TMEM106B Effect on Cognition in Parkinson’s Disease and Frontotemporal Dementia
Autor: | Sharon X. Xie, John Q. Trojanowski, Daniel Weintraub, David J. Irwin, Michael H Guo, Andrew Siderowf, Vivianna M. Van Deerlin, David A. Wolk, Jordan T. Mak, EunRan Suh, Alice Chen-Plotkin, Jacqueline Rick, Murray Grossman, Thomas F. Tropea |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Oncology Male medicine.medical_specialty Single-nucleotide polymorphism Nerve Tissue Proteins Neuropsychological Tests Article 03 medical and health sciences 0302 clinical medicine Cognition Internal medicine mental disorders medicine Dementia Humans Cognitive Dysfunction Longitudinal Studies Cognitive decline Aged business.industry Montreal Cognitive Assessment Membrane Proteins Parkinson Disease Middle Aged medicine.disease Mental Status and Dementia Tests 030104 developmental biology Neurology Frontotemporal Dementia Cohort Female Neurology (clinical) Alzheimer's disease business 030217 neurology & neurosurgery Frontotemporal dementia Follow-Up Studies |
Zdroj: | Ann Neurol |
Popis: | Objective Common variants near TMEM106B associate with risk of developing frontotemporal dementia (FTD). Emerging evidence suggests a role for TMEM106B in neurodegenerative processes beyond FTD. We evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases. Methods We longitudinally followed 870 subjects with diagnoses of Parkinson disease (PD; n = 179), FTD (n = 179), Alzheimer disease (AD; n = 300), memory-predominant mild cognitive impairment (MCI; n = 75), or neurologically normal control subjects (NC; n = 137) at the University of Pennsylvania (UPenn). All participants had annual Mini-Mental State Examination (MMSE; median follow-up duration = 3.0 years) and were genotyped at TMEM106B index single nucleotide polymorphism rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale-2 [DRS-2] and Montreal Cognitive Assessment [MoCA]) and to an international validation cohort (Parkinson's Progression Markers Initiative [PPMI], N = 371). Results The TMEM106B rs1990622T allele, linked to increased risk of FTD, associated with greater MMSE decline over time in PD subjects but not in AD or MCI subjects. For FTD subjects, rs1990622T associated with more rapid decrease in MMSE only under the minor-allele, rs1990622C , dominant model. Among PD patients, rs1990622T carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS-2 scores. Finally, in the PPMI cohort, TMEM106B risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores. Interpretation Irrespective of cognitive instrument or cohort assessed, TMEM106B acts as a genetic modifier for cognitive trajectory in PD. Our results implicate lysosomal dysfunction in the pathogenesis of cognitive decline in 2 different proteinopathies. ANN NEUROL 2019;85:801-811. |
Databáze: | OpenAIRE |
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