam, Michael J / Ruth, Thomas J / Schulzer, Michael / Sossi, Vesna / Stoessl, A Jon. ·Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada; Department of Neurobiology, Neurology, and Geriatrics, Xuanwu Hospital Capital Medical University, Beijing, China. · University of British Columbia-Okanagan Southern Medical Program, Kelowna, BC, Canada. · Department of Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada. · Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada. · Department of Neurobiology, Neurology, and Geriatrics, Xuanwu Hospital Capital Medical University, Beijing, China. · Department of Pathology, University of Washington, Seattle, WA, USA. · Veterans Affairs Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA. · Norwegian University of Science and Technology, Trondheim, Norway. · Mayo Clinic, Jacksonville, FL, USA. · Department of Chemistry, University of British Columbia, Vancouver, BC, Canada. · TRIUMF (Tri-University Meson Facility), Vancouver, BC, Canada. · Djavad Mowafaghian Centre for Brain Health, Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada. Electronic address: jstoessl@mail.ubc.ca. ·Lancet Neurol · Pubmed #29456161.

ABSTRACT: BACKGROUND: Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease. METHODS: Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N- FINDINGS: We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age. INTERPRETATION: LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinson's disease compared with healthy controls and in LRRK2 mutation carriers with Parkinson's disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells. FUNDING: Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation.

9 Article Association of a neuronal nitric oxide synthase gene polymorphism with levodopa-induced dyskinesia in Parkinson's disease. 2018

Santos-Lobato, Bruno Lopes / Borges, Vanderci / Ferraz, Henrique Ballalai / Mata, Ignacio Fernandez / Zabetian, Cyrus P / Tumas, Vitor. ·Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Research Support on Applied Neuroscience (NAPNA-USP), São Paulo, Brazil. Electronic address: bruls4@usp.br. · Department of Neurology, Federal University of São Paulo, São Paulo, SP, Brazil. Electronic address: vanderci.borges@gmail.com. · Department of Neurology, Federal University of São Paulo, São Paulo, SP, Brazil. Electronic address: henrique_ferraz@uol.com.br. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington, Seattle, WA, USA. Electronic address: nachofm@uw.edu. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington, Seattle, WA, USA. Electronic address: zabetian@u.washington.edu. · Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Research Support on Applied Neuroscience (NAPNA-USP), São Paulo, Brazil. Electronic address: tumasv@rnp.fmrp.usp.br. ·Nitric Oxide · Pubmed #28602747.

ABSTRACT: BACKGROUND: Levodopa-induced dyskinesia (LID) is a common complication of advanced Parkinson's disease (PD). PD physiopathology is associated with dopaminergic and non-dopaminergic pathways, including the nitric oxide system. The present study aims to examine the association of a neuronal nitric oxide synthase gene (NOS1) single nucleotide polymorphism (rs2682826) with LID in PD patients. METHODS AND RESULTS: We studied 186 PD patients using levodopa. The presence of LID was defined as a MDS-UPDRS Part IV score ≥1 on item 4.1. We tested for association between NOS1 rs2682826 and the presence, daily frequency, and functional impact of LID using regression models, adjusting for important covariates. There was no significant association between genotype and any of the LID-related variables examined. CONCLUSIONS: Our results suggest that this NOS1 polymorphism does not contribute to LID susceptibility or severity. However, additional studies that include a comprehensive set of NOS1 variants will be needed to fully define the role of this gene in LID.

10 Article Homocysteine and cognitive function in Parkinson's disease. 2017

Licking, Nicole / Murchison, Charles / Cholerton, Brenna / Zabetian, Cyrus P / Hu, Shu-Ching / Montine, Thomas J / Peterson-Hiller, Amie L / Chung, Kathryn A / Edwards, Karen / Leverenz, James B / Quinn, Joseph F. ·Department of Neurology, Oregon Health and Science University, Portland, OR, United States; Parkinson's Disease Research, Education, and Clinical Center, Portland Veterans Affairs Medical Center, Portland, OR, United States. · Department of Neurology, Oregon Health and Science University, Portland, OR, United States. · Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, United States. · Parkinson's Disease Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, United States; Department of Neurology, University of Washington, Seattle, WA, United States. · Department of Pathology, Stanford University, Palo Alto, CA, United States. · Department of Epidemiology, University of California at Irvine, United States. · Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States. · Department of Neurology, Oregon Health and Science University, Portland, OR, United States; Parkinson's Disease Research, Education, and Clinical Center, Portland Veterans Affairs Medical Center, Portland, OR, United States. Electronic address: quinnj@ohsu.edu. ·Parkinsonism Relat Disord · Pubmed #28807493.

ABSTRACT: INTRODUCTION: Increased plasma homocysteine (HC) is a risk factor for dementia in the general population. Levodopa therapy causes increased plasma HC, but it remains unclear whether elevated plasma HC is associated with cognitive impairment in Parkinson's disease (PD). METHODS: The study population includes all participants in the Pacific Northwest Udall Center (PANUC) Clinical cohort at the time of the study, consisting of 294 individuals with PD who had a standardized neuropsychological assessment and plasma collection for HC measurement. We tested the hypothesis that elevated plasma HC is inversely related to cognitive function in patients with PD. RESULTS: As expected, plasma HC was positively associated with age, disease duration, disease severity, and levodopa usage, while cognitive function was associated with age, education, gender, and APOE genotype, so subsequent analyses controlled for these covariates. When plasma HC was dichotomized as normal (<14 μmol/L) or elevated (≥14 μmol/L), subjects with hyper-homocysteinemia had lower scores on Digit Symbol (p = 0.031), Hopkins Verbal Learning Task (HVLT) Delayed Recall (p = 0.004), and semantic verbal fluency (p = 0.049). When examined as a continuous variable, plasma HC was inversely associated with HVLT Delayed Recall (p = 0.009)) and semantic verbal fluency (p = 0.004), but was not significantly related to Digit symbol, Trail-making test, Judgment of Line Orientation, phonemic verbal fluency, MMSE, or MOCA. When analysis was restricted to non-demented subjects (n = 231), the findings were unchanged. CONCLUSIONS: We conclude that plasma HC is significantly associated with some aspects of cognitive function in PD, and may represent a treatable risk factor for cognitive decline in PD.

11 Article Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease. 2017

Mata, Ignacio F / Johnson, Catherine O / Leverenz, James B / Weintraub, Daniel / Trojanowski, John Q / Van Deerlin, Vivianna M / Ritz, Beate / Rausch, Rebecca / Factor, Stewart A / Wood-Siverio, Cathy / Quinn, Joseph F / Chung, Kathryn A / Peterson-Hiller, Amie L / Espay, Alberto J / Revilla, Fredy J / Devoto, Johnna / Yearout, Dora / Hu, Shu-Ching / Cholerton, Brenna A / Montine, Thomas J / Edwards, Karen L / Zabetian, Cyrus P. ·Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. · Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, CA, USA. · Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. · Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA; Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA. · Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute on Aging, University of Pennsylvania, Philadelphia, PA, USA. · Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, CA, USA; Department of Environmental Health Sciences, School of Public Health, University of California Los Angeles, Los Angeles, CA, USA; Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA. · Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA. · Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA. · Portland Veterans Affairs Medical Center, Portland, OR, USA; Department of Neurology, Oregon Health and Science University, Portland, OR, USA. · Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA. · Division of Neurology at Greenville Health System and the University of South Carolina Medical School-Greenville, Greenville, SC, USA. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA. · Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. Electronic address: zabetian@u.washington.edu. ·Neurobiol Aging · Pubmed #28526295.

ABSTRACT: Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (P

12 Article Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. 2017

Wile, Daryl J / Agarwal, Pankaj A / Schulzer, Michael / Mak, Edwin / Dinelle, Katherine / Shahinfard, Elham / Vafai, Nasim / Hasegawa, Kazuko / Zhang, Jing / McKenzie, Jessamyn / Neilson, Nicole / Strongosky, Audrey / Uitti, Ryan J / Guttman, Mark / Zabetian, Cyrus P / Ding, Yu-Shin / Adam, Mike / Aasly, Jan / Wszolek, Zbigniew K / Farrer, Matthew / Sossi, Vesna / Stoessl, A Jon. ·University of British Columbia, Department of Medicine, Vancouver, BC, Canada. Electronic address: dwile@mail.ubc.ca. · Global Hospitals, Mumbai, India. · Department of Statistics, Vancouver, BC, Canada. · Pacific Parkinson's Research Centre, Vancouver, BC, Canada. · Department of Physics and Astronomy, Vancouver, BC, Canada. · Sagamihara National Hospital, Sagamihara, Japan. · Veterans Affairs Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA. · Mayo Clinic, Jacksonville, FL, USA. · Centre for Movement Disorders, Toronto, ON, Canada. · New York University School of Medicine, New York, NY, USA. · TRIUMF, Vancouver, BC, Canada. · Norwegian University of Science and Technology, Trondheim, Norway. · Department of Medical Genetics, Vancouver, BC, Canada. · University of British Columbia, Department of Medicine, Vancouver, BC, Canada; Pacific Parkinson's Research Centre, Vancouver, BC, Canada. ·Lancet Neurol · Pubmed #28336296.

