Publications by authors named "Rachel Saunders-Pullman"

101 Publications

Genetic Testing for Parkinson Disease: Are We Ready?

Neurol Clin Pract 2021 Feb;11(1):69-77

Department of Medical and Molecular Genetics (LC, JS, TF), Indiana University School of Medicine, Indianapolis; The Michael J. Fox Foundation for Parkinson's Research (CK, TH), New York; Parkinson's Foundation (AN), Miami, FL; Department of Neurology (JW, KP), Indiana University School of Medicine, Indianapolis; Department of Neurology (RNA), Columbia University Irving Medical Center, New York; Institute of Neurogenetics (CK), University of Lübeck, Germany; Department of Neurology (RS-P), Mount Sinai Beth Israel, New York; and Parkinson's Disease and Movement Disorders Center (TS), Northwestern University Feinberg School of Medicine, Chicago IL.

Purpose Of Review: With the advent of precision medicine and demand for genomic testing information, we may question whether it is time to offer genetic testing to our patients with Parkinson disease (PD). This review updates the current genetic landscape of PD, describes what genetic testing may offer, provides strategies for evaluating whom to test, and provides resources for the busy clinician.

Recent Findings: Patients with PD and their relatives, in various settings, have expressed an interest in learning their PD genetic status; however, physicians may be hesitant to widely offer testing due to the perceived low clinical utility of PD genetic test results. The rise of clinical trials available for patients with gene-specific PD and emerging information on genotype-phenotype correlations are starting to shift this discussion about testing.

Summary: By learning more about the various genetic testing options for PD and utility of results for patients and their care, clinicians may become more comfortable with widespread PD genetic testing in the research and clinical setting.
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http://dx.doi.org/10.1212/CPJ.0000000000000831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101316PMC
February 2021

Genome-wide association studies of LRRK2 modifiers of Parkinson's disease.

Ann Neurol 2021 May 2. Epub 2021 May 2.

23andMe, Inc., Sunnyvale, California, U.S.A.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.

Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genome-wide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these two proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value = 1.1E-07; age-at-onset top variant: P-value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.

Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.26094DOI Listing
May 2021

Association of Dual LRRK2 G2019S and GBA Variations With Parkinson Disease Progression.

JAMA Netw Open 2021 Apr 1;4(4):e215845. Epub 2021 Apr 1.

Department of Neurology, Mount Sinai Beth Israel, and Icahn School of Medicine, Mount Sinai, New York, New York.

Importance: Despite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual LRRK2 and GBA variations Parkinson disease (PD) than in GBA variation PD alone.

Objective: To evaluate the association of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in PD.

Design, Setting, And Participants: This longitudinal cohort study of continuous measures in LRRK2 PD, GBA PD, LRRK2/GBA PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-LRRK2-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for GBA and LRRK2 variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020.

Main Outcomes And Measures: The associations of LRRK2 G2019S and GBA genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale-Part III scores were examined using linear mixed effects models with PD duration as the time scale.

Results: Among 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had GBA PD, 155 (13.0%) had LRRK2 PD, 21 (1.8%) had LRRK2/GBA PD, and 889 (74.5%) had idiopathic PD. Patients with GBA PD had faster decline in MoCA than those with LRRK2/GBA PD (B [SE], -0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], -0.33 [0.09] points/y; P < .001), or idiopathic PD (B [SE], -0.23 [0.08] points/y; P = .005). There was a LRRK2 G2019S × GBA interaction in MoCA decline (B [SE], 0.22 [0.11] points/y; P = .04), but not after excluding severe GBA variations (B [SE], 0.12 [0.11] points/y; P = .28). Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004).

Conclusions And Relevance: These findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD. This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe GBA variation is warranted.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.5845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060834PMC
April 2021

Cognitive Functioning of Glucocerebrosidase () Non-manifesting Carriers.

Front Neurol 2021 26;12:635958. Epub 2021 Feb 26.

Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, NY, United States.

