@article{9f57a4475bcf4bce9078df84359016b2,
title = "GBA Variants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes",
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-[18F]fluoro-L-Dopa positron emission tomography (PET), [18F]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; [18F]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.",
keywords = "GBA, metabolomics, multimodal functional neuroimaging, Parkinson's disease genetics",
author = "Andrea Greuel and Trezzi, {Jean Pierre} and Enrico Glaab and Ruppert, {Marina C.} and Franziska Maier and Christian J{\"a}ger and Zdenka Hodak and Katja Lohmann and Yilong Ma and David Eidelberg and Lars Timmermann and Karsten Hiller and Marc Tittgemeyer and Alexander Drzezga and Nico Diederich and Carsten Eggers",
note = "Funding Information: A.G., J.‐P.T., M.C.R., F.M., C.J., Z.H., K.H., M.T., and N.D. have nothing to disclose. E.G. acknowledges funding support by the Fonds Nationale de la Recherche Luxembourg through the National Centre of Excellence in Research on Parkinson's disease (I1R‐BIC‐PFN‐15NCER) and as part of the grant project PD‐Strat (INTER/11651464). K.L. reports grants from the German Research Foundation, Federal Ministry of Education and Sciences, Damp Foundation, and International Parkinson and Movement Disorder Society. Y.M. has served as a coinvestigator on research grant from the National Institutes of Health in the United States. D.E. holds a patent “Identification and Uses of Brain Activity Networks.” L.T. received payments as a consultant for Medtronic Inc. and Boston Scientific and received honoraria as a speaker on symposia sponsored by Bial, Zambon Pharma, UCB Schwarz Pharma, Desitin Pharma, Medtronic, Boston Scientific, and Abbott. The institution of L.T., not L.T. personally, received funding by the German Research Foundation, the German Ministry of Education and Research, and Deutsche Parkinson Vereinigung. A.D. received research grants from German Research Foundation, Federal Ministry of Education and Research, and the European Union; research support from Siemens Healthineers, Life Molecular Imaging, GE Healthcare, and AVID Radiopharmaceuticals; speaker/advisory board honoraria from Siemens Healthineers, Sanofi, and GE Healthcare; and owns stock in Siemens Healthineers. C.E. received speaker's honoraria from Medtronic Inc. and honoraria for talks and consulting from Daiichi Sankyo Inc., Abbvie Inc., Bayer Vital GmbH, Phylarus Inc. Funding Information: The study was funded by the German Research Foundation (KFO 219, EG350/1–1; FOR 2488). Funding agency: Publisher Copyright: {\textcopyright} 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society",
year = "2020",
month = dec,
doi = "10.1002/mds.28225",
language = "English",
volume = "35",
pages = "2201--2210",
journal = "Movement Disorders",
issn = "0885-3185",
publisher = "John Wiley & Sons Inc.",
number = "12",
}