Free water imaging in PD

PD 中的免费水成像

• 批准号: 10647539
• 负责人: Kathleen Lombard Poston
• 金额: $ 50.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647539
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Animals; Attenuated; Autopsy; Behavior; Biological Markers; Brain; Cause of Death; Cessation of life; Clinical; Cognition; Cognitive; Data; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Etiology; Exhibits; Extracellular Space; Family; Free Association; Functional disorder; Funding; Future; Human; Image; Impaired cognition; Intervention; Investigation; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Lewy body pathology; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Medial; Mediation; Memory; Memory Loss; Motion; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Play; Proteins; Proxy; Request for Proposals; Research; Role; Sleep; Sleep disturbances; Symptoms; System; Technology; Temporal Lobe; Testing; Toxin; Water; abeta accumulation; actigraphy; age related neurodegeneration; alpha synuclein; behavioral phenotyping; brain tissue; cognitive function; cognitive testing; disability; disability-adjusted life years; high risk; in vivo; innovation; macromolecule; motor symptom; neurotoxic; novel; pathology imaging; potential biomarker; prevent; protein aggregation; sleep pattern; solute; synuclein; tau Proteins; tau aggregation; therapeutic development; therapeutically effective; wasting; water diffusion

PROJECT SUMMARY/ABSTRACT Dysfunction in protein clearance mechanisms is thought to underlie many neurodegenerative disorders, and specifically those with multi-etiology cognitive impairment and dementia. Abnormal protein accumulation of α- synuclein with aggregates in the form of Lewy bodies (LB) are found in Parkinson’s disease (PD) and β-amyloid (Aβ) and tau protein accumulations in Alzheimer’s disease (AD). However, multi-etiology dementia with mixed LB/AD pathology has been observed at autopsy in up to 80% of patients with Lewy Body Dementias, which includes PD Dementia (PDD) and the closely related Dementia with Lewy Bodies (DLB). For patients who first present with motor symptoms, Aβ and tau aggregation likely occurs somewhere between motor symptom onset and dementia. Understanding mechanisms of proteins clearance from brain tissue is critical to developing interventions prior to dementia onset, but these mechanisms remain controversial. Animal studies show evidence for several brain waste clearance pathways removing Aβ and tau from extracellular spaces in the brain, and for sleep playing a key role, during which an expansion of extracellular spaces appears to facilitate protein clearance. There are limited means of non-invasively evaluating the brain waste clearance system in vivo in human brains. We propose use of diffusion magnetic resonance imaging (dMRI) of free water (FW) and intra voxel incoherent motion (IVIM) that will be acquired during simultaneous PET-MR imaging, to identify the association of brain FW fraction (f) and flow measures with the accumulation of Aβ and tau proteins in patients across the Lewy Body Disease spectrum (PD/PDD/DLB). This high-risk R21 proposal requests funding for dMRI FW/IVIM sequence application and analysis of FW f and flow. These data will be integrated with the Aβ and tau PET, cognitive data, and sleep biomarkers, which are collected through the Stanford Alzheimer’s disease Research Center (ADRC). Leveraging the deeply phenotyped PD and DLB patient data with pure LB pathology and with mixed LB/AD pathology, through the Stanford ADRC, we propose two Specific Aims: 1. Determine associations of FW f and flow (dMRI) with Aβ and tau co-pathology (PET), and cognitive function, in PD and DLB 2. Determine associations of FW fraction and flow with sleep disturbance in PD and DLB. This proposal addresses a critical gap in understanding the role of FW diffusion within the context of Aβ and tau protein accumulation, disrupted sleep-wake behavior, and cognitive decline across the Lewy Body Disease spectrum.

项目摘要/摘要 蛋白质清除机制的功能障碍被认为是许多神经退行性疾病的基础，并且 α-的异常蛋白质积累 在帕金森氏病（PD）和β-淀粉样蛋白疾病中发现了具有Lewy体（LB）形式的聚集体的综合蛋白 （Aβ）和tau蛋白在阿尔茨海默氏病（AD）中积累。但是，多性痴呆症有混合 LB/AD病理学在尸检时观察到多达80％的Lewy身体痴呆症患者，这是LB/AD病理学 包括PD痴呆症（PDD）和与Lewy Bodies（DLB）紧密相关的痴呆症。对于第一次的患者 出现运动症状，Aβ和TAU聚集可能发生在运动症状发作之间 和痴呆症。了解脑组织清除蛋白质清除的机制对于发展至关重要 痴呆发作之前的干预措施，但这些机制仍然有争议。动物研究表明证据 对于几种脑部浪费清除途径，从大脑的细胞外空间中删除Aβ和TAU，对于 睡眠起着关键作用，在此期间，细胞外空间的扩展似乎有助于蛋白质 清除。非侵入性评估体内脑废物清除系统的方法有限 人的大脑。我们建议使用自由水（FW）和内部的扩散磁共振成像（DMRI） 在同时进行PET-MR成像期间将获得的体素不连贯运动（IVIM），以识别 脑FW馏分（F）和流量测量与患者Aβ和Tau蛋白的积累的关联 跨Lewy身体疾病谱（PD/PDD/DLB）。此高风险R21建议要求为DMRI提供资金 FW/IVIM序列应用和FW F和流量的分析。这些数据将与Aβ和TAU集成 宠物，认知数据和睡眠生物标志物是通过斯坦福大学阿尔茨海默氏病收集的 研究中心（ADRC）。利用纯LB病理的深层表型PD和DLB患者数据 通过混合LB/AD病理学，通过Stanford ADRC，我们提出了两个具体目标： 1。确定FW F和流量（DMRI）与Aβ和TAU副教科（PET）的关联以及认知 功能，在PD和DLB中 2。确定FW分数和流量与PD和DLB中的睡眠障碍的关联。 该提议解决了理解FW扩散在Aβ和TAU背景下的作用的关键差距 蛋白质积累，睡眠效果行为破坏以及路易人身体疾病的认知能力下降 光谱。