Linda Chang - US grants

human therapy evaluation; neurochemistry; HIV infections; AIDS therapy; AIDS dementia complex; bioimaging /biomedical imaging; human subject; nuclear magnetic resonance spectroscopy; clinical research;

human therapy evaluation; AIDS therapy; AIDS dementia complex; nuclear magnetic resonance spectroscopy; antiviral agents; virus load; cerebrospinal fluid; brain injury; brain metabolism; longitudinal human study; bioimaging /biomedical imaging; neuropsychological tests; human subject; clinical research;

methamphetamine; dopamine; brain imaging /visualization /scanning; drug abuse; bioimaging /biomedical imaging; human subject; clinical research; neuropsychological tests;

Project Summary/Abstract This is a competitive renewal application for a Mid-Career Investigator Award in Patient Oriented Research (K24 DA016170) for the candidate, Linda Chang, M.D., a Clinician-Scientist and Professor of Medicine (Neurology) at the University of Hawaii, John A. Burns School of Medicine (UH-JABSOM). During the past 5-years, Dr. Chang relocated from the Brookhaven National Laboratory in New York to UH- JABSOM, where she became a Professor. She relocated to Hawaii in order to continue her research in patients with methamphetamine abuse and to be involved in the development of a neuroscience research program. Since there was no clinical neuroimaging research at UH, she developed a Neuroscience and MR Research Program, including the acquisition of a 3 Tesla MR scanner, the development of an MR Research Center, and the recruitment of other investigators to conduct neuroimaging research in drug abuse and in neuroHIV/AIDS. The K24 award provided protected research time for her to continue her patient-oriented research at UH-JABSOM, and she was successful in obtaining a renewal of one R01 grant (2R01 MH61427) to study the aging effects of HIV patients and a new R01 grant (1R01 DA21016) to study children with prenatal methamphetamine exposure during the current K24 award period. In addition, she provided mentorship and guidance for 3 junior investigators who successfully obtained mentored K-awards that focused on neuroimaging studies of drugs of abuse after her arrival to UH (no one had a K-award prior to Dr. Chang's arrival at UH-JABSOM). She further obtained a program grant (1U54 NS056883) to develop expertise and provide mentoring to junior investigators in the applications of novel and advanced MR techniques to drug abuse and HIV research. The renewal of this K24 award will allow Dr. Chang to continue her productive research career and mentor junior investigators in patient-oriented research, especially in drug abuse and HIV. She will continue to focus her research on the evaluation of the dopaminergic system in HIV patients, including those with or without nicotine cigarette smoking, using pharmacological functional MRI with event-related design to study risk- taking behaviors and block design to evaluate attention and working memory. She will develop new skills needed to conduct event-related fMRI and in pharmacological fMRI studies. In addition, she will learn many new skills by collaborating with other basic scientists to conduct translational research to determine mechanisms underlying findings in the human studies. Her ongoing research activities, as well as the proposed research, will continue to provide ample opportunities for training junior investigators and students in patient-oriented research. The renewal of this award is needed to maintain her current level of release time from teaching and clinical responsibilities.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] This is a new application for a Midcareer Investigator Award in Patient-Oriented Research (K24). The applicant, Dr. Linda Chang, is a clinician-scientist and Chair of the Medical Department at Brookhaven National Laboratory (BNL). She has been the recipient of two NIH career development awards, first a two-year clinical associate physician (CAP) award through an NCRR-funded General Clinical Research Center (GCRC), followed by a NIDA-funded mentored scientist award for clinicians (K-20) for the past 5 years. She has achieved the intended goals of these NIH career development awards by becoming an independent scientist devoted to patient-oriented research. Specifically, through the mentored K-award, she has developed expertise in several advanced neuroimaging techniques and applied these techniques to study HIV-related brain disorders and drug abuse (cocaine, methamphetamine, and MDMA). Her independence is demonstrated by her receiving three independent research awards that utilize MR techniques to study HIV-associated brain injury and methamphetamine abuse; she is PI on two of these awards (by NINDS and NIDA) and Co-PI on the third award (by NIMH). In addition, she has begun to mentor junior clinician scientists, physicists, computer scientists and chemists, who are pursuing careers in patient-oriented research. She is currently mentoring five clinical scientists (two Assistant Professors and three post-doctoral fellows) and co-mentoring five physicists and computer scientists (three post-doctoral fellows and two pre-doctoral students). In addition, she has active collaborations with many NIDA-funded investigators in drug abuse and/or neuro-HIV research. The current application requests funding (60% salary) for 5-years to ensure that the candidate will have at least 75% protected time to conduct her ongoing research and to continue to mentor the junior clinician scientists. Since Dr. Chang is the Chair of the Medical Department, this award will lead to release of funds from the Department overhead, which will be used to hire an administrative person to minimize her administrative responsibilities. In support of Dr. Chang's career development and research program, BNL has granted her a one-year leave of absence as Chair, in order for her to re-establish her research program at this new location. However, she will need the K-24 award to continue her current level of research and mentoring activities over the next 5 years. In addition to working on the three ongoing R01 funded projects, the candidate plans to obtain additional training in PET, radiotracers and advance fMRI data analyses. This will allow her to develop new approaches to determine how dopaminergic abnormalities might contribute to the functional deficits in drug abuse and/or HIV, using currently available but separate neuroimaging techniques (dopamine studies with PET and BOLD-functional MRI), and taking advantage of the outstanding resources and collaborators at BNL. With the strong publication record, experienced collaborators, and novel approaches, the ongoing projects should be successfully renewed or extended, and lead to new directions in HIV and drug abuse research. [unreadable] [unreadable] [unreadable] [unreadable]

