Karl Goodkin - US grants

This 5 year project examines the effects of psychosocial stressors, social support, coping style and a supportive group intervention on psychological, neuroendocrine, immunological functioning and health status in bereaved HIV-1 seropositive and seronegative gay men. Two hundred and forty men will be randomly assigned to either a supportive group intervention or a minimal contact control condition. We will assess psycological (life stressors, social support and coping style), psychiatric (structured clinical interview, clinician rating of depression and anxiety, cognitive function), neuroendocrine relationships (ACTH, cortisol, catecholamines, beta endorphin), immunological (lymphocytephenotypes, proliferative response to mitogens, natural killer cell activity, immunoglobulin level), and health status (immunological progression, CDC stage, frequency of health care visits) before and after the intervention and at six month intervals over the subsequent 30 months. We will also use controls for nutritional status (general and specific nutrients) and (for those who progress) virological status (viral load and zidovudine resistance). We will enroll gay men who are within 3 months of bereavement of a close friend or lover and are either asymptomatic HIV-1 seropositive (CDC II or III with T4 cell counts >700 cells/mm(3) or HIV-1 seronegative gay men. The group intervention is proposed for 10 weeks, and a half hours for each session with two therapists experienced with HIV-1 infected individuals and terminal illness who are currently conducting such a group. The group is a semi-structured group with topics aimed at working through the grieving process. Intervention is structured to intervene on the basis of a psychosocial model we have noted to have significant association with distress in a natural history study of HIV-1 infected individuals. This model is comprised by 3 domains with their attendant parameters- (1) life stressors (controllability, predictability, and duration), social support (availability and satisfaction), and coping style (dispositional and situational). We have noted that increased life stressors, decreased social support and use of passive coping strategies are associated with increased psychological distress in HIV-1 infected individuals. Group intervention is aimed at each of these domains- (1) stress management, (2) increasing support, and (3) encouraging use of active coping strategies. We will examine (1) the impact of the intervention and (2) the predictive power of the model for level of psychological distress, immunological function and health status both cross- sectionally and longitudinally controlling for quality of the relationship, time since bereavement, number of bereavements, and life style factors. Finally, we propose to quantify serostatus differences in neuroendocrine associations between level of distress and immune function in relationship to the intervention.

This 5 year project examines the effects of bereavement and its predicted mediators -- other life stressor frequency, social support, and copying style -- on psychological, limbic-hypothalamic-pituitary-adrenal (LHPA) axis, immunological, physical health and virological outcomes in bereaved and non-bereaved HIV+ and HIV+ women. 180 women will be recruited; 60 non- bereaved HIV+ women (nHIV+ = 120) and 30 bereaved and 30 non-bereaved HIV- women (nHIV- =60). The bereaved will have lost a significant other to AIDS within the prior 6 months; all will be assessed at baseline and every 6 months for 2 years on psychological distress, increased LHPA axis measures (cortisol --controlling for CBG level, ratio with DHEA and DHEA-S, and 17 beta-estradiol level; ACTH; CRH) decreased immunological measures (lymphocyte proliferative responses to PHA and pokeweed, NKCC), decreased physical health status (laboratory progression markers; 1993 CDC stage change;' progression to AIDS), and increased virological measures (free p24 antigen level; plasma HIV RNA copy number by PCR), both cross-sectionally and longitudinally over a two year follow-up period. Bereavement will retain, such effects, controlling for other known potential psychosocial mediators of such associations, using a stressor-support-coping model described previously. This model will predict level of a changes in psychological distress, immunological measures, physical health status, and virological measures. Controls will be time since bereavement, number/type of losses, psychopathology (Axes I and II), quality/length of relationship.

