Igor Grant - US grants

human immunodeficiency virus 1; mental disorders; nervous system infection; neurologic manifestations;

spouses; caregivers; Alzheimer's disease; quality of life; social change; aging; central nervous system; home health care; clinical research; human subject;

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Explore the neurobehavioral complications of HIV, their neuropathogenesis and ultimately their implications.

In this competing renewal we request five years of support to continue our inquiry into adaptation and health outcomes among Alzheimer caregivers (CG). Our major hypotheses are: 1) that the chronic stress of caregiving will be reflected in physiologic measures of activation - altered hypothalmic-pituitary-adrenal (HPA) axis sensitivity, increased sympathoadrenal medullary (SAM) activity, and reduced natural killer (NK) cell activity; and 2) that over time those CG with highest caregiver stress will show the most significant physiological alterations which will be predictive of worsening CG health. The research is guided by a conceptual model which postulates that to understand the effect of stressors on CG health we must consider the influence of certain mediators and background characteristics. Stressors can be patient-derived (dementia, problem behaviors, help required) or environmental (life events) leading to CG role overload. Mediators are interpersonal (supports) and intrapersonal (self-concept, coping activity). Background characteristics include age, gender socioeconomic status, and past health. The outcomes of caregiving are conceptualized at 3 levels: physiologic (HPA alteration., SAM activation, NK activity), psychologic (anxiety, depression), and physical (symptoms, illness episodes). The study has two components. In the "field" study 200 spousal CG and 80 noncaregiving controls (NC) will be examined every 6 months for 5 years. Data will be gathered on state and needs of the patient, life stresses, resources, supports, medical events, and psychological state of CG. Blood samples for NK, cortisol, ACTH, norepinephrine, epinephrine and neuropeptide Y will be drawn in the CG home during a blood pressure postural reactivity protocol. Nested in the field study is our 'laboratory' study which will, for the first time, attempt to probe HPA axis sensitivity and SAM activation in CG experiencing varying levels of caregiver stress. Here we shall perform corticotropin releasing factor (CRF) infusion studies, as well as sympathetic reactivity studies with 60 CG and 30 NC "selected" to be free of major medical confounds (including medications). The data from this phase should move caregiver research closer to understanding mechanisms linking caregiver stress, physiological response, and health.

In this competing renewal we request five years of support to continue our inquiry into adaptation and health outcomes among Alzheimer caregivers (CG). Our major hypotheses are: 1) that the chronic stress of caregiving will be reflected in physiologic measures of activation - altered hypothalmic-pituitary-adrenal (HPA) axis sensitivity, increased sympathoadrenal medullary (SAM) activity, and reduced natural killer (NK) cell activity; and 2) that over time those CG with highest caregiver stress will show the most significant physiological alterations which will be predictive of worsening CG health. The research is guided by a conceptual model which postulates that to understand the effect of stressors on CG health we must consider the influence of certain mediators and background characteristics. Stressors can be patient-derived (dementia, problem behaviors, help required) or environmental (life events) leading to CG role overload. Mediators are interpersonal (supports) and intrapersonal (self-concept, coping activity). Background characteristics include age, gender socioeconomic status, and past health. The outcomes of caregiving are conceptualized at 3 levels: physiologic (HPA alteration., SAM activation, NK activity), psychologic (anxiety, depression), and physical (symptoms, illness episodes). The study has two components. In the "field" study 200 spousal CG and 80 noncaregiving controls (NC) will be examined every 6 months for 5 years. Data will be gathered on state and needs of the patient, life stresses, resources, supports, medical events, and psychological state of CG. Blood samples for NK, cortisol, ACTH, norepinephrine, epinephrine and neuropeptide Y will be drawn in the CG home during a blood pressure postural reactivity protocol. Nested in the field study is our 'laboratory' study which will, for the first time, attempt to probe HPA axis sensitivity and SAM activation in CG experiencing varying levels of caregiver stress. Here we shall perform corticotropin releasing factor (CRF) infusion studies, as well as sympathetic reactivity studies with 60 CG and 30 NC "selected" to be free of major medical confounds (including medications). The data from this phase should move caregiver research closer to understanding mechanisms linking caregiver stress, physiological response, and health.

The prime objective of the Coordinating Core is to assure the integrated, coherent, and effective implementation of the HNRC. To perform its coordinating duties in an efficient and accountable manner, this Core has been organized as four interacting units. The Director's Office is responsible for allocation of the human, fiscal, and physical resources of the HNRC. The Director's Office coordinates the activities of the HNRC on a day-to-day basis and has specific responsibility for assuring effective communication among investigators and staff, monitoring of protocol implementation in accordance with the approved grant, maintenance of effective communications between the HNRC and other parts of the University, our community and the Agency, and providing close monitoring of individual and overall budgets and expenses. The Participant Unit is responsible for identification, recruitment, consenting, and follow-up of participants. The Participant Unit also coordinates and monitors human subjects affairs, and reports to the Director on participant issues. The Data Management Unit provides the conceptual framework, procedures, software and hardware tools, and quality control mechanisms required to manage a complex and interactive set of data. Specific functions of the DM Unit include tracking of data collection, ensuring that appropriate data are promptly entered into the centralized database, and assuring the quality of data with regular review of completeness and accuracy; general management of the central database, including design and implementation of the database and programs to access data; management and maintenance of all computer hardware/software; and maintaining security and confidentiality of both physical and computer records. The Statistics Unit consults with various projects on design and data analysis plans, consults with investigators on statistical modeling, assists investigators in reducing data to composite variables of interest in preparation for specific analyses, conducts advanced analyses of study data including longitudinal, logistic and survival analyses, with particular emphasis on cross-core and cross-project analyses and explores new statistical methods of analysis while answering the specific program related research questions. Beyond the above-described four units, this Core also coordinates the activities of critical working groups within the HNRC. These include the Council of Investigators, which sets policy and reviews scientific progress on a regular basis; the Data, Statistics, and Publication Committee, which reviews analyses and publications; the Confidentiality Committee, which monitors human subjects protection; the Participants' Advisory Board, which provides feedback from participants to the Director; the Community Advisory Board, which provides advice and feedback on the functioning of the HNRC in various communities; and an external Scientific Advisory Board which provides periodic independent review of our progress.

