Giovanni Schifitto - US grants

The specific aim is to assess the relationship between autonomic nervous system dysfunction and interleukin production, specifically IL-2 and IL-4 as markers of T helper cell in HIV positive individuals. A similar relation will be sought between dehydroepiandrosterone dulphate and IL-2 and IL-4.

The objectives of the double-blind study were to demonstrate the effect of oxandrolone on muscle strength and the progression of weakness in boys with Duchenne's muscular dystrophy during a 6 months treatment period, and to evaluate the safety and tolerability of the drug in this population. This open-label, active therapy extension protocol will allow those boys who received placebo therapy during the first six months of the study to now receive active drug (oxandrolone), with evaluation of its effects. Boys who had received active therapy during the first six months of study will continue receiving oxandrolone, providing evaluation of the longer-term efficacy and safety of this treatment.

DESCRIPTION: (Provided by applicant): Cognitive impairment is a common complication of HIV- 1 infection that can lead to dementia. The use of potent anti-retroviral therapy has dramatically improved survival and decreased the incidence of systemic HIV complications, including neurological complications. However, the increased survival is likely responsible for the unchanged prevalence of neurological disorders shown recently in longitudinal studies (NEAD cohort). The implication of these findings are that although controlling HIV-1 replication remains the most important goal in the treatment of HIV infection and its neurological sequelae, pathological mechanisms indirectly linked to HIV infection may persist despite optimal viral suppression. This may explain why the presence of macrophage activation in the brain correlates best with dementia. This suggests that the best approach to treat cognitive impairment should consist of best anti-retroviral therapy and adjunctive therapy aimed at indirect mechanisms of neuronal injury. In the background of a systemic disease such as HIV infection treated with multiple drugs that have complex interactions, there are two important steps in the development of novel compounds for the treatment of cognitive impairment. The first step is to assess the pharmacokinetic interaction of a study drug with antiretrovirals (Phase Ia). The second step is to assess the safety and tolerability profile of a study drug in the HIV infected population (Phase Ib) rather than the normal HIV negative population. In such Phase I trials, in vivo brain metabolism (magnetic resonance spectroscopy) may be an important adjunctive tool to detect early cerebral changes that may not be evident clinically. We propose to establish a Phase I Clinical Trials Unit to perform hypothesis driven clinical trials of agents shown by our in vitro and in vivo models to favorably act on mechanisms thought to be critical in the pathogenesis of HIV dementia. The specific aims of this Clinical Trials Unit are: 1. to conduct a series (yearly) of Phase Ia pharmacokinetic interaction studies in HIV infected individuals; 2. to conduct a series (yearly) of Phase Ib clinical trials in HIV infected patients at risk for HIV dementia to ascertain safety and tolerability, and to assess the impact on cognitive performance and brain metabolism of novel therapeutic agents; 3. to operate a Clinical Trials Coordination Center to support and promote the rapid and efficient conduct of the Phase I trials. An infrastructure for conducting Phase II and III trials is already in place and would therefore fast track the transition from Phase I to later stages of drug development.