Mutations and variants in the glucocerebrosidase () gene are among the most common genetic risk factors for the development of Parkinson's disease (PD). Yet, penetrance is markedly reduced, and less is known about the burden of carrying a single mutation among those without diagnosed PD. Motor, cognitive, psychiatric, and olfactory functioning were assessed in 30 heterozygous mutation carriers without PD (the majority of whom had mild mutations) and 49 non-carriers without PD. Study focus was on domains affected in mutation carriers with PD, as well as those previously shown to be abnormal in mutation carriers without PD. mutation carriers showed poorer performance on the Stroop interference measure of executive functioning when controlling for age. There were no group differences in verbal memory, Montreal Cognitive Assessment (MoCA), overall motor score, or presence of REM sleep behavior disorder or depression. Although total olfaction scores did not differ, mutation carriers with hyposmia had lower global cognition scores than those without hyposmia. As anticipated by the low penetrance of mutations, these findings suggest that pre-manifest non-motor or motor features of PD may not present in most mutation carriers. However, there is support that there may be a subtle difference in executive functioning among some non-manifesting heterozygous mutation carriers, and, combined with olfaction, this may warrant additional scrutiny as a potential biomarker for pre-manifest and pre-clinical related PD.
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http://dx.doi.org/10.3389/fneur.2021.635958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952874PMC
February 2021

Seizure-related 6 homolog like 2 autoimmunity: Neurologic syndrome and antibody effects.

Neurol Neuroimmunol Neuroinflamm 2021 01 3;8(1). Epub 2020 Nov 3.

From the Neuroimmunology Program (J.L., M.G., M.P.-P., E.M.-H., J.P., A.S., J.D., L.S., F.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Service of Neurology (M.G., E.M.-H., A.S., J.D.), Hospital Clinic, Barcelona; Centro de Investigación Biomédica en Red (M.G., J.D., L.S.), Enfermedades Raras (CIBERER); Immunology Department (R.R.-G.), Centre Diagnòstic Biomèdic, Hospital Clinic, Barcelona; Neurology Department (L.G.-F.), Hospital General San Jorge, Huesca, Spain; Leiden University Medical Center (J.V.), Leiden, The Netherlands; Icahn School of Medicine (R.S.-P.), Mount Sinai Beth Israel, New York; Massachussetts General Hospital (L.R.-G.), Department of Neurology, Boston; UCSF Department of Neurology Memory and Aging Center (M.D.G.), San Francisco, CA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain; and Dr. Petit-Pedrol is now with Interdisciplinary Institute for Neuroscience, UMR 5297, Université de Bordeaux, Bordeaux, France.

Objective: To describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures.

Methods: SEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons.

Results: In addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54-69 years), and 2 were female. Patients presented with subacute gait ataxia, dysarthria, and mild extrapyramidal symptoms. Initial brain MRI was normal, and CSF pleocytosis was found in only 1 patient. None improved with immunotherapy. SEZ6L2-abs recognized conformational epitopes. IgG4 SEZ6L2-abs were found in all 4 patients, and it was the predominant subclass in 2. SEZ6L2-abs did not alter the number of total or synaptic SEZ6L2 or the AMPA glutamate receptor 1 (GluA1) clusters on the surface of hippocampal neurons.

Conclusions: SEZ6L2-abs associate with a subacute cerebellar syndrome with frequent extrapyramidal symptoms. The potential pathogenic effect of the antibodies is not mediated by internalization of the antigen.
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http://dx.doi.org/10.1212/NXI.0000000000000916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641326PMC
January 2021

Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.

Neurology 2021 01 12;96(4):e563-e574. Epub 2020 Oct 12.