This project addresses two overarching priorities on neurobehavioral research on HIV: (1) There is a need for a time efficient, sensitive and reliable method to assess HIV-1-associated neurocognitive disorder, especially in early phases of disease when most persons are medically asymptomatic. Existing approaches involve significant tradeoffs between time taken to assess a person and likelihood of detecting impairment. The recent development of a theory-driven computerized assessment (The Cambridge Neuropsychological Test Automated Battery (CANTAB)), which has been used successfully in detecting other forms of dementia, promises to be a useful advance methodologically. (2) Until recently, progress in understanding the neuropathogenesis of HIV has been hampered by lack of an appropriate animals model. The development of a Simian immunodeficiency virus (SIV) model in which Gold and Koob are capable of performing neurobehavioral testing of animals using a modified CANTAB approach presents an unparalleled opportunity for "human/infrahuman primate translation". Aim 1: To determine if HIV-1 infection in humans and SIV infection in monkeys produce similar neurocognitive impairments. Using human and monkey versions of CANTAB we will compare whether the qualitative features of neurobehavioral impairment are similar, and whether progression of disease is accompanied by similar generalization from a "fronto-striatal" to global impairment. Aim 2: To determine if CANTAB is a time-efficient, reliable, informative alternative to current lengthy neuropsychological (NP) assessments to detect and monitor HIV-1 neurocognitive disorders. Method Men and women will be recruited from the HNRC (60 AIDS, 60 HIV+ non-AIDS, and 60 HIV-controls). Subjects will receive CANTAB assessment annually for 5 years. Results of CANTAB will be related to the indepth NP and neuromedical assessments performed as part of the HNRC. Pattern and time related changes in CANTAB will be compared to similar data from monkeys in the Gold/Koob project. Significance As a result of these studies, we should be able to determine whether the SIV-infected monkeys represent a suitable animal neurobehavioral model of HIV CNS disease in humans, and whether CANTAB represents a suitable substitute, or even advance over, currently available lengthier NP assessments.

To find out about how changes in a person's life, life stress, influence health and cardiovascular disease in a group of spouses of patients with Alzheimer's disease.

stress management; psychological stressor; coping; stress; psychoneuroimmunology; Alzheimer's disease; caregivers; neuroendocrine system; social support network; adrenocorticotropic hormone; pituitary adrenal axis; cortisol; adrenal medulla; natural killer cells; blood pressure; marriage /marital status; home health care; neuropeptide Y; norepinephrine; hypothalamic pituitary axis; longitudinal human study; self concept; psychosomatic disorders; behavioral /social science research tag; radioimmunoassay; blood chemistry; human subject;

As part of the reconfiguration and expansion of the score of the San Diego CFAR, we wish to assure that CFAR serves as a state-of-the-art resource for investigators who may wish to use neurobehavioral and health related outcomes measures as predictors, outcome variables, or moderating variables in their various studies. To this end, the Behavioral and Health Function Core intends to provide both theoretical and practice expertise in the areas of neuropsychological assessment, research psychiatric diagnosis and assessment of mood, psychosocial Atkinson, Thomas L. Patterson, Samuel Bozzette, Robert K. Heaton, and Robert M. Kaplan- are all widely recognized experts in the fields of neuropsychiatry, neuropsychology, social psychology, behavioral medicine, and health/outcomes assessment. The core is divided into 4 components: Neurocognitive, Psychodiagnostic, Psychosocial Assessment, and Health Related Quality of Life. Each component has the capacity to provide expertise in planning research, selecting proper instrumentation, and can also provide practice assistance in developing pilot data to inform definitive new grant submissions. Because this core will interact with the existing NIMH funded HIV Neurobehavioral Research Center (HNRC), the neuropsychology component is available as a resource to CFAR at no cost. Other components are not funded by the HNRC and, therefore, require modest supplementation from CFAR for fractions of investigator time and to support part time technical personnel that can assist in training, gathering pilot data, and reviewing and/or analyzing preliminary behavioral data. In addition of the Behavioral and Health Function Core provides important deepening of CFAR's ability to be a multidisciplinary resource by adding neurobehavioral and health outcomes measurement expertise to existing and proposed basic science and biomedical cores.

