Synucleinopathies – Novel Targets in Early Diagnosis, Pathophysiology, and Therapeutic Approach

突触核蛋白病 – 早期诊断、病理生理学和治疗方法的新靶标

• 批准号: 10658876
• 负责人: Wolfgang Singer
• 金额: $ 76.53万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658876
• 关键词: American; Biological Markers; Categories; Cerebellar Ataxia; Cerebrospinal Fluid; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Collaborations; Data; Databases; Dementia with Lewy Bodies; Detection; Diagnosis; Diffusion; Disease; Disease Progression; Early Diagnosis; Enrollment; Failure; Functional disorder; Funding; Future; Goals; Grant; Image; Institution; Intervention; Laboratories; Lewy Body Disease; Limited Stage; Magnetic Resonance Imaging; Medicine; Modification; Motor; Movement Disorders; Multiple System Atrophy; Neurobehavioral Manifestations; Neurocognitive Deficit; Neurodegenerative Disorders; Neurons; Parkinson Disease; Parkinsonian Disorders; Participant; Patients; Pattern; Phenotype; Positioning Attribute; Predictive Value; Pure Autonomic Failures; REM Sleep Behavior Disorder; Resources; Severities; Sleep; Symptoms; Testing; Therapeutic; Therapy trial; Translating; Validation; advanced disease; alpha synuclein; associated symptom; behavioral neurology; biomarker evaluation; biomarker identification; cohort; falls; high risk; imaging biomarker; magnetic resonance imaging biomarker; morphometry; motor deficit; motor symptom; novel; participant enrollment; patient stratification; phenotypic biomarker; pre-clinical; predictive marker; prospective; recruit; research clinical testing; sleep abnormalities; synucleinopathy

PROJECT SUMMARY/ABSTRACT Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) comprise a group of neurodegenerative diseases that share the pathophysiological mechanism of abnormal aggregation of alpha-synuclein (αSyn). Promising attempts at disease modification in established synucleinopathies have failed, raising the important issue that patients who have clinically overt, established disease are too advanced for disease-modifying therapies to be efficacious. Therefore, strategies have evolved to allow for earlier disease detection and confirmation which was pursued in our current grant period with focus on pure autonomic failure (PAF). PAF has more recently been established as one of the synucleinopathies, and is characterized by isolated autonomic failure without motor or cognitive deficits, representing a pre-motor stage with high risk of conversion to MSA, PD, or DLB. The main goal of the current grant period was to identify and validate spinal fluid (CSF) and MRI biomarkers of conversion of PAF to motor synucleinopathies. We have accomplished that goal by identifying highly predictive mechanism-based CSF and MRI markers in established synucleinopathies, that when applied to the pre-motor stage can predict conversion and conversion phenotype. REM sleep behavior disorder (RBD) is a condition with close association with synucleinopathies and frequently presents as isolated RBD (iRBD) years before motor or cognitive symptoms develop. The relevance and implications of iRBD as prodromal synucleinopathy has been well recognized, but to date there are no reliable predictors of conversion, phenotype of conversion, or timing of conversion to an established synucleinopathy. We have expanded the biomarkers developed to predict PAF phenoconversion to iRBD patients and identified discrete CSF profiles akin to those seen in PAF and in manifest motor and cognitive synucleinopathies, so that we are now in a position to test the biomarker potential of these markers at the prodromal stage. In this renewal, we shall study sleep-study confirmed iRBD patients stratified by baseline CSF biomarker phenotype (MSA-, PD/DLB, or normal type) along with healthy control subjects with serial clinical evaluations combined with autonomic, CSF, and MRI biomarker studies. We will enhance the feasibility of reaching recruitment goals for each biomarker phenotype by enriching recruitment with participants in the North American Prodromal Synucleinopathy Consortium identified as biomarker phenotype required to reach our recruitment goals. Secondly, we will continue to follow PAF patients enrolled during the current grant period who have not yet phenoconverted to solidify the predictive value of developed biomarkers. The findings from this renewal proposal should result in establishing biomarkers for the pre-motor and prodromal stages of syncucleinopathies, which may translate to disease-modifying therapy trials standing a better chance at demonstrating efficacy, and which may eventually even allow for diagnosing selected neurodegenerative diseases at the preclinical stage.

