GBA Variants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes

Autor: Marina C. Ruppert, Alexander Drzezga, Enrico Glaab, Christian Jäger, Nico J. Diederich, Marc Tittgemeyer, Jean-Pierre Trezzi, David Eidelberg, Franziska Maier, Lars Timmermann, Carsten Eggers, Zdenka Hodak, Karsten Hiller, Katja Lohmann, Andrea Greuel, Yilong Ma
Přispěvatelé: Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center]
Rok vydání: 2020
Předmět:
0301 basic medicine
Oncology
Parkinson's disease
Movement disorders
Biotechnologie [F06] [Sciences du vivant]
Neurology [D14] [Human health sciences]
Disease
genetics [Glucosylceramidase]
Multidisciplinaire
généralités & autres [F99] [Sciences du vivant]
0302 clinical medicine
genetics [Parkinson Disease]
diagnostic imaging [Parkinson Disease]
Biotechnology [F06] [Life sciences]
genetics
medicine.diagnostic_test
Parkinson Disease
Parkinson's disease genetics
Phenotype
Neurology
statistics
Positron emission tomography
Glucosylceramidase
GBA
multimodal functional neuroimaging
medicine.symptom
medicine.medical_specialty
genetics [Mutation]
Neuroimaging
Multidisciplinary
general & others [F99] [Life sciences]
03 medical and health sciences
Internal medicine
medicine
Humans
Metabolomics
Dementia
ddc:610
Neurologie [D14] [Sciences de la santé humaine]
Lewy body
business.industry
multimodal
medicine.disease
functional
030104 developmental biology
Mutation
Neurology (clinical)
business
Glucocerebrosidase
030217 neurology & neurosurgery
Zdroj: Movement disorders 35(12), 2201-2210 (2020). doi:10.1002/mds.28225
ISSN: 1531-8257
0885-3185
DOI: 10.1002/mds.28225
Popis: Background Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. Objective This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. Methods GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Results Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. Conclusions This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Databáze: OpenAIRE
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