The overarching objective of this project is to establish a tissue bank comprised of CNS autopsy material from HIV-infected individuals who are well-characterized neuropsychologically and neuromedically within six months of death. The CNTN represents a collaboration of investigators from the NIMH-funded HIV Neurobehavioral Research Center (HNRC) in San Diego and from four California HIV network sites: University of Southern California/LA County, Cedars-Sinai/University of California, Los Angeles, University of California, Irvine, and the University of California, San Diego. Collectively, these sites follow over 4,300 AIDS patients. The specific aims of the CNTN are: 1) to identify a group of HIV plus persons with advanced disease who agree to be evaluated and consent to autopsy; 2) to characterize these individuals neuromedically and neurobehaviorally using a standardized protocol; 3) to assure that antemortem data are available within 6 months of death; 4) to perform autopsies within 24 hours of death; 5) to characterize the neuropathologic changes associated with HIV; 6) to establish a tissue registry and repository; 7) to establish a database that can support current and future investigator initiated studies integrating antemortem and postmortem data; 8) to establish a process whereby investigators can access tissue and data; and 9) to obtain control tissues. The CNTN consists of a structure and processes for identifying, characterizing and maintaining a cohort of 250 persons with advanced HIV disease in anticipation of their death, of harvesting CNS and other tissues promptly (n=50 annually), of describing, cataloging, and storing these at a central facility in San Diego, and making such materials and data available to investigators to perform scholarly work on neuroAIDS. At the end of 5 years, the CNTN proposes to acquire 209 sets of brain and other tissues from HIV plus individuals for whom there is detailed antemortem characterization. Fifty more brains are expected to be accumulated from other individuals dying with HIV disease, who have interesting neuropathology (e.g., PML), but for whom antemortem information is more limited. We will also accumulate 75 control brains from immunosuppressed patients dying after transplantation or from trauma. The CNTN sites will be coordinated by a core facility in San Diego including a Neuropathology and Banking Unit, a Protocol Monitoring Unit, and a Data Coordinating Unit. An Administrative Unit oversees the operations of the core and network sites, assisted by an internal multi- investigator committee as well as an external Scientific Advisory Board. The significance of the CNTN arises from the demographically and neuropathologically broad representation of cases that will be entered into the network from multiple sites in Southern California. The feasibility of the CNTN is supported by the experience of investigators in implementing standardized protocols of antemortem and postmortem evaluation, as well as the record of this team in successful multidisciplinary and multisite longitudinal investigations.

Both methamphetamine dependence and HIV disease can result in central nervous system (CNS) damage. The overall aim of this Program Project is to determine the influence of current and past methamphetamine dependence on the emergence of HIV-associated neurocognitive disorders. Background: As the incidence of HIV infections/new cases of AIDS attributable to homosexual/bisexual risk has declined, the proportion of cases related to drug abuse has risen. Methamphetamine use may contribute to HIV neurotoxicity both by facilitating transport of HIV into the CNS and by activating the same excitotoxic pathways that have been implicated in neural damage from HIV. Program Aims: 1) to define the influence of methamphetamine on expression of HIV neurobehavioral disorders; 2) to delineate the neurobiological bases of these disorders. Methods: This Program has five interacting Scientific Projects linked by a Core. Projects on Neuropsychology, MR Morphometry, and MR Spectroscopy explore the anatomic and functional effects of HIV and methamphetamine. Projects on Neuropathology and CSF Virology/Markers explore the mechanisms and pathways of neural damage. The general plan calls for recruiting 180 HIV+ and 120 HIV- methamphetamine dependent (METH+) persons and 180 HIV+ and 120 HIV- controls with a negative history of methamphetamine abuse and/or dependence (METH-). Subjects will be examined in a longitudinal study with annual multidisciplinary evaluations (medical, neurobehavioral). Subsets of participants will receive MR morphometric, MR spectroscopic, and neuropathologic studies. Significance: Both methamphetamine and HIV infection can damage the brain; the joint effects of these factors require exploration. Our studies on anatomic and functional brain changes in vivo linked to neuropathologic studies can address molecular mechanisms and selective neuronal vulnerability. The CSF studies will determine if CSF is an appropriate window into CNS events. Linking this Program to the NIMH funded HIV Neurobehavioral Research Center (HNRC) allows us to take advantage of the critical mass of investigators and staff with expertise in longitudinal neurobehavioral research on HIV, and capitalizes on availability of resources for evaluating and tracking participants, and for data management and statistics, thereby maximizing the economy of this study of methamphetamine dependent individuals.

data management; AIDS /HIV neuropathy; methamphetamine; statistics /biometry; biomedical facility; patient /disease registry; medical outreach /case finding;

The primary objective of the Coordinate Core is to assure the integrated, coherent, and effective operation of the HNRC. In order to provide investigators with essential information and support services in an efficient and accountable manner, the Coordinating Core has been organized into four interacting units. The Administrative Unit has overall responsibility for coordinating Center activities, organizing the annual evaluations of the Center and each of the Cores ("Annual Strategic Review"), and coordinating information dissemination to both the scientific and general communities. This Unit also insures that the HNRC complies with all institutional and Federal policies. The Participant Accrual and Retention (PAR) Unit recruits and maintains the longitudinal HNRC cohort (n=425), maintains a roster of potential targeted study participants, recruited them as required for specific HNRC-associated studies, and provides technical/consulting services to HNRC-affiliated grants. The Data Management Unit tracks all Center-related data and insures seamless interaction with external projects via an internet- accessible data resource system, and maintains the HNRC website for internal and external information dissemination. The Statistics Unit consults with investigators during project development and provides statistical services. In addition to the services provided as core resources, the PAR, Data Management, and Statistics Units each propose innovations with respect to methods development. Beyond the above described four units, this Core also coordinates the activities of critical internal and external working groups. The internal groups include the Council of Investigators (sets policy and reviews scientific progress on a regular basis); the Research Review Committee (reviews requests for Center resources, and provides a forum to discuss proposed studies and manuscripts); the Director's Staff (assists in the practical management of the Center); the Evaluation Committee (provides first level assessment of how well the HNRC is achieving its goals); and the Human Subjects Committee (monitors human subjects issues, especially confidentiality). The external groups include the Participant's Advisory Board (provides feedback from participants to the Director); the Community Advisory Board (provides advice and feedback on the functioning of the Center in various communities); and the Scientific Advisory Board (provides periodic independent review of our scientific and programmatic progress).

