James T. Becker, Ph.D. - US grants

This is a request for competing continuation funding for the study, "HIV1- related Neuropsychological Abnormalities" (ROI-MH45311), a project which evaluates the longitudinal course of cognitive function among a population-based sample of HIV-infected individuals. Although cross- sectional data demonstrate that symptomatic HIV+ individuals have increased rates of neuropsychological abnormalities, little is known about the progression of these deficits. Interpretation of most data is difficult because many studies focus on highly motivated volunteer subjects. Further, while the neuropsychological abnormalities in HIV+ individuals have been studied in relation to underlying neurologic disease, relatively little is known about the extent to which cognitive abnormalities may also be produced by diagnosable psychiatric disorder, or about whether - in the presence of established neurological disease and/or psychiatric disorder - other factors (e.g., HIV-related medical and psychosocial factors) act to increase HIV+ individuals' risk to display neuropsychological deficits. By delineating predictors and risk factors for neuropsychological deficits in HIV+ individuals, we may refine our models of the pattern of neuropsychiatric effects operating during the course of HIV infection. The Allegheny County Neuropsychiatric Survey evaluates the neuropsychological, psychosocial, and neurological consequences of HIV infection and AIDS among HIV+ community residents seeking prima medical care. The purpose of this application is to request three years of continuing funding to: enrich our current sample of HIV+ recruited men through our sentinel physician network, to add 50 new HIV+ women and 50 HIV- female controls from the same sentinel physician network, and to complete baseline, six month, and one year follow-up examinations of neuropsychological, psychiatric/psychosocial, and neurological status. This study data are relevant to the NIMH-mandated key research questions concerning the need to obtain an accurate understanding of the causes and predictors of HIV-related neurobehavioral impairments, addressing gaps on our current knowledge including: 1) how the virus affects higher thought processes; 2) why there is enormous individual variation in the behavioral effects; 3) what the relationship is between the immune system and psychological function; and 4) how personal and psychological factors (e.g., self-esteem) affects the mental health of HIV+ subjects, and may indirectly affect cognitive function.

Relatively little is known about the longitudinal course of neuropsychological abnormalities among patients with dementia syndromes. There is a lack of systematic longitudinal research examining the cognitive defects in dementia patients in relation to pre-existing and co-morbid psychiatric symptoms and syndromes, and neurological and medical diseases. This RSDA will allow the investigator to focus his research efforts in studying the natural history of dementia using a conceptually driven multifactorial approach. Using an existing database of 181 Alzheimer's disease patients, the occurrence, course and predictors of neuropsychological impairment will be determined. The role of psychiatric and neurological signs, symptoms, and syndromes in predicting the presence and pattern of cognitive deficits will be evaluated. Second, using data from an ongoing longitudinal study of the neuro-psychological abnormalities among HIV+ individuals seeking primary medical care, analyses will follow from a specific conceptual model of the neuropsychiatric predictors of presentation and investigate the functional CNS changes in dementia with Positron Emission Tomography. These studies will provide critical information about the natural history of dementia syndromes in the context of their overall neurobehavioral syndromes. The analyses will permit inferences about the nature of the neuro-anatomical defects associated with the observed syndromes, which will permit a more rational approach to evaluating therapeutics.

Patients with Alzheimer's disease (AD) have significant difficulties in their ability to retrieve verbal lexical and semantic knowledge early in the course of the disorder, in addition to the well-described alterations in episodic memory. Delineation of the neural systems that underlie this semantic memory impairment may lead to better understanding of the information processing defect, and the identification of those systems that are particularly vulnerable to early neuropathological change in AD. Because the representation and retrieval of semantic knowledge probably involves a distributed network of neocortical areas, it may be the ideal cognitive system for examining the functional manifestations of cortico- cortical disconnection in AD. The purpose of this project is to investigate the changes in semantic memory function which occur in normal aging and in dementia. Using well understood behavioral tasks which focus on lexical and semantic storage and retrieval, and associated information processing during Positron Emission Tomography (PET) scans, we will compare and contrast the brain regional activation during the performance of cognitive tasks related to lexical/semantic information processing between young (n=10) and old (n=10) normal control subjects, and patients with Probable Alzheimer's disease (n=10), in each of three studies. The AD patients will be matched with the elderly controls in terms of age, education, and sex, add with the young controls in terms of education and sex. The three studies will focus on Visual Confrontation Naming (Study #1), Visual Semantic Processing (Study #2), and Word Reading (Study #3). These studies share the common feature that they will permit study of processes related to semantic memory in AD, and permit the evaluation of hypotheses related to understanding the underlying defect responsible for the semantic memory loss.