DESCRIPTION: (provided by applicant) Cognitive impainnent is a common complication of HIV- I infection that can lead to dementia. Markers of immune activation in the central nervous system (CNS) have been shown to best correlate with the degree of cognitive impairment. Interestingly, most products of immune activation induce cytotoxicity via induction of oxidative stress. In this regard, our preliminary data indicate that levels of oxidative stress, measured by cerebrospinal fluid (CSF) induced changes in neuronal mitochondrial membrane potential and CSF levels of protein carbonyl, correlate with the severity of HIV-associated cognitive impairment. The mitochondrial membrane potential abnormalities can be reversed by drugs with antioxidant properties including selegiline (L-deprenyl). It is noteworthy that two preliminary studies suggest that selegiline may improve cognitive impairment associated with HIV infection. Based on these observations, the AIDS Clinical Trials Group (ACTG) has approved a large multicenter trial with selegiline (A5090). We hypothesize that oxidative stress is an important mechanism in the pathogenesis of HIV-associated cognitive impairment and will correlate with markers of cerebral injury as measured by magnetic resonance spectroscopy (MRS) and with established predictors of HIV-associated cognitive impairment including CSF HIV RNA (viral load) and B2 microglobulin levels. We also hypothesize that antioxidant compounds such as selegiline will improve the cognitive performance and metabolic markers of cerebral injury in HIV infected individuals and that this response will correlate with the levels of oxidative stress. We propose to further investigate the role of oxidative stress in HIV-associated cognitive impairment by addressing the following specific aims: 1) to compare markers of oxidative stress in the CSF among HIV infected subjects with and without cognitive impairment and 11W negative controls; 2) to assess the relationship between levels of oxidative stress and CSF HIV viral load and B2-microglobulin levels; 3) to assess the relationship between levels of oxidative stress and in vivo brain metabolism, as measured by MRS in HIV infected subjects with and without cognitive impairment; 4) to assess the effect of selegiline on CSF markers of oxidative stress and on in vivo brain metabolism (MRS) in subjects with 11W-associated cognitive impairment and to correlate changes in markers of oxidative stress with MRS and cognitive performance. The proposed study will take advantage of the ACTG supporting A5090 study and of the existing MRS consortium infrastructure that will allow us to perform multicenter MRS studies.

AIDS /HIV neuropathy; virus load; human immunodeficiency virus 1; virus RNA; pain; plasma; tumor necrosis factor alpha; cerebrospinal fluid; major histocompatibility complex; clinical research;

human therapy evaluation; HIV infections; AIDS dementia complex; pharmacokinetics; brain disorder chemotherapy; valproate; drug interactions; data management; brain metabolism; clinical trial phase I; drug screening /evaluation; cognition; patient oriented research; human subject; clinical research;

immune response; virus load; psychoneuroimmunology; human immunodeficiency virus; virus RNA; central nervous system disorders; plasma; clinical research;

nerve growth factors; biotherapeutic agent; sensory neuropathy; AIDS /HIV neuropathy; pain; nervous system disorder chemotherapy; analgesics; human therapy evaluation; clinical trials; patient oriented research; human subject; clinical research;

sensory neuropathy; AIDS /HIV neuropathy; age difference; cognition disorders; disease /disorder proneness /risk; HIV infections; enzyme activity; T lymphocyte; plasma; protease inhibitor; gene expression; immunoregulation; cytochrome P450; clinical research; human subject;

DESCRIPTION (provided by applicant): This application is a competing renewal, entitled Creatine Safety and Efficacy in HD: Coordination and Statistical Center, and is a companion application to that of Steven Hersch, M.D., PhD. from Massachusetts General Hospital (MGH), entitled Creatine Safety, Tolerability and Efficacy in Huntington's Disease: CREST- E. The primary aim of the study is to investigate the efficacy and long-term safety of chronic creatine monohydrate treatment in Huntington's disease (HD). The competitive renewal is necessary to complete the study that is now 64% accrued. HD is a dominantly inherited, fatal, neurodegenerative disorder for which there is no effective treatment. HD is characterized by the cellular expression of the mutant huntingtin protein, which leads to aberrant protein/protein interactions and a net effect of altered cellular functioning including impaired energy production, oxidative damage, and altered transcriptional regulation. HD manifests clinically with chorea, dystonia, personality changes, and cognitive impairment leading to the loss of independence and eventually death. Approximately 30,000 people in the United States have symptomatic HD, and an additional 150,000 healthy people are at genetic risk of developing HD. The disease burden to patients and their family is severe and is combined with an estimated economical cost to society of about two billion dollars per year. Preclinical and clinical data suggest that creatne may play a disease modifying role in HD. In HD transgenic and knock-in mice, creatine delays the onset and slows the progression of the pathologic phenotype in a dose dependent manner, extends survival, reduces neuropathology and reverses cerebral ATP deficiency. In our initial controlled study, creatine 8 g/d daily increased serum and brain levels of creatine and reduced a plasma marker of oxidative injury to DNA (8OH2'dG) that is otherwise elevated 3-4 fold in symptomatic HD. Our most recent work in HD suggests that creatine may slow brain atrophy, as measured by magnetic resonance morphometry. Based on the above preclinical and clinical data, the primary hypothesis of the study is that 40 grams daily of creatine or highest tolerated dose will slow the functional decline associated with HD. The specific aim of this proposal is to test this hypothesis in a longitudinal, randomized, double-blind, placebo-controlled clinical trial that is designed to achieve 84% power to detect a 25% or greater slowing of disease progression. The primary outcome is the annualized rate of change in total functional capacity. To achieve this goal, 650 subjects will be enrolled in this multicenter, international study and followed for a minimum of 12 months and a maximum of 48 months. The strong rationale and the lack of any therapeutic agent able to slow the progression of this devastating neurodegenerative disease justify the completion of this phase III clinical trial. Should the resuls of the trial show efficacy, the readily available and inexpensive manufacturing of creatine will no only decrease the burden of the disease but do so at very low cost.