The experiences of elderly caregivers of Alzheimer relatives (CG) can be viewed as a model of chronic human stress in aging. Our work in the past funding cycle has been guided by the notion that such stress is accompanied by increased sympathoadrenalmedullary (SAM) activation whose cardiovascular and molecular responses may be amplified by superimposed stressors such as excessive care demands relative to respite received ("vulnerable CG"). The results to date indicate heightened basal circulating epinephrine (E) in vulnerable CG, altered L-selectin cell adhesion molecule (CAM) expression, down- regulation of beta-adrenergic receptors of lymphocytes, but no systematic changes in heart rate or blood pressure variability. Vulnerable CG who received a two week respite intervention demonstrated lessened circulating E in response to stressors compared to wait-listed CG, but there were no systematic treatment-related changes in other variables. Pilot data revealed: 1) increased expression of procoagulation factors (especially D-Dimer) which correlated with amount of sleep disturbance and level of catecholamines; 2) Vulnerable CG had less total sleep time and more awakenings than nonvulnerable CG. In the proposed research we wish to refine our understanding of the molecular changes underlying chronic and acute stress in elderly caregiving. The basic theory is that the chronic stress of caregiving yields a state of relative SAM arousal reflected in greater resting and stressor-related releases of catecholamines. As outcome variables of chronic and acute stressors related to caregiving, we shall focus on coagulation factors and cellular adhesion molecules, each of which has been associated with heightened risk of cardiovascular morbidity and mortality. The general hypothesis is that elderly caregivers, versus noncaregiving controls (NC) will have greater SAM arousal and greater expression of coagulation and adhesion molecules. It is posited further that those caregivers who have background medical risks (history of cardiovascular disease or hypertension), and who experienced superimposed stressors, such as excessive caregiving demands, or other negative life events, will be selectively vulnerable to these physiological changes. Disturbed sleep environment is posited to be one of the pathways whereby caregiving stressors are translated into SAM arousal and molecular changes. The study design calls for recruitment of 120 elderly caregivers (CG) and 60 noncaregiving controls (NC). Laboratory-derived speech stressor tasks will be used to probe differences in SAM responsivity to speech stressors between CG and NC, as well as CG at several levels of "mismatch" between caregiving demand and respite received. At-home polysomnography and actigraphy will monitor sleep disruption, sleep disorders (e.g., sleep apnea), and circadian activity variation. In the longitudinal phase, subjects will be re-evaluated annually to determine if hypothesized recovery of SAM arousability occurs in those CG who have placed their spouse, or whose spouse has died. The results of this research should bring us closer to understanding the physiological and molecular mechanisms underlying increased morbidity in elderly persons under chronic stress.

DESCRIPTION (provided by applicant): This is a renewal application for the California NeuroAIDS Tissue Network (CNTN) in response to the RFA- MH-13-070. The overarching objective of the CNTN remains the same today as it was when it was first established in 1998: to serve as a tissue bank resource comprised of CNS autopsy material from HIV- infected individuals who are well characterized neuropsychological and neuromedically in life. The CNTN has been very successful in meeting this primary objective. To date, we have enrolled a total of 821 participants, including 303 autopsies, 39,600 aliquots of plasma, 27,500 aliquots of CSF, 18,700 aliquots of serum, and 5,600 aliquots of PBMCs. For the current application, we are restructuring our cohort to best target and obtain autopsies from high priority cases that are aligned with the three thematic priorities identified in the RFA: a) HIV eradication from CNS reservoirs; b) mechanisms of HIV-associated neurocognitive disorders (HAND) in the setting of long term HAART, and c) HIV and aging. Specifically, we will target continuation of HIV+ participants who 1) are at greatest risk for death, 2) have been on ART for more than 10 years, and are greater than 50 years of age, which will provide valuable cases to the NNTC resource that are aligned with the NIH three thematic priorities. Specifically, we will recruit a cohort of 4 older (65+ years old) participants from a new collaboration with the Eisenhower Medical Center (EMC) in Palm Springs given that more than 10% H1V+ persons in Riverside County are 65,or older. CNTN is an active participant in the National NeuroAIDS Tissue Consortium (NNTC), a partnership of four NIH-funded neuroAIDS tissue banks. CNTN contributes to the NNTC by: 1) leading the NNTC Neuropsychology and Psychiatry subcommittee and overseeing quality assurance for these data, 2) guiding the methods for historical antiretroviral collection, 3) contributing to the refinement of the common NNTC assessment and neuropathology protocols, 4) providing review and fulfillment of NNTC-wide tissue and sample requests, and 5) serving on the NNTC Steering Committee.. The CNTN will work closely with the NNTC to ensure continued success of this exceptional national and international resource for research on neuroAIDS.

DESCRIPTION (provided by applicant): The aim of this Program's revised renewal application is to clarify the mechanisms of methamphetamine (METH) potentiation of HIV neural injury. Given the prevalence of co-infection with hepatitis C (HCV), as well as the growing awareness of HCV as a co-factor in neural injury, the Program will examine the separate and combined effects of HIV, METH and HCV. Scientific hypotheses for the Program are based on an overall model proposing that HIV, METH and HCV can act both directly and indirectly through immune cell activation that alters the balance between neuroprotective and neurotoxic mediators, leading to injury of specific neuronal subpopulations in the neocortex and nigrostriatum. The Program utilizes a multifaceted and translational approach through six Projects (Neurocognitive, Neuromotor, fMRI, Carbon 13 Spectroscopy, Biomarkers, Neurobiology). Innovative directions include deployment of neurocognitive, neuromotor, and neuroimaging methods hypothesized to be more sensitive and specific in detecting underlying mechanisms of injury from HIV, METH, and HCV and linking these to in vivo and in vitro molecular studies. Programmatic scientific leadership, synergy, coordination, basic evaluating, and effective use of shared resources are provided by a Core served by the Executive, Participant Accrual and Retention, Data Management and Information Systems, Statistics, and Clinical Assessment Units. Through coordinated multidisciplinary research addressing the neurotoxic effects of HIV, METH and HCV at different levels of analysis we hope to achieve a more precise understanding of the nature and mechanisms of neural injury attributable to these factors. Understanding these mechanisms will provide a basis for the future development of targeted treatment interventions. The application has been strengthened by attending to reviewer concerns regarding participant recruitment and approach to confounds; by providing new preliminary data in the revised projects to support their feasibility and refine their hypotheses; and clarifying each Project's role in the Program's overall aims, as well as their synergy and interaction among themselves.

