Andrea Greuel1, Jean-Pierre Trezzi2,3, Enrico Glaab3, Marina C Ruppert1,4, Franziska Maier5, Christian Jäger3, Zdenka Hodak3, Katja Lohmann6, Yilong Ma7, David Eidelberg7, Lars Timmermann1, Karsten Hiller8, Marc Tittgemeyer9,10, Alexander Drzezga11,12,13, Nico Diederich14, Carsten Eggers1,4. 1. Department of Neurology, University Hospital Giessen and Marburg, Marburg, Germany. 2. Integrated Biobank of Luxembourg, Luxembourg Institute of Health, Dudelange, Luxembourg. 3. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg. 4. Center for Mind, Brain and Behavior, Universities of Marburg and Giessen, Marburg, Germany. 5. Department of Psychiatry and Psychotherapy, Medical Faculty, University Hospital of Cologne, Cologne, Germany. 6. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. 7. Center for Neurosciences, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, New York, USA. 8. Institute for Biochemistry, Biotechnology and Bioinformatics, University of Braunschweig, Braunschweig, Germany. 9. Max Planck Institute for Metabolism Research, Cologne, Germany. 10. Cologne Cluster of Excellence in Cellular Stress and Aging-Associated Disease, Cologne, Germany. 11. Department of Nuclear Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany. 12. German Center for Neurodegenerative Diseases, Bonn, Germany. 13. Cognitive Neuroscience, Institute of Neuroscience and Medicine, Research Center Jülich, Jülich, Germany. 14. Department of Neurology, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg.
Abstract
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.
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.
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