Leah H. Rubin, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): This application requests funding for a mentored predoctoral training program involving the use of psychoneuroendocrine research methods to better understand sex differences in schizophrenia. The general aim of the proposed research training program is to identify neuroendocrine mechanisms that contribute to variations in cognitive function in schizophrenia. The specific aims of the research are to characterize how individual variation in estrogen levels affects cognitive abilities that show a sex difference. The longer-term objective of the research program will be to apply didactic training in psychoneuroendocrinology and hands-on research training to the systematic investigation of sex differences in schizophrenia. Women with schizophrenia have decreased levels of estrogen, and variations in estrogen affects cognitive processes (e.g., verbal memory, visuospatial abilities) that are impaired in the disease. In the proposed study we will examine the effects of endogenous estrogen on cognition in schizophrenia using a non-invasive menstrual cycle paradigm. Sixty normally cycling women (30 healthy and 30 patients) will complete a battery of neuropsychological tests at two points in the menstrual cycle. Testing will occur at the early follicular (low estrogen and progesterone; days 2-4) phase and the midluteal (high hormones; days 21- 25) phase. Time between testing will be approximately 1.5-months (i.e., during two separate cycles). We will also examine cognitive function in 30 men with and 30 without schizophrenia at two points in time, at the first session and 1.5-months later. We hypothesize that women with schizophrenia will show improvements in clinical symptoms, visual scanning, and fine motor skills and perform worse on visuospatial abilities when estrogen levels are high compared to low levels of estrogen, and that these changes will correlate with changes in estradiol. Conversely, we predict that verbal abilities, including verbal fluency and verbal memory, will decrease during the midluteal compared to early follicular phase, and that these effects will correlate with changes in progesterone. These results will lay the foundation for a larger research program in this area by establishing sex differences in sexually dimorphic cognitive abilities (abilities where men or women show an advantage) in schizophrenia, and by demonstrating that deficits in these domains vary with endogenous hormone levels over the menstrual cycle. This new line of work can provide new insights into the potential modulatory effects of estrogen and progesterone in mediating symptoms and cognition in schizophrenia, and guide development of novel endocrine interventions to reduce the treatment resistant cognitive impairments that are a major cause of disability in schizophrenia. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Cognitive deficits remain prevalent among HIV+ individuals in the era of combination antiretroviral therapies, inhibiting adherence to life-saving treatments and lowering quality of life. HIV-infected women report high rates of exposure to acute and chronic stressors such as those resulting from the high prevalence of early childhood trauma as well as challenges related to HIV disease management in adulthood. These stressors can lead to profound and sustained negative physiological and psychological consequences including cognitive deficits and brain dysfunction. The primary goal of this project is to develop an independent scholarly program of research that addresses the role of stress and stress hormones on cognitive dysfunction among HIV+ women, with the ultimate objective of designing an intervention that lowers stress and improves cognition. This four- year program of training and research includes: 1) application of epidemiological and biostatistical methods to analysis of cognitive data from a large, longitudinal, multi-site cohort of HIV+ and HIV- women to study dysfunction associated with HIV status, especially among women with post-traumatic stress disorder (PTSD); and 2) conducting a pharmacological challenge study to better understand the mechanisms underlying stress and related cognitive dysfunction, and then using newly acquired knowledge to design an intervention to enhance cognitive function among HIV+ women. Training will include coursework, mentoring, and practical experience in advanced methods in epidemiology, biostatistics, pharmacological challenge studies, and intervention science in the context of HIV. Two studies are proposed. The first will characterize relationships between stress and cognition in HIV+ vs. HIV- women in the Women's Interagency HIV Study (WIHS), the largest prospective multicenter cohort study of at-risk women in the U.S. and the longest ongoing study of HIV disease progression in women. Based on preliminary results from data on ~1000 HIV+ women and uninfected controls, we will test the hypothesis that perceived stress and PTSD symptom severity are more strongly related to cognitive impairment in HIV+ than HIV- women, and that HIV-associated vulnerability to stress is most evident on tasks involving the prefrontal cortex. The second study is a hydrocortisone challenge study among HIV+ women contrasting those with (n=15) and without (n=15) a PTSD diagnosis to determine whether the former group shows greater prefrontal task impairment than the latter following hydrocortisone administration. Results of these two studies will provide a foundation for designing subsequent mechanistic and treatment studies (R01s) to improve cognition among HIV+ women, and submission of grant proposals to fund this line of inquiry. PUBLIC HEALTH RELEVANCE: HIV+ women's exposure to acute and chronic stressors is associated with cognitive and brain dysfunction that interferes with treatment adherence and lowers quality of life. Interventions based on a better understanding of neuroendocrine processes have the potential to enhance treatment adherence, lower morbidity and mortality, and reduce treatment costs, resulting in greater well-being for their these women and their families, and improved public health for our nation.