The Allegheny Neuropsychiatric Survey (MH45311) investigates the neuropsychological, psychosocial, and neurological consequences of HIV infection and AIDS among community residents seeking primary medical care with Allegheny County (PA). The purpose of this revised application is to seek continuation of funding in order to study, in detail, Minor Cognitive Motor Disorder (MCMD). The proposed extension will recruit an additional 160 HIV+subjects with AIDS, and 50 HIV- controls. The HIV+subjects will be evaluated every six months for three years, or until they are diagnosed with HIV-associated dementia (HAD). The intensive evaluations will study the cognitive, neurological, and psychosocial status of these individuals. Magnetic Resonance Imaging studies will evaluate the structural and functional integrity of the CNS. Plasma viral load (and a selected sample of CSF viral load) will indicate peripheral (and CNS) infection status. These data will be analyzed to address three specific questions: 1) what is the reliability of the diagnosis of MCMD?, 2) what are the neurobehavioral characteristics of patients with MCMD?, and 3) what factors are associated with transition points around MCMD; that is, what predicts transition from normal cognition to MCMD, and from MCMD to HIV- associated dementia? These data will address four linked hypotheses: 1) that MCMC can be reliably diagnosed, 2) that its hallmark is psychomotor slowing, 3) that the transition into MCMD is preceded in time by functional changes in the CNS, and 4) that MCMD and HAD are independent syndromes. These data will provide important information about the course of the cognitive impairment in HIV/AIDS. By studying MCMD in detail, and the factors that predict transition to MCMD and HAD, it may be possible to provide information useful to the development of rational treatment strategies directed at cognitive dysfunction.

Patients with Alzheimer's disease (AD) have significant difficulties in their ability to retrieve verbal lexical and semantic knowledge early in the course of the disorder, in addition to the well-described alterations in episodic memory. Delineation of the neural systems that underlie this semantic memory impairment may lead to better understanding of the information processing defect and the identification of those systems that are particularly vulnerable to early neuropathological change in AD. Because the representation and retrieval of semantic knowledge probably involves a distributed network of neocortical areas, it may be the ideal cognitive system for examining the functional manifestations of cortico- cortical disconnection in AD. Using a behavioral task that focuses on semantic memory and and associated information processing during functional Magnetic Resonance Imaging (fMRI) scans, we will compare and contrast the brain regional activation in a longitudinal follow-up study relating fMRI signal change and semantic memory function. Patients with AD (n=40), Mild Cognitive Impairment (n=20), or an Amnesic Syndrome (n=10) will be evaluated as well as age-matched controls (n=20). The patients will be scanned while performing Synonym Judgement, Homonym Judgement, and Visual Control Tasks. Signal change will be correlated with performance on Patterson and Hodges Semantic Memory Battery. This study will permit the evaluation of processes related to semantic memory in AD, and of hypotheses related to understanding the underlying defect responsible for the semantic memory loss. Based on our existing PET data from AD patients, we hypothesize that there will be focal deficit in the function of the inferior temporal lobe. This will, in turn, affect the function of the inferior frontal (related to response selection) and cerebellar cortices (related to response search) as they adapt to the altered functional circuitry in AD.

