Ned Sacktor - US grants

Cognitive impairment is a frequent manifestation of advanced HIV infection. The treatment response to antiretroviral medications is often brief and unsatisfactory. We conducted a randomized double-blind, placebo-controlled trial using a parallel group, 2x2 factorial design of deprenyl, a monoamine oxidase B inhibitor, (2.5 mg 3 times a week) and thioctic acid, an antioxidant, (600 mg every 12 hours) in 15 patients with HIV associated cognitive impairment. Informed, witnessed, signed consent was obtained from all participants or from the person with durable power of attorney. The double-blind, placebo-controlled phase of the study was 10 weeks. After this phase, patients were eligible to receive 10 weeks of open label drug. Evaluations included neurological and neuropsychological assessments, concurrent medications, concurrent AIDS-defining illnesses, adverse experiences, activities of daily living assessment, and routine safety labs. Deprenyl recipients showed improved performance on a test of verbal memory and 1 test of psychomotor speed, compared to patients not taking deprenyl. Thioctic acid recipients did not show neuropsychological testing improvement. Both deprenyl and thioctic acid were well tolerated with few adverse events. These results suggest that both drugs are well tolerated in patients with advanced HIV infection, but only deprenyl treated patients showed cognitive improvement. The trial was completed as of 1/10/96.

Antiretroviral agents are the only therapy currently used for treating HIV dementia, but the treatment response is often poor. Selegiline is an approved and marketed selective monoamine oxidase type B inhibitor. However, at very low dosages in in vitro and in vivo systems, it blocks the formation of oxygen radicals and has a trophic effect on injured neurons through the stimulation of anti-apoptotic factors. A previous randomized double-blind, placebo-controlled trial of low dose oral selegiline suggested that selegiline treatment is associated with cognitive improvement in subjects with HIV-associated cognitive impairment. This study will evaluate the safety, tolerability, and efficacy of transdermal selegiline in patients with HIV-associated cognitive impairment. Transdermal selegiline has been well tolerated in healthy volunteers and in patients with Alzheimer's disease.

Routine neuroimaging with computerization tomography (CT) or magnetic resonance imaging (MRI) in HIV infection is useful for identifying generalized atrophy and structural lesions such as intracranial infections or tumors. In the absence of such lesions, qualitative CT or MRI is not sufficiently sensitive to evaluate the transition from HIV infection with normal cognitive function to minor or major cognitive impairment. Functional MRI (FMRI) is a novel neuroimaging tool which provides maps of human brain activation with high spatial and temporal resolution. The technique is a non-invasive assessment of changes in regional cerebral blood flow in response to a specific cognitive task. Functional neuroimaging may detect subtle alterations in neurological function before clinical and structural abnormalities develop. Another major advantage of fMRI is that it is non-invasive, requires no radioisotopes or ionizing radiation, and is repeatable. This study evaluates the fMRI activation pattern in response to a test of psychomotor speed in HIV- infected patients and HIV-controls. Subjects with psychomotor slowing consistent with early HIV dementia and HIV-controls will be selected. The cognitive paradigm chosen for investigation is psychomotor-function and its putative subcomponents. the subcomponents of principal interest include executing a cognitive operation and performance of a motor act. To investigate the functional integrity of these subcomponents in fMRI, we will perform a time course analysis of cerebral blood oxygenation/flow changes during performance of "baseline" and "activated" cognitive tasks for that given subcomponent.