The overall objective of the Neuroimaging Core is to provide the HNRC and associated investigators unique, non-invasive methods for: 1) in vivo detection and measurement of HIV-related brain damage, 2) elucidation of pathological mechanisms that give rise to this damage, 3) further investigation of the functional consequences using fMRI, and 4) identification of neural correlates of treatment success and failure. In the current funding period, the Core has (1) supported 21 extramurally funded projects, resulting in, for example, findings discriminating HIV-related from age-related white matter abnormalities, convergent and divergent patterns of brain structural abnormalities in HIV infection and methamphetamine dependence, fMRI evidence of compensatory activation in response to neural dysfunction in HIV, and MR spectroscopy detection of potential central neuronal injury related to antiretroviral treatment;(2) trained 12 postdoctoral, graduate, and undergraduate trainees in neuroimaging research;and (3) provided consultation and assistance to national and international collaborators in two multicenter trials. Our aims in the proposed renewal period are to accomplish the following: a) acquisition of high-resolution structural images and tissue metabolite measures to evaluate late-stage HIV disease;b) application of morphometry techniques, designed specifically for this population, to measure tissue loss and damage;c) support of other HNRC, national, and international neuroimaging investigations with consultation and training;d) contribution of data and expertise for the development of improved automated morphometry tools;and e) education of the HIV research community regarding promising new imaging methods for NeuroAIDS research. Additionally, during the next funding period specific new method developmental studies will be initiated to define the histological characteristics of visible abnormalities on in vivo MRI in individual cases that come to autopsy, employing novel high-resolution histological and imaging methods to understand of the meaning of MRI-visible abnormalities This Core will enhance HNRC transdisciplinary aims through close collaboration with other HNRC Cores, particularly the Neuromedical, Neurobehavioral, and Neurobiology. These broad-ranging functions of the Neuroimaging Core ensure state of the art neuroimaging support for HNRC-associated studies, close integration between the interdisciplinary HNRC investigative team, and, as appropriate, linkage to the larger national and international neuroimaging community.

AIDS /HIV neuropathy

AIDS /HIV neuropathy

AIDS /HIV neuropathy; laboratory mouse; pathologic process

The Neurobehavioral (NB) Core complements and expands the resource, scientific, and leadership objectives of the HNRC in improving the effectiveness and public health impact of local, national, and international neuroAIDS research. Building on its accomplishments during the prior funding period, the NB Core aims to provide: 1) Performance scores on individual neuropsychological (NP) measures, as well as clinically and objectively derived global and domain-specific ratings of NP functioning;2) global and domainspecific determinations of NP change in individual participants using validated clinical and actuarial methods; 3) consensus diagnoses of HIV-associated neurocognitive disorders;4) self-assessment of cognitive and neuropsychiatric complaints and related difficulties experienced in everyday life;5) current and lifetime history of mood and substance-related diagnoses;6) laboratory-based measures of everyday functioning abilities, including medication management, work-related abilities and automobile driving;and 7) technical assistance, training, certification, consultation, and career development mentoring. The scientific aims of the NB Core include: 1) Advancing scientific knowledge on the nature and extent of the neurobehavioral effects of HIV disease in older adults and adolescents;2) examining the impact of HIV and aging specifically on prospective memory and associated problems in everyday functioning;and 3) facilitating the development and implementation of national and international research efforts regarding the neurobehavioral effects of HIV and disease co-factors. Innovations include: 1) Utilization of paradigms derived from cognitive neuropsychology to elucidate the component processes of cognitive deficits in HIV, which may improve the detection and differential diagnosis of HIV-associated neurocognitive disorders;and 2) Continued development and validation of culturally relevant neurobehavioral instruments, including the generation of normative standards for minority and international populations. In summary, the NB Core enhances the resource, scientific, and clinical relevance of the HNRC by focusing on scientific questions related to the impact of HIV on cognitive, affective, and adaptive functions, which further augments the transdisciplinary aims of scientific Cores that focus on the biologic (e.g., neuropathological) consequences of HIV infection.

AIDS /HIV neuropathy; human immunodeficiency virus

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overarching objective of this program is to deepen our understanding of the mechanisms of additive neurological injury from methamphetamine (METH) and HIV. Recognizing that infection with the Hepatitis C virus may also contribute to such injury and give frequent HCV infection wtih METH abusers, the program will undertake the first systematic exploration of the more complex interactions amount METH, HIV and HCV in determining neurobehavioral disturbance.

The general objective of this contract is to assess the long-term effects of potent antiretroviral therapy (ART) on HIV-induced disease of the nervous system, focusing on the complete range of neurologic, neuropsychological, and neurobehavioral outcomes of ART therapy. The data collected from these studies will provide a resource for assessment of the impact of CNS infections on overall HIV-1 disease progression. This data resource is particularly significant, given the current intense interest in latent CNS reservoirs and the potential for reseeding of peripheral compartments by drug resistant strains of HIV-1. The Contractor shall initiate, manage and coordinate a cross sectional and longitudinal multi-site study of 5 years duration with adequate statistical power to address the above objective, in accordance with an approved protocol. The Contractor shall provide a paradigm for obtaining patient sampling size estimates in order to ensure that reliable conclusions with acceptable statistical power can be drawn from the data. The Government estimates that 4-6 sites will be utilized in this study, to assess 400-500 subjects per year, and that 10-20% of these subjects will be followed for a longer period of time. Sites shall be selected through a competition process, after award, with the concurrence of the NIMH. The Contractor will be responsible for central coordination including recruiting study sites, protocol development and finalizing the study design, preparing informed consent documents, providing data forms, training, centralized communication, data entry and management, quality control procedures, site monitoring, statistical analysis, report writing and other related activities. Procedures shall be developed for the collection, storage, retrieval and final disposition of patient samples. For subjects that are going to be followed, the Contractor will need to retain and store blood and plasma samples. The Contractor shall propose a centralized laboratory site to receive, process, and store study samples.

