R01AG070826

Imaging Brain Iron and Protein Aggregation with MRI for Assessing Alzheimer's Disease Pathology and Progression - Abstract

Alzheimer's Disease (AD) affects over 5 million Americans and is expected to affect 2-3-fold more in the next few decades. AD is associated with aggregation of amyloid-beta (AB) and phosphorylated tau proteins. Curiously, burden of AB, classically considered the most important AD pathological hallmark, is not enough to indicate clinical decline or progression. For example, cognitive-normal elders may also carry high levels of AB and recent clinical trials aiming to reduce AB have generally failed to improve patients' conditions. Therefore, developing biomarkers that can better predict clinical outcome and progression are needed.

Confluent evidence shows that regional brain magnetic susceptibility measured by MRI differs between AD patients and healthy controls, and importantly such changes may predict cognitive decline. However, it is unclear what causes these susceptibility changes in AD. While iron deposition has been widely suspected as the underlying cause, our recent study has discovered that aggregation of AB and tau by itself produces strong diamagnetic susceptibility, opposite of the paramagnetic susceptibility generated by iron deposition. The opposing magnetic susceptibility of iron and aggregated pathological proteins poses a significant challenge as current MRI-based magnetic susceptibility mapping algorithms cannot differentiate iron from other colocalizing diamagnetic susceptibility sources within the same voxel.

Our goal is to develop a novel technique that can differentially quantify molecular sources of magnetic susceptibility and test whether the resulting susceptibility components can serve as markers of progressive AD pathology. We will test our techniques and hypothesis utilizing a unique capability that combines in cranio MRI at autopsy with histological examinations. We have developed innovative histological processing methods that allow voxel-to-voxel matching between MRI and histology in 3D, thus permitting the examination of the relationship between magnetic susceptibility components and the neuropathology underlying AD.

If successful, our techniques and findings might ultimately allow the detection of AD-related neuropathology at much earlier stages, permit intervention before neurons become irretrievably damaged, and non-invasively assess disease progression. These techniques, once standardized, will be highly cost-effective, widely accessible, and readily implementable in non-specialized clinical imaging centers, thus better serving the growing population of AD patients.

Regents Of The University Of California

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]

California United States

State-Wide

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

Amendment Since initial award the End Date has been extended from 01/31/26 to 01/31/27 and the total obligations have increased 362% from $709,446 to $3,281,078.