Imaging Advancements in Small Vessel and CSF Flow Pathophysiology of Pre-clinical Alzheimer's Disease

临床前阿尔茨海默氏病小血管和脑脊液流病理生理学的成像进展

• 批准号: 9912701
• 负责人: HOWARD J AIZENSTEIN
• 金额: $ 73.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912701
• 关键词: Abeta clearance; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Brain; Brain imaging; Carbon Dioxide; Cardiac; Cerebral small vessel disease; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Clinical; Collaborations; Dementia; Detection; Development; Elderly; Engineering; FDA approved; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Government; Guidelines; Head; Heating; Human; Hypertension; Image; Impaired cognition; Individual; Inflammatory; Institutes; Lesion; Link; Magnetic Resonance Imaging; Measures; Methods; Microcirculation; Microvascular Dysfunction; Minnesota; Molecular; Morphology; Neck; Neurologic; Observational Study; Pathology; Pathway interactions; Patients; Physiologic pulse; Population Study; Positron-Emission Tomography; Prevention; Protocols documentation; Pulsatile Flow; Resolution; Risk; Risk Factors; Role; Scanning; Scientist; Senile Plaques; Signal Transduction; Spin Labels; Structure; System; Technology; Time; Venous; White Matter Hyperintensity; Work; arteriole; cerebral microvasculature; cerebrovascular; clinically relevant; cognitive load; design; fluid flow; follow-up; human imaging; imaging biomarker; imaging modality; imaging study; improved; in vivo; indexing; magnetic resonance imaging biomarker; multimodality; neuropathology; pre-clinical; predictive modeling; prospective; radio frequency; recruit; tau Proteins; temporal measurement

Project Summary/Abstract: There is a well-established association between small vessel disease (SVD, microangiopathy) and Alzheimer's disease (AD). The underlying mechanisms for associations between small vessels and the AD cascade remain unclear. Some of the association between SVD and AD is due to the cumulative cognitive burden from independent pathologies (AD and SVD) leading to early manifestation of the clinical syndrome of AD. It is becomingly recognized that another way in which SVD and AD are related is through bi-directional interaction at molecular and cellular levels: e.g., inflammatory factors associated with Aβ plaques contribute to SVD. Furthermore, an emerging hypothesis is that decreased pulsatility of small arterioles decreases cerebral spinal fluid (CSF) clearance of amyloid, putting someone at risk of AD. A better understanding of the underlying mechanisms relating SVD and AD is especially important as it can identify prevention and treatment targets. This proposed transdisciplinary (Multi-PI) proposal aims to develop advanced MRI methods (hardware, acquisition, and analysis) with 7T human imaging and study the pathways linking small vessel and CSF flow pathophysiology to AD. It will be achieved through a consortium consisting of expertise at 1) U. of Pittsburgh - MRI acquisition and analysis-, and AD; 2) FDA -RF-heating matters in relation guidelines-; 3) U. of Minnesota - MRI acquisition-; 4) Quality Electrodynamics Inc. (QED) -integration of patient friendly hardware-; and Montreal Neurological Institute -MRI analysis-. We will examine small vessel morphology, cerebrovascular reactivity (CVR), and CSF flow, all of which are inter-related components in AD pathophysiology. For instance, small vessel lesions (in part due to amyloid angiopathy) may disrupt CVR, and consequently interfere with Aβ clearance. The study is designed as a prospective observational study of older adults without dementia: 30 amyloid positive, and 30 amyloid negative (n = 60). We will leverage two ongoing studies (RF1AG025516 & R01AG052446) of AD pathology for recruitment, clinical characterization and PET imaging. Individuals are scanned at baseline (Aim 1) using current state of the art technology. Throughout we will work on MRI development (Aim 2). At 2-year follow up individuals will be scanned again with the same protocol as at baseline, and will also undergo scanning with the newly developed technology (Aim 3). In summary, this study develops, applies and validates advanced imaging of small vessel morphology, CVR, and CSF flow and other traditional MRI biomarkers to characterize pre-clinical AD, and potentially identify targets for prevention and/or treatment. The proposal takes advantage of recent and proposed advances in a timely and recently FDA-approved technology (7T human MRI) and collaborations between: a) scientists, engineers, and clinicians; b) leading 7T human MRI centers and a coil company; and c) a governmental regulatory agency.

项目总结/文摘: