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Principal Investigator: Lynn PULLIAM
Organization: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
Fiscal Year: 2024
Award: $559,096
Funding agency: National Institute of Mental Health
Cognitive impairment in chronic well-controlled HIV infection continues to affect from 30%-60%
of individuals. Mechanisms are still unknown but probably associated with continued
neuroinflammation. Biomarkers for cognitive impairment have been inconsistent although
neuroimaging has emerged as a possibility. Unfortunately, imaging is expensive with limited
access. Exosomes are small microvesicles shed from most all cells under normal and pathologic
conditions. The cellular cargo packaged into exosomes can represent the state of the parent cell.
We have isolated neuron-derived exosomes (NDE) in plasma using a 2-step isolation procedure
and a cell surface neuron specific antibody. We have shown in a recently completed R21 using
mass spectroscopy that NDE are rich in over 50 neuronal proteins. In addition, using proximity
extension analysis (PEA) for neurology biomarkers, we identified an additional 28 proteins that
were present. At least 7 proteins were statistically significantly differentially expressed in HIV
infection alone, neurocognitive impairment in HIV+ women versus men and 1 protein that was
significantly correlated with age and impairment. Several NDE proteins correlate with cognitive
domains and several differentiate HIV cognitive impairment from Alzheimer’s disease. Our
overall hypothesis is that NDE can be used to diagnose cognitive impairment in HIV infection
and that men and women have different proteins in NDE that will influence diagnosis and
treatment. We further plan to differentiate mild cognitive impairment with that associated with a
pre-Alzheimer’s mild cognitive impairment (MCI) diagnosis. To test this hypothesis, we propose
the following Specific Aims: (1) Select and verify a set of neuronal exosome proteins that predict
and diagnose HIV cognitive impairment with aging in women and men, (2) Determine whether
neuronal exosome cargo can differentiate HIV-associated cognitive impairment from mild
MCI/Alzheimer’s disease (3) Correlate HIV NDE protein targets and cognitive domains
associated with neuroimaging markers of injury and (4) Establish a rapid ultrasensitive assay
using verified neuronal exosome target proteins for diagnosis of HIV cognitive impairment in a
longitudinal cohort. We will utilize a multidisciplinary approach that includes basic research of
protein targets correlated with cognitive domains and clinical diagnosis using neuroimaging
correlation with selected biomarker proteins. These results will have major impact on treatment
and cure of HIV in the brain as fluid biomarkers are discovered and the health of the neuron can
be assessed in “real time.”
Terms: <AD dementia><AIDS><AIDS Virus><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Affect><After Care><After-Treatment><Aftercare><Age><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimers Dementia><Amphoterin><Amphoterin Gene><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Antibodies><Antigens><Assay><Aβ><Basic Research><Basic Science><Bioassay><Biological Assay><Biological Markers><Blood Plasma><Brain><Brain Nervous System><CALL protein><CamL1 Gene Product><Cell Body><Cell Surface Glycoprotein L1><Cell surface><Cells><Chromosomal Protein, Nonhistone, HMG1><Chromosomal Protein, Nonhistone, HMG1 Gene><Chronic><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Cohort Studies><Communicable Diseases><Concurrent Studies><Diagnosis><Discipline><Disturbance in cognition><Encephalon><F11 Glycoprotein><FM1 Gene Product><Funding><General Radiology><Goals><HIV><HIV 1 associated neurocognitive disorder><HIV Infections><HIV Seronegativities><HIV Seronegativity><HIV associated neurocognitive deficit><HIV associated neurocognitive impairment><HIV diagnosis><HIV induced neurocognitive deficit><HIV induced neurocognitive impairment><HIV negative><HIV neurocognitive impairment><HIV related cognitive dysfunction><HIV related cognitive impairment><HIV-1 associated neurocognitive deficit><HIV-1 associated neurocognitive disorder><HIV-1 associated neurocognitive impairment><HIV-associated cognitive dysfunction><HIV-associated cognitive impairment><HIV-associated neurocognitive disorder><HMG-1><HMG-1 Gene><HMG-1 Protein><HMG1><HMG1 Gene><HMG3><HMG3 Gene><HMGB1><HMGB1 Protein><HMGB1 gene><HTLV-III Infections><HTLV-III Seronegativities><HTLV-III Seronegativity><HTLV-III-LAV Infections><Hand><Health><Heparin-Binding Protein p30><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1><High-Mobility Group Box 1 Gene><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><IQ Deficit><Image><Impaired cognition><Impairment><Incubated><Individual><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Injury><L1 Cell Adhesion Molecule><L1CAM><LAV-HTLV-III><Label><Light><Liquid substance><Long-term cohort><Longitudinal cohort><Longterm cohort><Lymphadenopathy-Associated Virus><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Monitor><NGF-Inducible Glycoprotein><NIH><NILE Glycoprotein><NILE Protein><National Institutes of Health><Nerve Cells><Nerve Growth Factor-Inducible Large External Glycoprotein><Nerve Unit><Neural Adhesion Molecule L1><Neural Cell><Neural Cell Adhesion Molecule L1><Neurocognitive Deficit><Neurocognitive Impairment in HIV><Neurocognitive Impairment in HIV-1><Neurocyte><Neurology><Neurons><Neurosciences Research><Nonhistone Chromosomal Protein HGM1><Nonhistone Chromosomal Protein HGM1 Gene><Oligo><Oligonucleotides><Parents><Pathogenesis><Pathologic><Persons><Photoradiation><Plasma><Plasma Serum><Primary Senile Degenerative Dementia><Probability><Procedures><Prognosis><Proteins><Radiology><Radiology Specialty><Recovery><Reticuloendothelial System, Serum, Plasma><SBP-1><SBP-1 Gene><Sulfoglucuronyl Carbohydrate Binding Protein><Sulfoglucuronyl Carbohydrate Binding Protein Gene><Techniques><Technology><Testing><Time><United States National Institutes of Health><Virus Replication><Virus-HIV><Woman><Women's Interagency HIV Study><a beta peptide><abeta><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><ages><aging population><amyloid beta><amyloid-b protein><beta amyloid fibril><bio-markers><biologic marker><biomarker><biomarker selection><brain health><clinical diagnosis><cognitive dysfunction><cognitive loss><cohort><comparing females and males><comparing women and men><differential expression><differentially expressed><exosome><extracellular vesicles><female treatment><females compared to males><females compared with males><females versus males><females vs males><fluid><hands><imaging><immunogen><improved><injuries><intelligence quotient deficit><interdisciplinary approach><interest><liquid><men><microvesicles><mild cognitive disorder><mild cognitive impairment><multidisciplinary approach><neural><neural imaging><neural inflammation><neuro-imaging><neurocognitive decline><neurocognitive disorder><neurocognitive impairment><neurofilament><neuroimaging><neuroimaging biomarker><neuroimaging marker><neuroinflammation><neuroinflammatory><neurological imaging><neuronal><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oligos><parent><peripheral blood><population aging><post treatment><primary degenerative dementia><protein biomarkers><protein markers><senile dementia of the Alzheimer type><soluble amyloid precursor protein><transcriptional differences><treat females><treat women><treatment among females><treatment among women><treatment in females><treatment in women><viral multiplication><viral replication><virus multiplication><women compared to men><women compared with men><women versus men><women vs men><women's treatment>