DESCRIPTION (provided by applicant): Cognitive deficits persist despite the availability of effective therapies for HIV. New data indicates that, in contrast to men, delayed memory impairments are a central feature of cognitive impairment in HIV+ women. Furthermore, stress interacts with HIV serostatus to negatively impact verbal memory in particular. This application proposes to investigate stress-associated increases in glucocorticoids (GCs) as a potential contributor to verbal memory deficits in HIV+ women. GCs are released after a stressor and are the key mediator of the relationship between stress and memory dysfunction in non-HIV-infected individuals. Correlational evidence suggests that healthy women are more vulnerable to the cognitive effects of GCs than healthy men. Here we propose to extend this research to HIV and specifically examine the causal role of GCs response on cognitive function. Specifically, we propose to investigate sex differences in the impact of hydrocortisone on cognitive function in HIV in a double-blind, placebo-controlled, cross-over study in 82 HIV+ adults (41 men, 41 women). An innovative feature of this design builds on recent evidence that the effects of GCs on cognition depends on the timing of the cognitive assessment in relation to stress hormone exposure. Therefore, we propose to examine how GCs impact cognitive function both acutely (30 minutes post- intervention) and after a delay (240 minutes post-intervention). We hypothesize that the magnitude of acute and delayed impairments on verbal memory will be greater in HIV+ women compared to HIV+ men. To the best of our knowledge, this will be the first pharmacologic challenge study to elucidate the cognitive effects of GCs in HIV. Such a demonstration will provide critical insights into stress-related increases in GCs as a mechanism underlying the apparent greater deficit in verbal memory in HIV+ women compared to men. Identifying this mechanism is a critical first step in the design of clinical trials aimed at lowerng stress and GCs in order to improve cognitive function, particularly in HIV+ women.

PROJECT SUMMARY/ABSTRACT Despite the availability of effective antiretroviral therapies, cognitive deficits remain prevalent in HIV-infected (HIV+) individuals. HIV+ women show prominent deficits in verbal learning and memory, and stress is a major contributor to these deficits. In fact, we have shown that stress has more profound effects on verbal memory in HIV+ women than in HIV-uninfected (HIV-) women. Our structural and functional neuroimaging findings link these stress-related memory impairments in HIV+ women to prefrontal cortical atrophy and decreased prefrontal cortex (PFC) functioning. Cortisol, a glucocorticoid that is released following a stressor and which is elevated with chronic stress, is known to influence both hippocampal and PFC function. Clinically, this is relevant because LDH can be administered exogenously and safely in the form of low-dose hydrocortisone (LDH). In healthy individuals, LDH impairs cognition, but in individuals with post-traumatic stress disorder (PTSD) LDH enhances cognition. We recently extended this line of LDH research to HIV in a pilot study of a single dose of LDH (10mg) in HIV+ women with high levels of perceived stress but no current psychiatric comorbidities. Notably, verbal learning and memory improved 4 hours following treatment with LDH compared to placebo. Although the mechanisms contributing to this effect are unknown, LDH normalizes stress-induced alterations in the hypothalamic-pituitary-adrenal (HPA) axis and inflammation. Here we propose to examine the robustness and clinical significance of these findings in a larger sample of HIV+ women demonstrating cognitive dysfunction and reporting high levels of stress, trauma history, and mental health risk factors. Women meeting enrollment criteria will complete three cognitive assessments. The first and second assessments will be embedded in a double- blind, placebo-controlled, cross-over study of a single administration of LDH (10 mg in pill form) versus placebo (targeted n=100). The within-subject design controls for common cofounds (e.g., psychological risk factors, substance use history) that could complicate interpretation of LDH effects in a population of HIV+ women. We will measure cognitive performance 30 minutes and 4 hours post-dosing, because an emerging literature shows that the cognitive effects of LDH depends on timing of the assessment post-dosing. The 30-minute assessment addresses how the maximal cortisol levels following LDH affect cognition. This immediate assessment is standard in studies of stress and cognition and allows for comparisons with the broader literature. More novel and clinically important is the 4-hour assessment which occurs post-peak, when cortisol levels are more steady state and typical of the broader daily cortisol profile following LDH. The third assessment will take place after 4 weeks of treatment with LDH or placebo. That assessment addresses the clinical significance and safety of longer-term LDH treatment. Lastly, we will explore glucocorticoids and inflammation and immune activation as mechanisms by which LDH might affect cognition. [This novel study will be the first to target mental health related mechanisms (e.g., HPA axis dysregulation) to enhance cognition in HIV+ women. If in 5-years this study verifies and extends our initial findings that LDH enhances cognition in HIV+ women then we will have identified a novel therapeutic target for further clinical and mechanistic investigations.]

