R01AG074330

Upregulated Norepinephrine Synthesis Capacity in Aging - Project Summary

The locus coeruleus (LC) is a small nucleus in the brainstem that is vulnerable to the accumulation of abnormal tau protein, a neuropathological hallmark of Alzheimer's disease (AD). The LC is structurally connected to the temporal lobe and may play a role in transmitting abnormal tau through trans-neuronal spread. The LC is the primary producer of the neuromodulator norepinephrine, which is essential for normal attention and memory function. Beyond its role in cognition, norepinephrine serves a myriad of neuroprotective roles, including inhibition of oxidative stress, maintenance of the blood-brain barrier, and anti-inflammatory processes. The occurrence of hyperphosphorylated tau in the LC has been linked with the loss of norepinephrine-producing LC neurons. The targeting and neurodegeneration of the LC is particularly insidious due to the combined loss of cognition-enhancing neuromodulation and loss of neuroprotective functions, paving the way for disease acceleration and propagation.

Despite insults to the LC, there is evidence for upregulation of norepinephrine metabolism in healthy aging, mild cognitive impairment, and AD. We propose that upregulation of norepinephrine synthesis in the remaining LC cells represents a mechanism of neurochemical compensation that, in some individuals, wards off cognitive decline and protects against disease spread. In healthy older adult humans, we will define relationships between LC structural integrity and norepinephrine synthesis levels (Aim 1). We will determine the extent to which elevated norepinephrine synthesis confers a benefit to memory performance (Aim 2). Finally, we will test the hypothesis that elevated norepinephrine synthesis is associated with reduced tau accumulation longitudinally (Aim 3).

This multimodal study will combine state-of-the-art magnetic resonance imaging (MRI) to measure LC structural integrity, [18F]fluoro-M-tyrosine positron emission tomography (PET) to measure norepinephrine/dopamine synthesis capacity, [18F]MK-6240 PET to measure tau pathology, and plasma measures of AB42/40. If successful, this research will provide new understanding of the neurochemical basis of individual differences in disease progression and will launch a novel avenue of investigation into the role of norepinephrine in disease resilience (supporting maintenance of cognitive function despite pathology) and disease resistance (combating disease spread).

Brandeis 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]

Waltham, Massachusetts 024532728 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 250% from $1,386,326 to $4,846,427.