R01AG077541

The Inflammatory Mechanisms Underlying Olfactory Dysfunction in Prognosis of TBI Progression to Dementia - Project Summary

20–68% of traumatic brain injury (TBI) patients exhibit trauma-associated olfactory deficits (OD) which can compromise not only the quality of life but also cognitive and neuropsychiatric functions. Although post-traumatic anosmia has been documented in the medical literature for more than a century, neither the underlying mechanisms nor treatment remain clear. Moreover, the occurrence of TBI significantly increases risk for the development of Alzheimer's disease (AD) or non-AD forms of dementia.

Recent studies of OD have focused on its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Thus, TBI survivors with OD may be an early sign heralding its progression to dementia. AD pathogenesis revealed that the peripheral olfactory pathways including the olfactory bulb (OB) are the potential structural candidates responsible for OD in prodromal AD. Emerging studies have associated OD with the presence of OB inflammatory response, suggesting that OB pathology may provide a mechanistic link between TBI and AD or dementia.

Recent data indicate that TBI-induced rapid and persistent pro-inflammatory responses in the OB were accompanied by increased phosphorylated tau and OB atrophy, resulting in early and persistent olfactory deficits. New data indicate that microglia-mediated inflammation contributed to neuronal hyperexcitation in the OB which was mitigated in the absence of HV1, a newly discovered microglial ion channel required for NADPH oxidase-dependent generation of reactive oxygen species.

Based on these findings and our preliminary data, we hypothesize that early after TBI microglial HV1-mediated inflammation in the OB contributes to hyperexcitation of local neurons leading to olfactory dysfunction, thus heralding its progression to late-onset neurodegeneration. With multidisciplinary approaches including the Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic inhibition of OB microglia, microglia-specific and inducible HV1 KO mice combined with microscopy and biochemical approaches, and comprehensive neurobehavioral testing, we will examine neuroinflammation and neurodegeneration in the OB in a well-established controlled cortical impact mouse TBI model and their correlation with OD and late-onset dementia-like behaviors (Aim 1).

Furthermore, powerful in vivo and in vitro electrophysiological approaches will be applied to characterize detrimental effects of TBI-induced inflammation on network and synaptic functions in the OB (Aim 2). Lastly, we will determine whether genetic or pharmacological inhibition of inflammatory pathways in the OB through intranasal delivery mitigates TBI-induced inflammation and neurodegeneration thus improves functional outcomes (Aim 3).

Our study will be the first to link olfactory dysfunction to dementia and neurodegeneration following TBI. Our findings will potentially shed light on developing effective approaches for early and accurate diagnosis of TBI-associated OD in the development of neurodegeneration and dementia.

University Of Maryland, Baltimore

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]

Baltimore, Maryland 21201 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 384% from $644,702 to $3,122,074.