ABSTRACT: BACKGROUND: People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. METHODS: We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage ( FINDINGS: Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and INTERPRETATION: Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. FUNDING: Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada.

13 Article An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression. 2017

Yang, Li / Stewart, Tessandra / Shi, Min / Pottiez, Gwenael / Dator, Romel / Wu, Rui / Aro, Patrick / Schuster, Robert J / Ginghina, Carmen / Pan, Catherine / Gao, Yuqian / Qian, Weijun / Zabetian, Cyrus P / Hu, Shu-Ching / Quinn, Joseph F / Zhang, Jing. ·Department of Pathology, University of Washington, Seattle, WA, USA. · Department of Pathology, No. 3 Hospital of Beijing University, Beijing, China. · Pacific Northwest National Laboratory, Richland, WA, USA. · Parkinson's Disease Research and Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. · Department of Neurology, Oregon Health and Science University, Portland, OR, USA. · Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing, 100083, China. ·Proteomics Clin Appl · Pubmed #28319654.

ABSTRACT: AIM: The alpha-synuclein (α-syn) level in human cerebrospinal fluid (CSF), as measured by immunoassays, is promising as a Parkinson's disease (PD) biomarker. However, the levels of total α-syn are inconsistent among studies with large cohorts and different measurement platforms. Total α-syn level also does not correlate with disease severity or progression. Here, the authors developed a highly sensitive MRM method to measure absolute CSF α-syn peptide concentrations without prior enrichment or fractionation, aiming to discover new candidate biomarkers. RESULTS: Six peptides covering 73% of protein sequence were reliably identified, and two were consistently quantified in cross-sectional and longitudinal cohorts. Absolute concentration of α-syn in human CSF was determined to be 2.1 ng/mL. A unique α-syn peptide, TVEGAGSIAAATGFVK (81-96), displayed excellent correlation with previous immunoassay results in two independent PD cohorts (p < 0.001), correlated with disease severity, and its changes significantly tracked the disease progression longitudinally. CONCLUSIONS: An MRM assay to quantify human CSF α-syn was developed and optimized. Sixty clinical samples from cross-sectional and longitudinal PD cohorts were analyzed with this approach. Although further larger scale validation is needed, the results suggest that α-syn peptide could serve as a promising biomarker in PD diagnosis and progression.

14 Article Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome. 2017

Hill-Burns, Erin M / Debelius, Justine W / Morton, James T / Wissemann, William T / Lewis, Matthew R / Wallen, Zachary D / Peddada, Shyamal D / Factor, Stewart A / Molho, Eric / Zabetian, Cyrus P / Knight, Rob / Payami, Haydeh. ·Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Department of Pediatrics, University of California San Diego, La Jolla, California, USA. · Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA. · Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. · Department of Neurology, Albany Medical College, Albany, New York, USA. · Veterans Affairs Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, Washington, USA. · Center for Microbiome Innovation, University of California San Diego, La Jolla, California, USA. · Center for Genomic Medicine, HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA. ·Mov Disord · Pubmed #28195358.

ABSTRACT: BACKGROUND: There is mounting evidence for a connection between the gut and Parkinson's disease (PD). Dysbiosis of gut microbiota could explain several features of PD. OBJECTIVE: The objective of this study was to determine if PD involves dysbiosis of gut microbiome, disentangle effects of confounders, and identify candidate taxa and functional pathways to guide research. METHODS: A total of 197 PD cases and 130 controls were studied. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from stool. Metadata were collected on 39 potential confounders including medications, diet, gastrointestinal symptoms, and demographics. Statistical analyses were conducted while controlling for potential confounders and correcting for multiple testing. We tested differences in the overall microbial composition, taxa abundance, and functional pathways. RESULTS: Independent microbial signatures were detected for PD (P = 4E-5), participants' region of residence within the United States (P = 3E-3), age (P = 0.03), sex (P = 1E-3), and dietary fruits/vegetables (P = 0.01). Among patients, independent signals were detected for catechol-O-methyltransferase-inhibitors (P = 4E-4), anticholinergics (P = 5E-3), and possibly carbidopa/levodopa (P = 0.05). We found significantly altered abundances of the Bifidobacteriaceae, Christensenellaceae, [Tissierellaceae], Lachnospiraceae, Lactobacillaceae, Pasteurellaceae, and Verrucomicrobiaceae families. Functional predictions revealed changes in numerous pathways, including the metabolism of plant-derived compounds and xenobiotics degradation. CONCLUSION: PD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD. © 2017 International Parkinson and Movement Disorder Society.