From the Departments of Biomedical Engineering (A.G.S., S.B.B.) and Neurology (A.G.S.), Case Western University School of Medicine; Neurological Institute (A.G.S.), University Hospitals Cleveland; Neurology Service (A.G.S.), Louis Stokes Cleveland VA Medical Center, OH; Department of Neurology (L.S., G.K.-B., A.F., S. Factor, H.A.J.), Human Genetics (H.A.J.), and Pediatrics (H.A.J.), Emory University School of Medicine, Atlanta, GA; Institute of Neurogenetics (C.K., J.J., S.L., N.B., A.M., T.B.), University of Lübeck, Germany; Department of Neurology (M.V., E.R., C.B.), Pitié-Salpêtrière Hospital, Paris, France; Department of Neurology (J.J.), Baylor College of Medicine, Houston, TX; Neurology and Neurosurgery (J.J.-S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Neurology (N.P.), Henry Ford Health System, West Bloomfield, MI; Department of Psychiatry and Neurology (L.M.), Baylor College of Medicine, Houston, TX; Department of Neurological Sciences (C.C.), Rush University Medical Center, Chicago, IL; Department of Neurology (R.L.B.), University of Rochester, NY; Department of Neurology (B.D.B.), University of Colorado School of Medicine, Aurora; Department of Neurology (I.M., A.W.S.), Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville; Department of Neurology (S.G.R.), University of Maryland School of Medicine, Baltimore; University of Tennessee Health Science Center (M.S.L.), Memphis; Department of Neurosciences (A.B.), Mental Health and Sensory Organs, Suicide Prevention Center, Sant'Andrea Hospital, Sapienza University of Rome; IRCCS Neuromed (G.F.), Pozzilli, Italy; The University of Alabama at Birmingham (N.S.); Methodist Neurological Institute (W.O.), Houston, TX; Department of Neurology (S.P.R.), University of New Mexico Health Sciences Center, Albuquerque; Department of Neurology (R.S.-P.), Mount Sinai Beth Israel, New York, NY; Lou Ruvo Center for Brain Health (Z.M.), Cleveland Clinic, Las Vegas, NV; Booth Gardner Parkinson's Care Center (P.A.), Kirkland, WA; Mayo Clinic (C.A.), Scottsdale, AZ; Andre Barbeau Movement Disorders Unit (S.C.), Montreal University Hospital Center (CHUM); Movement Disorder Clinic (S.H.F.), Toronto Western Hospital, Division of Neurology University of Toronto, Canada; UC Davis School of Medicine (A.B.), Sacramento; The Parkinson's and Movement Disorder Institute (D.T.), Orange Coast Memorial Medical Center, Fountain Valley, CA; Department of Medicine (O.S.), Medical Genetics, and Pediatrics, University of Alberta, Canada; Department of Neurology (S. Frank), Beth Israel Deaconess Medical Center, Boston, MA; and Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy (J.P.), Washington University School of Medicine, St Louis, MO.

Objective: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia.

Methods: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition.

Results: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics.

Conclusion: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.
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http://dx.doi.org/10.1212/WNL.0000000000011049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905789PMC
January 2021

Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance.

Mov Disord 2020 10 14;35(10):1755-1764. Epub 2020 Jul 14.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown.

Objectives: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD.

Methods: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups.

Results: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (OR , 0.38; 95% CI, 0.21-0.67 and OR , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (OR , 0.19; 95% CI, 0.07-0.50 and OR , 0.51; 95% CI, 0.28-0.91).

Conclusions: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572560PMC
October 2020

Defining research priorities in dystonia.

Neurology 2020 03 25;94(12):526-537. Epub 2020 Feb 25.

From the Division of Clinical Research (C.L.), National Institute of Neurological Disorders and Stroke, National Institutes of Health; Harvard Medical School (L.O., N.S.), Massachusetts General Hospital, Boston, MA; University of Alabama, Birmingham (D.S.), Birmingham, AL; Medical Neurology Branch (M.H.), NINDS, NIH, Bethesda, MD; Division of Neuroscience (B.-A.S., C.S.-F.), NINDS, NIH, Bethesda, MD; Department of Neurology (B.D.B.), University of Colorado Denver, Aurora, CO; Duke University School of Medicine, Durham, NC; RUCDR/Infinite Biologics (J.C.M.), Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ; Washington University School of Medicine (J.S.P.), St Louis, MO; Department of Neurology (S.E.P.R.), University of New Mexico Health Sciences Center, Albuquerque, NM; Department of Neurology (R.S.-P.), Icahn School of Medicine at Mount Sinai, New York, NY; Coriell Institute for Medical Research (L.S.), Camden, NJ; Department of Neuroscience (R.S.), Baylor College of Medicine, Houston, TX; Harvard Medical School (K.S.), Department of Otolaryngology, Head and Neck Surgery, Massachusetts Eye and Ear Institute, Boston, MA; Department of Neurological Surgery (P.A.S.), University of California San Francisco, San Francisco, CA; Division of Extramural Activities (A.T.), NINDS, NIH, Rockville, MD; and Department of Neurology (J.V.), University of Minnesota, Minneapolis, MN.

Objective: Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities.

Methods: The NIH convened leaders in the field for a 2-day workshop. The participants addressed the natural history of the disease, the underlying etiology, the pathophysiology, relevant research technologies, research resources, and therapeutic approaches and attempted to prioritize dystonia research recommendations.

Results: The heterogeneity of dystonia poses challenges to research and therapy development. Much can be learned from specific genetic subtypes, and the disorder can be conceptualized along clinical, etiology, and pathophysiology axes. Advances in research technology and pooled resources can accelerate progress. Although etiologically based therapies would be optimal, a focus on circuit abnormalities can provide a convergent common target for symptomatic therapies across dystonia subtypes. The discussions have been integrated into a comprehensive review of all aspects of dystonia.

