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Accelerated non-atherosclerotic brain arterial aging relationship to Alzheimer's disease

加速非动脉粥样硬化性脑动脉老化与阿尔茨海默病的关系

基本信息

批准号：
10414070
负责人：
Jose Gutierrez
金额：
$ 69.45万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414070
关键词：
3xTg-AD mouse AD transgenic mice Address Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk American Amyloid Amyloid beta-Protein Amyloidosis Animals Arteries Astrocytes Astrocytosis Atherosclerosis Autopsy Biological Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Brain Infarction Caliber Cerebrovascular Disorders Clinical Clinical Trials Cognition Connective Tissue Diseases Data Dementia Deposition Development Dilatation - action Disease Distal Elastases Elastin Functional disorder Future General Population Genetic Goals Gold HIV Human Hypertension Image Immunofluorescence Immunologic Immunohistochemistry Impaired cognition Individual Intervention Ipsilateral MMP2 gene Magnetic Resonance Imaging Measures Mediating Metabolism Metalloproteases Methods Modeling Molecular Mus Nerve Degeneration Neurofibrillary Tangles Neuronal Dysfunction Neurons Participant Pathologic Pathologic Processes Pathology Pathway interactions Persons Pharmaceutical Preparations Phenotype Population Population Study Positron-Emission Tomography Predisposition Preventive measure Reporting Resolution Resources Risk Risk Factors Role Sampling Signal Transduction Stenosis Tauopathies Testing Uncertainty Vascular Diseases abeta deposition arterial remodeling arteriole base brain cell cerebrovascular cisterna magna cognitive performance cohort dementia risk high risk in vivo multi-ethnic multidisciplinary neglect neuroinflammation new therapeutic target novel novel therapeutics population based prevent tau Proteins therapeutic target trait translational potential white matter damage

项目摘要

PROJECT SUMMARY/ABSTRACT: The societal burden of Alzheimer's disease (AD) is expected to rise, and in the absence of effective preventive measures, more than 13 million Americans are projected to have AD by 2050. The prevailing understanding of AD is that amyloid beta (Aβ) deposition in the brain leads to AD and that modifying Aβ deposition may prevent, slow, or arrest AD. In addition to Aβ deposition, individuals with AD often suffer from vascular disease. Although the majority of brain large artery studies have focused on intracranial large artery atherosclerosis (ILAA), ILAA is not the only brain large artery phenotype that relates to AD. Dolichoectasia, on the other hand, is a form of non-atherosclerotic brain arterial aging (BAA) phenotype that consists of dilatation and/or tortuosity. Brain arterial dilatation, dolichoectasia being its most pathological form, is associated with hypertension in the general population, connective tissue disorders, HIV, and aging. We thus propose a change in the paradigm of brain large artery disease that goes beyond atherosclerosis and/or stenosis, and incorporates non-atherosclerotic BAA as a distinct pathological phenotype. We have demonstrated that non- atherosclerotic BAA relates to Alzheimer pathology independent of atherosclerosis and brain infarcts. We have gathered preliminary data showing that brain arterial diameters are associated non-linearly with cognition, so that individuals with narrowed or dilated brain arteries have poorer cognitive performance compared with those with average arterial diameters. This proposal aims to elucidate whether BAA modifies the susceptibility to dementia via arteriolar/capillary dysfunction, neuronal/white matter damage, and/or directly via Aβ/tau metabolism. Aim 1 leverages an existing population-based cohort to obtain an MRI measure of non- atherosclerotic BAA and relate to ipsilateral marker of neurodegeneration. Aim 2 focuses on identifying specific cellular and structural changes that relate to non-atherosclerotic BAA with a precision so far not available in living individuals using the gold standard. In Aim 3, using transgenic AD mice, we will model BAA to validate the biological principle that non-atherosclerotic BAA can cause aging of distal arterioles and promote parenchymal degeneration, exploring potential therapeutic targets. The paradigm presented here has no precedent in the field of brain arterial remodeling. We propose not only to study BAA with unprecedented depth and resources but also to contextualize it with translatable imaging traits that may further evolve this field.

项目总结/文摘: