Department of Biosciences, Università degli Studi di Milano, Milan, Italy.
Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy.
Brain Pathol. 2024 Nov;34(6):e13284. doi: 10.1111/bpa.13284. Epub 2024 Sep 1.
The main genetic risk factors for Parkinson's disease (PD) are presently represented by variants in GBA1 gene encoding for the β-glucocerebrosidase (GCase). Searching for a peripheral biomarker that can be used for selecting and monitoring patients in clinical trials targeting GBA1-associated PD (GBA1-PD) is a current challenge. We previously demonstrated that α-synuclein oligomers expressed as proximity ligation assay (PLA) score in synaptic terminals of skin biopsy are a reliable biomarker for distinguishing idiopathic PD (iPD) from healthy controls (HC). This cross-sectional study investigates an unexplored cohort of GBA1-PD (n = 27) compared to 28 HC, and 36 iPD cases to (i) analyze α-synuclein oligomers and quantify them throughout PLA score, (ii) investigate GCase expression in brain and synaptic terminals targeting the sweat gland, (iii) unravel indicators that could differentiate patients with specific GBA1 mutations. PLA score discriminates GBA1-PD from HC with sensitivity = 88.9% (95% CI 70.84-97.65), specificity = 88.5% (95% CI 69.85-97.55), and PPV = 88.9% (95% CI 73.24-95.90), AUC value = 0.927 (95% CI 0.859-0.996). No difference was found between GBA1-PD patients and iPD, suggesting a common pathological pathway based on α-synuclein oligomers. GCase score did not differ in GBA1-PD, iPD, and HC in the synaptic terminals, whereas a positive correlation was found between PLA score and GCase score. Moreover, a significant increase in synaptic density was observed in GBA1-PD compared to iPD and HC (P < 0.0001). Employing ROC curve to discriminate GBA1-PD from iPD, we found an AUC value for synaptic density = 0.855 (95% CI 0.749-0.961) with sensitivity = 85.2% (95% CI 66.27%-95.81%), specificity = 77.1% (95% CI 59.86%-89.58%), and PPV = 74.19% (60.53%-84.35%). The highest synaptic density values were observed in p.N409S patients. This work points out to the value of both PLA score and synaptic density in distinguishing GBA1-PD from iPD and to their potential to stratify and monitor patients in the context of new pathway-specific therapeutic options.
帕金森病（PD）的主要遗传风险因素目前由编码β-葡糖苷脑苷脂酶（GCase）的 GBA1 基因中的变体代表。寻找可用于在针对 GBA1 相关 PD（GBA1-PD）的临床试验中选择和监测患者的外周生物标志物是当前的挑战。我们之前证明，皮肤活检中突触末梢表达的α-突触核蛋白寡聚体作为接近连接分析（PLA）评分是区分特发性 PD（iPD）与健康对照（HC）的可靠生物标志物。本横断面研究调查了一个尚未探索的 GBA1-PD 队列（n=27）与 28 名 HC 和 36 名 iPD 病例，以（i）分析 α-突触核蛋白寡聚体并通过 PLA 评分对其进行量化，（ii）研究针对汗腺的大脑和突触末梢中的 GCase 表达，（iii）揭示可区分具有特定 GBA1 突变的患者的指标。PLA 评分可将 GBA1-PD 与 HC 区分开来，其灵敏度为 88.9%（95%CI 70.84-97.65），特异性为 88.5%（95%CI 69.85-97.55），PPV 为 88.9%（95%CI 73.24-95.90），AUC 值为 0.927（95%CI 0.859-0.996）。GBA1-PD 患者与 iPD 之间未发现差异，这表明基于α-突触核蛋白寡聚体存在共同的病理途径。在突触末梢中，GBA1-PD、iPD 和 HC 之间的 GCase 评分没有差异，但 PLA 评分与 GCase 评分之间存在正相关。此外，与 iPD 和 HC 相比，GBA1-PD 中观察到突触密度显著增加（P<0.0001）。使用 ROC 曲线将 GBA1-PD 与 iPD 区分开来，我们发现突触密度的 AUC 值为 0.855（95%CI 0.749-0.961），灵敏度为 85.2%（95%CI 66.27%-95.81%），特异性为 77.1%（95%CI 59.86%-89.58%），PPV 为 74.19%（60.53%-84.35%）。p.N409S 患者的突触密度值最高。这项工作指出了 PLA 评分和突触密度在区分 GBA1-PD 与 iPD 中的价值，以及它们在新的特定途径治疗选择的背景下分层和监测患者的潜力。
