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      Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease


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          Background: The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established.

          Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients.

          Methods: We analyzed the coding regions of the amyloid-beta precursor protein ( APP), Presenilin 1 and 2 ( PSEN1, PSEN2), and Granulin ( GRN) genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES) data by single variant and gene base (SKAT-O and burden tests) analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status.

          Results: Known AD pathogenic mutations in the PSEN1 (p.A79V) and PSEN2 (p.V148I) genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients ( p = 2.0 × 10 −4), independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site.

          Conclusions: Pathogenic mutations in the Alzheimer disease-causing genes ( PSEN1 and PSEN2) are found in sporadic PD patients. PD patients with cognitive decline carry rare variants in dementia-causing genes. Variants in genes causing Mendelian neurodegenerative diseases exhibit pleiotropic effects.

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          Most cited references57

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          Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.

          Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.
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            Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease.

            Due to the high prevalence of mild cognitive impairment (MCI) and dementia in Parkinson disease (PD), routine cognitive screening is important for the optimal management of patients with PD. The Montreal Cognitive Assessment (MoCA) is more sensitive than the commonly used Mini-Mental State Examination (MMSE) in detecting MCI and dementia in patients without PD, but its validity in PD has not been established. A representative sample of 132 patients with PD at 2 movement disorders centers was administered the MoCA, MMSE, and a neuropsychological battery with operationalized criteria for deficits. MCI and PD dementia (PDD) criteria were applied by an investigator blinded to the MoCA and MMSE results. The discriminant validity of the MoCA and MMSE as screening and diagnostic instruments was ascertained. Approximately one third of the sample met diagnostic criteria for a cognitive disorder (12.9% PDD and 17.4% MCI). Mean (SD) MoCA and MMSE scores were 25.0 (3.8) and 28.1 (2.0). The overall discriminant validity for detection of any cognitive disorder was similar for the MoCA and the MMSE (receiver operating characteristic area under the curve [95% confidence interval]): MoCA (0.79 [0.72, 0.87]) and MMSE (0.76 [0.67, 0.85]), but as a screening instrument the MoCA (optimal cutoff point = 26/27, 64% correctly diagnosed, lack of ceiling effect) was superior to the MMSE (optimal cutoff point = 29/30, 54% correctly diagnosed, presence of ceiling effect). The Montreal Cognitive Assessment, but not the Mini-Mental State Examination, has adequate psychometric properties as a screening instrument for the detection of mild cognitive impairment or dementia in Parkinson disease. However, a positive screen using either instrument requires additional assessment due to suboptimal specificity at the recommended screening cutoff point.
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              The MoCA: well-suited screen for cognitive impairment in Parkinson disease.

              To establish the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) when screening externally validated cognition in Parkinson disease (PD), by comparison with a PD-focused test (Scales for Outcomes in Parkinson disease-Cognition [SCOPA-COG]) and the standardized Mini-Mental State Examination (S-MMSE) as benchmarks. A convenience sample of 114 patients with idiopathic PD and 47 healthy controls was examined in a movement disorders center. The 21 patients with dementia (PD-D) were diagnosed using Movement Disorders Society criteria, externally validated by detailed independent functional and neuropsychological tests. The 21 patients with mild cognitive impairment (PD-MCI) scored 1.5 SD or more below normative data in at least 2 measures in 1 of 4 cognitive domains. Other patients had normal cognition (PD-N). Primary outcomes using receiver operating characteristic (ROC) curve analyses showed that all 3 mental status tests produced excellent discrimination of PD-D from patients without dementia (area under the curve [AUC], 87%-91%) and PD-MCI from PD-N patients (AUC, 78%-90%), but the MoCA was generally better suited across both assessments. The optimal MoCA screening cutoffs were <21/30 for PD-D (sensitivity 81%; specificity 95%; negative predictive value [NPV] 92%) and <26/30 for PD-MCI (sensitivity 90%; specificity 75%; NPV 95%). Further support that the MoCA is at least equivalent to the SCOPA-COG, and superior to the S-MMSE, came from the simultaneous classification of the 3 PD patient groups (volumes under a 3-dimensional ROC surface, chance = 17%: MoCA 79%, confidence interval [CI] 70%-89%; SCOPA-COG 74%, CI 62%-86%; MMSE-Sevens item 56%, CI 44%-68%; MMSE-World item 62%, CI 50%-73%). The MoCA is a suitably accurate, brief test when screening all levels of cognition in PD.

                Author and article information

                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                10 April 2018
                : 12
                : 230
                [1] 1Department of Psychiatry, Washington University , Saint Louis, MO, United States
                [2] 2Department of Neurology, Washington University , Saint Louis, MO, United States
                [3] 3Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III , Madrid, Spain
                [4] 4Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Fundació per la Recerca Biomèdica i Social Mútua Terrassa , Terrassa, Barcelona, Spain
                [5] 5Department of Neurology and Neurosurgery, Hospital Universitario de Burgos , Burgos, Spain
                [6] 6Departments of Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University , Saint Louis, MO, United States
                [7] 7Department of Medicine, Washington University , Saint Louis, MO, United States
                Author notes

                Edited by: Leo P. Sugrue, University of California, San Francisco, United States

                Reviewed by: Maria Shadrina, Institute of Molecular Genetics (RAS), Russia; Jennifer Fifita, Macquarie University, Australia

                *Correspondence: Bruno A. Benitez babenitez@ 123456wustl.edu

                This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience

                †These authors have contributed equally to this work.

                Copyright © 2018 Ibanez, Dube, Davis, Fernandez, Budde, Cooper, Diez-Fairen, Ortega-Cubero, Pastor, Perlmutter, Cruchaga and Benitez.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 13 December 2017
                : 23 March 2018
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 90, Pages: 10, Words: 9348
                Funded by: National Institute of Neurological Disorders and Stroke 10.13039/100000065
                Award ID: NS075321
                Award ID: NS41509
                Award ID: NS058714
                Award ID: R01-AG035083
                Original Research

                parkinson disease,dementia,cognitive impairment,rare variants,app,psen1,psen2,grn
                parkinson disease, dementia, cognitive impairment, rare variants, app, psen1, psen2, grn


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