DESCRIPTION (provided by applicant): During the course of the HIV/AIDS epidemic there has been one constant - ten percent of all new cases occur in adults over the age of 50. In spite of this, the vast majority of all HIV/AIDS research has focused or individuals younger than 50. With the increasing survival of AIDS patients, and the unrelenting rate of new infectiodcases, the number of AIDS patients over 50 years of age is growing. Our lack of understanding about how age and HIV/AIDS interact is becoming increasingly problematic, no more so than in the area of the neurocognitive manifestations of AIDS, since age is itself an important predictor of neurocognitive syndromes- In spite of the known links between age and various neuropsychiatric disorders - including dementia - it has only been recently that much attention has been paid to the possible interactions between HIV/AIDS and aging and neuropsychiatric presentation. The purpose of this study is to compare and contrast neuropsychological deficits, including brain structural and functional abnormalities associated with HIV/AIDS as a function of chronological age. In particular, we will characterize the neuroimaging and neuropsychological defects in older individuals with AIDS focusing on two distinct neuropathologies that can lead to impairment - one via mesial temporal dysfunction (aging), and the other via basal ganglia dysfunction (AIDS). By carefully characterizing the neuropsychological deficits (including those identified using brain imaging technology) we will be better able to understand the interactive effects of agingand HIVIAIDS.

[unreadable] DESCRIPTION (provided by applicant): The neurocognitive manifestations of HIV/AIDS have long been recognized as important for the management, survival, and quality of life of affected patients and their families. Following the advent of Highly active anti-retroviral therapy (HAART) the incidence of HIV-associated dementia (HAD) has fallen, but the prevalence of the milder forms of HIV-related cognitive disorders has risen. This is important because alterations in cognitive function can have significant impact on work and social activities, mood, and perceived quality of life. To date, pharmacological management of HIV-associated cognitive disorders - apart from HAART - have met with limited success (e.g., Peptide T, Ritalin). Therefore, it appears reasonable to ask whether the use of non-pharmacological tools might help alleviate or ameliorate the symptoms of the milder forms of cognitive impairment, and thus improve mood and activities of daily living. The purpose of this application is to request funds to allow us to complete a feasibility/pilot study of the merits of using an internet-based cognitive stimulation program (CSP) to improve the cognitive functions and quality of life of individuals with HIV/AIDS, and, secondarily, to detect such changes using a computerized assessment tool designed for use in a health care practitioner's office (Computer-Based Assessment of Mild Cognitive Impairment (CAMCI)). [unreadable] [unreadable] There has been little success in treating the cognitive (thinking) problems associated with HIV/AIDS using medications. The purpose of this study is to determine whether an internet-based cognitive "stimulation" program might help HIV-infected individuals think more clearly. If this is true, then it means that people with mild forms of cognitive impairment may be able to help themselves to get better. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The neurocognitive manifestations of HIV/AIDS are important for the management, survival, and quality of life of affected patients and their families. Following the advent of Highly Active Anti- Retroviral Therapy (HAART) the incidence of HIV-associated dementia (HAD) has fallen, but the prevalence of the milder forms of HIV-related cognitive disorders has risen. This is important because alterations in cognitive function can have significant impact on work and social activities, mood, and perceived quality of life. The recent NIH-sponsored Consensus Conference on Diagnosis of HIV-Associated Neurocognitive disorders concluded that one major weakness in the field was a lack of a useful neuroimaging marker for HAD and the milder MNCD;although there have been advances in MRI-based measurement of cerebral blood flow and in functional MRI, these methods have limitations. One emerging technology that has not, to date, been applied to HIV/AIDS is magnetoencephalography (MEG). However, before MEG can be used in HIV/AIDS clinical or research settings, it is necessary to establish some prerequisite information. Specifically, it is critical to to determine the reliability (over minutes/hours) and stability (over months) of the MEG signal over time, and to compare and contrast MEG activity relative to fMRI. The purpose of this pilot study is to obtain these critical preliminary data in order to establish the utility of MEG in evaluating HAD and MCMD. PUBLIC HEALTH RELEVANCE The purpose of this research is to understand whether, and by how much the data obtained using a very sensitive brain imaging technology will change simply by repeating the experiment. This is important because without this information it is difficult to know how reliable (reproducible) study results are, and this can have a major impact in terms of the interpretation (understanding) of any future studies.

[unreadable] DESCRIPTION (provided by applicant): There is a host of evidence showing CNS damage from drug use/abuse (DA) and HIV/AIDS. However, the majority of these studies assume that it is the direct effects of these factors on the CNS that result in altered cognition. The purpose of this exploratory study is to evaluate a different mechanism - namely, that alterations in vascular function are at least partial mediators of the effects of DA and HIV/AIDS on cognition. If the overall hypothesis is correct, that means that many of the CNS changes associated with DA and HIV/AIDS are secondary to vascular changes, and this might explain why there are synergistic effects between these conditions on cognition, and would suggest pathways for the treatment and prevention of cognitive changes in DA and HIV/AIDS that have not been typically exploited. In order to evaluate the hypothesis that alterations in CNS vasculature are at least partially responsible for the cognitive changes in DA and HIV/AIDS, we will take advantage of a novel technique available through magnetic resonance imaging - Arterial Spin Labelling. This technique allows for the measurement and mapping of regional cerebral blood flow (rCBF) without the use of contrast agents or ionizing radiation. In addition, by challenging the subject to breathe CO2 during the scan, it is possible to measure the acute vascular response to hypercapnia. The purpose of this exploratory study is to allow us to obtain the data necessary to develop a larger scale, multi-center study of the association between vascular integrity, DA, HIV/AIDS and CNS structural and functional integrity. Before using these state-of-the-art methods for measuring both "acute" (i.e., hypercapnic) and "chronic" (i.e., resting) rCBF as biomarkers for tracking disease and for investigating the underlying pathophysiology of HAD and associated conditions, it is necessary to establish some basic information regarding the stability and validity of the techniques. The purpose of this study is to evaluate rCBF in individuals with HIV/AIDS with and without concomitant drug abuse. Specifically, we will determine the extent to which rCBF is stable over 24 weeks of study, and determine the criterion validity of the MRI technique using concomitant O15 -water positron emission tomography (PET) measures of RCBF. Individuals with HIV/AIDS may have difficulty thinking. Individuals who use drugs may also have difficulty with their thinking. It is also true that people with HIV/AIDS or who use drugs may have problems with their circulation (blood vessels). This could mean that not enough blood is getting to the brain, or that the blood vessels in the brain do not respond correctly when the brain needs more blood. It is possible to measure blood flow in the brain using a technique called magnetic resonance imaging, which can take pictures showing how fast blood is moving through various parts of the brain. The purpose of this exploratory study is to begin to use this new technology to study blood flow in the brains of people with HIV/AIDS and drug abuse. We are interested in knowing whether changes in their circulation may be responsible for some of the changes in their ability to think. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The proportion of persons living with HIV/AIDS who are over 50 rose to 22.5% of all cases in 2004. Our lack of understanding about how age and HIV/AIDS interact is becoming increasingly problematic, no more so than in the area of the neurocognitive manifestations of AIDS, since age is itself an important predictor of neurocognitive syndromes. In spite of the known links between age and various neuropsychiatric disorders including dementia, only recently has much attention has been paid to the possible interactions between HIV disease, aging and neuropsychiatric presentation. The purpose of this application is to obtain funding to compare and contrast brain structural and functional abnormalities associated with HIV/AIDS as a function of cardiovascular abnormalities. As the rate of cardiovascular disease increases with age, so too do the consequences of those disorders including abnormalities in the small vessel in the brain, decreased grey matter volume, altered white matter integrity, and changes in regional cerebral blood flow. Understanding how these normal consequences of aging are affected by HIV is important for clinical care, the development of new treatment strategies, and understanding the pathophysiology of HIV-Associated Neurocognitive Disorder. We will evaluate the cardiovascular, cognitive, and brain structure/function status of 340 men participating in the cardiovascular substudy of the Multicenter AIDS Cohort Study (MACS). We will take advantage of the nearly 25 years of prior clinical and neuropsychological data, combined with the new CVD variables (e.g., coronary calcium, carotid intima-media thickness) and MRI findings (anatomic, diffusion imaging, blood flow, and spectroscopy) to address a series of linked hypotheses concerning brain structural and functional abnormalities, and their relationship to CVD variables, HIV serostatus, and markers of the severity of the HIV infection. The MACS is accumulating evidence of the importance of medical comorbidities as risk modifiers for the clinical expression of a neuropathological process, likely due to a decrease in "cognitive reserve". We will evaluate this model by using both cross-sectional and longitudinal data from the study participants who range in age from 50 to 75 years old. We will test the hypothesis that small vessel disease and its consequences not only alter brain structure and function, but by doing so, decrease brain/cognitive reserve, allowing the effects of HIV disease to be expressed earlier, and at a less "severe" clinical stage. If this hypothesis is supported it could potentially alter the way in which we approach the treatment of HIV disease among patients with access to appropriate medical management. We propose that HIV and CVD have direct effects on brain structure/function, and that CNS integrity is the direct link to cognitive functions;CVD is itself predicted by advancing age. We predict that HIV infection moderates the strength of the pathway between CVD and brain structure. That is, the effects of CVD on brain structure/function will be augmented in the HIV-infected men relative to the uninfected men. PUBLIC HEALTH RELEVANCE: In the present study we will measure the functions of the heart and the brain in a group of 340 men (age 50-75 years old) who participate in the cardiovascular substudy of the Multicenter AIDS Cohort Study. This group of men has been in research for as long as 25 years, and we will combine those old data with the new information we will gather here to try to learn how HIV/AIDS affects the heart and the brain, and whether or not this is important for the development of problems with memory and cognition.

The role of imaging technologies in dementia research is rapidly expanding. An imperative for noninvasive tools with early diagnostic capability - prior to the development of clinical signs/symptoms of dementia - has resulted from the development of effective forms of pharmacological and nonpharmacological therapy for Alzheimer's disease (AD). Neuroimaging data, especially when combined with clinical, neuropsychological, and genetic information may be uniquely useful for diagnosis and therapeutic monitoring, as well as guiding further drug discovery. The Neuroimaging Core (Core F) will continue to support structural and functional magnetic resonance imaging (MRI) in ADRC participants and provide the infrastructure for developing state-of-the-art MRI and functional MRI (fMRI) in aging and dementia. The Core will further assist in the expansion of the role of positron emission tomography (PET) studies of aging and dementia by focusing on the recent development of Pittsburgh Compound B (PiB), a marker for brain beta-amyloid deposition. The Core has implemented and maintained efficient procedures for acquiring, archiving, and interpreting MRI examinations performed as part of the ADRC patient evaluation. The Neuroimaging Core is accruing similar MRI examinations in healthy elderly comparison subjects, as emphasized by our external advisors, and we have further established a normative database of structural MRI data that is available to ADRC and related investigators. During the next five years, the Neuroimaging Core will continue to develop and distribute technology for acquiring and interpreting structural and functional image data in support of AD research. The Core will advance the overall goals of the Center by supporting and promoting research that increases our understanding of the etiology and pathogenesis of AD and to facilitate new therapies and therapeutic monitoring.

DESCRIPTION (provided by applicant): HIV disease is becoming more of a chronic condition in countries with good access to medical care. In the area of NeuroAIDS there is no acknowledged, useful biomarker for the cognitive disorder associated with HIV disease (i.e., HIV-Associated Neurocognitive Disorder (HAND)), independent of the cognitive tests. Magnetic resonance imaging and positron emission tomography have been tried, but have yet to fulfill their promise {Price, 2007 #6509}. One emerging technology that has only recently been applied to HIV Disease - by our research team - is magnetoencephalography (MEG). MEG is a non-invasive technique for measuring neuronal activity by recording the magnetic fields induced by synchronized neuronal currents. MEG has the highest spatial and temporal resolution of any current neuroimaging technology, and is used most commonly in the clinical evaluation of patients with seizure disorders, and by cognitive neuroscientists to investigate electrophysiological responses of the CNS. Unlike techniques such as functional MRI, MEG does not rely on the blood-oxygen level dependent response in order to generate responses. Thus, it will be very important to determine whether MEG can identify abnormal brain function in HIV Disease - especially when cognitive dysfunction is mild and not yet affecting activities of daily living. Our team has demonstrated that we can differentiate infected from uninfected study subjects, that there may be an independent MEG-derived variable that is sensitive to cognitive dysfunction, and that MEG signals are stable over a 6-month period. The preliminary research was conducted in the context of an R03-funded study, so the overall goal of this new R21 research project is to obtain the necessary additional data from 30 infected individuals (and 10 controls) to finalize the design for a larger, longitudinal study. These data will allow us to begi to characterize the neurocognitive outcomes of HIV Disease using a highly sensitive electrophysiological tool.

Core F: Neuroimaging Core Abstract: The overall goal of the University of Pittsburgh Alzheimer's Disease Research Center (PITT-ADRC) is to perform and promote research that increases our understanding of: 1) the etiology and pathogenesis of Alzheimer's disease (AD), 2) the mechanisms underlying the cognitive and behavioral symptoms of AD, and 3) to develop strategies that will result in effective early diagnoses and treatments for AD and related dementias. The Neuroimaging Core will support these Center-wide goals by developing and applying cutting edge neuroimaging technology to studies that are focused on early and presymptomatic stages of the AD spectrum. As the search for preclinical biomarkers continues, it is becoming increasingly clear that functional and structural brain imaging data may hold the key to identifying the earliest pathological manifestations of AD prior to any meaningful clinical change. The Neuroimaging Core will continue to develop and distribute technology for acquiring and interpreting brain functional and structural imaging data in the support of AD research. The Core will advance the Center goals by supporting and promoting research that increases our understanding of the etiology and pathogenesis of AD, and facilitates the development of new therapies and methods for monitoring therapeutic efficacy. The Core maintains data sets of structural imaging on individuals enrolled through the Clinical Core (currently 934 MRI datasets), and we continue to work on the expansion of leading edge analytic technologies, and novel radiotracer ligands measured with Positron Emission Tomography (PET) (i.e., PiB and T807, Projects 1 and 2). Our developmental work includes the high definition quantification of white matter fiber tracts, and measurement of functional networks based on high resolution functional imaging. We will validate and implement methodologies and statistical techniques (e.g., functional connectivity, data mining) in order to provide ADRC investigators with state-of-the-art tools.

? DESCRIPTION (provided by applicant): This is a resubmission of our application in response to PAR-14-281, Connectomes Related to Human Disease: research cohorts should be comprised of individuals with neurodegenerative diseases associated with aging such as Alzheimer's disease (preclinical, early- and late-onset), other dementias of aging, and/or age-related cognitive disorders such as Mild Cognitive Impairment (early, mild and late MCI). The organizing principle of our research plan is the idea that the expression of cognitive dysfunction in the elderly is the result of two independent processes - the first is the neuropathology associated with AD, and the second the neuropathological changes as a consequence of vascular disease. While synaptic loss, senile plaques, and neurofibrillary tangles are the functional and diagnostic hallmarks of AD, it is the structural changes as a consequence of vascular disease that reduce brain reserve and compensation, resulting in an earlier expression of the clinical DAT syndrome. This work is being completed under the auspices of the Human Connectome Project (HCP). We will implement the HCP LifeSpan imaging protocol, and will use the HCP behavioral and cognitive assessments as specified in FOA. We will enroll 200 individuals from the University of Pittsburgh Alzheimer's Disease Research Center: 125 with DAT and 75 with prodromal AD. All subjects will meet research-level diagnostic criteria for their syndromes, and all will be in active follow-up in the ADRC. We will also enroll 200 cognitively normal individuals, 50-89 years old, from ongoing studies of community-dwelling elders. All of the cognitively normal individuals will have had at least five years of antecedent data available to this study for the purpose of cognitive classification and extraction of health-related data. Th participants enrolled into this HCP disease-related study will be stratified by age (50/decade/group) with equal representation of African- Americans and women. 200 individuals (100 patients/100 controls) will be selected for additional neuroimaging using the HCP Magnetoencephalography (MEG) protocol. Each of the participants will contribute the HCP-specified demographic, behavioral and laboratory data. We will acquire data relative to vascular risk. 200 individuals will also have in vivo amyloid imaging, and 100 of these participants will have 2-year longitudinal follow-up. All of the data will be made publicly available under the HCP guidelines using the Connectome Coordination Facility. Locally, we will use these data to address specific questions related to structure, function, AD, aging and vascular disease in multi-modality studies leveraging the differential advantages of MRI, fMRI, MEG, and in vivo A? imaging.

Project Summary/Abstract HIV-infected adults in the western world have a life expectancy near that of the general population, but are at a significantly elevated risk of developing cognitive deficits. Such impairments are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected individuals, and research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). Substance use disorders (SUD) are also more prevalent in the HIV-infected population, yet their relative contribution to the increased rate of cognitive impairment in this group remains poorly understood. A key barrier to progress in this area has been the historic lack of diagnostic tests and biomarkers that can precisely assess the neurological complications of HIV-infection, which has all but precluded quantification of the additive impact of SUD comorbidity. This barrier is central to RFA-DA-18-023, which requests applications that ?foster biomarker and signature identification that could advance the clinical assessment of the degree of deterioration or damage, of functional reserve, and of resilience of host defense mechanisms, towards HIV- infection and comorbidity of HIV with SUDs.? Specifically, the RFA requests proposals that identify biomarkers derived from blood, plasma, noninvasive neuroimaging modalities, and/or other sources, with an emphasis on biomarkers that can be quantitated, with levels assessed for their ability to predict disease progression. The current project directly targets the scientific gaps identified in this RFA, Identification of Biomarkers of HIV Pathogenesis and Substance Abuse Comorbidity, using a multipronged approach that includes state-of-the-art neurophysiological, structural, and spectroscopic noninvasive imaging, cognitive assessment, and cellular and molecular analyses of blood/plasma in the context of cannabis use disorder (CUD). Specifically, the Signatures of Cannabis Abuse in NeuroHIV (SCAN) Consortium will utilize advanced magnetoencephalographic (MEG) imaging to quantify the neural dynamics serving cognitive processing, 3-Tesla MRI and multimodal parcellation methods to map brain architecture, functional MRI (fMRI) for hemodynamics and intrinsic networks, and 7-Tesla spectroscopic imaging to quantify local GABA levels across the brain. These data will be integrated with a comprehensive molecular screen that includes 35 plasma biomarkers covering the immune, inflammatory, coagulation, endothelial, and neurological systems, a 10-color flow cytometry panel delineating CD4 and CD8 T cells, B cells, NK cells, monocyte subsets, and activation markers, known clinical markers, and mitochondrial function in immune cells using the Seahorse Analyzer method. To enhance rigor, demographically-matched groups of uninfected controls with and without CUD will be enrolled, which will enable the interaction of HIV and CUD to be quantified. In sum, to truly meet the goals of this RFA, we will use a broad range of neuroimaging, molecular, and cellular functional assays to uncover biomarker signatures of HIV and CUD that will enable identification of early dysfunction, progression, and prognosis, enabling future preventative and treatment trials.