The CNS dysfunction SWG will facilitate interdisciplinary collaborations focusing on approaches to better understanding CNS dysfunction among people with HIV. Our goals are: 1. Promote the growth of our diverse team through provision of resources and mentorship to young clinician and non-clinician investigators who have new interest in HIV research. We are particularly well-positioned to foster the success of those with interests in computational approaches to stratification and clinical prediction modeling, validation of biomarker targets for precision imaging, identification of new biomarkers (with informatics), and development of new precision techniques such as molecular-genetic imaging. ? Number of junior investigators involved with CNS dysfunction SWG ? Number of collaborations established within & across CFAR, including individuals new to HIV research or HIV-experienced & new to CNS dysfunction research ? Number of abstracts/manuscripts submitted by these junior or new investigators to CNS dysfunction HIV research ? Number of CFAR/P30 pilot or other awards to these junior or new investigators to CNS dysfunction HIV research 2. Facilitate the development and success of new protocols that generate new data (e.g., clinical, neuroimaging, biospecimens) or use existing clinical datasets such as the electronic health record (EHR), multi-domain neuropsychological and mental health data, biospecimen characteristics, and neuroimaging toward characterizing people with HIV with CNS dysfunction and comorbidities ? # of submitted NIH or other grants related to NeuroHIV ? # of submitted protocols that include novel expertise from outside the field of HIV/AIDS research ? # new manuscripts in NeuroHIV ? # CFAR scholar awards

PROJECT SUMMARY/ABSTRACT Despite the availability of effective antiretroviral therapies, cognitive deficits remain prevalent in HIV-infected (HIV+) individuals. HIV+ women show prominent deficits in verbal learning and memory, and stress is a major contributor to these deficits. In fact, we have shown that stress has more profound effects on verbal memory in HIV+ women than in HIV-uninfected (HIV-) women. Our structural and functional neuroimaging findings link these stress-related memory impairments in HIV+ women to prefrontal cortical atrophy and decreased prefrontal cortex (PFC) functioning. Cortisol, a glucocorticoid that is released following a stressor and which is elevated with chronic stress, is known to influence both hippocampal and PFC function. Clinically, this is relevant because LDH can be administered exogenously and safely in the form of low-dose hydrocortisone (LDH). In healthy individuals, LDH impairs cognition, but in individuals with post-traumatic stress disorder (PTSD) LDH enhances cognition. We recently extended this line of LDH research to HIV in a pilot study of a single dose of LDH (10mg) in HIV+ women with high levels of perceived stress but no current psychiatric comorbidities. Notably, verbal learning and memory improved 4 hours following treatment with LDH compared to placebo. Although the mechanisms contributing to this effect are unknown, LDH normalizes stress-induced alterations in the hypothalamic-pituitary-adrenal (HPA) axis and inflammation. Here we propose to examine the robustness and clinical significance of these findings in a larger sample of HIV+ women demonstrating cognitive dysfunction and reporting high levels of stress, trauma history, and mental health risk factors. Women meeting enrollment criteria will complete three cognitive assessments. The first and second assessments will be embedded in a double- blind, placebo-controlled, cross-over study of a single administration of LDH (10 mg in pill form) versus placebo (targeted n=100). The within-subject design controls for common cofounds (e.g., psychological risk factors, substance use history) that could complicate interpretation of LDH effects in a population of HIV+ women. We will measure cognitive performance 30 minutes and 4 hours post-dosing, because an emerging literature shows that the cognitive effects of LDH depends on timing of the assessment post-dosing. The 30-minute assessment addresses how the maximal cortisol levels following LDH affect