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

• 批准号: 10642967
• 负责人: XUEMEI HUANG
• 金额: $ 74.28万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642967
• 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; Probability; Process; Progressive Supranuclear Palsy; Sample Size; Serum; 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; brain magnetic resonance imaging; clinical diagnosis; clinical practice; clinical translation; cohort; comparison control; 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

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.

项目总结/摘要 帕金森综合征（PS）是常见的进行性神经退行性疾病，包括 一系列的运动障碍。尽管他们有着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 基底神经节（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发病是基于神经元细胞损失或死亡的模式， 神经胶质增生和分子标记。在PS中，最常见的形式是帕金森病（PD），定义为 病理学表现为BG黑质（SN）中的神经元丢失和α-突触核蛋白（αSyn）阳性 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 (PSP)和多系统萎缩（MSA）也是常见的PS，并且已知在不同的神经元丢失。 包括BG、脑桥、小脑和相关结构的脑区域。PSP的特征是tau阳性 在神经胶质和神经元中均存在α-Syn包涵体，而MSA通常具有神经胶质细胞质包涵体， 肯定的：第目前，没有体内生物标志物被批准用于区分这些临床相似的综合征，捕获 独特的病理模式和分子特征，和/或跟踪每个PS的进展。的 文献和我们的初步数据导致我们的前提是，结合最先进的多模态MRI（目的 1)与错误折叠的αSyn和tau的生物流体标记物（Aim 2）将产生客观和定量的 提供关于PS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学的见解。 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生物标志物项目的支持下， 招募并研究了总计270名PS患者（120名PD、27名PSP、30名MSA）和93名对照的队列。数据 迄今为止收集的数据包括纵向多模态MRI（T1、T2、扩散和敏感性）、临床数据（NIH 公共数据元素-CDE）和生物流体（血浆、血清和CSF）。我们还有24个死后的大脑 这个cohort。拟议的研究将特别具有成本效益，利用现有的队列，数据， 储存生物液体，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组和对照组中的受试者进行横断面分析，每个PS组和对照组中的受试者≥40例， 纵向分析，到2023年至少有60个死后大脑。与多PI博士领导的团队合作。 Kanthasamy（爱荷华州），Aim 1将确定PS中MRI的不同模式及其临床/病理 印刷受体.目的2将测试外泌体错误折叠的αSyn和tau作为PS及其进展的生物标志物。目标3 将结合联合收割机多模式MRI和错误折叠的αSyn/tau来区分PS/描绘进展。成功 完成这些目标可能会揭示生物标志物，这将是重要的临床和鉴别诊断， PS的诊断和评估潜在的疾病改善疗法。

项目成果

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage.

• DOI: 10.1002/mds.29062
• 发表时间: 2022-08
• 期刊: MOVEMENT DISORDERS
• 影响因子: 8.6
• 作者: Du, Guangwei;Wang, Ernest;Sica, Christopher;Chen, Hairong;De Jesus, Sol;Lewis, Mechelle M.;Kong, Lan;Connor, James;Mailman, Richard B.;Huang, Xuemei
• 通讯作者: Huang, Xuemei

Synergic control of action in levodopa-naïve Parkinson's disease patients: II. Multi-muscle synergies stabilizing vertical posture.

• DOI: 10.1007/s00221-020-05947-z
• 发表时间: 2020-12
• 期刊: Experimental brain research
• 影响因子: 2
• 作者: Freitas SMSF;de Freitas PB;Falaki A;Corson T;Lewis MM;Huang X;Latash ML
• 通讯作者: Latash ML

Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders.

• DOI: 10.3389/fnins.2022.836605
• 发表时间: 2022
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Padhi P;Worth C;Zenitsky G;Jin H;Sambamurti K;Anantharam V;Kanthasamy A;Kanthasamy AG
• 通讯作者: Kanthasamy AG

Lexical-semantic search related to side of onset and putamen volume in Parkinson's disease.

• DOI: 10.1016/j.bandl.2020.104841
• 发表时间: 2020-10
• 期刊: Brain and language
• 影响因子: 2.5
• 作者: Wagner D;Eslinger PJ;Sterling NW;Du G;Lee EY;Styner M;Lewis MM;Huang X
• 通讯作者: Huang X

Blinded RT-QuIC Analysis of α-Synuclein Biomarker in Skin Tissue From Parkinson's Disease Patients.

• DOI: 10.1002/mds.28242
• 发表时间: 2020-12
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Manne S;Kondru N;Jin H;Serrano GE;Anantharam V;Kanthasamy A;Adler CH;Beach TG;Kanthasamy AG
• 通讯作者: Kanthasamy AG