DESCRIPTION (Applicant's Abstract): Over 14 percent of persons diagnosed with AIDS in South florida and 10 percent nationally are over age 50 years. Although HIV infection is frequently accompanied by cognitive impairment without disorder, minor cognitive-motor disorder (MCMD) or HIV-associated dementia (HAD), few HIV+ individuals over age 50 years have been studied to date. Yet, HIV-associated disease progression may be more rapid in older individuals, and HIV affects many of the same cognitive processes altered by aging. Further, age appears to be an independent risk factor of HAD. The overall objective of the proposed study is to determine whether aging and HIV infection have a synergistic effect on the frequency and rate of progression of cognitive impairment and cognitive-motor disorder (MCMD and HAD). That is, are the effects of both aging and HIV on cognition significantly greater than the simple sum of the effects of each one alone? If so, these effects on cognition are expected on self-perceived functional status related to cognition and on the level and rate of decline in overall activities of daily living. Age has been associated not only with decreased CD4 cell count in HIV+ individuals but also with increased plasma viral load. Hence, it is hypothesized that older HIV+ individuals will show increased viral load and decreased CD4 cell count (as well as rate of change) than the comparison groups, controlling for anti-retroviral medication use (and adherence), CDC stage of disease, hemoglobin level, and other factors related to clinical disease progression. Moreover, the investigators have recently reported that cognitive-motor impairment in the otherwise asymptomatic stage of infection is associated with an increased risk of mortality. A longitudinal study is proposed herein of 286 total subjects -- 106 late symptomatic (AIDS-diagnosed) individuals (53 older, 53 younger); 106 early symptomatic (non-AIDS) HIV+ individuals (53 older, 53 younger) and 74 HIV- control subjects (37 older, 37 younger). Performance on a cognitive battery sensitive to HIV serostatus; cognitive-motor impairment and disorder (MCMD and HAD); functional status; plasma HIV load; CD4 cell count; and mortality are the proposed outcomes, controlling for sociodemographics, distressed mood, Axis I disorder, physical health status, alcohol/psychoactive substance use, prescribed medication use, pain, fatigue, and nutritional status.

DESCRIPTION (adapted from applicant's abstract): With > 25 million Hispanics, the USA has the fifth largest Hispanic population in the world. Hispanics represent an estimated 13 percent of the total US population and 20 percent among AIDS cases - one and half times as many. Moreover, the AIDS incidence rate among Hispanics in 1998 was almost four times that of European Americans, documenting continued over-representation among Hispanics over time. Yet, primary Spanish speaking subjects have been neglected in the research conducted to date on the prevalence and rate of change of HIV-associated deficits in cognitive-motor performance, the prevalence of HIV-associated cognitive-motor disorders, and relevant changes in functional status. Therefore, it is currently unknown whether primary Spanish speakers resemble or differ from bilingual Hispanic Americans, European- Americans, African Americans, and other ethnic groups. Miami-Dade County residents are 55 percent Hispanic. However, the term "Hispanic" is misleading, as it embraces a wide subcultural diversity -- particularly in the Miami area (where Cubans, Nicaraguan, Puerto Ricans, Hondurans, Panamanians, Ecuadorians, Colombians, Peruvians, Venezuelans, and other "Hispanics" abound). Simultaneously, the prevalence rate of AIDS cases among those > 50 years locally is 14 percent, compared to 11 percent nationally. Moreover, Hispanics represent 32 percent of total AIDS cases locally but are over-represented at 36 percent among older individuals. We are currently conducting an NIMH-funded study of the impact of aging and HIV on cognitive-motor impairment and disorder, functional status and disease progression (by CD4 cell count, plasma viral load, and mortality) in 212 HIV+ (106 > 50 years old and 106 from 20-39 years old) - balanced by early and late symptomatic stages of disease, compared to 74 HIV- (37 older; 37 younger). Herein, we propose to extend the cohort to 456 total participants by adding 170 primary Spanish speakers (100 HIV+; 70 HIV-) to be tested on a translated neuropsychological battery for the first time, to our knowledge. Current study hypotheses will be investigated in the collapsed cohort and in the primary Spanish speakers alone. -