This protocol allows us to capture longitudinal information from HIV seropositive subjects providing an active surveillance system for the identification of HIV-associated cognitive impairment and dementia among patients referred to the HIV Neurology Consultation services, from the Multicenter AIDS Cohort Study (MACS) and patients from the Johns Hopkins Moore Clinic (for patients with HIV infection). In publications this year, in the MACS, we showed that baseline plasma viral load predicts the development of HIV-associated dementia and sensory neuropathy (Childs, 1999). Combination antiretroviral therapy including protease inhibitors improves cognitive impairment (Sacktor, 1998). Highly active antiretroviral therapy has also decreased the incidence of HIV-associated neurological diseases (Sacktor, 1999). In another study, (Adamson et al 1999) found that increasing severity of HIV-associated dementia was associated with increased levels of inducible nitric oxide synthas (iNOS).

neuroimaging; magnetic resonance imaging; HIV infections; nervous system infection; AIDS dementia complex; pathologic process; biomarker; pharmacology; immune response; human immunodeficiency virus; virus load; AIDS therapy; brain metabolism; blood brain barrier; antiviral agents; combination chemotherapy; drug metabolism; host organism interaction; virus infection mechanism; longitudinal human study; patient oriented research; human subject; bioimaging /biomedical imaging; neuropsychological tests; clinical research;

AIDS /HIV neuropathy; cognition disorders; epidemiology; AIDS dementia complex; HIV infections; functional ability; performance; protease inhibitor; disease /disorder proneness /risk; antiviral agents; combination chemotherapy; AIDS therapy; longitudinal human study; cognition; human therapy evaluation; clinical research; human subject;

DESCRIPTION (provided by applicant): HIV dementia (HIV-D) is one of the most common causes of dementia in young adults in the United States. Aberrant immune activation and oxidative stress within the central nervous system (CMS) play a significant role in the development of HIV-D. Disruptions in cytokine and redox balance produce reactive oxygen species which can attack proteins, deoxynucleic acids, and lipid membranes resulting in cellular dysfunction and cell death. Recent data from our group demonstrate increases in several markers of oxidative stress, specifically, ceramide, sphingomyelin, and 4-hydroxynonenal (HNE). The project will assemble a cohort of HIV+ individuals with varying degrees of neurocognitive impairment: 1) to define the association between markers of oxidative stress and HIV-D in a cohort of HAART-treated subjects and to determine the relationship between these markers and laboratory markers of macrophage and astrocyte activation and neuroimaging markers of inflammation and neuronal injury, 2) to determine whether markers of oxidative stress predict either the reversibility or the progression of HIV-D, and 3) to determine whether the antioxidant treatment, minocycline is safe in patients with HIV-D, improves HIV associated cognitive impairment, and decreases markers of oxidative stress. We propose the first large-scale prospective study to quantify novel markers of oxidative stress in individuals with HIV-associated cognitive impairment receiving HAART. This proposal examines the interrelationship between these markers and novel immune activation and neuroimaging markers of inflammation and neuronal injury to define the role of oxidative stress in the pathogenesis of HIV-D. This proposal will potentially identify new cellular targets of HIV-D treatment, and we will initiate a controlled clinical trial to test a new agent for the treatment of HIV-D. We believe that oxidative stress plays a significant role in the development of HIV-D, and strategies to decrease oxidative stress may serve as a useful therapeutic target to treat HIV-D.

