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 尤其是那些有多种病因的认知障碍和痴呆症患者。α-蛋白异常积聚 在帕金森病(PD)和β-淀粉样蛋白中发现了以路易小体(Lb)形式聚集的突触核蛋白 (aβ)和tau蛋白在阿尔茨海默病(AD)中的积累。然而，多病因痴呆与混合性痴呆 在高达80%的路易体痴呆患者的尸检中观察到了LB/AD病理，其中 包括帕金森病痴呆(PDD)和与路易小体密切相关的痴呆(DLB)。适用于第一个 出现运动症状，β和tau的聚集可能发生在运动症状开始之间的某个地方 和痴呆症。了解脑组织清除蛋白质的机制对发育至关重要。 在痴呆症发作之前进行干预，但这些机制仍然存在争议。动物研究表明有证据表明 对于从脑细胞外间隙中清除Aβ和tau的几种脑废物清除途径，以及对于 睡眠起着关键作用，在此期间，细胞外空间的扩张似乎有助于蛋白质的分泌 通行证。在体内非侵入性评价脑废物清除系统的手段有限 人类的大脑。我们建议使用弥散磁共振成像(DMRI)的游离水(FW)和 体素非相干运动(IVIM)，将在同步PET-MR成像过程中获取，以识别 患者脑FW分数(F)和血流测量与Aβ和tau蛋白蓄积的关系 整个路易体疾病谱(PD/PDD/DLB)。此高风险R21提案要求为dMRI提供资金 FW/IVIM序列应用及FW、F、FLOW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记物，这些都是通过斯坦福阿尔茨海默病收集的 研究中心(ADRC)。利用具有纯LB病理的深度表型PD和DLB患者数据 对于混合的LB/AD病理，我们通过斯坦福ADRC提出了两个具体目标： 1.确定FW f和Flow(DMRI)与Aβ和tau共同病理以及认知的关系 函数，在PD和DLB中 2.确定PD和DLB患者FW分数和Flow与睡眠障碍的关系。 这一建议解决了在理解β和tau背景下FW扩散的作用方面的一个关键差距 路易体病患者的蛋白质堆积、睡眠-觉醒行为紊乱和认知能力下降 频谱。