DESCRIPTION (provided by applicant): This application requests funding for the study coordination, data management, and biostatistical support for a Phase III clinical trial of creatine in Huntington's disease (HD). This is a companion application to that of Steven M. Hersch, MD, PhD, from Massachusetts General Hospital (MGH), entitled Creatine Safety, Tolerability & Efficacy (CREST-E). HD is an autosomal dominant, uniformly progressive neurodegenerative disorder characterized clinically by movement disorders, personality changes, and cognitive impairment. Approximately 30,000 people in the United States have clinical manifestations of HD, and an additional 150,000 healthy people are thought to be at immediate risk for developing HD. There are no effective treatments for HD and HD progresses relentlessly causing disability and death. Evidence from mouse models of HD and human studies suggests that creatine may slow the course of HD in a dose dependent manner. Pilot data on serum and brain bioavailability, tolerability, HD signs and symptoms, and biomarkers indicate that 30-grams daily of creatine is an optimal dose. We propose to test the hypothesis that creatine can slow the decline of HD by conducting a randomized, double-blinded, placebo-controlled, parallel group trial of 30 grams daily of creatine in 650 symptomatic individuals with HD. The primary outcome variable will be the change from baseline to Month 36 in the Total Functional Capacity (TFC) score. The study will have 96% power to detect a clinically relevant 25% slowing in TFC. The trial will be conducted under the auspices of the Huntington Study Group (HSG) at approximately 42 sites worldwide. This project is consistent with the NCCAM mission of exploring alternative therapies such as creatine with scientifically rigorous studies. There are important public health implications of this study. If the study is positive, it would be a breakthrough in HD research that would change HD clinical care and would spur research into similar compounds for a host of related neurodegenerative diseases. Additionally, the study will provide critical information on the long-term safety of high dose creatine, which is widely used among healthy athletes and patients with a variety of neurodegenerative disorders and other diseases. This will allow NCCAM to distribute authoritative information to the public about the safety of creatine.

