GBAVariants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes
GBAVariants in Parkinson's Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes
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DOI：
10.1002/mds.28225
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发表时间：
2020-08-27
影响因子：
8.6
通讯作者：
Eggers, Carsten
中科院分区：
文献类型：
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作者：
Greuel, Andrea;Trezzi, Jean-Pierre;Eggers, Carsten
背景GBA基因（NM_000157.3）的改变是帕金森病（PD）最重要的遗传危险因素。双等位基因GBA突变导致溶酶体贮积症戈谢病。GBA变异体p.E365K和p.T408M与PD相关，但与戈谢病无关。这些变异的病理生理作用需要进一步探讨。目的分析携带GBA突变体p.E365K和p.T408M的PD患者的临床、神经心理学、代谢和神经影像学表型。方法对56例中期PD患者进行GBA基因测序。将GBA变异携带者与非携带者在临床病史和症状、神经心理学特征、代谢组学和多模式神经影像学方面进行比较。进行血浆气相色谱-质谱联用、6-[F-18]氟-L-多巴正电子发射断层扫描（PET）、[F-18]氟脱氧葡萄糖PET和静息态功能磁共振成像。结果13例GBA变异携带者（7例为p.E365K，6例为p.T408M）均经测序证实。1例患者携带aGBA突变（p.N409S）并被排除。两组的临床病史和症状无显著差异。变异携带者的整体认知能力较低。代谢组学组差异提示携带者与非携带者相比更严重的PD相关改变。两次PET扫描都显示出更晚期疾病的迹象; [F-18]氟脱氧葡萄糖PET和功能磁共振成像显示携带者与路易体痴呆和PD痴呆的相似性。结论这是第一个全面评估帕金森病患者GBA变异体（神经）生物学表型的研究。代谢组学和神经影像学检测到更显着的组间差异比临床和行为评价。这些改变可能有希望监测针对葡萄糖脑苷脂酶代谢的疾病改善治疗的效果。(c)2020作者。运动障碍由Wiley Periodicals LLC出版。国际帕金森和运动障碍协会（International Parkinson and Movement Disorder Society）
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.