ABSTRACT The overall goal of the University of Pittsburgh ADRC is to perform and promote research that increases our understanding of: 1) the etiology and pathogenesis of Alzheimer's disease (AD), 2) the mechanisms underlying the cognitive and behavioral symptoms of AD, and 3) to develop strategies that will result in effective early diagnoses and treatments for AD and related dementias. The Neuroimaging Core will support these Center- wide goals by developing and applying cutting edge neuroimaging technology to studies that are focused on early and presymptomatic stages of the AD spectrum. As the search for preclinical biomarkers continues, it is becoming increasingly clear that functional and structural brain imaging data may hold the key to identifying the earliest pathological manifestations of AD prior to any meaningful clinical change. The Neuroimaging Core will continue to develop and distribute technology for acquiring and interpreting brain functional and structural imaging data in the support of AD research. The Core will advance the Center goals by supporting and promoting research that increases our understanding of the etiology and pathogenesis of AD, and facilitates the development of new therapies and methods for monitoring therapeutic efficacy. The Core maintains data sets of structural imaging on individuals enrolled through the Clinical Core, and we continue to work on the expansion of leading edge analytic technologies, and novel radiotracer ligands measured with Positron Emission Tomography (PET) (i.e., PiB, AV-1451 and 11C-UCB-J, Projects 1 and 2). The goal of this Revision application is to augment the acquisition of brain imaging data (both MRI and PET), standardize the analysis of all imaging data acquired from ADRC participants, and to make these data available to ADRC investigators, collaborators, and large data repositories (e.g., NACC, ENIGMA) for further analysis.

Project Summary/Abstract HIV-infected adults in the western world have a life expectancy near that of the general population, but are at a significantly elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected individuals. Research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). While the mechanisms underlying these deficits are not well understood, numerous human neuroimaging studies have examined the brain areas that may be involved, and overall these studies have been largely successful in identifying the critical hubs and networks. However, many questions remain regarding basic circuit dysfunction within these brain regions, and consequently there is a clear and common need to further investigate the neural dynamics and connectivity, as well as other key physiological parameters that may underlie the development and progression of HIV-related cognitive dysfunction. This proposal responds to RFA-MH-18-610, which requests proposals that ?advance knowledge of the etiology of mild to moderate forms of HIV-related cognitive dysfunction by clarifying the role played by altered neuronal circuits, receptors, and networks,? using ?novel neuro-electrophysiological and neuroimaging techniques.? The Multimodal Imaging of NeuroHIV Dynamics (MIND) Consortium responds to this call with an innovative, large- scale multimodal neuroimaging study that uses the latest breakthroughs in instrumentation and data analyses to identify the pathophysiology of neuroHIV in virally-suppressed adults. Specifically, the consortium will use advanced magnetoencephalographic (MEG) imaging to quantify the region- and circuit-level neural dynamics serving cognitive processing, 3-Tesla MRI and multimodal parcellation methods to map areal brain architecture, functional MRI (fMRI) for hemodynamics and intrinsic networks, and 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to quantify GABA levels in multi-voxel slabs of interest identified by the functional modalities. The investigative team includes a unique combination of experts in MEG, MRI/fMRI, MRSI, and cognitive psychology from the University of Nebraska and University of Pittsburgh Medical Centers (UNMC/UPMC). In addition, this consortium will harness existing resources such as the Multicenter AIDS Cohort Study (MACS) database and the National NeuroAIDS Tissue Consortium (NNTC) and, consistent with the RFA, will follow the Research Domain Criteria (RDoC) framework to define cognitive constructs. The consortium?s overarching hypothesis is that HIV-infected adults will exhibit aberrations in local inhibitory circuits, and that these deficits will alter gamma oscillations and thereby impair neuronal coding and interregional functional connectivity in the theta range. Such gamma deficits would provide robust explanatory power for the breadth of pathophysiological findings in the existent literature, and the MIND study is uniquely powered to investigate the underlying sources of these deficits, which are likely multifactorial (e.g., medical history, lifestyle factors, CNS viral penetration).