项目概要/摘要 帕金森病 (PD)、路易体痴呆 (DLB) 和多系统萎缩症 (MSA) 包括 一组具有共同异常聚集病理生理机制的神经退行性疾病 α-突触核蛋白（αSyn）。在已确定的突触核蛋白病中进行疾病修饰的有希望的尝试已经 失败了，提出了一个重要问题：临床上患有明显的、已确诊疾病的患者已经处于晚期 使疾病缓解疗法有效。因此，策略已经发展到可以更早地 我们当前资助期间所追求的疾病检测和确认，重点是纯 自主神经衰竭（PAF）。 PAF 最近被确定为突触核蛋白病之一，并且 其特征是孤立的自主神经衰竭，没有运动或认知缺陷，代表运动前阶段 转换为 MSA、PD 或 DLB 的风险很高。当前拨款期的主要目标是确定和 验证 PAF 转化为运动突触核蛋白病的脊髓液 (CSF) 和 MRI 生物标志物。我们有 通过在已建立的模型中识别基于高度预测机制的 CSF 和 MRI 标记物来实现这一目标 突触核蛋白病，当应用于运动前阶段时可以预测转换和转换表型。 快速眼动睡眠行为障碍 (RBD) 是一种与突触核蛋白病密切相关的疾病，并且经常发生 在运动或认知症状出现前数年，表现为孤立的 RBD (iRBD)。相关性和 iRBD 作为前驱突触核蛋白病的影响已得到广泛认可，但迄今为止还没有可靠的证据 转化的预测因素、转化的表型或转化为已确定的突触核蛋白病的时间。 我们已将开发用于预测 IRBD 患者 PAF 表型转化的生物标志物扩展至 iRBD 患者并确定 离散的 CSF 特征类似于 PAF 以及明显的运动和认知突触核蛋白病中所见的特征，因此 我们现在能够在前驱阶段测试这些标记物的生物标记物潜力。 在本次更新中，我们将研究根据基线 CSF 生物标志物分层的睡眠研究证实的 iRBD 患者 表型（MSA-、PD/DLB 或正常型）以及健康对照受试者进行了系列临床评估 结合自主神经、脑脊液和 MRI 生物标志物研究。我们将增强达成目标的可行性 通过丰富北方参与者的招募来确定每种生物标志物表型的招募目标 美国前驱突触核蛋白病联盟确定为达到我们的目标所需的生物标志物表型 招聘目标。其次，我们将继续跟踪当前资助期内入组的 PAF 患者 尚未进行表型转化以巩固已开发生物标志物的预测价值。 这项更新提案的结果应该会导致建立运动前和运动前的生物标志物。 共核蛋白病的前驱阶段，这可能转化为疾病修饰治疗试验 更好的机会证明疗效，最终甚至可能允许诊断选定的 临床前阶段的神经退行性疾病。

项目成果

Loss of putative GABAergic neurons in the ventrolateral medulla in multiple system atrophy.

多系统萎缩中腹外侧髓质中假定的 GABA 能神经元的丧失。

• DOI: 10.1093/sleep/zsab074
• 发表时间: 2021
• 期刊: Sleep
• 影响因子: 5.6
• 作者: Schmeichel,AnnM;Coon,ElizabethA;Parisi,JosephE;Singer,Wolfgang;Low,PhillipA;Benarroch,EduardoE
• 通讯作者: Benarroch,EduardoE

Elimination of spurious absent sweat response in QSWEAT recordings.

消除 QSWEAT 记录中虚假的缺汗反应。

• DOI: 10.1016/j.autneu.2019.102589
• 发表时间: 2019
• 期刊: Autonomic neuroscience : basic & clinical
• 作者: Corfits,Jeanne;Singer,Wolfgang;Sandroni,Paola;Fealey,RobertD;Coon,ElizabethA;Benarroch,EduardoE;Berini,SarahE;Mauermann,MichelleL;Sletten,DavidM;Cutsforth-Gregory,JeremyK;Schmelzer,JamesD;Low,PhillipA
• 通讯作者: Low,PhillipA

Recent advances in establishing fluid biomarkers for the diagnosis and differentiation of alpha-synucleinopathies - a mini review.

• DOI: 10.1007/s10286-022-00882-1
• 发表时间: 2022-08
• 期刊: CLINICAL AUTONOMIC RESEARCH
• 影响因子: 5.8
• 作者: Singer, Wolfgang

Anhidrosis in multiple system atrophy involves pre- and postganglionic sudomotor dysfunction.

• DOI: 10.1002/mds.26864
• 发表时间: 2017-03
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Coon EA;Fealey RD;Sletten DM;Mandrekar JN;Benarroch EE;Sandroni P;Low PA;Singer W
• 通讯作者: Singer W

Neurofilament Light Chain in Spinal Fluid and Plasma in Multiple System Atrophy - A Prospective, Longitudinal Biomarker Study.

多系统萎缩中脊髓液和血浆中的神经丝轻链 - 一项前瞻性纵向生物标志物研究。

• DOI: 10.21203/rs.3.rs-3201386/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Singer,Wolfgang;Schmeichel,AnnM;Sletten,DavidM;Gehrking,TonetteL;Gehrking,JadeA;Trejo-Lopez,Jorge;Suarez,MarianaD;Anderson,JenniferK;Bass,PamelaH;Lesnick,TimothyG;Low,PhillipA
• 通讯作者: Low,PhillipA