Department of Neurology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
Department of Neurology, Division of Clinical Neuropsychology, University of Groningen, University Medical Center, 9713 GZ Groningen, The Netherlands.
Brain. 2024 Mar 1;147(3):900-910. doi: 10.1093/brain/awad323.
The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects-with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non-GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable.
最常见的帕金森病遗传风险因素是 GBA1 突变，该突变编码溶酶体酶葡萄糖脑苷脂酶。携带 GBA1 突变的患者（GBA-PD）表现出更早的发病年龄和更快的疾病进展，认知障碍更严重，姿势不稳和步态问题更严重。这些 GBA-PD 特征表明胆碱能系统病理学更严重。使用囊泡乙酰胆碱转运体配体 18F-F-氟乙基苯甲氧基苯并咪唑（18F-FEOBV PET）进行正电子发射断层扫描（PET）成像，为研究胆碱能变化及其与 GBA-PD 临床特征的关系提供了机会。该研究调查了 123 名新诊断的、未经治疗的帕金森病患者，这些患者在 PET 成像上证实存在前多巴胺能缺陷。对唾液样本进行了全基因 GBA1 测序，以评估 GBA1 变体。患者接受了广泛的认知领域神经心理学评估、使用统一帕金森病评定量表进行的运动评估、脑 MRI、测量纹状体与枕叶之间比值的多巴胺能 PET 以及 18F-FEOBV PET。我们使用体素和感兴趣区的方法研究了 GBA-PD 携带者和非 GBA1 突变携带者（非 GBA-PD）之间的区域性胆碱能神经支配差异。使用双样本 t 检验模型的 t 映射之间的重叠程度使用 Dice 相似系数进行量化。17 名（13.8%）患者有 GBA1 突变。在诊断时，GBA-PD 和非 GBA-PD 之间在临床特征和多巴胺能比值方面没有发现显著差异。与对照组相比，GBA-PD 和非 GBA-PD 组的 18F-FEOBV 结合均较低。Dice（P < 0.05，簇大小为 100）显示 GBA-PD 和非 GBA-PD 图谱之间具有良好的重叠（0.7326）。与对照组相比，GBA-PD 患者的 18F-FEOBV 结合在枕叶、顶叶、颞叶和额叶皮质中比非 GBA-PD 患者更为广泛（P < 0.05，FDR 校正）。在感兴趣区分析（Bonferroni 校正）中，GBA-PD 中左侧海马旁回受影响更大。新发性 GBA-PD 显示区域性胆碱能终末配体结合的独特分布。尽管帕金森病组在临床上无法区分，但与健康对照组相比，GBA-PD 与非 GBA-PD 相比表现出更广泛的胆碱能去神经支配。需要更大的样本量来验证这些发现。我们的研究结果表明，在 GBA1 突变之前，携带 GBA1 突变的帕金森病患者（de novo GBA-PD）和非携带 GBA1 突变的帕金森病患者（non-GBA-PD）的区域性胆碱能系统变化具有不同的模式。在携带与非携带者之间出现临床表型差异之前，携带 GBA1 突变的帕金森病患者（de novo GBA-PD）和非携带 GBA1 突变的帕金森病患者（non-GBA-PD）显示出不同的胆碱能系统变化模式。
