GBA pathway markers for Lewy body dementias

β-葡萄糖脑苷脂酶基因（GBA）通路的功能障碍在遗传学、神经病理学和 与路易体痴呆症有关GBA通路导向的标记物和治疗提供了一种 这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 生物标志物引导的去/不去决定需要一套测试工具，其中包括靶点的分子生物标志物 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通路的破坏是否是 在一项对435名路易体痴呆患者进行的大型横断面研究中， 身体痴呆，健康对照，和疾病控制与其他痴呆使用目标，定量质量 用于50种途径鞘脂的光谱测定和用于β-葡糖脑苷脂酶活性的测定。此外，委员会认为， 我们将探讨GBA途径中的定量或定性变化是否与GBA突变状态有关， 临床疾病严重程度和临床诊断。在目标2中，我们将确定GBA通路标记物是否 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、CSF和血液样本， 扩大NINDS帕金森病生物标志物项目的收集。 这些分析将把遗传线索转化为临床试验标记。他们将创造所需的工具 用于创新的、受遗传学启发的、生物标志物指导的路易体痴呆II期试验， 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.