cognition. This immediate assessment is standard in studies of stress and cognition and allows for comparisons with the broader literature. More novel and clinically important is the 4-hour assessment which occurs post-peak, when cortisol levels are more steady state and typical of the broader daily cortisol profile following LDH. The third assessment will take place after 4 weeks of treatment with LDH or placebo. That assessment addresses the clinical significance and safety of longer-term LDH treatment. Lastly, we will explore glucocorticoids and inflammation and immune activation as mechanisms by which LDH might affect cognition. [This novel study will be the first to target mental health related mechanisms (e.g., HPA axis dysregulation) to enhance cognition in HIV+ women. If in 5-years this study verifies and extends our initial findings that LDH enhances cognition in HIV+ women then we will have identified a novel therapeutic target for further clinical and mechanistic investigations.]

Mental health disorders including depression and neurocognitive impairment (NCI) are the most common central nervous system (CNS) complications of HIV infection despite effective antiretroviral therapy (ART). It is estimated that 40-50% of HIV+ individuals have at least one mental health disorder. Uganda, a low-income country in Sub- Saharan Africa (SSA) has ~1.5 million people living with HIV (PLWH) many of whom are on ART. Despite ART use, CNS complications, which are notably heterogeneous, persist among PLWH. Uganda provides a unique setting for advancing our understanding of major depressive disorder [MDD] and NCI, because common confounding conditions in the United States such as cerebrovascular disease risk factors and illicit drug use (e.g., narcotics, cocaine) are rare in Uganda. We propose to address the overarching hypothesis that there is substantial heterogeneity in MDD and NCI in PLWH and that psychosocial determinants (e.g., sexual and physical trauma, violence) are likely contributors to this heterogeneity. Addressing the heterogeneity in MDD and NCI is critical to advancing our understanding of cognitive phenotypes. To accomplish our aims, we will use a novel methodology for mental health in HIV research, the NIMH Research Domain Criteria (RDoC) framework, which recognizes heterogeneity, to first examine behavioral phenotypes among PLWH followed by studies to understand the functional consequences of these phenotypes and the underlying pathophysiology in these phenotypes. Our study results should lead to more accurate diagnosis, prognosis, and targeted interventions for MDD and NCI in HIV infection globally. We plan to cost-effectively leverage the established infrastructure and data from our previous Rakai Neurology Cohort Study to examine the following aims: Aim 1: Examine separate and interactive effects of HIV and psychosocial determinants on CNS dysfunction in PLWH. Hyp 1. Exposure to sexual/physical trauma or violence will interact with HIV in this population and will be associated with greater impairments/decline in declarative memory, cognitive control, and NVS. Aim 2: Examine effects of psychosocial determinants and CNS dysfunction on ART adherence in PLWH. Hyp 2. Exposure to sexual/physical trauma or violence and/or impairments/decline in declarative memory, cognitive control, and NVS will adversely affect ART adherence. Exploratory Aim 3: Determine biomarkers that relate most strongly and reliably to CNS dysfunction in the context of HIV and/or psychosocial determinants. Hyp 3: Different biomarkers of neuronal damage and CNS inflammation will relate to patterns of impairment/decline in declarative memory, cognitive control, motor, and NVS in the context of HIV and/or exposure to sexual/physical trauma or violence. We will also build capacity to evaluate and conduct research in mental health disorders and introduce new measures of adherence to our cohort. Our proposal addresses several high priority research topics for the NIH Office of AIDS Research including HIV-associated comorbidities, basic research to understand the pathogenesis of mental health disorders in HIV infection, and research to identify viral reservoirs that could lead to a cure for HIV infection.

