R01AG070987

Extracranial Carotid Atherosclerosis Contributions to Cognitive Impairment and Alzheimer's Disease Risk - Project Summary/Abstract

There is a growing need to understand the mechanisms and treatment options associated with vascular contributions to Alzheimer's disease (AD) and other forms of dementia and cognitive dysfunction. Early brain changes associated with AD and cognitive dysfunction, such as white matter lesion (WML) burden, hypoperfusion, and metabolic mismatch, have vascular risk factors including hypertension, diabetes, aging, and smoking. These structural and functional brain changes are often considered secondary to intracranial cerebral small vessel disease.

In contrast, our preliminary data indicate that extracranial carotid artery disease (ECAD) contributes to brain pathology. Treatment with carotid endarterectomy (CEA) to surgically remove the plaque decreases accumulation of WMLs and neurofibrillary tangles, increases structural connectivity, and, most importantly, improves cognition. ECAD primarily signifies atherosclerosis of the carotid bifurcation, where plaque accumulation is uniquely prevalent compared to other cerebrovascular locations. Carotid arteries play a major role in brain physiology as they bring the majority of blood and nutrients to the brain.

We hypothesize that mechanisms of ECAD contribution to Alzheimer's disease and cognitive dysfunction are likely multifactorial and include embolic phenomena, decreased blood flow, and endothelial activation/inflammation. The interplay between these modifiable factors and non-modifiable risks, such as age, sex, and APOE status, likely contributes to neurodegeneration that can lead to cognitive dysfunction.

Our aims 1 and 2 use cross-sectional studies to evaluate potential mechanisms of ECAD contribution to AD-related brain structure and function changes. Subject evaluation includes neurocognitive testing and quantification of MRI-defined structural parameters, WML accumulation, Alzheimer's disease blood-based biomarkers, and systemic, cerebral, and carotid markers of inflammation. Aim 3 employs a prospective, controlled cohort study evaluating the treatment of ECAD with CEA to determine which patients show improved cognitive function (responders) and what factors are drivers of this response.

This project will define quantifiable measures of brain structural changes leading to neurodegeneration and cognitive dysfunction in subjects with ECAD. This should further build the impetus for clinical trials that change the management of patients with ECAD. In addition, our study offers the exciting opportunity to reveal novel insights into early Alzheimer's disease risk and specific mechanisms of vascular contributions.

Understanding the unique contribution of ECAD to AD/cognitive dysfunction risk is particularly compelling because effective treatments exist for ECAD yet are not currently offered for the treatment/prevention of cognitive dysfunction.

University Of Arizona

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]

Tucson, Arizona 857240001 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 666% from $844,972 to $6,475,434.