AIDS; AIDS Dementia; AIDS Dementia Complex; AIDS Virus; AIDS with dementia; AIDS-related dementia; AIDS/HIV; AIDS/HIV problem; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immune Deficiency Syndrome related dementia; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Affect; Africa South of the Sahara; Age; Aged 65 and Over; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Amentia; Anti-Retroviral Agents; Antirejection Therapy; Antiretroviral Agents; Antiretroviral Therapy, Highly Active; Behavioral; Blood Plasma; CD4 Lymphocyte Count; CD4+ Cell Counts; CD4+ Counts; Cells; Clinic; Clinical; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Collaborations; Communicable Diseases; Condition; Country; Data; Dementia; Dementia Complex, AIDS-Related; Dementia Complex, Acquired Immune Deficiency Syndrome; Dementia Due to HIV Disease; Dementia associated with AIDS; Dementia in human immunodeficiency virus (HIV) disease; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Dementia, Vascular; Development; Dideoxynucleosides; Disease Progression; Disturbance in cognition; Drug usage; Drugs; Dysfunction; Early Diagnosis; Elderly; Elderly, over 65; Epidemic; Epidemiology; Exposure to; Frequencies (time pattern); Frequency; Functional disorder; Future; Gene Products, RNA; HAART; HIV; HIV Dementia; HIV Infections; HIV associated dementia; HIV diagnosis; HIV-1; HIV-1 associated dementia; HIV-1 dementia; HIV-Associated Cognitive Motor Complex; HIV-I; HIV-related dementia; HIV/AIDS; HIV/AIDS problem; HIV1; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Highly Active Antiretroviral Therapy; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Immunodeficiency Virus Type 1, Human; Immunologic Deficiency Syndrome, Acquired; Immunosuppression Effect; Immunosuppressions (Physiology); Immunosuppressive Effect; Immunosuppressive Therapy; Impaired cognition; Impairment; Individual; Infection; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases and Manifestations; Infectious Disorder; Infrastructure; LAV-HTLV-III; Life; Longitudinal Studies; Lymphadenopathy-Associated Virus; Measures; Medication; Morbidity; Morbidity - disease rate; Motor; Natural immunosuppression; Nervous System Diseases; Nervous System Physiology; Neurocognitive; Neurologic; Neurologic Disorders; Neurologic Manifestations; Neurologic Signs and Symptoms; Neurologic function; Neurological; Neurological Disorders; Neurological Manifestations; Neurological function; Neuropathy; Neuropsychologic Tests; Neuropsychological Tests; PNS Diseases; Patients; Performance; Peripheral Nerve Diseases; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Peripheral Nervous System Disorders; Peripheral Neuropathy; Peripheral Sensory Neuropathy; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiopathology; Plasma; Prevalence; Primary Senile Degenerative Dementia; Prospective Studies; Protocols, Treatment; Public Health; RGM; RNA; RNA, Non-Polyadenylated; Range; Regimen; Research Infrastructure; Research Resources; Resources; Reticuloendothelial System, Serum, Plasma; Ribonucleic Acid; Risk; Risk Factors; Scientist; Score; Serum, Plasma; Sub-Saharan Africa; Subsaharan Africa; Symptoms; T-Lymphotropic Virus Type III Infections, Human; T4 Lymphocyte Count; Tanzania; Therapeutic immunosuppression; Therapy, Anti-Rejection; Training; Treatment Protocols; Treatment Regimen; Treatment Schedule; Uganda; United Republic of Tanzania; United States; Vascular Dementia; Virulence; Virus-HIV; advanced age; anti-retroviral; anti-retroviral therapy, highly active; antiretroviral; antiretroviral therapy; artificial immunosuppression; base; cognitive dysfunction; cognitive loss; cognitively impaired; cohort; ddNus; dementia of the Alzheimer type; drug use; drug/agent; early detection; elders; experiment; experimental research; experimental study; geriatric; human T cell leukemia virus III; human T lymphotropic virus III; immunosuppression; late life; later life; long-term study; nervous system disorder; nervous system function; neural manifestation; neurological disease; neuropathic; neurovirulence; older adult; older person; pathophysiology; prevent; preventing; primary degenerative dementia; public health medicine (field); research study; senile dementia of the Alzheimer type; senior citizen; sensory neuropathy

