R01AG091718

Clarifying the association of depressive symptoms with cortico-limbic tau, cerebral blood flow, neurodegeneration, and longitudinal cognitive decline in individuals with mild cognitive impairment - Project summary

Symptoms of depression, including mild subsyndromal symptoms of depression (SSD) and more severe late life major depression (LLD), are among the strongest predictors of accelerated cognitive decline and have been associated with up to a 4-fold increased risk of dementia.

However, studies linking depressive symptoms to amyloid-β (Aβ), neurodegeneration (brain volume), and measures of cerebrovascular disease (white matter hyperintensities; WMH) in older adults have not sufficiently explained accelerated cognitive decline in these individuals.

There is now compelling evidence to suggest that greater spread and accumulation of hyperphosphorylated tau protein (neurofibrillary tangles) is more strongly associated with depressive symptoms than Aβ deposition and is likely also a significant factor contributing to cognitive dysfunction and cognitive decline attributed to depressive symptoms in older adults.

Emerging data also suggests that reductions in cerebral blood flow (CBF) and brain volumes associated with depressive symptomatology are also linked to tau accumulation.

However, there have been no previous studies that have investigated the relationship of cortico-limbic tau burden in MCI with more severe symptoms of depression, i.e., LLD.

Further, nearly all extant studies investigating tau deposition in neurodegenerative diseases of aging exclude both current major depression and significant depression history.

Evaluating individuals with chronic LLD is an important avenue to clarify the relationships of tau with depressive symptomatology which would inform development of targeted interventions for cognitive decline in older adults.

Recent advances in positron emission tomography (PET) radioligands with high sensitivity and specificity to tau accumulation in limbic structures are ideally suited for this work.

The goals of this study are to:

1) Evaluate the association of depressive symptoms, and features of depression, with cortico-limbic tau binding in a diverse sample of individuals with MCI;

2) Clarify the relative associations of depression severity and tau deposition, in addition to brain volume, Aβ, CBF, and WMH with cognition at baseline; and

3) Evaluate the relative association of baseline cortico-limbic tau and other neurobiological features (brain volume, Aβ, CBF, WMH) with accelerated cognitive decline and course of depressive symptoms over 30 months.

For the proposed five-year study, 110 MCI participants with chronic LLD will be enrolled at the University of California - San Francisco (UCSF) to obtain measures of regional [18F]-MK-6240 tau PET and florbetaben Aβ PET binding, magnetic resonance imaging (MRI) measures of brain volume, CBF, and WMH, and genetic and clinical data.

Data from 165 MCI SSD and 165 MCI with no depressive symptoms (MCI ND) participants will be obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-4) database for statistical analyses.

We will use advanced image harmonization methods to integrate imaging datasets and dissect patterns of neuropathology (Aβ and tau), neurodegeneration, CBF, and WMH associated with depressive symptomatology and cognitive dysfunction.

San Francisco 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]

San Francisco, California 941434200 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)

Amendment Since initial award the total obligations have increased 116% from $1,711,908 to $3,689,364.