RF1AG078304

Combining Computational Methods, RDOC, and Big Neuroimaging Data to Understand Mechanisms of Neuropsychiatric Symptoms in Alzheimer's Disease

More than 6 million Americans suffer from Alzheimer's disease (AD), the most common age-associated, neurodegenerative dementia. 80% of AD patients also exhibit neuropsychiatric symptoms (NPS), including depression, anxiety, agitation, aggression, apathy, and others. NPS in AD respond poorly to conventional treatments and can lead to severe functional impairment and consequent increased caregiver burden.

While NPS occur during "normal" aging, there is profound disease-related degeneration in neurocircuitry in AD that may be a mechanism for the differences in clinical course of NPS and lack of response to conventional NPS treatments in AD patients. Our proposed study aims to identify relationships between the neurocircuitry underlying NPS and AD neurocircuit degeneration that ultimately may drive worse outcomes in AD with NPS.

Neurodegeneration in AD first targets the hippocampus and temporal regions, then spreads along other nodes of the default mode network (DMN), a key brain circuit implicated in cognition and emotions. Functional magnetic resonance imaging (fMRI) studies have shown that impairments in access and engagement of the DMN with the central executive network (CEN; cognitive processing) and salience network (SN; salience mapping) underlie psychopathology. We apply this "triple network" model which links neurocircuitry of NPS to AD neurodegeneration to investigate the mechanisms of NPS in AD.

In addition, we apply NIMH's Research Domain Criteria (RDOC) framework, which casts brain disorders as extremes from the normal range of behavior. We propose secondary analyses of RDOC-related measures from Human Connectome Project (HCP) young adult and aging lifespan datasets, and the HCP disordered emotional states, anxiety and depression, Alzheimer's disease, and brain aging and dementia datasets, using computational methods for big data analysis that inherently embody the principles of RDOC, treating NPS and AD as having extremes from normal values of brain-behavior mappings.

First, we identify brain circuits for RDOC negative and positive valence and cognitive system constructs, then map these circuits to behavior and self-report measures. We then construct normative models of brain-behavior mappings in healthy individuals, then apply those models to disentangle the complex interactions between NPS and AD. Our overall hypothesis is that deviations from normative values of RDOC-related triple network brain-behavior mappings will elucidate mechanisms of NPS in AD.

We maximize scientific rigor via a very large sample size for our study, and by adopting Repronomics practices designed for replicable and generalizable neuroimaging research.

The Mclean Hospital Corporation

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]

Belmont, Massachusetts 02478 United States

Single Zip Code

Novel Mechanism Research on Neuropsychiatric Symptoms (NPS) in Alzheimer's Dementia (R01 Clinical Trial Optional) (PAR-20-157)

Amendment Since initial award the End Date has been extended from 08/31/25 to 08/31/27 and the total obligations have increased 82% from $2,432,945 to $4,421,675.