DESCRIPTION (provided by applicant): Primary Spanish speaking subjects have been neglected in the research conducted to date on the prevalence of HIV-l-associated cognitive-motor disorder. Argentina is a moderate-resource country that has been highly impacted by the AIDS epidemic. Fundacion Huesped (FH) is the largest clinic for the primary care of HIV-1 infected individuals in Argentina and is highly influential in care delivery policies there. While FH has integrated mental health side-by-side with general medical care since its inception, there is no routine screening of cognitive-motor disorders (minor cognitive-motor disorder and HIV-1 associated dementia). This project will provide a training program to FH staff on the diagnosis and treatment of HIV-1 associated cognitive-motor disorders during the first six months. The educational impact of the program will then be evaluated. Upon confirmation of training by a knowledge-based examination, the second phase of the project will commence During this phase a total of 150 consecutive HIV-1 infected patients seen at the FH will be screened for cognitive-motor disorders. The rate of diagnostic agreement between the University of Miami staff and the Argentinean team will be determined over the first 50 patients. Discrepancies will be reviewed and presented around achieving diagnostic consensus. The final phase of the project will be the review of the last 100 patients seen and any discrepancies amongst these cases. Treatment plan recommendations will also be incorporated into the educational plan and review of cases, although criteria justifying agreement on treatment plan are not as highly developed. Results will be used to validate the HIV University of Miami Annotated Neuropsychological test battery in Spanish (the HUMANS battery) in a homogeneous Spanish-speaking culture (that of Argentina). Current NIMH-funded study hypotheses on aging and HIV-1 infection in Miami will also be preliminarily investigated in the Argentinean cohort to be accrued with the aim of developing a subsequent R01 grant application.

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 purpose of this research study is to compare the frequency, nature and severity of cognitive impairment (e.g., memory;attention);neurocognitive disorders;and functional status between younger (18-39 years) and older (50 years and older) individuals infected with HIV (Human Immunodeficiency Virus) in its symptomatic stages. The relationship of aging to plasma viral load and to immunological decrements over time will also be assessed.

[unreadable] DESCRIPTION (provided by applicant): This is a proposal to advance the use of the techniques of H magnetic resonance spectroscopy (MRS) and MRS imaging (MRSI) in HIV-1 infection. MRS quantification of glutamate - related to neuronal excitotoxicity and cell death - and myo-inositol - related to microglial proliferation - is acknowledged to be of growing significance in HIV-1 infection. To maximize their utility, further refinement is needed of the MRS techniques used to separate glutamine from glutamate and myo-inositol from taurine. After preliminary validation of this methodology, these measures will be related to both clinical [neuropsychological (NP) performance; minor cognitive-motor disorder (MCMD)] and pathophysiological indices (plasma HIV-1 RNA load; CD4 cell count; cytotoxic T lymphocyte count). We will recruit our sample from our renewed NIMH funded R-01 study examining the interaction of aging and HIV-1 infection on the foregoing measures. In that cohort, 327 participants in four groups - older HIV-1+, younger HIV-1+, older HIV-1- and younger HIV-1- - are anticipated to be available over the project period. This proposal will use a 3.0T Siemens Trio system in the frontal grey matter, the frontal subcortical white matter, and the basal ganglia. Those with a diagnosis of MCMD (n=25) will be compared to HIV-1+ individuals without NP impairment (n=25) and to a HIV-1- seronegative control group (n=25). The primary hypotheses relate to the association of increased glutamatergic transmission and myo-inositol concentrations with the diagnosis, symptom profile, and severity of MCMD. Secondary hypotheses relate increased glutamatergic transmission and myo-inositol concentrations to NP performance deficits in the domains of attention, information processing speed, working memory, episodic memory, visuoconstructive skills, abstraction/executive function, language, and motor skills. Support of this study would lead to a subsequent larger, longitudinal R01 proposal aimed at further investigating the impact of this methodological development. This research is significant in that it relates to the potential for increased clinical utility of the non-invasive, brief, in vivo technique of 'H MRS for measuring brain tissue metabolites directly from specified brain regions in order to document the diagnosis of HIV-1 associated MCMD as well as its progression and treatment response. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): By the year 2015, it is estimated that 50% of HIV-1 infected persons in the US will be 50 or older. HIV-1 affects much the same cognitive processes as those altered by aging, and HIV-1-associated clinical disease progression appears more rapid in older individuals. The longitudinal data from over 20 years in the Multi- Center AIDS Cohort Study (MACS) provides an unparalleled opportunity to examine the relationship of older age to HIV-1-associated cognitive impairment. Our prior work has demonstrated associations between older age and HIV-1-associated neuropsychological performance, symptoms of minor cognitive-motor disorder, immune measures (CD4/CD8 ratio;CD8 cell percentage), and plasma viral load. The overall objective of the proposed MACS database study is to determine whether aging and HIV-1 infection have a synergistic effect on the frequency and rate of the progression of neurocognitive impairment and disorder (MCMD and HAD), pre- and post-HAART. That is, are the effects of both aging and HIV-1 infection on cognition significantly greater than the simple sum of the effects of each factor alone? We plan to create four sub-groups from the MACS sample: older (>50) and younger (18-39) HIV-1-seropositive and older and younger HIV-1-seronegative individuals. Control variables will include sociodemographic characteristics;antiretroviral medication regimen used (by CNS penetration and adherence);CDC clinical disease stage;CD4 cell nadir;depressed and anxious mood levels;alcohol and psychoactive substance use;prescribed psychotropic medication use;HIV-1- associated physical symptom burden;comorbid medical conditions;pain and fatigue levels;and global nutritional status. We also plan to examine the contribution of the presence of HIV-1-associated neurocognitive impairment and disorder to decreased functional status as well as to increased mortality rates, pre- and post-HAART. A well-controlled examination of the comprehensive and extensive longitudinal MACS study data set could generate new and clinically significant information upon which to guide future clinical interventions to address the needs of this rapidly growing group of HIV-1 infected patients today. Until the late-1990s, older age and HIV-1 infection were thought to be non-overlapping health issues. Between 1996 and 1997, newly reported AIDS cases among older persons increased by 12.6%. By the year 2015, it is estimated that 50% of HIV-1 infected persons in the US will be 50 or older. Older age at onset of AIDS is a risk factor for the occurrence of and the more rapid development of HIV-associated dementia as well as minor cognitive-motor disorder and sub-clinical neurocognitive impairment.

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 purpose of this research study is to compare the frequency, nature and severity of cognitive impairment (e.g., memory;attention);neurocognitive disorders;and functional status between younger (18-39 years) and older (50 years and older) individuals infected with HIV (Human Immunodeficiency Virus) in its symptomatic stages. The relationship of aging to plasma viral load and to immunological decrements over time will also be assessed. This study will establish a repository at CSMC for plasma and peripheral blood mononuclear cells (PBMCs), urine specimen, and cervical tissue for the "HIV and Aging" (Pro00012492) IRB approved study. The repository's focus will be to provide information on the frequency, nature and severity of problems in cognition (e.g., memory;attention) that occur in younger (18-39 years) [n=20] and older (50 years and older) [n=20] individuals infected with HIV. HIV negative individuals in the same younger [n=20] and older [n=20] age groups are asked to participate as controls. This repository will be established for the investigation of the relationship between cognition and clinical laboratory progression measures in the blood that are markers of HIV clinical progression. Information may be obtained that will serve as predictors for the subsequent development of cognitive problems in older vs. younger HIV+ persons. These predictors will also potentially include genetic markers. Blood samples will be drawn for a total of 120ml over the course of the study. 