neurotoxicology; cognition disorders; brain metabolism; marijuana abuse; brain electrical activity; neural information processing; HIV infections; immunosuppression; brain disorder diagnosis; noninvasive diagnosis; chemotherapy; patient oriented research; magnetic resonance imaging; human subject; clinical research;

central nervous system stimulants; HIV infections; drug abuse; cerebrovascular disorder diagnosis; neurotoxicology; neuropharmacology; brain imaging /visualization /scanning; blood vessel disorder; brain circulation; patient oriented research; clinical research; human subject;

[unreadable] DESCRIPTION (provided by applicant): Our initial project aimed to 1) determine the neural correlates of attentional impairment in HIV-patients with cognitive motor complex (HIV-CMC) using functional MRI (fMRI), and 2) show that fMRI may detect abnormal brain activation in HIV patients with normal neuropsychological function. We have made significant progress despite the relocation and technical delays associated with a scanner upgrade; our work resulted in 8 papers (6 published and 2 in press), 2 manuscripts submitted, and 4 more in preparation (data collection completed and presented at recent meetings, ISMRM and HIV Workshop). We have achieved our two major aims and proven 3 of the 4 original hypotheses. Work from the initial project period provided us with significant experience and strong preliminary data for this new proposal. The new proposal has the following three aims: 1) To evaluate the possible additive or interactive effects of HIV and aging on brain metabolites using longitudinal follow-up proton magnetic resonance spectroscopy (MRS) studies. 2) To evaluate the possible additive or interactive effects of HIV and aging on brain function, especially attention and working memory, as measured by longitudinal blood-oxygenation-level-dependent functional MRI (BOLD-fMRI). 3) To determine the relationships between brain metabolite abnormalities and brain activation in the setting of HIV and aging. These relationships will provide cross-modality validation of the pathophysiological changes associated with HIV and aging. Based on our preliminary data, we hypothesize that compared to younger HIV subjects, less young (>=40 years) HIV individuals will show higher age-related increase in glial markers (choline, myoinositol) and additional decreased neuronal marker N-acetylaspartate on MRS. In addition, less young HIV patients will have more rapid age-related decline in parietal and frontal BOLD activation during attention and working memory tasks on BOLD-fMRI, over the 5-year period. We also hypothesize that the elevated glial markers and total creatine will be related to increased attentional modulation (usage of brain reserve or deactivation of adjacent or same brain regions) on brain activation. To test these hypotheses, we will enroll 75 HIV-patients and 75 seronegative controls (ages 18-80 years, 75% men, and approximately equal distribution across the decades in each group), and follow them annually over a 5-year period. This will enable us to compare the groups both cross-sectionally as well as longitudinally. The knowledge gained from this study will provide a better understanding of how HIV affects the aging brain (even at middle age), and may lead to future preventive measures (e.g. neuroprotective or anti-inflammatory treatments). [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application is in response to RFA DA05-007. Clinical and preclinical observations suggest that prenatal methamphetamine (METH) exposure may lead to abnormal brain structures and neurochemistry. Little is known about how these brain changes (structural and chemical) relate to cognitive development. Our preliminary cross-sectional studies in children exposed to METH prenatally provide strong evidence that these children have smaller subcortical brain structures and brain metabolite abnormalities on proton MR spectroscopy (1H MRS), along with decreased performance on neuropsychological tests. Our preliminary data also suggest that these children do not show appropriate age-related increases in some subcortical structures (putamen, globus pallidus, and hippocampi). High resolution MRI, coupled with novel image processing technques, can precisely quantify volumes of brain structures while 1H MRS can reliably and non-invasively quantify neurochemicals that reflect neuronal density (N-acetyl aspartate or NAA) and other cellular markers (choline-compounds, total creatine, myoinositol, glutamate plus glutamine) in selected brain regions. Our primary Specific Aims are: 1) To assess changes in brain structure (on MRI) and brain metabolite concentrations (on 1H MRS) in young children (age 3 years) who were exposed to METH in utero, and to follow these changes longitudinally and annually until age 7 years. 