Gbavariants In Parkinson'S Disease: Clinical, Metabolomic, And Multimodal Neuroimaging Phenotypes

Background Alterations in theGBAgene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). BiallelicGBAmutations cause the lysosomal storage disorder Gaucher's disease. TheGBAvariants 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 theGBAvariants p.E365K and p.T408M. Methods GBAwas sequenced in 56 patients with mid-stage PD. Carriers ofGBAvariants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[F-18]fluoro-L-Dopa positron emission tomography (PET), [F-18]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Results Sequence analysis detected 13 heterozygousGBAvariant carriers (7 with p.E365K, 6 with p.T408M). One patient carried aGBAmutation (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; [F-18]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 ofGBAvariants 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. (c) 2020 The Authors.Movement Disorderspublished by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.