DESCRIPTION (provided by applicant): Combination antiretroviral therapy (cART) has changed the natural history of HIV infection, a remarkable achievement that allows those individuals that can tolerate and are compliant with the regimen a survival rate that is getting closer to those that are not infected. However, despite this great success, cART has not eliminated HIV-associated neurocognitive disorders (HAND). Because HAND is progressive even in those taking cART, it has been suggested that the residual viral replication may be sufficient to maintain an inflammatory response that leads to neuronal injury. Thus better CNS penetrating agents should be useful. However, several reports suggest that cART itself may be neurotoxic and at least in part responsible for the persistence and progression of cognitive impairment. Adding to this scenario is the increased survival of HIV infected individuals which it means that the HIV infected population is getting older and the interaction cART- aging may be synergistic in terms of CNS injury. Defining the potential central nervous system (CNS) toxicity associated with cART exposure and its interaction with aging, will create the bases for changing current practices such as adjusting cART doses, especially in the elderly who may be more vulnerable to cART effect and investigating the best combinations of ART with least CNS toxicity. Findings from this research would also provide impetus to develop new drugs with a better CNS profile. Therefore, the primary aim of this proposal is to determine whether chronic exposure to cART alters brain structure and function and whether this differs in young versus older HIV infected individuals. The primary hypothesis is that chronic exposure to cART will affect neural function, as assessed by decreased resting cerebral blood flow (measured by arterial spin labeling) and alter white matter integrity as assessed by diffusion tensor imaging metrics [decreased fractional anisotropy (FA) and increased mean diffusivity (MD)]. These effects on brain structure and function will be more pronounced in older as compared to younger HIV infected subjects because the impact of cART on cellular energy homeostasis is expected to be greater in older vs. younger subjects. We have chosen changes in these neuroimaging biomarkers as primary outcomes of CNS injury because of their sensitivity although measurements of cognitive performance will be used as secondary outcomes. To investigate the interaction cART-aging and to estimate the contribution of HIV infection in subjects on stable cART and well controlled viral replication, we propose to establish a cohort of younger (40 subjects <50 years of age) and older (40 subjects e 50 years of age) ART naive subjects starting cART. These subjects will be age-matched to HIV- controls. An additional 30 HIV infected long-term non progressors will be enrolled to measure the effect of residual HIV replication on the brain in the absence of cART. It is expected that it will take 24-30 months to enroll the subjects who will then be followed for two years. Previous neuroimaging studies suggest observable changes within two years thus cART neurotoxicity, should be measurable within the two-year follow-up.

? DESCRIPTION: Several reports suggest that HIV infected individuals present signs of accelerated vascular aging including atherosclerosis (AS). Available data suggest that the immune dysregualtion associated with HIV infection, not completely restored by the use of combination antiretroviral therapy (cART), plays a role in AS. However, cART directly or indirectly may also play an important role in AS. It has been suggested that the following four events during the aging process are key to evoke AS; 1) Telomere (TL) shortening-mediated DNA damage and apoptosis, 2) impairment of vascular reactivity, 3) inflammation, and 4) impairment of efferocytosis (phagocytosis). In this regard, our group has reported that p90RSK-ERK5 module plays a crucial role in endothelial (EC) dysfunction. Our preliminary data show that cART-induced p90RSK activation inhibited ERK5 transcriptional activity and cART also increased sCD40L plasma levels. Interestingly, sCD40L also increase the activation of p90RSK. Furthermore cART-induced p90RSK activation inhibited ERK5 transcriptional activity thus decreased M? efferocytosis. Lastly, we found that cART caused TL shortening via p90RSK activation, leading to DNA damage and apoptosis. Both increased apoptosis and impairment of efferocytosis evoke secondary stress responses via releasing cellular components including cell-free DNA (cfDNA) and high mobility group box 1 (HMGB1). Based on the rationale above, we propose a novel hypothesis centered on p90RSK activation which provides a link, not previously described, to several observations suggesting an association between cART and accelerated AS in HIV infected individuals. We will test this hypothesis in a 3- year longitudinal study of 180 HIV+ individuals (viral load d50 c/ml) aged e 50 years who are therefore at increased risk of developing measurable changes in markers of AS such as carotid intima-media thickness (CIMT) and carotid artery stiffness (CAS). 90 HIV- controls will be matched for age, gender and Reynolds CVD risk score. We will assess the effect of cART and sCD40L on p90RSK in participants-derived monocytes and secondary stress responses both in monocytes (HMGB1) and plasma (HMGB1, 8-OHdG). We will further define the causal effect of cART and sCD40L on p90RSK-induced accelerated aging of EC and M? in animal studies. Specific Aims: AIM 1. To determine whether chronic exposure to cART and elevated plasma levels of sCD40L in older HIV infected individuals are associated with p90RSK activation leading to enhanced aging of monocytes (reduce telomere length, reduced efferocytosis) and whether these measures of monocyte aging are associated with markers of atherosclerosis (CIMT and CAS). AIM 2. To determine whether the markers of secondary stress response (monocytic and plasma levels of HMGB1, plasma levels of 8-hydroxy-2'- deoxyguanosine (8-OHdG)) in cART-treated older HIV infected individuals are associated with measures of CIMT and CAS. AIM 3. To determine in vitro and in small animal models, the causal effect of cART and sCD40L on p90RSK activation leading to cellular aging of EC and M? which underlie AS.

HIV infected individuals, especially those older, are at increased risk of developing cerebrovascular disease (CBVD). While most of the recent investigations have focused on large vessel disease, cerebral small vessel disease (CSVD) has received much less attention despite its known role and long-term effect on cognitive performance and potentially more direct link to HIV-associated immune dysregulation. CSVD is diagnosed via neuroimaging. Typical findings include small subcortical infarcts, lacunes, white matter hyperintensity, enlarged perivascular spaces, cerebral microbleeds and brain atrophy. Quantitative MR techniques assess indirectly the altered microcirculation and blood brain barrier (BBB) by measuring vascular reactivity, cerebral blood flow, white matter microstructure and tissue susceptibility. Importantly, these quantitative imaging modalities can measure even subtle brain abnormalities that escape the evaluation by standard clinical imaging techniques. CSVD has been associated with markers secreted by myeloid cells. This is particularly relevant to HIV infected individuals. We and others have shown that the aberrant platelet activation during HIV/SIV infection causes an increase in platelet-monocyte complexes (PMCs) that drives monocyte maturation from CD14+/CD16- to the pro-inflammatory CD14(low)/CD16+ phenotype and that the reduced numbers of CD14+/CD16- monocytes are associated with pro-AS changes, BBB permeability and aging. Thus, PMCs could serve as markers and a therapeutic target of CSVD. Based on these observations, we hypothesize that PMCs, by affecting vascular permeability and reactivity, play a crucial role in mediating CSVD, especially in older HIV infected individuals. In a well characterize cohort for CBVD risk factors that includes an older-enriched HIV population (age?50) and age matched uninfected individuals, we propose to address the following Specific Aims pertinent to CSVD in a 3-year longitudinal study. In Aim 1 we will assess whether changes in vascular reactivity (measured via rs-fMRI) and white matter microstructural integrity (measured via DTI) are associated with levels of PMCs. In Sub-Aim 1 we will determine whether areas with increased tissue susceptibility and decreased vascular reactivity are associated with decreased cerebral blood flow (CBF). In Aim 2 we will determine whether changes vascular reactivity and white matter microstructural integrity are associated with soluble products of pro-inflammatory monocytes (plasma levels of sCD163, neopterin, and HMGB1), platelet activation (platelet factor 4 [PF-4]) and with plasma markers of endothelial dysfunction (intercellular adhesion molecule 1 [sICAM- 1], vascular cellular adhesion molecule-1 [sVCAM-1], osteoprotegerin and lipoprotein-associated phospholipase A2 [Lp-PLA2] mass). In Sub-Aim 2 we will determine whether changes in brain iron deposition are associated with levels of PMCs, PF-4, plasma monocyte and endothelial soluble products. In Aim 3 we will model data generated from the previous aims in the context of cognitive performance.

Abstract: With an aging HIV population, it is becoming increasingly difficult to disentangle central nervous system (CNS) injury due to HIV from that due to comorbidities such as vascular disease. A commonality between HIV infection and aging is that both can be considered inflammatory conditions; thus HIV and aging can be expected to have an additive, if not synergistic, negative effect on the CNS. The driver of CNS injury in HIV infected individuals on combination antiretroviral therapy (cART) is likely multifactorial, and may include HIV viral products, antiretrovirals CNS toxicity, traditional vascular risk factors and persistent CNS immune activation. Pro-inflammatory monocytes, such as those expressing tissue factor (TF+), are well-positioned to mediate both inflammation and coagulopathy, thus likely to play a role in CNS injury. TF+ monocytes are increased in HIV+ individuals, even in those on effective cART. Their ability to mediate both inflammation and coagulopathy can lead to dysregulation of the CNS microcirculation, followed by ischemia, and then to demyelination. This last effect is visible as white matter hyperintensities (WMH) in standard clinical MRI studies, for example FLAIR sequence. More advanced pulse sequences, such as diffusion weighted imaging, can provide quantitative measurements of abnormal white matter microstructure integrity even when there is no visible WMH on FLAIR. Well-treated HIV+ individuals are expected to have a very slow neurocognitive decline which is also reflected in small, neuroimaging changes overtime. Therefore, it may take several years for those imaging changes reflecting CNS injury to become quantifiable with standard methodology. We propose novel methodologies that reproducibly construct structural and functional connectomes across subjects and between populations, thus further improving our understanding in the evolution of HIV-associated CNS injury. These novel methods are based on a rigorous statistical approach which will provide the reliability needed to ascertain small changes overtime. We propose to implement these methodologies while investigating the role of TF+ monocytes, immune cells at the crossroad of inflammation and coagulopathy, thus likely involved in HIV-associated CNS injury, especially in an older population. The specific aims listed below will be investigated in a three-year longitudinal cohort of 110 HIV+ participants and 110 HIV- age, gender and vascular risk factors matched controls. We have chosen a cohort that is primarily composed of participants age ?50 thus at greater risk of vascular disease. Aim 1. To assess via novel methodologies the longitudinal changes in the trajectory of brain structural connectome and functional connectivity in HIV infected compared to HIV seronegative individuals in the context of intermediaries of inflammation and coagulopathy (soluble CD14 and CD163, D-dimer, soluble tissue factor and TF+ monocytes). Aim 2. To assess the mediation effect of structural connectome, functional connectivity and cerebral cortical thickness on specific cognitive domains.

Persistent immune activation remains a key concern in the cART era and it is likely to synergize with the effects of aging. The results of this interaction are likely contributing to the high prevalence of vascular disease, including cerebral small vessel disease (CSVD), observed in older HIV infected individuals. The qualitative assessment of CVSD via standard clinical MR pulse sequences, provides a superficial assessment of the brain microstructure damage. More importantly, it does not offer a full understanding of pathomechanisms of CNS injury. In this regard, we propose to combine the information provided by two MR modalities that assess the integrity of tissue microstructure, MR elastography (MRE) and neurite-orientation- dispersion density imaging (NODDI). We hypothesize that the combination of these modalities can help us understand how immune activation affects the intracellular and extracellular neuronal compartments (NODDI) and associated changes in tissue viscoelastic properties (MRE). We will also be able to assess quantitatively the relationship among these imaging metrics and peripheral blood markers of immune activation and neuronal and glia dysfunction. Furthermore, we will be able to assess how changes in intracellular and extracellular neuronal compartments and changes in brain viscoelastic properties affect cognitive performance. MRE metrics have been shown to be altered in several neurodegenerative disorders and neuroinflammatory disorders such as multiple sclerosis. However, there is no data on its usefulness in the context of HIV infection. Neither are there data that incorporate MRE, NODDI, makers of immune activation, neuronal and glia dysfunction and cognitive performance, providing a comprehensive picture of how neuroinflammation is linked to CNS injury and decreased cognitive performance. The lack of knowledge has prompted us to submit this proposal. To our knowledge, this study represents the first application of brain MRE to assess the overall hypothesis that HIV-associated immune activation affects the brain viscoelastic properties, leading to cognitive dysfunction. To minimize cost and increase efficiency, we propose to address the specific aims listed below in a cross-sectional study that will co-enroll 60 participants (30 HIV+ and 30 HIV-) in our ongoing longitudinal study of HIV-associated CSVD (RO1 AG054328). The CSVD cohort has enrolled 140 of the expected 220 participants (110 HIV+, 110 HIV-). The study is on target to complete the enrolment by the summer of 2019. In Aim 1, we will assess whether HIV infection influences brain viscoelastic properties and whether these changes are associated with systemic markers of immune activation (soluble CD14 and CD163, D-dimer, soluble tissue factor and TF+ monocytes). In Aim 2, we will investigate the relationship between brain viscoelastic properties, neurites (axons and dendrites) morphology and the correlation of these imaging metrics to plasma levels of markers of neuronal and astrocyte dysfunction. In Aim 3, we will determine if MRE and diffusion MR metrics are associated with cognitive performance.