15 Article Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. 2017

Irwin, David J / Grossman, Murray / Weintraub, Daniel / Hurtig, Howard I / Duda, John E / Xie, Sharon X / Lee, Edward B / Van Deerlin, Vivianna M / Lopez, Oscar L / Kofler, Julia K / Nelson, Peter T / Jicha, Gregory A / Woltjer, Randy / Quinn, Joseph F / Kaye, Jeffery / Leverenz, James B / Tsuang, Debby / Longfellow, Katelan / Yearout, Dora / Kukull, Walter / Keene, C Dirk / Montine, Thomas J / Zabetian, Cyrus P / Trojanowski, John Q. ·Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K Udall Parkinson's Disease Center Of Excellence, Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: dirwin@mail.med.upenn.edu. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K Udall Parkinson's Disease Center Of Excellence, Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K Udall Parkinson's Disease Center Of Excellence, Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Parkinson's Disease Research, Education and Clinical Center, Michael J Crescenz VA Medical Center, Philadelphia, PA, USA. · Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Parkinson's Disease Research, Education and Clinical Center, Michael J Crescenz VA Medical Center, Philadelphia, PA, USA. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K Udall Parkinson's Disease Center Of Excellence, Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Morris K Udall Parkinson's Disease Center Of Excellence, Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. · Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Pathology, University of Kentucky, Lexington, KY, USA. · Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. · Department of Pathology, Oregon Health and Science University, Portland, OR, USA. · Department of Neurology, Oregon Health and Science University, Portland, OR, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA. · Department of Neurology, Oregon Health and Science University, Portland, OR, USA. · Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic Foundation, Cleveland, OH, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA. · Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA; Northwest Parkinson's Disease Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA. · Department of Epidemiology, University of Washington School of Medicine, Seattle, WA, USA. · Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA. · Department of Pathology, Standford University, Stanford, CA, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA; Pacific Udall Center, University of Washington School of Medicine, Seattle, WA, USA; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; Northwest Parkinson's Disease Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA. ·Lancet Neurol · Pubmed #27979356.

ABSTRACT: BACKGROUND: Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. METHODS: In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. FINDINGS: On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β -4·0, 95% CI -5·5 to -2·6; p<0·0001; R INTERPRETATION: Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. FUNDING: US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).

16 Article Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. 2016

Davis, Marie Y / Johnson, Catherine O / Leverenz, James B / Weintraub, Daniel / Trojanowski, John Q / Chen-Plotkin, Alice / Van Deerlin, Vivianna M / Quinn, Joseph F / Chung, Kathryn A / Peterson-Hiller, Amie L / Rosenthal, Liana S / Dawson, Ted M / Albert, Marilyn S / Goldman, Jennifer G / Stebbins, Glenn T / Bernard, Bryan / Wszolek, Zbigniew K / Ross, Owen A / Dickson, Dennis W / Eidelberg, David / Mattis, Paul J / Niethammer, Martin / Yearout, Dora / Hu, Shu-Ching / Cholerton, Brenna A / Smith, Megan / Mata, Ignacio F / Montine, Thomas J / Edwards, Karen L / Zabetian, Cyrus P. ·Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Department of Neurology, University of Washington School of Medicine, Seattle. · Department of Neurology, University of Washington School of Medicine, Seattle. · Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio. · Department of Psychiatry, University of Pennsylvania, Philadelphia. · Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia. · Department of Neurology, University of Pennsylvania, Philadelphia. · Portland Veterans Affairs Medical Center, Portland, Oregon8Department of Neurology, Oregon Health and Science University, Portland. · Neurodegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland10Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Neurodegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland10Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland11Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland12Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois. · Department of Neurology, Mayo Clinic, Jacksonville, Florida. · Department of Neuroscience, Mayo Clinic, Jacksonville, Florida. · Center for Neurosciences, Feinstein Institute for Medical Research, Manhasset, New York17Department of Neurology, Northwell Health, Manhasset, New York. · Center for Neurosciences, Feinstein Institute for Medical Research, Manhasset, New York. · Veterans Affairs Puget Sound Health Care System, Seattle, Washington18Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle. · Department of Epidemiology, University of California, Irvine, School of Medicine. · Department of Pathology, University of Washington School of Medicine, Seattle. ·JAMA Neurol · Pubmed #27571329.