There currently are no uniformly accepted clinical, neuroimaging, or laboratory outcome measures for clinical trials for the treatment of HIV associated neurocognitive disorders (HAND). The goals and objectives of this Core are: 1) to provide the resources necessary to continue a clinical cohort of well-characterized HIV+ and demographically-matched HIV- individuals for studies evaluating new outcome measures and surrogate markers for clinical trials of HAND, 2) to liaise with other NIMH Centers or other funded IPCPs involved in NeuroAIDs therapeutic work to help identify potential candidate agents, 3) to provide the resources necessary to design and conduct small pilot studies to evaluate potential novel compounds to treat HAND, 4) to maintain a data infrastructure to allow for efficient querying of clinical and laboratory data, 5) to provide statistical support for studies involving the Center Grant resources, 6) to provide a resource for linkage with ongoing Neuro-AIDS trial consortia. The Clinical Outcomes Core provides support for a cohort of 150 HIV+ and 50 HIV- individuals which is used to evaluate both neurocognitive and novel functional assessments. Stored CSF and blood specimens from cohort participants are used to validate surrogate markers. Participants with a well characterized HAND stage from the Clinical Outcomes Cohort are used for developmental projects. The Core also evaluates safety, tolerability, and efficacy outcome measures for new compounds for the treatment of HAND. Thus, the Core provides a service to develop improved outcome measures for use in clinical trials, and obtains preliminary data for candidate drugs of safety and tolerability. The Core will also obtain data to determine the sample size needed for larger, confirmatory studies of efficacy.

DESCRIPTION (provided by applicant): More than 75% of HIV+ individuals over the age of 50 now die from non-HIV related causes, suggesting that the causes of cognitive impairment among older HIV+ individuals may overlap with those among elderly HIV- individuals. The cause of HIV-associated neurocognitive disorders (HAND) among older HIV+ individuals is not well established and could be due to the HIV virus itself, the earlier onset of neurodegenerative diseases such as Alzheimer's disease (AD) or microvascular ischemic (small stroke) associated cognitive impairment. Based upon previous studies, we hypothesize a new conceptual framework that cerebrovascular disease co-morbidity may contribute to cognitive impairment among HIV+ individuals in the 50-59 year age group and neurodegenerative conditions such as AD and cerebrovascular disease contribute to the increased frequency of cognitive impairment among HIV+ individuals in the ? 60 year subgroup. Positron emission tomography (PET) with [18F] AV-45 to detect increased amyloid uptake, a characteristic finding in AD, can be used to identify the contribution of this specific pathophysiological mechanism for cognitive impairment in older HIV+ individuals and is likely to be available for clinical use in 2012. The specific aimsof our proposal are: 1) to determine whether abnormal amyloid accumulation in brain as measured by PET [18F] AV-45 is present among young, younger aged, and older aged HIV+ individuals, 2) to determine whether abnormal amyloid accumulation in brain is present in older (50-59 year and ? 60 year old) HIV+ individuals with HAND, and 3) to determine whether abnormal amyloid accumulation predicts executive functioning decline in older HIV+ individuals. We hypothesize that 1) PET [18F] AV-45 will be detected in HIV+ individuals, and will be chronologically inappropriate compared to age-matched HIV- individuals, 2) PET [18F] AV-45 will have increased uptake in older HIV+ individuals with HAND compared to older HIV+ individuals without HAND, and 3) increased PET [18F] AV-45 uptake will predict executive functioning decline in older HIV+ individuals. Other novel neuroimaging markers of AD, vascular disease, and abnormal lipid metabolism will also be examined for their association with both PET [18F] AV-45 uptake in HIV+ individuals with HAND, and their ability to predict executive functioning decline. Our proposal will be the first application of [18F] AV-45, a novel radiopharmaceutical tracer, in older HIV+ individuals with and without HAND and age and demographically matched HIV- individuals. Our proposal will increase our understanding of pathogenetic mechanisms of cognitive impairment in both 50-59 year old and ? 60 year old HIV+ individuals with HAND, the latter group an age range not previously examined in detail. The identification and validation of PET AV-45 as a surrogate marker for HAND in older HIV+ individuals could serve to identify patients at risk for cognitive decline, and may identify cellular targets for therapeutic intervention.

