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.

项目概要/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 特别是那些患有多病因认知障碍和痴呆症的人。 α-蛋白异常积累 在帕金森病 (PD) 和 β-淀粉样蛋白中发现了具有路易体 (LB) 形式聚集体的突触核蛋白 (Aβ) 和 tau 蛋白在阿尔茨海默病 (AD) 中的积累。然而，多病因混合性痴呆 在高达 80% 的路易体痴呆患者尸检中观察到 LB/AD 病理学，这 包括PD痴呆（PDD）和密切相关的路易体痴呆（DLB）。对于首先 出现运动症状时，Aβ 和 tau 蛋白聚集可能发生在运动症状发作之间的某个时间 和痴呆症。了解脑组织中蛋白质清除的机制对于发育至关重要 痴呆症发病前的干预措施，但这些机制仍然存在争议。动物研究显示证据 用于清除大脑细胞外空间中的 Aβ 和 tau 蛋白的多种脑废物清除途径，以及 睡眠起着关键作用，在此期间细胞外空间的扩张似乎有利于蛋白质 清除。在体内非侵入性评估脑废物清除系统的方法有限。 人类的大脑。我们建议使用自由水（FW）和内部的扩散磁共振成像（dMRI） 体素不相干运动 (IVIM) 将在同时 PET-MR 成像期间采集，以识别 大脑 FW 分数 (f) 和流量测量与患者 Aβ 和 tau 蛋白积累的关联 路易体病谱 (PD/PDD/DLB)。这项高风险的 R21 提案要求为 dMRI 提供资金 FW/IVIM 序列应用以及 FW f 和流程分析。这些数据将与 Aβ 和 tau 整合 通过斯坦福阿尔茨海默病收集的 PET、认知数据和睡眠生物标志物 研究中心（ADRC）。利用深度表型 PD 和 DLB 患者数据与纯 LB 病理学 对于混合性 LB/AD 病理学，通过斯坦福大学 ADRC，我们提出了两个具体目标： 1. 确定 FW f 和血流 (dMRI) 与 Aβ 和 tau 共同病理学 (PET) 以及认知的关联 PD 和 DLB 中的函数 2. 确定 FW 分数和流量与 PD 和 DLB 睡眠障碍的关联。 该提案解决了在 Aβ 和 tau 背景下理解 FW 扩散作用的关键差距 路易体病的蛋白质积累、睡眠-觉醒行为紊乱和认知能力下降 光谱。