PROJECT SUMMARY/ABSTRACT Despite the availability of effective antiretroviral therapies, cognitive deficits persist in HIV-infected (HIV+) individuals. For example, in the Women's Interagency HIV Study (WIHS), HIV+ virally suppressed (HIV+VS) women showed neurocognitive impairment (NCI) in verbal learning and memory as well as working memory, attention and executive function. These domains of cognitive performance relate to the declarative memory and cognitive control subdomains of the NIMH Research Domain Criteria (RDoC), a framework that has not yet been leveraged to advance understanding of the mechanisms contributing to patterns of NCI in HIV. There is a strong scientific premise that HIV-associated brain injury stems from immunological processes, particularly neuroinflammation, mediated by cells of the monocyte/macrophage lineage. In support of this view, studies by our team and others demonstrate that NCI in HIV is associated with microglial activation and monocyte activation. In this proposal, our multidisciplinary team will provide innovation to this line of inquiry by conducting a longitudinal neuroimaging study that not only uses the RDoC framework but also assesses neuroinflammation. Building on our cross-sectional neuroimaging studies, we will first use task-based functional magnetic resonance imaging (fMRI) and resting state fMRI in HIV+VS individuals and HIV-uninfected individuals to identify the neural circuitry contributing to deficits in declarative memory and cognitive control. Second, we will use positron emission tomography (PET) to assess HIV-related alterations in chronic neuroinflammation in relation to NCI. Third, we will computationally integrate the multimodal imaging data in relation to changes in cognitive performance over time. To achieve our goal, we propose a single-site, longitudinal study in phenotypically well- characterized HIV+VS (N=100) and HIV- controls (N=50) from the WIHS and Multicenter AIDS Cohort Study (MACS). Participants will complete neuroimaging assessments (resting state and task-based fMRI, structural MRI, diffusion-weighted MRI) annually for three years and cognitive assessments every six months over that same time. The longitudinal design allows an assessment of the reproducibility of key findings over time and the sensitivity of these neuroimaging measures to changes in cognitive performance. To examine HIV-related alterations in chronic neuroinflammation, a subset of individuals (total n =42; 24 HIV+VS) will also complete PET assessments using [11C]DPA-713 (DPA). In keeping with NIH research priorities, after 5 years of potential funding, the impact of this R01 on the field will be to inform our understanding of the mechanisms linked to neurological comorbidity and to provide novel, more sensitive neuroimaging biomarkers to guide testing of new cognitive therapies for HIV+ individuals.

PROJECT SUMMARY ? OVERALL HIV-associated neurocognitive disorders (HAND) remain very prevalent, even among aviremic HIV+ individuals treated with CART. In the era of CART, the prevalence of HAND in HIV+ individuals with advanced infection remains around 40-50% [1, 2], and HAND may now be the most common form of young-age neurocognitive impairment globally [1]. Currently there are no uniformly accepted clinical, neuroimaging, or laboratory outcome measures for clinical trials for the treatment of HAND. HIV-related neuroscience research at Johns Hopkins University has focused on this challenging problem, exploring critical pathogenic mechanisms for neurological damage. Despite tremendous efforts to understand the mechanisms underlying the persistence of HAND, no definitive adjunctive therapeutics have yet entered clinical practice. There is also an unfilled need to develop surrogate markers and more robust and simpler screening instruments for HAND, to allow for earlier detection, for tracking of the course of HAND, and improving the efficiency of clinical trials. Until the NIMH Center was established at JHU collaborations had been limited by the lack of a central organizing structure for this type of research, and limited resources to facilitate cross-disciplinary and translational research. The JHU NIMH Center has addressed these needs over the past 11 years and has provided a resource to catalyze interdisciplinary research in HIV neuroscience, with the aim of leading to new therapies. Accomplishments of the Center are highlighted in the Overall Strategy section and in each individual core, and the key accomplishment is our proven ability to move HAND therapeutics from the discovery phase, through animal models, and on to clinical trials, with the ultimate goal of shifting clinical practice.