The Program Project Core was designed to ensure coherent support, communication, and synergy across the scientific Projects. The Core was specifically developed to achieve the following aims: (1) to manage human subject accrual and retention activities, which will include maintaining productive, cooperative relationships with the participants and the communities in which they reside;(2) to coordinate clinical assessments to characterize participants on relevant independent variables and potential confounds, including accumulation and distribution of demographic information, medical and substance use histories, psychiatric diagnoses (e.g., substance-related disorders), and laboratory data (e.g., viral load);(3) to provide the scientific Projects with data management support and guidance;(4) to supply statistical expertise and support to the scientific Projects;(5) to oversee and coordinate the activities of the various scientific Projects in an effort to ensure reliable exchange of information and collaborative interaction between Projects;and (6) to promote and ensure the Program Project's adherence to relevant federal, University, and IRB requirements. To accomplish these aims, the Core will consist of the following closely interacting Units, which will be overseen by the Principal Investigator: (1) Executive Unit;(2) Participant Accrual and Retention (PAR) Unit;(3) Clinical Assessment Assessment Unit;(4) Data Management and Information Systems Unit; and (5) Statistics Unit. In addition, the Core will coordinate the activities of critical internal and external working groups that support the aims of the Program Project, including the Council of Investigators, Director's Staff, Joint Research Review Committee, Confidentiality Committee, Participant's Advisory Board, Community Advisory Board, and Scientific Advisory Board. The Core is complemented by resources of the HIV Neurobehavioral Research Center (HNRC), which will enhance its economy and efficiency.

DESCRIPTION (provided by applicant): HIV and methamphetamine (METH) commonly co-occur and remain a major burden on the healthcare system, due in part to their individual and combined toxic effects on neural systems that underlie higher-level neurocognitive functions, such as risky decision-making. Building on the accomplishments of the prior 3 years of funding, this renewal application of the Translational Methamphetamine AIDS Research Center (TMARC) will elucidate the neurobiological mechanisms and everyday impact of METH/HIV-induced central nervous system (CNS) injury using a translational approach guided by a conceptual model that emphasizes both continuity (e.g., decision-making) and novel (e.g., aging, social cognition) themes. Human research Projects will examine the effects of HIV, METH, and aging on: risk taking, decision-making, and inhibitory deficits (P1); functional and structural connectivity in risk taking (P2); and social cognition and HIV transmission risk (P3). Extending and complementing the human studies are 2 animal Projects using HIV/gp120 and inducible Tat transgenic mouse models, which will examine the effects of METH and aging on cognition and social behavior (P4), as well as gene expression in the context of behavioral and neuropathological changes (P5). A third animal Project, nested within P1, will enhance translation of the human studies on decision-making to animals. TMARC will provide scientific leadership, technical support, and opportunities for training to coalesce the efforts of an interdisciplinary group of Investigators, which will include 3 scientific Cores (i.e., Behavioral Assessment and Medical; Neuroimaging; and Neuroscience and Animal Models). The renewal also includes a new Pilot and Developmental Core, which will support innovative pilot studies and foster the development of junior scientists. An Administrative Coordinating Core will continue to synergize all TMARC activities by way of an Executive Unit, which oversees Units on Data Management and Information Systems, Statistics, and Participant accrual and tracking. Thus, in the renewal period, TMARC endeavors to expand its role as a local and national resource for translational multidisciplinary research and training in the neuroscience of addictions and neuroAIDS.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overarching objective of this program is to deepen our understanding of the mechanisms of additive neurological injury from methamphetamine (METH) and HIV. Recognizing that infection with the Hepatitis C virus may also contribute to such injury and give frequent HCV infection wtih METH abusers, the program will undertake the first systematic exploration of the more complex interactions amount METH, HIV and HCV in determining neurobehavioral disturbance.

The CNS HIV Antiretroviral Therapy Effects Research (CHARTER) was funded in 2002 with the aim of exploring the changing presentation of HIV neurological complications in the context of Highly Active Antiretroviral Therapy (HAART). The six performance sites of CHARTER (Johns Hopkins University, Mt. Sinai Medical School, University of California at San Diego, University of Texas Medical Branch at Galveston, University of Washington, Washington University at St. Louis), were able to standardize neuromedical, neuropsychological, psychiatric, neuropathy, and imaging protocols along with on-going quality assurance procedures. Two key conclusions to emerge from the CHARTER project are that HIV-Associated Neurocognitive Disorders (HAND) and peripheral neuropathy remain highly prevalent despite effective HIV treatments that have significantly reduced mortality and non-neurologic morbidities. The CHARTER project has accumulated invaluable clinical and research data with longitudinal data being collected on 674 participants. Data includes neuromedical characterization, neuropsychological functioning, psychiatric and drug abuse variables, treatment data, brain imaging, and viral and host genetics information. Each CHARTER visit generates approximately 4000 individual variables; currently the database contains over 5 million data points. A key component of the CHARTER project is to serve as a catalyst for additional studies and analyses by making this wealth of samples and data available to investigators. In order to continue to make samples and data sets available to the NeuroAIDS community, ¿CHARTER as a Resource¿ will be enhanced with the following; 1) CHARTER Imaging Utilities; 2) Document Collaboration Utilities to facilitate cross institutional collaboration (e.g., check-in/check-out systems, change tracking and automated document back-ups); 3) User Management Enhancements (e.g., access to warehoused data and community based utilities to foster cross institutional collaboration); and 4) Data Dictionary Enhancements. In addition, CHARTER as a Resource will solicit feedback from users to further enhance the Resource utilities. These enhancements will complement carefully constructed and established mechanisms for a) announcing the availability of the resource, b) soliciting requests, c) facilitating scientific review of all requests, and d) processing and distributing samples and data to scientific requestors.