ABSTRACT: Importance: Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. Objective: To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. Design, Setting, and Participants: The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. Main Outcomes and Measures: Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. Results: Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95% CI, 1.72-7.58; P = .002), E326K (β = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (β = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95% CI, 0.23-0.53; P = .01) and E326K (β = 0.64; 95% CI, 0.43-0.86; P = .002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progressed to mild cognitive impairment or dementia. Conclusions and Relevance: GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

17 Article Arguing against the proposed definition changes of PD. 2016

Boeve, Bradley F / Dickson, Dennis W / Duda, John E / Ferman, Tanis J / Galasko, Douglas R / Galvin, James E / Goldman, Jennifer G / Growdon, John H / Hurtig, Howard I / Kaufer, Daniel I / Kantarci, Kejal / Leverenz, James B / Lippa, Carol F / Lopez, Oscar L / McKeith, Ian G / Singleton, Andrew B / Taylor, Angela / Tsuang, Debby / Weintraub, Daniel / Zabetian, Cyrus P. ·Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Departments of Pathology and Neuroscience, Mayo Clinic, Jacksonville, Florida, USA. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. · Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Jacksonville, Florida, USA. · Department of Neurosciences, University of California, San Diego, California, USA. · Marcus Neuroscience Institute, Florida Atlantic University, Boca Raton, Florida, USA. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Department of Neurology, Harvard Medical School at Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. · Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio, USA. · Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA. · Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Institute of Ageing, Newcastle University, Newcastle upon Tyne, UK. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Lewy Body Dementia Association, Lilburn, Georgia, USA. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA. · Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA. ·Mov Disord · Pubmed #27492190.

ABSTRACT: As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled "Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease." In particular, we suggest that the 1-year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, "PD (dementia with Lewy bodies subtype)," will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

18 Article Identification of genetic modifiers of age-at-onset for familial Parkinson's disease. 2016

Hill-Burns, Erin M / Ross, Owen A / Wissemann, William T / Soto-Ortolaza, Alexandra I / Zareparsi, Sepideh / Siuda, Joanna / Lynch, Timothy / Wszolek, Zbigniew K / Silburn, Peter A / Mellick, George D / Ritz, Beate / Scherzer, Clemens R / Zabetian, Cyrus P / Factor, Stewart A / Breheny, Patrick J / Payami, Haydeh. ·Department of Neurology, University of Alabama at Birmingham, AL, USA. · Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA. · Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, OR, USA. · Department of Neurology, Medical University of Silesia, Katowice, Poland. · Dublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland. · Department of Neurology, Mayo Clinic Jacksonville, FL, USA. · Eskitis Institute for Drug Discovery, Griffith University, Queensland, Australia. · Department of Epidemiology, Fielding School of Public Health and Neurology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · The Neurogenomics Laboratory, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA, USA. · VA Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA, USA. · Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA. · Department of Biostatistics, University of Iowa, Iowa City, IA, USA. · Department of Neurology, University of Alabama at Birmingham, AL, USA haydehpayami@uabmc.edu. · Center for Genomic Medicine, HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA. ·Hum Mol Genet · Pubmed #27402877.

ABSTRACT: Parkinson's disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from the NeuroGenetics Research Consortium (NGRC); an additional 737 familial PD and 2363 non-familial PD were used for replication. In familial PD, two signals were detected and replicated robustly: one mapped to LHFPL2 on 5q14.1 (P

19 Article Smoking and haptoglobin phenotype modulate serum ferritin and haptoglobin levels in Parkinson disease. 2016

Costa-Mallen, Paola / Zabetian, Cyrus P / Hu, Shu-Ching / Agarwal, Pinky / Yearout, Dora / Checkoway, Harvey. ·Bastyr University Research Institute, 14500 Juanita Drive NE, Kenmore, WA, 98028, USA. pcostamallen@bastyr.edu. · Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA, 98108, USA. · Department of Neurology, University of Washington, 325 Ninth Avenue, 3EH70, Seattle, WA, 98104, USA. · Booth Gardner Parkinson's Care Center, Evergreen Health, 12040 NE 128th Street, Mailstop 11, Kirkland, WA, 98034, USA. · Department of Family and Public Health, University of California San Diego, 9500 Gilman Drive #0725, La Jolla, CA, 92093, USA. ·J Neural Transm (Vienna) · Pubmed #27349967.

