R01AG075876

Cerebrovascular Remodeling and Neurodegenerative Changes in Alzheimer's Disease - Project Summary

Alzheimer's disease, the most common cause of dementia and the sixth most common cause of death, afflicts nearly 6 million people in the United States. Alzheimer's disease is a major economic burden to our society, with an annual cost of more than $250 billion.

Cerebrovascular integrity is critical for proper metabolism and perfusion of the brain. Compliance of large cerebral arteries is crucial as these arteries dampen the pulsatile pressure and protect the microcirculation and blood-brain barrier from damage. Cerebrovascular dysfunction can have detrimental impacts on the brain. Growing evidence suggests that cerebrovascular dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease and can potentially be used as a biomarker for preclinical Alzheimer's disease.

The overall goal of this project is to unravel the close relationship between cerebrovascular remodeling and the progression of Alzheimer's disease. Our preliminary study suggested that with pathological progression of Alzheimer's disease, the human cerebral artery showed progressive stiffening, structural breakdown, and increased smooth muscle cell atrophy. We thus hypothesize that the structural and functional changes in large cerebrovasculature are correlated with neurodegeneration and the accumulation of amyloid-β, other toxic metabolites, and tau pathology in the brain.

Building upon our multidisciplinary expertise in vascular mechanobiology, precision mass spectrometry, advanced optical imaging, immunohistochemistry, vascular biology, and neuropathology of Alzheimer's disease, we will test this hypothesis in three aims:

Aim 1) To determine cerebrovascular remodeling (biomechanical, structural, and compositional changes) in the frontal and temporal lobes in Alzheimer's disease.
Aim 2) To determine the association between cerebrovascular remodeling and Alzheimer's disease pathological changes in the frontal and temporal lobes of the brain.
Aim 3) To examine the association between cerebrovascular remodeling and antemortem cognitive status and neuropsychological test performance.

We will use no or low atherosclerotic cerebrovascular and brain tissue from 100 age- and sex-matched brain donors from the NIA-funded BU Alzheimer's Disease Research Center with 1) no Alzheimer's disease pathology, 2) low Alzheimer's disease pathology, and 3) intermediate/high Alzheimer's disease pathology. These brain donors have completed annual National Alzheimer's Coordinating Center Uniform Data Set evaluations during life and have available consensus-based cognitive diagnoses.

This proposal is designed to leverage existing resources to make new discoveries. The matched and parallel studies of cerebral vessels and brain tissue will provide new understandings of the temporal development of cerebrovascular remodeling and Alzheimer's disease. Understanding the role of vascular remodeling in Alzheimer's disease may lead to the discovery of new treatment options and directions for interventions to stave off Alzheimer's disease.

Trustees Of Boston University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Boston, Massachusetts 02215 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 285% from $824,997 to $3,178,600.