The CNS HIV Antiretroviral Therapy Effects Research (CHARTER) was funded in 2002 in response to RFA NIMH-00-AI-0005 with the aim of exploring the changing presentation of HIV neurological complications in the context of highly active antiretroviral therapy (HAART). CHARTER[unreadable]s major aims were to determine how central and peripheral nervous system complications of HIV were being affected by different histories and regimens of ART. To address these initial aims, CHARTER identified six performance sites (Johns Hopkins University, Mt. Sinai Medical School, University of California at San Diego, University of Texas Medical Branch at Galveston, University of Washington, Washington University at St. Louis), representing a diverse participant pool as well as investigators with expertise in various aspects of neuroAIDS. Standardized neuromedical, neurolopsychological, psychiatric, neuropathy, and imaging protocols were implemented, along with on-going quality assurance procedures. To date, CHARTER has examined 1599 participants cross-sectionally, 674 participants longitudinally over 3210 visits, and is currently following 289 participants through August 2010. Numerous important findings have emanated from both CHARTER investigators and external researchers using CHARTER-generated data and samples. Two key conclusions to emerge from the CHARTER project are that HIV-associated neurocognitive disorders (HAND) and peripheral neuropathy remain highly prevalent despite effective HIV treatments that have significantly reduced mortality and non-neurologic morbidities.

The Coordinating Core is made up of four interacting components. Administrative Unit: overall responsibility for coordinating Center activities with input from the ET, including communications, resource management, evaluation, and insuring compliance with institutional and Federal policies; Data Management and Information Svstems Unit: manages all Center-related data to insure seamless interaction among cores and affiliated research projects; supports the HNRC website and videoconferencing; Statistics Unit: consults with investigators during all study stages, from design to final analyses; also provides ad hoc consultation; Participant Accrual and Retention (PAR) Unit: Recruits and retains participants for specific studies, and maintains the HNRC cohort so it is accessible to investigators to jump start new projects. Since these four components, which might ordinarily be separate cores, are part of one coherent core, we ran into space limitations given the 10-page limit per core. Previously, Dr. Dianne Rausch (NIMH) authorized a 3-page Addendum for each of the Units. This Addendum (section 17) can be found following item 16. Resource Sharing. Also included in the Addendum is a listing of the projects that have utilized the various Units ofthe Coordinating Core.

This CNS HIV Antiretroviral Therapy Effects Research Extension (CHARTER Extension) is a continuation of the epidemiological longitudinal study of the participants being studied under the existing award, N01MH22005, entitled, [unreadable]CNS HIV Antiretroviral Therapy Effects Research (CHARTER)[unreadable], which was awarded to the University of California at San Diego (UCSD) in September 2002. This contract is due to expire on August 31, 2010. This follow-on study to CHARTER is expected to collect valuable research data over the course of the next 5 years, such as neuromedical characterization, neuropsychological functioning, psychiatric and drug abuse variables, treatment data, various brain imaging results, and viral and host genetics information from specific groups of subjects. This data will ultimately be included with the accumulated clinical and research data stored.

DESCRIPTION (provided by applicant): Neurocognitive impairment (NCI) continues to be a frequent complication of HIV infection. Drug abuse represents one of the risk factors for persisting NCI. In this study we propose to examine one potential mechanism whereby heroin abuse increases risk for NCI in HIV infected persons. We hypothesize that the physiological stress of repeated abstinence syndromes that heroin addicts experience may trigger physiologic events that favor viral injury of the brain. Specifically, we propose that abstinence induces significant hypothalamic-pituitary-adrenal axis (HPA) and sympathoadrenal medullary (SAM) activation leading to immunological changes, e.g., increased lymphocyte and monocyte activation and trafficking across the blood-brain-barrier, as well as induction of various proinflammatory molecules that may also favor neuroinflammation. To establish a proof of principle for this hypothesis we propose a R21 preliminary study, which will examine 50 heroin-detoxifying individuals in Russia. Medical, virologic, neuroendocrine, immune, and virologic assays will be conducted at 3 time points - immediately upon beginning detoxification; 7 days later; and approximately 4 weeks after initial detoxification. We shall relate changes in HPA and SAM activation to fluxes in proinflammatory biomarkers and alterations in virologic control, and link these to fluctuations in neurocognitive impairment. The research will be conducted via a collaboration between investigators at the Valdman Institute of Pharmacology, Pavlov State Medical University, Saint Petersburg, Russia, the HIV Neurobehavioral Research Program at the University of California, San Diego, with consultation from Dr. George Woody at the University of Pennsylvania. Performing this research in Russia is opportune for two reasons: 1) heroin use is the major HIV risk factor in Eastern Europe, hence this work has high relevance; 2) heroin detox practice in Russia dictates symptomatic management, but not opioid substitution (e.g., methadone). This makes it feasible to study withdrawal effects in a clinical setting. If successful in establishing this collaboration and providing initial proof of principle, this study ay lead to more mature research on effects of instituting antiretroviral treatment and naltrexone therapy to reduce likelihood of neurotoxic events during detoxification.