ABSTRACT: The phenotype Hp 2-1 of haptoglobin has been previously associated with increased risk of Parkinson disease (PD) and with serum iron abnormalities in PD patients. Tobacco smoking has been consistently observed in epidemiology studies to be inversely related to PD risk, with mechanisms that remain uncertain. We recently observed that the protective effect of smoking on PD risk is stronger among subjects of haptoglobin Hp 2-2 and Hp 1-1 phenotypes, and weaker among subjects of haptoglobin Hp 2-1 phenotype. In this PD case-control study, we investigated whether tobacco smoking was associated with changes in serum haptoglobin and ferritin concentration that depended on haptoglobin phenotype among 106 PD patients and 238 controls without PD or other neurodegenerative disorders. Serum ferritin concentration, serum haptoglobin concentration, haptoglobin phenotype, and smoking data information of cases and controls were obtained. Differences in haptoglobin and ferritin concentration by smoking status and pack-years of smoking were calculated as well as regression between pack-years and haptoglobin and ferritin concentration, and the effect of haptoglobin phenotype on these parameters. Tobacco smoking was associated with an elevation in serum haptoglobin concentration, especially among healthy controls of haptoglobin Hp 2-2 phenotype, and with an elevation in ferritin concentration especially among PD patients of haptoglobin Hp 2-1 phenotype. These findings suggest that an elevation in haptoglobin concentration, preferentially among subjects of haptoglobin Hp 2-2 phenotype, could be a contributing factor to the protective effect of smoking on PD risk.

20 Article CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. 2016

Shi, Min / Kovac, Andrej / Korff, Ane / Cook, Travis J / Ginghina, Carmen / Bullock, Kristin M / Yang, Li / Stewart, Tessandra / Zheng, Danfeng / Aro, Patrick / Atik, Anzari / Kerr, Kathleen F / Zabetian, Cyrus P / Peskind, Elaine R / Hu, Shu-Ching / Quinn, Joseph F / Galasko, Douglas R / Montine, Thomas J / Banks, William A / Zhang, Jing. ·Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA. · Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA; Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovak Republic. · Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA. · Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA; Department of Pathology, Peking University Health Science Center and Peking University Third Hospital, Beijing, China. · Department of Biostatistics, University of Washington, Seattle, WA, USA. · Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. · Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA; Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. · Department of Neurology, Oregon Health and Science University, Portland, OR, USA. · Department of Neurosciences and Shiley-Marcos Alzheimer's Disease Research Center, University of California at San Diego, La Jolla, CA, USA. · Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA; Department of Pathology, Peking University Health Science Center and Peking University Third Hospital, Beijing, China. Electronic address: zhangj@uw.edu. ·Alzheimers Dement · Pubmed #27234211.

ABSTRACT: INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood. METHODS: Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects. RESULTS: The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau. CONCLUSIONS: Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD.

21 Article The discovery of LRRK2 p.R1441S, a novel mutation for Parkinson's disease, adds to the complexity of a mutational hotspot. 2016

Mata, Ignacio F / Davis, Marie Y / Lopez, Alexis N / Dorschner, Michael O / Martinez, Erica / Yearout, Dora / Cholerton, Brenna A / Hu, Shu-Ching / Edwards, Karen L / Bird, Thomas D / Zabetian, Cyrus P. ·Veterans Affairs Puget Sound Health Care System, Seattle, Washington. · Department of Neurology, University of Washington School of Medicine, Seattle, Washington. · Department of Medicine, University of Michigan, Ann Arbor, Michigan. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington. · Department of Pathology, University of Washington, Seattle, Washington. · Department of Epidemiology, University of California, Irvine, California. · Veterans Affairs Puget Sound Health Care System, Seattle, Washington. zabetian@u.washington.edu. · Department of Neurology, University of Washington School of Medicine, Seattle, Washington. zabetian@u.washington.edu. ·Am J Med Genet B Neuropsychiatr Genet · Pubmed #27111571.

ABSTRACT: Mutations in the LRRK2 gene result in autosomal dominant, late onset Parkinson's disease (PD). Three such mutations (p.R1441C, p.R1441G, and p.R1441H) are known to occur within codon 1441, and haplotype analyses indicate that each one has arisen independently on multiple occasions. We sequenced the entire coding region of 18 casual genes for PD or other parkinsonian neurodegenerative disorders in the proband of a family with autosomal dominant PD. We discovered a new missense mutation in the LRRK2 gene, c.4321C>A (p.R1441S). The mutation was predicted to be highly deleterious in silico (Combined Annotation Dependent Depletion score of 25.5) and segregated with disease in the pedigree. The clinical characteristics of affected family members were similar to those described in PD families with other mutations in LRRK2 codon 1441 and included resting tremor, rigidity, bradykinesia, unilateral onset, and a good response to levodopa. Age at onset ranged from 41 to 76. Two of the affected members of the pedigree underwent detailed, longitudinal neuropsychological testing, and both displayed evidence of mild cognitive deficits at or slightly preceding the onset of motor symptoms. LRRK2 p.R1441S represents the fourth pathogenic mutation observed within codon 1441 and its discovery adds to the remarkable complexity of a mutational hotspot within the ROC domain of the LRRK2 protein. © 2016 Wiley Periodicals, Inc.

