Defining the clinical utility of CSF biomarkers of neurodegeneration in HIV+ elders

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ABSTRACT This is an application for a K23 award for Dr. Joanna Hellmuth, a behavioral neurology fellow at the University of California, San Francisco (UCSF) Memory and Aging Center (MAC). Dr. Hellmuth is establishing herself as a junior investigator conducting patient-oriented clinical research in geriatric neuroHIV, including the neuropathogenesis of HIV-Associated Neurocognitive Disorder (HAND) and approaches to accurately diagnose, treat and prevent this condition. This K23 will provide Dr. Hellmuth with the resources and support essential to accomplish the following goals: (1) to gain proficiency in cerebrospinal fluid (CSF) biomarker analysis and methodologies; (2) to advance her understanding of the indicators of neurodegeneration, including interpretation of cerebrospinal (CSF) neurodegenerative biomarkers and amyloid PET scans; (3) to gain advanced skills in longitudinal neuroimaging techniques and statistical analyses addressing multivariable and longitudinal modeling; and (5) primary mentorship in the operations of clinical research. To achieve these goals, Dr. Hellmuth has assembled a mentoring team of a primary mentor, Dr. Victor Valcour (HIV-associated cognitive disorders; multimodal neuroimaging in HIV; clinical research in geriatric neuroHIV); and two co- mentors, Dr. Gil Rabinovici (multi-modal neuroimaging in Alzheimer’s disease (AD); biomarkers that improve diagnostic accuracy of AD) and Dr. Henrik Zetterberg (clinical neurochemistry; CSF and plasma biomarkers for the early diagnosis of neurodegenerative disorders, including AD). The proposed research project addresses the diagnostic dilemma of how to accurately diagnose HIV+ elders with cognitive impairment, as their age increases the risk for an Alzheimer’s disease (AD) diagnosis, however the symptoms could reflect HIV-Associated Neurocognitive Disorder (HAND). Dr. Hellmuth will examine a longitudinal panel of CSF biomarkers of AD, ones that are perturbed in some reports of HIV patients, in a unique clinical sample: HIV+ elders with mild symptomatic cognitive impairment who have had AD neuropathology ruled out by amyloid PET scan, and are virally suppressed with antiretroviral therapy. Through this, she will establish the utility of these CSF AD biomarkers in HIV+ elders on treatment, explore the associations between these CSF AD biomarkers and markers of persistent CSF immune activation, and see how both AD and immune activation markers can predict accelerated brain atrophy in HAND. Dr. Hellmuth’s K23 training will prepare her to conduct independent, clinical research in geriatric neuroHIV using CSF biomarkers and neuroimaging, and will prepare her to successfully apply for an R01, and become a leader in the field of geriatric neuroHIV.