SUMMARY The UR-Udall Center's Clinical Core has the capability to conduct remote assessments nationally and in- person assessments locally. For a decade, the Core's investigators have pioneered the use of video visits to conduct phenotypic assessments of individuals with PD and other neurodegenerative conditions. These efforts have involved novel partners, including 23andMe, pharmaceutical companies, and the Michael J. Fox Foundation. The largest effort connected 166 participants with PD in 39 states all to a single research ?site.? The Core will use simple, secure video conference software and inexpensive web cameras to support Project 2 and enable the first virtual, national longitudinal study of LRRK2 carriers with and without PD. The Clinical Core also has extensive experience conducting in-person assessments to evaluate the relationship between traditional measures and those conducted with novel sensors, including smartphones and wearable sensors that are part of Projects 3 and 4. In addition, the Clinical Core and its outstanding partners can recruit research participants nationally and internationally. In one smartphone study, over 15,000 individuals nationally enrolled in seven months, and in another, we recruited 1600 participants from ~13 countries. The Clinical Core will be led by Dr. Giovanni Schifitto, a NIH-funded investigator who has helped lead multiple large scale clinical research efforts, and will be supported by a cadre of junior and senior clinical investigators with extensive experience conducting remote and in-person research evaluations. The Core will also include John Wilbanks, the Chief Commons Officer at Sage Bionetworks and one of the country's leading thinkers and practitioners of informed consent, to help guide the Center's multiple remote studies. Supported by experts in project and data management, the Clinical Core is poised to be an outstanding resource for the UR-Udall Center, the network of Udall Centers, and the broader PD community.

Project Summary Metabolic syndrome (MetS) is a constellation of risk factors for cardiovascular disease and type 2 diabetes mellitus which frequently occur together. The consequences of MetS extend beyond the increased risk of vascular-metabolic disease. Data is emerging suggesting causality between MetS and cerebral small vessel disease. MetS is associated with an increased incidence of vascular dementia and progression from mild cognitive impairment to dementia. MetS cause endothelial dysfunction and low-level inflammation of adipose tissue. MetS-associated endothelial dysfunction is independent of obesity status with an increased number of MetS abnormalities correlating with more endothelial dysfunction. Middle cerebral artery stiffening with impaired blood flow is associated with a higher MetS score. Enhanced access to effective combination antiretroviral therapy (cART) improved the life expectancy of people living with HIV (PLWH) substantially. Longevity, however, presents unique health challenges, one being the development of non-communicable diseases including MetS. Emerging data from sub-Saharan Africa indicate a higher prevalence of MetS among PLWH compared with their HIV-negative counterparts. The incidence of MetS in PLWH is predicted to increase. Abdominal obesity is reaching alarming proportions in PLWH in sub-Saharan Africa on cART with the prevalence similar to that of high-income countries. Antiretroviral regimens were associated with higher treatment-emergent MetS. Given the growing HIV-positive population with MetS, and that both MetS and HIV are chronic inflammatory conditions, there is an urgent need to identify effective and affordable pharmacotherapy that addresses modifiable aspects of vascular disease. Metformin has been shown to affect endothelial cells by inhibiting several inflammatory molecules. Pilot clinical trial data support that metformin significantly improves endothelial function, even in short-term treatment. Metformin is a low-cost and well-known drug used for the management of abnormal glucose homeostasis in people with type 2 diabetes. Metformin is widely available in public service settings and is considered to have a clinical effect beyond glucose lowering. Based on the rationale above, we propose to study metformin in HIV- positive participants with MetS who are virologically suppressed by standard of care cART to receive open-label metformin to assess its effect on cerebrovascular function. The purpose of this pilot study in PLWH with MetS is to obtain preliminary data on the effect of metformin on cerebrovascular function using non-invasive neuroimaging biomarkers. Furthermore, we will test the hypothesis that metformin mediates the cerebrovascular changes in part via endothelial regulation by using a comprehensive panel of endothelial functional and soluble markers which will be correlated with the imaging metrics. The results of the study will form the basis for a future clinical trial that will assess the beneficial effect of metformin in reducing the burden of cerebral small vessel disease in PLWH.