40ml will be collected at the baseline visit, and 40 ml will be collected at the two annual follow-up visits. Part of the specimens will sent to UCLA for later virologic assays to be conducted en masse. It will not be necessary to share identifiable PHI with investigators at UCLA. No specimens will be sent from UCLA to CSMC. UCLA investigators will not interact with subjects, either here or at UCLA, for the purposes of this research. Also, CSMC investigators will not interact with subjects at UCLA for the purposes of this research. The samples to be sent to UCLA are 2 10 ml. tubes of peripheral blood from aging study participants in which PBMCs will be isolated. The remaining 20 ml are for long-term storage for other future, yet-to-be-planned assays. The urine and cervical tissue (from the Pap smear) specimens will be collected under the Aging Study and will be included as remnant samples. Cerebrospinal fluid was collected under previously approved protocols for this repository and will be maintained in this repository. The remainder of the samples (serum, plasma, and CSF) from the NIMH repository for one of these prior protocols (the NIMH's Peptide T Trial) will be transferred to CSMC. This is a continuation of a research project initiated at the University of Miami, where 279 subjects were previously enrolled. 80 more subjects will be recruited at CSMC. Data collected from participants at the University of Miami will be incorporated as part of the research conducted at CSMC. A plasma and peripheral blood mononuclear cell (PBMC) repository was included from the inception of the NIH-funded research project and will be necessary to continue in order for the renewal from which it is hoped that novel studies may be performed to further generate data beyond the scope of the actual proposal itself on the basis of the funding for this research. PBMCs will be stored to provide future resources to explore other important measures. This repository will be maintained at CSMC only. There are no collaborating repository sites, and the University of Miami will no longer be involved as a site of the study. Study investigators to be included from this point onward will be from CSMC and UCLA (working on sub-contract to CSMC). The University of Miami has been so notified, and the study was closed with the University of Miami IRB upon the PI[unreadable]s departure from that institution. This repository will also contain de-identified samples that can be used to address questions related to the presence/absence of HIV from the University of Miami collected by Dr. Goodkin during three previous NIH-funded research studies. The entire repository will be maintained and monitored by the parent HIV &Aging Study Investigators of protocol 12492. (AME 7646) REGARDING NIMH SAMPLES WHICH WILL BE TRANSFERRED TO CSMC : The Deputy Director of the NIMH AIDS Program Office, Dr. Dianne Rausch, requested that the PI maintain the remainder of the repository from that trial for the NIMH and that the samples be transferred from the NIMH's repository site to CSMC. The proposed CSMC repository addition from NIMH consists solely of plasma, serum, and CSF samples (which are the same tissue types originally included in the current repository from that trial). - No personal identifiers will be associated with the samples to be transferred. - The information that will be associated with the samples being transferred from the NIMH's repository will be coded. - CSMC investigators will not have access to the linking list associated with information from other study sites. -The researchers at this site have access solely to the linking list for those participants that were recruited at the PI's prior institution. [The study was completed before the PI moved to CSMC in 2007]. The specific aims for the HIV &Aging study samples are: Plasma, peripheral blood mononuclear cells, and remnant samples of urine and cervicel smears will be added to the previously stored samples to provide future resources to explore other measures related to HIV and aging, such as T cell receptor excision circles (TRECs), which may explain an interaction between thymic involution with older age and decreased thymic emigrants as well as long-term immune reconstitution with highly active antiretroviral therapy (known as "HAART"). It is anticipated that novel studies may be performed to further generate data beyond the scope of the actual proposal itself on the basis of this repository. In addition, the existing plasma, PBMCs, urine, CSF and cervical smears from the three prior NIMH HIV/AIDS studies of the PI will continue to be retained for questions related to the presence/absence and impact of HIV infection. The remainder of the samples (serum, plasma, and CSF) from the NIMH repository for one of these NIMH HIV/AIDS prior protocols (the NIMH's Peptide T Trial) will be transferred to CSMC.