22 Article Transcriptomic Profiling of Extracellular RNAs Present in Cerebrospinal Fluid Identifies Differentially Expressed Transcripts in Parkinson's Disease. 2016

Hossein-Nezhad, Arash / Fatemi, Roya Pedram / Ahmad, Rili / Peskind, Elaine R / Zabetian, Cyrus P / Hu, Shu-Ching / Shi, Min / Wahlestedt, Claes / Zhang, Jing / Faghihi, Mohammad Ali. ·Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA. · Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA. · Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. · Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. · Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. · Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA. · John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. ·J Parkinsons Dis · Pubmed #26889637.

ABSTRACT: BACKGROUND: Parkinson's disease (PD) is a debilitating neurological disorder for which prognostic and diagnostic biomarkers are lacking. Cerebrospinal fluid (CSF) is an accessible body fluid that comes into direct contact with the central nervous system (CNS) and acts as a nuclease-free repository where RNA transcripts shed by brain tissues can reside for extended periods of time. OBJECTIVE: We studied the RNA species present in the CSF of PD patients to identify novel diagnostic biomarkers. METHODS: Small volumes of CSF from 27 PD patients and 30 healthy age- and sex-matched controls were used for RNA extraction followed by next-generation sequencing (RNA-seq) using the Illumina platform. CSF contains a number of fragmented RNA species that were individually sequenced and analyzed. Comparing PD to control subjects, we observed a pool of dysregulated sequencing tags that were further analyzed and validated by quantitative real-time PCR (qRT-PCR). RESULTS: A total of 201 differentially expressed sequencing tags (DETs), including 92 up-regulated and 109 down-regulated DETs were identified. We validated the following DETs by real time PCR in the patient samples: Dnmt1, Ezh2, CCR3, SSTR5,PTPRC, UBC, NDUFV2, BMP7, SCN9, SCN9 antisense (AC010127.3), and long noncoding RNAs AC079630 and UC001lva.4 (close to the LRRK2 gene locus), as potential PD biomarkers. CONCLUSIONS: The CSF is a unique environment that contains many species of RNA. Our work demonstrates that CSF can potentially be used to identify biomarkers for the detection and tracking of disease progression and evaluation of therapeutic outcomes.

23 Article GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. 2016

Mata, Ignacio F / Leverenz, James B / Weintraub, Daniel / Trojanowski, John Q / Chen-Plotkin, Alice / Van Deerlin, Vivianna M / Ritz, Beate / Rausch, Rebecca / Factor, Stewart A / Wood-Siverio, Cathy / Quinn, Joseph F / Chung, Kathryn A / Peterson-Hiller, Amie L / Goldman, Jennifer G / Stebbins, Glenn T / Bernard, Bryan / Espay, Alberto J / Revilla, Fredy J / Devoto, Johnna / Rosenthal, Liana S / Dawson, Ted M / Albert, Marilyn S / Tsuang, Debby / Huston, Haley / Yearout, Dora / Hu, Shu-Ching / Cholerton, Brenna A / Montine, Thomas J / Edwards, Karen L / Zabetian, Cyrus P. ·Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA. · Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA. · Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA. · Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA. · Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, California, USA. · Department of Environmental Health Sciences, School of Public Health, University of California Los Angeles, Los Angeles, California, USA. · Department of Neurology, University of California Los Angeles, Los Angeles, California, USA. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. · Portland Veterans Affairs Medical Center, Portland, Oregon, USA. · Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio, USA. · Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Solomon H. Snyder Department of Neuroscience and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA. · Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA. · Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, California, USA. ·Mov Disord · Pubmed #26296077.

ABSTRACT: BACKGROUND: Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. METHODS: We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections. RESULTS: Mutation carriers (n = 60; 4.4%) and E326K carriers (n = 65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio = 5.1; P = 9.7 × 10(-6) ; E326K, odds ratio = 6.4; P = 5.7 × 10(-7) ) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc ] = 9.0 × 10(-4) ; E326K, Pc  = 0.036), Trail Making B-A (mutations, Pc  = 0.018; E326K, Pc  = 0.018), and Benton Judgment of Line Orientation (mutations, Pc  = 0.0045; E326K, Pc  = 0.0013). CONCLUSIONS: Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.

24 Article Screening of cognitive impairment in patients with Parkinson's disease: diagnostic validity of the Brazilian versions of the Montreal Cognitive Assessment and the Addenbrooke's Cognitive Examination-Revised. 2015

Sobreira, Emmanuelle / Pena-Pereira, Márcio A / Eckeli, Alan L / Sobreira-Neto, Manoel A / Chagas, Marcos H N / Foss, Maria P / Cholerton, Brenna / Zabetian, Cyrus P / Mata, Ignacio F / Tumas, Vitor. ·Departamento de Neurociências e Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. · Department of Psychiatry and Behavioral Sciences, School of Medicine, University of Washington, Seattle, WA, USA. · Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA. ·Arq Neuropsiquiatr · Pubmed #26517216.