Conclusion: Overall research priorities include the generation and integration of high-quality phenotypic and genotypic data, reproducing key features in cellular and animal models, both of basic cellular mechanisms and phenotypes, leveraging new research technologies, and targeting circuit-level dysfunction with therapeutic interventions. Collaboration is necessary both for collection of large data sets and integration of different research methods.
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http://dx.doi.org/10.1212/WNL.0000000000009140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274927PMC
March 2020

LRRK2 and GBA Variants Exert Distinct Influences on Parkinson's Disease-Specific Metabolic Networks.

Cereb Cortex 2020 05;30(5):2867-2878

Center for Neurosciences, The Feinstein Institutes for Medical Research, Manhasset, NY 10030, USA.

The natural history of idiopathic Parkinson's disease (PD) varies considerably across patients. While PD is generally sporadic, there are known genetic influences: the two most common, mutations in the LRRK2 or GBA1 gene, are associated with slower and more aggressive progression, respectively. Here, we applied graph theory to metabolic brain imaging to understand the effects of genotype on the organization of previously established PD-specific networks. We found that closely matched PD patient groups with the LRRK2-G2019S mutation (PD-LRRK2) or GBA1 variants (PD-GBA) expressed the same disease networks as sporadic disease (sPD), but PD-LRRK2 and PD-GBA patients exhibited abnormal increases in network connectivity that were not present in sPD. Using a community detection strategy, we found that the location and modular distribution of these connections differed strikingly across genotypes. In PD-LRRK2, connections were gained within the network core, with the formation of distinct functional pathways linking the cerebellum and putamen. In PD-GBA, by contrast, the majority of functional connections were formed outside the core, involving corticocortical pathways at the network periphery. Strategically localized connections within the core in PD-LRRK2 may maintain PD network activity at lower levels than in PD-GBA, resulting in a less aggressive clinical course.
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http://dx.doi.org/10.1093/cercor/bhz280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197067PMC
May 2020

Cervical dystonia incidence and diagnostic delay in a multiethnic population.

Mov Disord 2020 03 27;35(3):450-456. Epub 2019 Nov 27.

Department of Neurology, School of Medicine, University of California, San Francisco, California, USA.

Background: Current cervical dystonia (CD) incidence estimates are based on small numbers in relatively ethnically homogenous populations. The frequency and consequences of delayed CD diagnosis is poorly characterized.

Objectives: To determine CD incidence and characterize CD diagnostic delay within a large, multiethnic integrated health maintenance organization.

Methods: We identified incident CD cases using electronic medical records and multistage screening of more than 3 million Kaiser Permanente Northern California members from January 1, 2003, to December 31, 2007. A final diagnosis was made by movement disorders specialist consensus. Diagnostic delay was measured by questionnaire and health utilization data. Incidence rates were estimated assuming a Poisson distribution of cases and directly standardized to the 2000 U.S. census. Multivariate logistic regression models were employed to assess diagnoses and behaviors preceding CD compared with matched controls, adjusting for age, sex, and membership duration.

Results: CD incidence was 1.18/100,000 person-years (95% confidence interval [CI], 0.35-2.0; women, 1.81; men, 0.52) based on 200 cases over 15.4 million person-years. Incidence increased with age. Half of the CD patients interviewed reported diagnostic delay. Diagnoses more common in CD patients before the index date included essential tremor (odds ratio [OR] 68.1; 95% CI, 28.2-164.5), cervical disc disease (OR 3.83; 95% CI, 2.8-5.2), neck sprain/strain (OR 2.77; 95% CI, 1.99-3.62), anxiety (OR 2.24; 95% CI, 1.63-3.11) and depression (OR 1.94; 95% CI, 1.4-2.68).

Conclusions: CD incidence is greater in women and increases with age. Diagnostic delay is common and associated with adverse effects. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27927DOI Listing
March 2020

Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition.

Neurobiol Dis 2019 12 16;132:104577. Epub 2019 Aug 16.

Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Dominant mutations of ATP1A3, a neuronal Na,K-ATPase α subunit isoform, cause neurological disorders with an exceptionally wide range of severity. Several new mutations and their phenotypes are reported here (p.Asp366His, p.Asp742Tyr, p.Asp743His, p.Leu924Pro, and a VUS, p.Arg463Cys). Mutations associated with mild or severe phenotypes [rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), or early infantile epileptic encephalopathy (EIEE)] were expressed in HEK-293 cells. Paradoxically, the severity of human symptoms did not correlate with whether there was enough residual activity to support cell survival. We hypothesized that distinct cellular consequences may result not only from pump inactivation but also from protein misfolding. Biosynthesis was investigated in four tetracycline-inducible isogenic cell lines representing different human phenotypes. Two cell biological complications were found. First, there was impaired trafficking of αβ complex to Golgi apparatus and plasma membrane, as well as changes in cell morphology, for two mutations that produced microcephaly or regions of brain atrophy in patients. Second, there was competition between exogenous mutant ATP1A3 (α3) and endogenous ATP1A1 (α1) so that their sum was constant. This predicts that in patients, the ratio of normal to mutant ATP1A3 proteins will vary when misfolding occurs. At the two extremes, the results suggest that a heterozygous mutation that only impairs Na,K-ATPase activity will produce relatively mild disease, while one that activates the unfolded protein response could produce severe disease and may result in death of neurons independently of ion pump inactivation.
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http://dx.doi.org/10.1016/j.nbd.2019.104577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397496PMC
December 2019

Inflammatory Bowel Disease and Parkinson's Disease: A Reply to Letter to the Editor of Shih-Wei Lai.

Inflamm Bowel Dis 2019 09;25(10):e127

Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1093/ibd/izz181DOI Listing
September 2019

Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls.

Mov Disord 2019 09 26;34(9):1392-1398. Epub 2019 Jul 26.

Department of Neurology, Mount Sinai Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls.

Methods: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients.

Results: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients.

Conclusions: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754269PMC
September 2019

When to Start Levodopa Therapy for Parkinson's Disease.

N Engl J Med 2019 01;380(4):389-390

From the Icahn School of Medicine at Mt. Sinai, New York.

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http://dx.doi.org/10.1056/NEJMe1814611DOI Listing
January 2019

DMS as an orthogonal separation to LC/ESI/MS/MS for quantifying isomeric cerebrosides in plasma and cerebrospinal fluid.

J Lipid Res 2019 01 9;60(1):200-211. Epub 2018 Nov 9.

Neural Regeneration Laboratory and India Taylor Lipidomics Research Platform, Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada

Cerebrosides, including glucosylceramides (GlcCers) and galactosylceramides (GalCers), are important membrane components of animal cells with deficiencies resulting in devastating lysosomal storage disorders. Their quantification is essential for disease diagnosis and a better understanding of disease mechanisms. The simultaneous quantification of GlcCer and GalCer isomers is, however, particularly challenging due to their virtually identical structures. To address this challenge, we developed a new LC/MS-based method using differential ion mobility spectrometry (DMS) capable of rapidly and reproducibly separating and quantifying isomeric cerebrosides in a single run. We show that this LC/ESI/DMS/MS/MS method exhibits robust quantitative performance within an analyte concentration range of 2.8-355 nM. We further report the simultaneous quantification of nine GlcCers (16:0, 18:0, 20:0, 22:0, 23:0, 24:1, 24:0, 25:0, and 26:0) and five GalCers (16:0, 22:0, 23:0, 24:1, and 24:0) molecular species in human plasma, as well as six GalCers (18:0, 22:0, 23:0, 24:1, 24:0 and 25:0) and two GlcCers (24:1 and 24:0) in human cerebrospinal fluid. Our method expands the potential of DMS technology in the field of glycosphingolipid analysis for both biomarker discovery and drug screening by enabling the unambiguous assignment and quantification of cerebroside lipid species in biological samples.
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http://dx.doi.org/10.1194/jlr.D089797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314254PMC
January 2019

DMS as an orthogonal separation to LC/ESI/MS/MS for quantifying isomeric cerebrosides in plasma and cerebrospinal fluid.

J Lipid Res 2019 01 9;60(1):200-211. Epub 2018 Nov 9.

Neural Regeneration Laboratory and India Taylor Lipidomics Research Platform, Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada

Cerebrosides, including glucosylceramides (GlcCers) and galactosylceramides (GalCers), are important membrane components of animal cells with deficiencies resulting in devastating lysosomal storage disorders. Their quantification is essential for disease diagnosis and a better understanding of disease mechanisms. The simultaneous quantification of GlcCer and GalCer isomers is, however, particularly challenging due to their virtually identical structures. To address this challenge, we developed a new LC/MS-based method using differential ion mobility spectrometry (DMS) capable of rapidly and reproducibly separating and quantifying isomeric cerebrosides in a single run. We show that this LC/ESI/DMS/MS/MS method exhibits robust quantitative performance within an analyte concentration range of 2.8-355 nM. We further report the simultaneous quantification of nine GlcCers (16:0, 18:0, 20:0, 22:0, 23:0, 24:1, 24:0, 25:0, and 26:0) and five GalCers (16:0, 22:0, 23:0, 24:1, and 24:0) molecular species in human plasma, as well as six GalCers (18:0, 22:0, 23:0, 24:1, 24:0 and 25:0) and two GlcCers (24:1 and 24:0) in human cerebrospinal fluid. Our method expands the potential of DMS technology in the field of glycosphingolipid analysis for both biomarker discovery and drug screening by enabling the unambiguous assignment and quantification of cerebroside lipid species in biological samples.
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http://dx.doi.org/10.1194/jlr.D089797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314254PMC
January 2019

