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

帕金森综合征多模式生物标志物的发现、进展和病理相关性

基本信息

批准号：
10439912
负责人：
XUEMEI HUANG
金额：
$ 154.86万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439912
关键词：
Autopsy Basal Ganglia Basic Science Biochemical Biological Assay Biological Markers Bradykinesia Brain Brain Pathology Brain region Cerebellum Cessation of life Characteristics Clinical Clinical Data Collaborations Common Data Element Consent Control Groups Cross-Sectional Studies Cytoplasmic Inclusion Data Data Set Diagnosis Differential Diagnosis Diffusion Disease Disease Progression Foundations Functional disorder Future Gliosis Investigation Iowa Lead Lewy Bodies Literature Magnetic Resonance Imaging Measurement Measures Modality Molecular Motor Movement Multiple System Atrophy National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Parkinson Disease Parkinsonian Disorders Pathologic Patients Pattern Plasma Pontine structure Predisposition Process Progressive Supranuclear Palsy Sample Size Staging Structure Substantia nigra structure Syndrome Tauopathies Testing Thick Time Translational Research Tremor United States National Institutes of Health Water Work alpha synuclein atypical parkinsonism base brain magnetic resonance imaging clinical diagnosis clinical practice cohort cost efficient diagnostic criteria disability exosome in vivo indexing insight longitudinal analysis molecular marker multimodality neuron loss neuronal patterning neuropathology programs protein aggregation rate of change recruit synucleinopathy tau Proteins tau-1

项目摘要

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.

项目摘要/摘要帕金森综合症（PS）是涵盖的常见和进行性神经退行性疾病一系列运动障碍。尽管它们具有独特的病理特征和大脑的模式更改，PS会导致重叠的电动标志，包括Bradykinesia，刚度和/或震颤，可能是由于巴萨神经节（BG）和小脑相关结构的共同功能障碍。当前的诊断和分期 PS以及其他神经退行性疾病的基于神经元细胞丧失或死亡的模式，神经胶质和分子标记。在PS中，最常见的形式是定义的帕金森氏病（PD）在病理上因BG的底膜（Sn）的神经元丧失和α-突触核蛋白（αSyn）阳性的存在 Lewy身体（LB）聚集，尽管还涉及许多其他区域。进行性上麻痹（PSP）和多系统萎缩（MSA）也是常见的PS，并且以不同的神经元损失而闻名包括BG，PON，小脑和相关结构在内的大脑区域。 PSP的特征具有tau阳性神经胶质和神经元中的夹杂物，而MSA通常具有神经胶质细胞质夹杂物为α-Syn 积极的。目前，没有批准体内生物标志物来区分这些临床上相似的综合征，捕获独特的病理模式和分子特征和/或跟踪每个PS的进展。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MRI（AIM 1）使用错误折叠的αSyn和Tau的生物流体标记（AIM 2）将产生客观和定量提供有关PS的免费信息，彼此区分PS的生物标志物，量化疾病进展，并提供有关与每种疾病的独特神经病理学的见解 PS。自2012年以来，由Ninds PD Biomarker计划支持的Huang博士领导的宾夕法尼亚州立团队已有招募并研究了总计270名PS患者（120 PD，27 PSP，30 MSA）和93个对照组的队列。数据迄今为止收集的包括纵向多模式MRI（T1，T2，扩散和敏感性），临床数据（NIH 常见数据元素-CDE）和生物流体（等离子体，血清和CSF）。我们也有24个验尸大脑这个队列。拟议的研究将通过利用现有的队列，数据及其来尤其成本效益存放的生物流体，并将扩大PSP和MSA患者的样本量。这将产生≥60的总数据集每个PS和对照组的受试者进行横截面分析，每个PS的40个，对照组，用于对照组纵向分析，到2023年≥60次尸体后大脑。 Kanthasamy（爱荷华州），AIM 1将确定PS中MRI的独特模式及其临床/病理学基材。 AIM 2将测试外泌体错误折叠的αSyn和Tau作为PS及其进行的生物标志物。目标3 将结合多模式MRI和倒数αSyn/tau，以区分PS/DELINEATE进程。成功这些目标的完成可能会揭示生物标志物在临床和差异中很重要 PS的诊断，并评估潜在的疾病改良疗法。