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Molecular and Physiological Mechanisms of Hypertensive Cerebral Microangiopathy

高血压脑微血管病的分子和生理机制

基本信息

批准号：
10451369
负责人：
Mahmut Edip Gurol
金额：
$ 42万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451369
关键词：
Adult Age-Years Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid Amyloid Proteins Amyloid beta-Protein Atrophic Basal Ganglia Blood Pressure Blood Vessels Brain Brain Diseases Brain Injuries Brain Pathology Brain hemorrhage Carbon Dioxide Cerebral small vessel disease Cerebrovascular Disorders Cerebrovascular system Cerebrum Cessation of life Clinical Trials Design Cognition Cognitive Dementia Deposition Diagnosis Elderly Exhibits Foundations Functional Imaging Functional Magnetic Resonance Imaging Functional disorder Hypertension Hypertensive Intracerebral Hemorrhage Impaired cognition Impairment Injury Ischemic Stroke Lesion Link Magnetic Resonance Imaging Measures Mediating Mediator of activation protein Methodology Methods Microvascular Dysfunction Molecular Multimodal Imaging National Institute of Neurological Disorders and Stroke Nerve Degeneration Pathologic Pathology Patients Physiological Physiology Pittsburgh Compound-B Population Positron-Emission Tomography Preventive Process Proteins Randomized Controlled Trials Recommendation Research Research Priority Risk Factors Severities Severity of illness Source Stimulus Structure Survivors Testing Therapeutic Therapeutic Studies United States United States National Institutes of Health Vascular Cognitive Impairment Vascular Dementia Vascular Diseases White Matter Hyperintensity aging population biomarker development brain tissue cerebrovascular cognitive change cohort dementia risk design disability experimental study gray matter human model imaging approach imaging biomarker innovation multidisciplinary multimodality non-demented novel novel marker population based preservation prevent symposium targeted treatment tau Proteins tau aggregation tissue injury vascular cognitive impairment and dementia white matter

项目摘要

Project Summary The small vessel diseases of the brain are responsible not only for ischemic and hemorrhagic strokes but also vascular cognitive impairment and dementia, major sources of disability and death in older adults. Despite the fact that hypertensive cerebral small vessel disease (HTN-cSVD) is the most common type of brain microangiopathy, the mechanisms linking this condition to brain tissue injury and cognitive impairment are unknown, therefore no specific preventive or therapeutic method targeting physiopathological processes exist. We propose a systematic, multidisciplinary analysis of the mechanisms underlying HTN-cSVD related cerebrovascular dysfunction, impaired perivascular clearance and their connections to brain damage including pathological amyloid/tau protein accumulations. The unique patient cohort is composed of nondemented survivors of a hypertensive intracerebral hemorrhage (HTN-ICH), a well-characterized indicator of severe HTN- cSVD. Specific experiments are designed to compare advanced physiological MRI measures of vascular reactivity and vascular compliance between patients with HTN-ICH and healthy older adults in addition to delineating the relationship of vascular dysfunction with established markers of HTN-cSVD [Specific Aim (SA) 1a and 1b]. These experiments are geared towards testing the hypothesis that HTN-cSVD causes vascular dysfunction which in turn might mediate larger-scale brain tissue injury. The second set of experiments will test the potential effects of HTN-cSVD on accumulation of amyloid and tau proteins in the brain, answering the key question of whether decreased clearance related to small vessel dysfunction might contribute to the accumulation of these pathological hallmarks of Alzheimer’s Disease (SA 2a and 2b). The third set of studies will analyze the effects of vascular, structural and molecular changes on cognition using both cross-sectional and longitudinal assessments (SA 3a and 3b). The proposal builds on a wide range of cutting-edge methodologic advances such as multimodal physiological imaging with 7T ultrahigh field functional MRI, molecular Aß and tau PET imaging, and the use of state-of-the-art structural imaging markers of HTN-cSVD. Successful completion of the proposed highly translational experiments will determine the physiological and molecular mechanisms of brain tissue damage related to HTN-cSVD and the impact of these processes on cognition. These results will represent a major step towards understanding the contributions of the most common vascular brain disease (HTN-cSVD) to dementia, thereby allowing design of clinical trials aimed at preserving or enhancing vascular function using validated imaging markers of the vascular physiology.

项目总结