Repeated Spiral Drawings in Essential Tremor: a Possible Limb-Based Measure of Motor Learning.

Cerebellum 2019 Apr;18(2):178-187

Department of Neurology, Clinical Motor Physiology Laboratory, Columbia University Medical Center, 710 West 168th Street, New York, NY, 10032, USA.

To investigate changes in tremor severity over repeated spiral drawings to assess whether learning deficits can be evaluated directly in a limb in essential tremor (ET). A motor learning deficit in ET, possibly mediated by cerebellar pathways, has been established in eye-blink conditioning studies, but not paradigms measuring from an affected, tremulous limb. Computerized spiral analysis captures multiple characteristics of Archimedean spirals and quantifies performance through calculated indices. Sequential spiral drawing has recently been suggested to demonstrate improvement across trials among ET subjects. One hundred and sixty-one ET and 80 age-matched control subjects drew 10 consecutive spirals on a digitizing tablet. Degree of severity (DoS), a weighted, computational score of spiral execution that takes into account spiral shape and line smoothness, previously validated against a clinical rating scale, was calculated in both groups. Tremor amplitude (Ampl), an independent index of tremor size, measured in centimeters, was also calculated. Changes in DoS and Ampl across trials were assessed using linear regression with slope evaluations. Both groups demonstrated improvement in DoS across trials, but with less improvement in the ET group compared to controls. Ampl demonstrated a tendency to worsen across trials in ET subjects. ET subjects demonstrated less improvement than controls when drawing sequential spirals, suggesting a possible motor learning deficit in ET, here captured in an affected limb. DoS improved independently of Ampl, showing that DoS and Ampl are separable motor physiologic components in ET that may be independently mediated.
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http://dx.doi.org/10.1007/s12311-018-0974-xDOI Listing
April 2019

Finding useful biomarkers for Parkinson's disease.

Sci Transl Med 2018 08;10(454)

Center for Advanced Parkinson's Disease Research and Precision Neurology Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact.
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http://dx.doi.org/10.1126/scitranslmed.aam6003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097233PMC
August 2018

Digitized spiral analysis may be a potential biomarker for brachial dystonia.

Parkinsonism Relat Disord 2018 12 20;57:16-21. Epub 2018 Jul 20.

Department of Neurology, Mount Sinai Beth Israel and Icahn School of Medicine at Mount Sinai, Suite 5J, 10 Union Square East, New York, NY, 10003, USA.

Introduction: Objective measures for detection and quantification of dystonic movements may guide both diagnosis and clinical monitoring. Digitized spiral analysis is a non-invasive method used to assess upper limb motor control in movement disorders and may have utility in dystonia. We aimed to determine if digitized spiral analysis can distinguish dystonia subjects from controls, and evaluated correlation with a validated clinical rating scale.

Methods: Kinematic, dynamic, and spatial attributes of Archimedean spirals drawn with an inking pen on a digitizing tablet were compared for participants with brachial dystonia and either Tor1A (DYT1) (n = 15) or THAP1 (DYT6) mutations (n = 12) and age and gender matched controls (n = 27) using Receiver Operator Characteristics (ROC) analysis. Spiral indices including an overall degree of severity (DoS) were also calculated and correlated with clinical severity ratings as measured by the Burke-Fahn-Marsden scale.

Results: Dystonia spirals had significantly higher severity scores as well as higher measures of spiral irregularity compared to controls. ROC analysis demonstrated that the DoS score had good discriminative ability to distinguish dystonia spirals from controls, with an Area Under the Curve (AUC) of 0.87. Measures of spiral irregularity correlated with validated clinical rates of dystonia severity in the analyzed arm, with one particular index, Residue of Theta vs R, showing the highest correlation (r = 0.55, p = 0.005).

Conclusion: Digitized spiral analysis may be a promising non-invasive method to objectively quantify brachial dystonia. It may also be a useful way to monitor subtle changes in dystonia severity over time not captured with current clinical rating scales.
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http://dx.doi.org/10.1016/j.parkreldis.2018.07.004DOI Listing
December 2018

Inflammatory Bowel Disease and Parkinson's Disease: A Nationwide Swedish Cohort Study.

Inflamm Bowel Dis 2019 01;25(1):111-123

Clinical Epidemiology Unit, Department of Medicine Solna, Stockholm, Sweden.

Background: Few studies have examined the association between inflammatory bowel disease (IBD) and Parkinson's disease (PD).

Methods: To estimate the incidence and relative risk of PD development in a cohort of adult IBD, we included all incident IBD patients (n = 39,652) in the Swedish National Patient Register (NPR) between 2002 and 2014 (ulcerative colitis [UC]: n = 24,422; Crohn's disease [CD]: n = 11,418; IBD-unclassified [IBD-U]: n = 3812). Each IBD patient was matched for sex, age, year, and place of residence with up to 10 reference individuals (n = 396,520). In a cohort design, all incident PD occurring after the index date was included from the NPR. In a case-control design, all incident PD occurring before the index date was included. The association between IBD and PD and vice versa was investigated by multivariable Cox and logistic regression.

Results: In IBD, there were 103 cases of incident PD, resulting in hazard ratios (HRs) for PD of 1.3 (95% confidence interval [CI], 1.0-1.7; P = 0.04) in UC, 1.1 (95% CI, 0.7-1.7) in CD, and 1.7 (95% CI, 0.8-3.0) in IBD-U. However, these effects disappeared when adjusting for number of medical visits during follow-up to minimize potential surveillance bias. In a case-control analysis, IBD patients were more likely to have prevalent PD at the time of IBD diagnosis than matched controls, with odds ratios of 1.4 (95% CI, 1.2-1.8) in all IBD patients, 1.4 (95% CI, 1.1-1.9) for UC, and 1.6 (95% CI, 1.1-2.3) for CD patients alone.

Conclusions: IBD is associated with an increased risk of PD, but some of this association might be explained by surveillance bias. 10.1093/ibd/izy190_video1izy190.video15785623138001.
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http://dx.doi.org/10.1093/ibd/izy190DOI Listing
January 2019

Application of the Movement Disorder Society prodromal criteria in healthy G2019S-LRRK2 carriers.

Mov Disord 2018 Jul 30;33(6):966-973. Epub 2018 Mar 30.

Movement Disorders Unit, Neurological Institute, Tel Aviv Medical Center, Tel-Aviv, Israel.

Background: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD.

Objectives: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters.

Methods: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49.2 ± 12.3 months). Likelihood ratios and probability estimations were calculated based on the International Parkinson and Movement Disorder Society Research Criteria for Prodromal Parkinson's Disease markers and examined for each assessment point.

Results: One hundred twenty healthy carriers (49.53 ± 13.4 years; 54% female) and 111 healthy noncarriers (48.43 ± 15.79 years; 49% female) participated in this study. Probability scores were significantly higher in healthy carriers than healthy noncarriers (P < 0.0001). Of the 20 participants (8.6%) who met criteria for probable prodromal PD at baseline, 17 were healthy carriers. Participants who reached the threshold were older (P < 0.0001), had higher UPDRS-III (P < 0.001), lower cognitive function (P = 0.001), and more nonmotor symptoms (P < 0.0001), compared to those who did not. Ten participants were diagnosed with incident PD within 5 years from baseline resulting in a specificity of 91.82% (95% confidence interval: 86.69-96.94), sensitivity of 80% (95% confidence interval: 55.21-100), positive predictive value of 47.06% (95% confidence interval: 23.33-70.79), and negative predictive value of 98.06% (95% confidence interval: 95.39-100). All 10 phenoconvertors were G2019S-LRRK2 carriers.

Conclusions: The results showed the utility of using the criteria and high sensitivity and specificity in identifying prodromal PD in this high-risk unique cohort. These results may be valuable for future disease modification clinical trials. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105406PMC
July 2018

Chitinase-3-like Protein 1: A Progranulin Downstream Molecule and Potential Biomarker for Gaucher Disease.

EBioMedicine 2018 Feb 31;28:251-260. Epub 2018 Jan 31.

Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

We recently reported that progranulin (PGRN) is a novel regulator of glucocerebrosidase and its deficiency associates with Gaucher Diseases (GD) (Jian et al., 2016a; Jian et al., 2018). To isolate the relevant downstream molecules, we performed a whole genome microarray and mass spectrometry analysis, which led to the isolation of Chitinase-3-like-1 (CHI3L1) as one of the up-regulated genes in PGRN null mice. Elevated levels of CHI3L1 were confirmed by immunoblotting and immunohistochemistry. In contrast, treatment with recombinant Pcgin, a derivative of PGRN, as well as imigluerase, significantly reduced the expressions of CHI3L1 in both PGRN null GD model and the fibroblasts from GD patients. Serum levels of CHIT1, a clinical biomarker for GD, were significantly higher in GD patients than healthy controls (51.16±2.824ng/ml vs 35.07±2.099ng/ml, p<0.001). Similar to CHIT1, serum CHI3L1 was also significantly increased in GD patients compared with healthy controls (1736±152.1pg/ml vs 684.7±68.20pg/ml, p<0.001). Whereas the PGRN level is significantly reduced in GD patients as compared to the healthy control (91.56±3.986ng/ml vs 150.6±4.501, p<0.001). Collectively, these results indicate that CHI3L1 may be a previously unrecognized biomarker for diagnosing GD and for evaluating the therapeutic effects of new GD drug(s).
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http://dx.doi.org/10.1016/j.ebiom.2018.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835567PMC
February 2018

Progression in the LRRK2-Asssociated Parkinson Disease Population.

JAMA Neurol 2018 03;75(3):312-319

Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, New York.

Importance: Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials.

Objective: To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation.

Design, Setting, And Participants: A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis.

Main Outcomes And Measures: Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores.

Results: Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08).

Conclusions And Relevance: Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.
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http://dx.doi.org/10.1001/jamaneurol.2017.4019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885854PMC
March 2018

Sex differences in LRRK2 G2019S and idiopathic Parkinson's Disease.

Ann Clin Transl Neurol 2017 11 19;4(11):801-810. Epub 2017 Oct 19.

Department of Neurology Mount Sinai Beth Israel Medical Center New York New York.

Objective: To evaluate sex differences and the relative effect of G2019S mutations in Parkinson's disease (PD).

Methods: 530 PD carriers and 759 noncarrier PD (idiopathic, IPD) evaluated as part of the Fox Foundation (MJFF) Consortium were included. All participants completed a study visit including information on clinical features, treatment, examination, and motor and nonmotor questionnaires. Clinical features were compared between men and women separately for IPD and PD; and features were compared between IPD and PD separately for men and women.

Results: : men had higher levodopa equivalency dose (LED), worse activities of daily living and motoric severity but lower complications of therapy (UPDRS-IV). IPD women had higher olfaction and thermoregulatory scores and were more likely to report family history of PD. Among : Male predominance was not observed among G2019S cases. Women had worse UPDRS-IV but better olfaction. : men and women had better olfaction than IPD counterparts. men demonstrated lower motor and higher cognitive, RBD and thermoregulation scores than IPD men and women had greater UDPRS-IV and rates of dyskinesia.

Interpretation: There were clinical differences between sexes with a more severe phenotype in IPD men and more complications of therapy in women. The more severe male phenotype was moderated by , with men and women showing less diversity of phenotype. Our study supports that both genetics and sex drive phenotype, and thus trials in and IPD should consider gender stratification in design or analysis.
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http://dx.doi.org/10.1002/acn3.489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682117PMC
November 2017

Cognitive and motor functioning in elderly glucocerebrosidase mutation carriers.

Neurobiol Aging 2017 10 24;58:239.e1-239.e7. Epub 2017 Jun 24.

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Neurology, Mount Sinai Beth Israel, New York, NY, USA.

Mutations in the glucocerebrosidase (GBA) gene are a strong genetic risk factor for the development of Parkinson's disease and dementia with Lewy Bodies. However the penetrance of GBA mutations is low for these diseases in heterozygous carriers. The aim of this study was to examine the relationship between mutation status and cognitive and motor functioning in a sample of community-dwelling older adults. Using linear mixed effects models, we examined the effect of heterozygous mutation status on 736 community-dwelling older adults (≥70 years) without dementia or Parkinson's disease assessed over an average of 6 years, 28 of whom had a single GBA mutation (primarily N370S). Verbal memory was measured using the picture version of the Free and Cued Selective Reminding Test, and carriers showed significantly (p < 0.05) greater decline in verbal memory over time. There was no difference in motor function or any other cognitive domain. Taken together, these results suggest an effect, but an overall limited burden, of harboring a single GBA mutation in aging mutation carriers.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647652PMC
October 2017