R01AG073362

Microstructural Changes in Gray and White Matter in Aging and AD - Project Summary

Accumulating neuropathological and animal studies suggest that AD pathology impacts brain microstructure years before the clinical manifestation of the disease. Various processes are involved, including alterations in dendritic arborization and spines, neurite morphology, synaptic density, and axonal transport and packing. Until recently, the evaluation of these microstructural properties and their association with AD pathology has been mainly limited to postmortem tissue.

Recent advances in MRI techniques have provided us with the ability to measure cortical and white matter microstructural properties, such as neurite morphology and macromolecular tissue content, in human in vivo. In the proposed study, we will employ a set of advanced quantitative MRI sequences and analytical approaches to measure changes in cortical and white matter neurite morphology and macromolecular content in preclinical AD. We will also examine their association with cognitive outcomes, amyloid, and tau pathology measured by PET.

We have recently demonstrated the utility of these measures in detecting alterations in cortical and white matter neurite and macromolecular content in a sample of healthy older adults and patients with amnestic mild cognitive impairment. We have also tested the association between these measures and AD pathology in a small sample of older adults with confirmed AD pathology. Teaming up with experts in early AD characterization and AD pathology and leveraging Stanford ADRC PET-MR and deep phenotyping resources, we will study the following aims on a sample of 120 older adults who have a clinical consensus diagnosis of either cognitively normal controls (HC) or mild cognitive impairment (MCI) and will be confirmed to be Aβ- or Aβ+ based on ADRC amyloid PET data.

We will examine cross-sectional and longitudinal changes in cortical microstructural properties, including neurite density (NDI) and orientation dispersion index (ODI) (Aim 1), and in white matter microstructural and macromolecular tissue properties, including NDI, ODI, and macromolecular tissue volume (MTV) (Aim 2), along with their association with cognitive outcomes and AD pathology identified by PET. Taking a network-neuroscience approach, we will also examine connectome-level microstructural changes in preclinical AD and will test the utility of a multi-layer network framework for integrating measures across modalities (microstructural, molecular, PET, cognition) to capture the heterogeneity of AD.

The proposed systematic investigation of microstructural and molecular changes in cortical and white matter in preclinical AD and their association with AD pathology and cognitive outcomes in a well-characterized preclinical AD sample can provide unique insight regarding AD development in the early stages of the disease. It can significantly improve our mechanistic understanding of AD. The outcomes also have the potential to inform the development of experimental treatments, monitoring their effectiveness, and predicting cognitive and clinical trajectories of preclinical AD patients.

The Leland Stanford Junior 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]

Palo Alto, California 94304 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 283% from $786,485 to $3,008,953.