GBA pathway markers for Lewy body dementias

β-葡萄糖脑苷酶基因(Gba)途径的功能障碍是从遗传学、神经病理学和 生化检测显示与路易体痴呆有关。GBA途径导向的标记和治疗提供了一种 为快速实施旨在减缓疾病进展的药物的概念验证试验提供了机会。一个 生物标记物引导的通过/不通过决策需要测试工具包，其中包括针对目标的分子生物标记物 参与、药物反应和疾病进展。 在目标1中，我们将确定血浆和脑脊液中GBA途径的中断是否 在一项对435名路易体痴呆患者的大型横断面研究中，明确与路易体痴呆有关 身体痴呆症、健康对照和其他痴呆症的疾病控制使用有针对性的定量质量 光谱分析50途径鞘糖脂和β-葡萄糖脑苷酶活性的测定。此外， 我们将探索GBA途径中的数量或质量变化是否会影响GBA突变状态， 临床疾病严重程度和临床诊断。在目标2中，我们将确定GBA途径标记是否 纵向跟踪路易体痴呆的疾病进展。在目标3中，我们将纵向收集临床 来自哈佛附属医院的100名DLB、PDD患者和对照组的数据、脑脊液和血液样本 扩展NINDS帕金森氏病生物标记物计划集合。 这些分析将把遗传线索转化为临床试验标记。他们将创建所需的工具 用于路易体痴呆的创新、遗传学启发、生物标志物指导的II期试验，以及一般情况下 丰富PDBP资源。

Dysfunction of the β-glucocerebrosidase gene (GBA) pathway is genetically, neuropathologically, and biochemically implicated in Lewy body dementias. GBA pathway-directed markers and treatments offer an opportunity for rapidly implementing proof-of-concept trials of drugs designed to slow disease progression. A tool kit of tests is needed for biomarkers-guided go/no-go decisions that includes molecular biomarkers for target engagement, drug response, and disease progression. In Aim 1, we will determine, whether disruption of the GBA pathway in plasma and cerebrospinal fluid is specifically associated with Lewy body dementias in a large, cross-sectional study of 435 individuals with Lewy body dementias, healthy controls, and disease controls with other dementias using targeted, quantitative mass spectrometry assays for fifty pathway sphingolipids and an assay for β-glucocerebrosidase activity. Moreover, we will explore whether quantitative or qualitative changes in the GBA pathway inform on GBA mutation status, clinical disease severity, and clinical diagnosis. In Aim 2, we will determine, whether GBA pathway markers longitudinally track disease progression in Lewy body dementias. In Aim 3, we will longitudinally collect clinical data, CSF, and blood samples of 100 patients with DLB, PDD and controls from Harvard-affiliated hospitals and expand the NINDS Parkinson's Disease Biomarkers Program collection. These analyses will translate genetic clues into clinical trials markers. They will create the tools needed for innovative, genetics-inspired, biomarkers-guided phase II trials for Lewy body dementias and generally enrich the PDBP resource.