R01AG069960

Pathological Mechanisms of White Matter Hyperintensities - Summary

This project applies advanced in vivo imaging to determine the pathological mechanisms of white matter hyperintensities (WMHS) and their contribution to cognitive decline in older adults at risk of Alzheimer's disease (AD). WMHS are bright patches on T2-MRI but do not inform the pathology underlying their appearance.

Our work is innovative because it utilizes, for the first time, non-invasive methods to quantify axon and myelin rarefaction, fluid retention, WMHS-associated cortical atrophy, and blood-brain barrier dysfunction as in vivo drivers of WMHS formation. We will also test typical pathological markers of WMHS, i.e., hypoperfusion and compromised vascular reactivity. All imaging measurements will be validated against well-established CSF markers.

Our scientific premise is that different locations of WMHS (deep vs. periventricular) correspond to distinct mechanisms (vascular vs. neurodegenerative) and cognitive profiles. Thus, our work will allow the use of pathological drivers of WMHS to develop targeted strategies to stop their growth and ameliorate associated cognitive decline in the future.

In Aim 1, we will test the hypothesis that vascular pathology predominates in deep WMHS by measuring cortical cerebral blood flow, vascular reactivity, and blood-brain barrier dysfunction. We will use specialized arterial spin labeling and a hypercapnic functional MRI approach for these measurements. We will validate measurements with CSF markers of vascular injury (E-selectin), inflammation (adhesion molecules, VCAM/ICAM), and blood-brain barrier permeability (albumin extravasation).

In Aim 2, we will test the hypothesis that neurodegenerative pathology predominates in periventricular WMHS by measuring axon rarefaction, demyelination, and fluid retention using advanced diffusion imaging and myelin water fraction imaging. Validation markers will be CSF levels of tau and myelin basic protein. In independent ex vivo samples of donor brain tissue, we will quantify vascular pathology using smooth muscle actin and albumin immunohistochemical stains in the two WMHS. We will also quantify axon and myelin density in the WMHS and normal-appearing white matter and perform neuron counting in gray matter using an array of stains. Postmortem MRI will be used to identify WMHS on donor brains. The quantitative neuropathology will serve as an independent validation of our hypotheses regarding WMHS location and mechanisms.

In Aim 3, we will test the hypothesis that deep WMHS interrupt discrete short-range association fibers and striatal fibers, causing specific cognitive deficits, especially those related to processing speed. Periventricular WMHS, on the other hand, interrupt long-range association tracts causing global cognitive impairment. We will use mediation analysis to explain whether the two types of WMHS influence the relationship between the different imaging markers and distinct cognitive symptoms.

The proposal takes advantage of the cores and affiliates of the University of Washington's Alzheimer's Disease Research Center for recruitment, lumbar punctures, CSF analyses, postmortem MRI matched to ex vivo tissue sections, and systematic anatomic sampling of those sections, ensuring the success of the PI's first independent R01.

University Of Kansas Medical Center Research Institute

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]

Kansas City, Kansas 66160 United States

Single Zip Code

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-24-254)

Amendment Since initial award the total obligations have increased 385% from $722,562 to $3,507,792.