Lewy-body pathology with aggregation of abnormal conformations of the protein alpha-synuclein (α-Syn) represent the histopathological hallmarks of Parkinson’s disease (PD). Genetic prototypes such as PD due to mutations in the alpha-synuclein gene (SNCA) offer the opportunity to evaluate α-Syn-related profiles in patient-derived biomaterial. We identified a family with a SNCA triplication and assessed the index patient for CSF α-Syn seeding capacity and levels of total α-Syn along with other neurodegenerative CSF markers (Aβ_1-42, total-Tau, phospho-Tau, NFL). As no published CSF data in patients with SNCA triplication are available, we descriptively compared his CSF profiles to those of sporadic PD patients and PD patients with GBA mutations as these are also specifically associated with prominent α-Syn pathology. Additionally, skin biopsies with staining for phospho-α-Syn were done. To assess cerebral glucose metabolism and brain atrophy combined positron emission tomography and magnetic resonance imaging ([¹⁸F]FDG-PET/MRI) was performed. Age at onset was 24 years and motor impairment was accompanied by prominent non-motor symptoms with early development of dementia, depression, REM sleep behavior disorder, hyposmia, and dysautonomia. Correspondingly, PET-MRI showed hypometabolism and atrophy in frontal, temporoparietal and occipital regions. CSF levels of total α-Syn were threefold higher and RT-QuIC showed remarkable α-Syn seeding activity in all kinetic categories in the SNCA_Triplication patient compared to patients with GBA mutations. Our results are consistent with findings that not only mutant forms but also overexpression of the wild-type α-Syn protein lead to PD and PD dementia and show a striking CSF α-Syn seeding profile, thus substantiating the role of RT-QuIC as a specific in vivo biomarker of α-Syn brain pathology.

具有蛋白质 α-突触核蛋白 (α-Syn) 异常构象聚集的路易体病理学代表帕金森病 (PD) 的组织病理学特征。由于α-突触核蛋白基因 ( SNCA ) 的突变导致的遗传原型（例如 PD ）为评估患者衍生的生物材料中的 α-Syn 相关谱提供了机会。我们确定了一个具有SNCA 三倍体的家族，并评估了指标患者的 CSF α-Syn 播种能力和总 α-Syn 水平以及其他神经退行性 CSF 标志物（Aβ _1-42、总 Tau、磷酸化 Tau、NFL）。由于没有发表SNCA患者的 CSF 数据由于存在三倍体，我们将他的 CSF 特征与散发性 PD 患者和具有GBA突变的 PD 患者进行了描述性比较，因为这些也与突出的 α-Syn 病理学特别相关。此外，还进行了带有磷酸-α-Syn 染色的皮肤活检。评估脑葡萄糖代谢和脑萎缩联合正电子发射断层扫描和磁共振成像（[ ¹⁸F]FDG-PET/MRI)进行。发病年龄为 24 岁，运动障碍伴有明显的非运动症状，早期发展为痴呆、抑郁、REM 睡眠行为障碍、嗅觉减退和自主神经功能障碍。相应地，PET-MRI显示额叶、颞顶叶和枕叶区域代谢减退和萎缩。与GBA患者相比， SNCA _Triplication患者的 CSF 总 α-Syn 水平高出三倍，RT-QuIC 在所有动力学类别中均显示出显着的 α-Syn 播种活性突变。我们的结果与以下发现一致，即不仅突变形式而且野生型 α-Syn 蛋白的过表达导致 PD 和 PD 痴呆，并显示出惊人的 CSF α-Syn 播种特征，从而证实了 RT-QuIC 作为一种α-Syn 脑病理学的特异性体内生物标志物。