PROJECT SUMMARY - CLINICAL CORE The prevalence of HAND in HIV+ individuals with advanced infection remains around 40-50%, and HAND may now be the most common form of young-age neurocognitive impairment globally. Currently there are no uniformly accepted clinical, neuroimaging, or laboratory outcome measures for clinical trials for the treatment of HAND. This Core provides the support necessary to evaluate new outcome measures of CNS function including both neurocognitive assessments (e.g., screening tests for HAND) and performance based functional assessments. In addition, the Core will provide well-characterized individuals for developmental projects such as novel neuroimaging outcomes which may be more sensitive to CNS dysfunction and response to treatment than neuropsychological test measures. The Clinical Core will also provide well-characterized individuals for evaluating novel laboratory markers identified in the Biomarker Core. Specifically, we will examine markers of cell stress, neuronal injury, and energy metabolism, which are also being used as platforms for therapeutic targets in our Therapeutic Core. The goals and objectives of this Core are as follows: 1) To maintain a clinical cohort of well-characterized HIV+ and demographically-matched HIV- individuals to improve the efficiency of accruing and conducting clinical trials, 2) To liaise with other NIMH Centers, other funded IPCPs, the AIDS Clinical Trials Group (ACTG), the Johns Hopkins University Center for AIDS Research (JHU CFAR), Institute for Clinical and Translational Research (ICTR), and the Johns Hopkins University (JHU) Drug Discovery unit to assist in the development of interventional therapeutics for HAND, 3) To provide the infrastructure and resources necessary to conduct small early phase studies to evaluate therapeutics for HAND including novel drugs, neuromodulation and behavioral strategies, 4) To maintain a data infrastructure to allow for efficient querying of clinical and laboratory data, 5) To provide statistical support for all studies involving the Center Grant resources.

PROJECT SUMMARY/ABSTRACT Neuropsychiatric complications persist in people with HIV (PWH) despite suppressive antiretroviral therapy. Two common, often disabling conditions in PWH are cognitive impairment (CI) and major depressive disorder (MDD). However, the pathophysiology of central nervous system (CNS) dysfunction in PWH that results in these conditions remain elusive and thus a HIV high priority topic. The trafficking of activated peripheral blood mononuclear cells (PBMCs), specifically CD14+CD16+ monocytes, into brains of virally suppressed (VS)-PWH has emerged a putative contributor to neuroinflammation. We propose to test our hypothesis that VS-PWH will have blood brain barrier (BBB) disruption mechanistically linked to targeted, circulating soluble cytokines/chemokines and upregulation of PBMC surface proteins. The latter interact with tight junction and adherens junction proteins to weaken the BBB, promoting PBMC diapedesis into brain. BBB disruption may promote persistent neuroinflammation and altered neuronal activity contributing to neuropsychiatric sequela. To this end, we propose cross-sectional imaging and lumbar puncture to assess BBB integrity, with baseline and longitudinal neuropsychiatric assessments and blood sampling. 350 VS-PWH and 100 HIV-uninfected (HIV-) individuals will be recruited from the Johns G. Bartlett Clinic within the Johns Hopkins Hospital and in the surrounding Baltimore community. First, we aim to assess the effects of well-controlled HIV on the BBB and its contribution to neuropsychiatric conditions (Aim 1). We will assess BBB integrity using a novel, non-contrast magnetic resonance imaging technique that uses water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST), to determine BBB permeability to water, and thereby to small molecules. We have shown this to be sensitive to BBB change in mild cognitive impairment, a precursor to Alzheimer?s disease. Moreover, we have found WEPCAST to be well-tolerated and estimate PS values well in VS-PWH. Second, we aim to assess the relationship between circulating soluble markers, PBMC-associated markers, and BBB permeability to small molecules, which collectively may promote diapedesis into brain (Aim 2). We target factors implicated in a heightened transmigration of activated PBMCs across the BBB into brain, where they may contribute to neuronal damage and neuropsychiatric burden in VS-PWH. Finally, we aim to examine the relationship of activated PBMCs that transmigrate an intact BBB model to BBB permeability to small molecules (Aim 3). We innovate with the real-time assessment of ex vivo cellular function (BBB model) and in vivo BBB measures (WEPCAST). After 5 years of funding, this R01 will advance our understanding of BBB integrity and related PBMC migration into the brains of VS-PWH, which may contribute to neuroinflammation and related neuropsychiatric burden. These findings will inform next steps in the development of therapeutic approaches to minimize PBMC contribution to neuroinflammation in VS-PWH.