DESCRIPTION (provided by applicant): HIV associated neurocognitive disorder (HAND) is a common neurological complication of HIV in the US, and our preliminary data suggest that 31% of HIV+ individuals in Uganda may have HIV dementia, the most severe stage of HAND. HIV- associated psychiatric morbidity is also common. There is also evidence that HIV subtype D is associated with more prevalent neurocognitive morbidity than subtype A in individuals with advanced immunosuppression. However, there are no large population based studies of the neurocognitive or psychiatric status of HIV+ African individuals. The Rakai Health Sciences Program (RHSP), Uganda, offers a unique opportunity to conduct such research. The RHSP can identify HIV+ individuals with moderate (CD4 350-500) and more severe (CD4 ?200) immunosuppression from its population based cohort and HIV clinic services. Rakai District is also one of the few regions where a heterosexual epidemic involves different HIV subtypes (A, D, recombinants), enabling us to compare subtype effects on co-morbidities. Specific aims are: 1. At baseline, to assess whether ART naïve HIV+ adults aged ? 20 years with moderate immunosuppression (CD4 350-500), and advanced immunosuppression (CD4 ? 200) experience key neurocognitive/psychiatric co-morbidities, and reduced functional status, compared to age and gender matched HIV- adults in the same Rakai population (the latter will provide normative data as yet unavailable in rural Uganda), 2. To assess the trajectory of these co-morbidities in the HIV+s at two years of follow-up by HIV subtype and level of immunosuppression prior to and after ART initiation, and 3. To define the level of compartmentalized virus in the CSF of individuals with and without dementia stratified by HIV subtype. Hypotheses: 1. ART naïve HIV+ individuals with moderate and advanced immunosuppression have higher prevalence and severity of neurocognitive/psychiatric morbidity, and functional disability, compared to HIV- persons in the same communities, 2. ART will reduce the prevalence and severity of co-morbidities, but rates will remain significantly higher than in HIV- persons, 3. Neurological co-morbidities in HIV+ persons, whether or not they are on ART, adversely affect functional status, increasing health and social support needs, 4. HIV subtype D is associated with an accelerated risk of dementia than subtype A among individuals with advanced immunosuppression, 5. Greater viral genetic compartmentalization in the CSF correlates with dementia and is increased with subtype D compared to A. The study will provide epidemiological and clinical data for the development of prevention and support programs related to neurocognitive /psychiatric co-morbidities, and mechanistic data on HIV-related CNS pathology.

ABSTRACT (Project 3. Clinical Trial) The future treatment for HAND will likely need to include both antiretroviral therapy and adjunctive therapy to treat central nervous system (CNS) specific pathogenetic mechanisms. Insulin is involved in multiple CNS functions including food intake, metabolism, learning, and memory. Insulin has neuroprotective properties demonstrated in cell culture experiments and in vivo models, which provide strong evidence for its use as a therapeutic agent to treat HAND. The brain delivery of insulin administered via a novel nasal drug delivery device has been shown to have CNS protective, restorative, and cognitive enhancing effects in over 15 independent clinical studies. In addition to standard neuropsychological testing, the proposed clinical trial will use several novel brain imaging and CSF surrogate markers to monitor the effects of intranasal insulin therapy in HAND patients. We will conduct a 24 week double-blinded, placebo-controlled Phase I/II trial of intranasal insulin for the treatment of HAND. Participants will be randomly assigned to one of two groups: 1) Intranasal insulin, or 2) placebo administered with a nasal drug delivery device. We will enroll 40 HIV+ individuals on stable (> 6 months) antiretroviral regimens with cognitive impairment over a 3-year period. Blood tests will include fasting glucose and insulin levels. Neuroimaging markers will include magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) to evaluate neuronal injury, inflammation, and cerebral blood flow. CSF specimens will measure HIV RNA levels, and lipid and protein measures of oxidative stress, and markers of energy metabolism, neuronal injury and immune activation. These combined approaches will examine specific mechanisms of efficacy for CNS protection of intranasal insulin in HIV+ individuals. Outcomes from these studies could have important implications for the design and implementation of future insulin modifying therapies and other neuroprotective compounds for HAND.

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 ? 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.