The Administrative and Coordinating Core (ACC) is led by TMARC Pl/PD Dr. Grant and is responsible for ensuring the integrated, coherent, and effective scientific operations of TMARC. The ACC is organized into four interacting units that have successfully supported the many activities of TMARC in an efficient and accountable manner over the past funding period. The Executive Unit will continue provide overall scientific and programmatic leadership, coordinate Center activities, oversee information dissemination to both the scientific and general communities, and ensure TMARC's responsible fiscal management and compliance with all university and federal policies. The Data Management and Information Systems Unit has built an effective infrastructure during the first few years of TMARC's existence that is used to track all Center-related data, facilitate seamless interaction with external projects via an Internet-accessible data resource system, and maintain the TMARC web site for efficient information dissemination. The Statistics Unit consults with investigators during all phases of project development, implementation, and publication. The Participant Unit recruits, schedules, and enrolls human participants for all current and future TMARC Projects. The ACC is aided by several working groups, including: the Council of Investigators (sets policy and reviews scientific progress); the Research Review Committee (reviews requests for Center resources and provides a forum to discuss proposed studies and manuscripts); the Executive Committee (assists in the day-to-day management and evaluation of the Center); and the Human and Animal Subject Welfare Committee (monitors animal and human/Institutional Review Board (IRB) issues, especially confidentiality). We will also continue to utilize our active external working groups that include the Scientific Advisory Board (provides periodic independent review of TMARC scientific and programmatic progress), a Participant Advisory Board (provides consumer feedback from participants in TMARC), and a Community Advisory Board (provides community advice). Through these processes and structures the ACC ensures the synergy and thematic integration of TMARC and provide central coordination for training and new projects.

Project Summary The availability of effective and generally well-tolerated antiretroviral therapy for people with HIV has translated into dramatically longer survival and life expectancy. While efforts at disease prevention and cure are needed and ongoing, an important focus is now on understanding the symptoms and co-morbidities of people living with HIV (PLWH). For example, fatigue and difficulty sleeping are very commonly reported by PLWH even while HIV is suppressed and with normal CD4 counts. Coronary artery disease, diabetes mellitus and neurocognitive decline are now recognized as important complications of HIV/ART. These symptoms and co-morbidities important in PLWH may also be symptoms and consequences of obstructive sleep apnea (OSA). OSA is defined by repetitive collapse of the upper airway during sleep, which leads to transient hypoxemia and arousals from sleep, and is associated with all of the cardiovascular, metabolic, and neurocognitive consequences listed above. OSA has been reported to occur in up to 70% of PLWH, but few are diagnosed and even fewer (<4% in some cohorts) are treated. OSA is increasingly recognized as a multifactorial disorder that can occur in different people for different reasons, not only due to anatomical predisposition (collapsibility of the upper airway), but also related to low arousal threshold (wake up too easily), dysfunction in upper airway dilator muscles and instability in ventilatory control. Through careful measurement of these underlying factors and the symptoms experienced by PLWH, this proposal seeks to understand how different mechanisms underlying OSA ? endotypes ? lead to different symptoms or consequences ? phenotypes ? in PLWH. For example, whether OSA contributes to fatigue in an individual with HIV, or whether that fatigue will improve with treatment of OSA, is not known. Our goals are: - To understand the contribution of OSA to symptoms important for PLWH, such as fatigue and cardiovascular disease - To compare the impact of different OSA endotypes on phenotypes on PLWH - To understand how underlying endotype mediates changes in phenotype seen with treatment of OSA

ABSTRACT Alcohol and drug abuse are highly prevalent in persons with HIV infection and may contribute to the persistence of HIV Associated Neurocognitive Disorder (HAND) even among those receiving modern antiretroviral treatment. The mechanisms of HAND persistence are not fully understood, but alcohol abuse can increase risk of HAND. We hypothesize that neuroendocrine and immunologic dysregulation occasioned by withdrawal from alcohol can set the stage for HAND not only because severe withdrawal can injure the brain, but also due to disruption of virologic control, and associated systemic and neuroinflammation. The overall aim of this proposal is to determine if alcohol abstinence-induced hypothalamic-pituitary axis (HPA), sympathoadrenalmedullary (SAM), and immune dysregulation acutely (during alcohol withdrawal) disrupt HIV control, and increase likelihood of neurocognitive (NC) impairment; and to determine whether the extent of normalization of HPA and SAM after a further 3 weeks of abstinence relates to improved immune parameters, virologic control and NC functioning. To establish plausibility of this hypothesis we propose to examine 50 alcohol dependent HIV infected persons undergoing inpatient detoxification at the St. Petersburg (Russian Federation) City Addiction Hospital, associated with the Pavlov Medical University at three time points: on admission; at 7 days; and after 28 days, thereby relating the time course of fluctuation in HPA, SAM, immune and virologic markers to intensity of withdrawal symptoms and neurocognitive changes during peak physiologic disturbance, and after resolution of acute withdrawal symptoms. The research brings together a binational team that includes investigators from the UCSD HIV Neurobehavioral Research Program and the Valdman Institute of Pharmacology, Pavlov State Medical University, Saint Petersburg, Russia, with consultation from Dr. George Woody at the University of Pennsylvania. Performing this research in Russia is opportune because: 1) alcohol abuse is a risk factor for both HIV transmission and mortality in Russia and Eastern Europe, hence this work has high global relevance; 2) alcohol detox practice in Russia occurs in an in-patient hospital setting rather than the more typical outpatient or brief stay detox settings in the US. This makes it feasible to study effects of withdrawal on HIV control longitudinally in a clinical setting. If proof of principle is supported, our findings can lead to more mature research on effects of instituting antiretroviral treatment and pharmacologic and behavioral interventions to prevent relapse and reduce likelihood of neurotoxic events during detoxification in HIV+ persons, and to altered practice guidelines for the management of HIV infected persons at risk for undergoing alcohol withdrawal. !