R01NS126086

Sex Differences in the Contribution of Cerebrovascular Injury and Immune Activation to Neurocognitive Impairment in HIV Infection - Project Summary

Neurocognitive Impairment (NCI) affects up to 50% of persons living with HIV (PWH), including individuals with well-controlled infection. Biological sex is an important determinant of NCI among PWH. The strongest available evidence indicates that women with HIV have greater cognitive deficits globally than men with HIV and, most prominently, in learning, memory, and processing speed.

Although women make up half of the world's HIV population, few studies have focused on the mechanisms underlying sex differences in the prevalence and pathogenesis of NCI in PWH, despite the consequences that these differences could have on developing distinct therapeutic approaches to NCI for women and men.

At least two pathways may differentially impact cognitive health in women and men with HIV, both through their association with cerebrovascular injury: (1) cardiovascular disease (CVD) risk factors and (2) immune activation and inflammation. Our central hypothesis is that NCI is more prevalent in women with HIV than in men with HIV due to greater burden and progression of cerebrovascular injury from increased susceptibility to the effects of CVD risk factors and immune activation.

In Aim 1, we will determine if sex modifies the association of CVD risk factors and immune activation with cerebrovascular injury in PWH. In Aim 2, we will compare the burden and progression of cerebrovascular injury between women and men with HIV. In Aim 3, we will examine the extent to which cerebrovascular injury mediates the higher prevalence of NCI and decline in women with HIV and if sex modifies the association between cerebrovascular injury and NCI.

To achieve our aims, we propose a prospective study that will leverage the research platform provided by the NIH-funded Multicenter AIDS Cohort Study (MACS)/Women's Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS). We will enroll 150 women (100 post-menopausal and 50 pre-menopausal women) and 100 age-matched men from the MWCCS to ensure the study is adequately powered to determine if sex modifies the associations between CVD risk factors, immune activation, cerebrovascular injury, and NCI.

To the longitudinal neuropsychological data and stored blood specimens collected in the MWCCS study, we will add a comprehensive cerebrovascular imaging assessment, including of cerebral vasoreactivity, large artery, and small vessel disease, that will yield a complete profile of cerebrovascular injury. We will also measure immune activation and inflammatory markers that are associated with both cerebrovascular injury and NCI in PWH and have been shown to be higher in women compared with men.

The findings of this study will provide new information on sex differences in the burden and progression of cerebrovascular disease and in the pathogenesis of NCI in PWH, which will inform the rational design of clinical trials, including the target study population, in which to test interventions to prevent and treat NCI in PWH.

San Francisco Regents Of The University Of California

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (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. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND 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.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

San Francisco, California 941153511 United States

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

Amendment Since initial award the total obligations have increased 388% from $663,700 to $3,238,534.