ABSTRACT: OBJECTIVE: The aim of the present study is to examine the accuracy of the Brazilian versions of the Montreal Cognitive Assessment (MoCA) and the Addenbrooke's Cognitive Examination-Revised (ACE-R) to screen for mild cognitive impairment (PDMCI) and dementia (PDD) in patients with Parkinson's disease (PD). METHOD: Both scales were administered to a final convenience sample of 79 patients with PD. Patients were evaluated by a neurologist, a psychiatrist and a neuropsychologist using UPDRS, Hoehn and Yahr and Schwab and England scales, global deterioration scale, a psychiatric structured interview, Mattis Dementia Rating Scale and other cognitive tests. RESULTS: There were 32 patients with PDMCI and 17 patients with PDD. The MoCA and the ACE-R were able to discriminate patients with PDD from the others. CONCLUSION: Both scales showed to be useful to screen for dementia but not for mild cognitive impairment in patients with PD.

25 Article The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease. 2015

Mata, Ignacio F / Jang, Yongwoo / Kim, Chun-Hyung / Hanna, David S / Dorschner, Michael O / Samii, Ali / Agarwal, Pinky / Roberts, John W / Klepitskaya, Olga / Shprecher, David R / Chung, Kathryn A / Factor, Stewart A / Espay, Alberto J / Revilla, Fredy J / Higgins, Donald S / Litvan, Irene / Leverenz, James B / Yearout, Dora / Inca-Martinez, Miguel / Martinez, Erica / Thompson, Tiffany R / Cholerton, Brenna A / Hu, Shu-Ching / Edwards, Karen L / Kim, Kwang-Soo / Zabetian, Cyrus P. ·Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. nachofm@uw.edu. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. nachofm@uw.edu. · Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA, USA. yjang@mclean.harvard.edu. · Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA, USA. chkim@mclean.harvard.edu. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. dshanna@uw.edu. · Department of Pathology, University of Washington, Seattle, WA, USA. dshanna@uw.edu. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. mod@uw.edu. · Department of Pathology, University of Washington, Seattle, WA, USA. mod@uw.edu. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. asamii@uw.edu. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. asamii@uw.edu. · Booth Gardner Parkinson's Care Center, Evergreen Hospital Medical Center, Kirkland, WA, USA. PAgarwal2@evergreenhealthcare.org. · Virginia Mason Medical Center, Seattle, WA, USA. John.Roberts@vmmc.org. · Department of Neurology, University of Colorado, Denver, USA. Olga.Klepitskaya@ucdenver.edu. · Department of Neurology, University of Utah, Salt Lake City, UT, USA. David.Shprecher@hsc.utah.edu. · Parkinson's Disease Research, Education, and Clinical Center, Portland Veterans Affairs Medical Center, Portland, OR, USA. chungka@ohsu.edu. · Department of Neurology, Oregon Health and Science University, Portland, OR, USA. chungka@ohsu.edu. · Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA. sfactor@emory.edu. · Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA. espayaj@ucmail.uc.edu. · Division of Neurology at Greenville Health System and the University of South Carolina Medical School-Greenville, Greenville, SC, USA. revillf@gmail.com. · Samuel Stratton Veterans Affairs Medical Center, Albany, NY, USA. higgind@mail.amc.edu. · Movement Disorder Center, Department of Neurosciences, University of California, San Diego, CA, USA. ilitvan@ucsd.edu. · Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA. leverej@ccf.org. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. doray@uw.edu. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. doray@uw.edu. · Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru. miguel.inca.martinez@gmail.com. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. ekovak@uw.edu. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. ekovak@uw.edu. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. iamtiff@uw.edu. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. bchol@uw.edu. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. bchol@uw.edu. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. shuching@uw.edu. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. shuching@uw.edu. · Department of Epidemiology, University of California, Irvine, CA, USA. kedward1@uci.edu. · Molecular Neurobiology Laboratory, Department of Psychiatry and Program in Neuroscience, McLean Hospital/Harvard Medical School, Belmont, MA, USA. kskim@mclean.harvard.edu. · Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. zabetian@u.washington.edu. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. zabetian@u.washington.edu. ·Mol Neurodegener · Pubmed #26399558.

ABSTRACT: OBJECTIVE: To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD). METHODS: We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. RESULTS: We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. CONCLUSIONS: Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders.

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