Discovery of Multimodal Biomarkers for Parkinsonian Syndromes, Their Progression, and Pathological Relevance

项目摘要/摘要 帕金森综合征是一种常见的进行性神经退行性疾病，包括 一系列的行动障碍。尽管他们独特的病理特征和大脑模式 变化，PS引起重叠的运动体征，包括运动迟缓，僵硬，和/或震颤，可能是由于 共同的基底节(BG)和小脑相关结构功能障碍。目前的诊断和分期 PS以及其他神经退行性疾病的基础是神经细胞丢失或死亡的模式， 神经胶质增多症和分子标志物。在PS中，最常见的形式是帕金森病(PD)，定义为 BG黑质(SN)神经元丢失和α-突触核蛋白(αSyn)阳性引起的病理改变 路易体(Lb)聚集，尽管许多其他区域也参与其中。进行性核上性麻痹 多系统萎缩(MSA)和多系统萎缩(PSP)也是常见的PS，并以不同类型的神经元丢失而闻名 大脑区域包括BG、脑桥、小脑及相关结构。PSP具有tau阳性的特征 胶质细胞和神经元中都有包涵体，而大脑中隔核典型的胶质细胞质包涵体是α-syn 阳性。目前，还没有活体生物标记物被批准用来区分这些临床相似的症状 独特的病理模式和分子特征，和/或跟踪每个PS的进展。这个 文献和我们的初步数据导致我们的前提是结合最先进的多模式磁共振成像(AIM 1)用错折叠的α、syn和tau的生物流体标记(目标2)将产生客观和定量的 生物标记物(S)，提供有关PS的补充信息，将PS彼此区分， 量化疾病进展，并提供与每种疾病相关的独特神经病理的洞察 PS.自2012年以来，由黄博士领导的宾夕法尼亚州立大学团队在NINDS PD Biomarker Program的支持下， 招募和研究了270例PS患者(PD 120例，PSP 27例，MSA 30例)和93例对照组。数据 到目前为止收集的包括纵向多模式MRI(T1、T2、扩散和敏感度)、临床数据(NIH 公共数据元素(CDE)和生物体液(血浆、血清和脑脊液)。我们还发现了24个死后大脑 这群人。拟议的研究将通过利用现有的队列、数据和其 储存生物体液，并将扩大PSP和MSA患者的样本规模。这将产生≥60的总数据集 每个PS组和对照组的受试者进行横断面分析，每个PS组的≥为40，对照组为 纵向分析，到2023年，≥将达到60个死后大脑。与多名PI-Dr领导的团队合作。 Kanthasamy(爱荷华州)，Aim 1将确定PS的不同MRI模式及其临床/病理 底物。AIM 2将测试胞外体错误折叠的α、syn和tau作为PS及其进展的生物标志物。目标3 将结合多模式磁共振成像和错误折叠的αSYN/TAU来区分PS/勾画进展。成功者 这些目标的完成可能揭示出对临床和鉴别诊断有重要意义的生物标志物。 PS的诊断，以及评估潜在的疾病修改疗法。

Project Summary/Abstract Parkinsonian syndromes (PS) are common and progressive neurodegenerative disorders that encompass a spectrum of movement disabilities. Despite their distinctive pathological signatures and patterns of brain changes, PS cause overlapping motor signs including bradykinesia, rigidity, and/or tremor, probably due to shared dysfunction of basal ganglia (BG)- and cerebellar-related structures. The current diagnosis and staging of PS as well as other neurodegenerative diseases are based on the pattern of neuronal cell loss or death, gliosis, and molecular markers. Among PS, the most common form is Parkinson's disease (PD), defined pathologically by neuronal loss in the substantia nigra (SN) of the BG and presence of α-synuclein (αSyn) positive Lewy body (LB) aggregation, although many other regions also are involved. Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are also common PS, and are known for neuronal loss in different brain regions including the BG, pons, cerebellum, and related structures. PSP characteristically has tau-positive inclusions in both glia and neurons, whereas MSA typically has glial cytoplasmic inclusions that are α-Syn positive. Currently, no in vivo biomarkers are approved to differentiate these clinically similar syndromes, capture the distinctive pathological pattern and molecular characteristics, and/or track the progression of each PS. The literature and our preliminary data lead to our premise that combining state-of-the-art multimodal MRI (Aim 1) with biofluid markers of misfolded αSyn and tau (Aim 2) will yield objective and quantitative biomarker(s) that provide complimentary information about PS, differentiate PS from each other, quantify disease progression, and provide insights into the unique neuropathology associated with each PS. Since 2012, the Penn State team led by Dr. Huang, supported by the NINDS PD Biomarker Program, has recruited and studied a cohort totaling 270 PS patients (120 PD, 27 PSP, 30 MSA) and 93 Controls. Data collected to date include longitudinal multimodal MRI (T1, T2, diffusion & susceptibility), clinical data (NIH common data elements-CDE), and biofluids (plasma, serum, & CSF). We also have 24 postmortem brains from this cohort. The proposed study will be especially cost-efficient by leveraging this existing cohort, data, and its banked biofluids, and will expand the sample size of PSP and MSA patients. This will yield a total dataset of ≥60 subjects in each PS and control group for cross-sectional analyses, ≥40 in each PS and control group for longitudinal analyses, and ≥60 postmortem brains by 2023. In collaboration with the team led by multi-PI Dr. Kanthasamy (Iowa State), Aim 1 will determine the distinct patterns of MRI in PS and their clinical/pathological substrates. Aim 2 will test exosomal misfolded αSyn and tau as biomarkers for PS & their progressions. Aim 3 will combine multimodal MRI & misfolded αSyn/tau to discriminate PS/delineate progression. The successful completion of these Aims may reveal biomarkers that would be of importance in the clinical and differential diagnosis of PS, and in assessing potential disease-modifying therapies.