2) To evaluate neuropsychological performance in these children on a yearly basis over the same time period (ages 3-7 years). 3) To evaluate how structural and chemical brain abnormalities (on MRI and 1H MRS) are related to cognitive development in children exposed to METH prenatally. We will follow 120 children (60 with and 60 without prenatal METH exposure) over the course of 5 years, to determine temporal changes in brain metabolite levels, morphometry and neuropsychological performance during early childhood development. Most of these children will be co-enrolled and have been followed since birth in the NIDA-funded Infant Development, Environment and Lifestyle ("IDEAL") study, which assesses infant neurobehavioral development. Detailed maternal drug use, psychosocial and mood evaluations will be performed and correlated with biological brain changes in these children.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] The goal of the proposed SNRP at UHM-John A. Burns School of Medicine (JABSOM) is to develop a critical mass of neuroscientists who will focus their research efforts on health problems that are highly prevalent in Hawai'i, particularly among the under-represented minority populations. These neuroscientists are trained in a variety of disciplines and will contribute to and collaborate on five interdisciplinary projects proposed in this application. The scientific issues to be explored in the proposed research program will involve the understanding of neurotoxic effects of the major drugs of abuse in Hawaii [i.e. methamphetamine (Meth) and marijuana] and to learn whether prenatal methamphetamine exposure might affect neonatal brain development. [unreadable] [unreadable] The problems of Meth and marijuana abuse affect the underserved minorities, specifically Pacific islanders, and Asians, in Hawai'i more than other populations. Furthermore, although the population infected with HIV is relatively smaller compared to some major metropolitan areas, the rising infection rate among the Asian Pacific Islanders is a concern to the local Department of Health. Therefore, we will also explore possible mechanisms of brain injury in HIV. To achieve this goal, the following are the scientific objectives: 1) To evaluate changes in brain function in individuals with substance-dependence (specifically with methamphetamine and with marijuana); 2) to evaluate possible brain changes in neonates with prenatal methamphetamine exposure; 3) to develop in vivo markers of oxidative stress and determine whether changes in these markers are related to neurotoxicity in HIV subjects with or without Meth abuse. [unreadable] [unreadable] We also propose the following programmatic objectives: 1) to build strong interdisciplinary teams of researchers to study brain-related changes associated with substance abuse (especially methamphetamine and marijuana, which are highly prevalent in Hawaii) and with HIV/AIDS; 2) to provide mentoring to junior investigators and graduate students, including medical students, residents and fellows, for their career development; 3) to provide a forum for inter-disciplinary learning through bi-monthly research seminars and bi-monthly journal clubs. These scientific and programmatic objectives will be achieved through the four interdisciplinary projects, an administrative-clinical-training core and a technical core proposed in this application. [unreadable] [unreadable] PROJECT 1 [unreadable] [unreadable] PI: Edward Chronicle, Ph.D. [unreadable] [unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] The acute use of cannabis by humans has well-known effects on cognition, emotion, motor behavior and perception, via the action of THC at CB1 receptors in the central nervous system. The long-term consequences of cannabis use are less well understood. It is possible that changes in the brains of cannabis users have not hitherto been detected because appropriately sensitive and targeted methods have not been used. We propose to employ two powerful neuroscientific tools to search for subtle deficits in brain function in cannabis users. First, transcranial magnetic stimulation (TMS) protocols will be used to probe the functional status of motor and visual cortices in chronic users. We hypothesize that active frequent cannabis users will show changes in performance reflective of decreased excitability and a gain of inhibitory function, and that these changes will correlate with measures of estimated cumulative THC intake. Second, the technique of interleaving TMS with BOLD signal acquisition in fMRI will allow assessment of the extent and magnitude of motor system response to a localized and calibrated cortical stimulus. We hypothesize that a reduction in excitability is likely to result in a decrease in the extent of the induced BOLD signal in active frequent users, which will again be correlated with measures of cumulative THC intake. Third, we will extend previous BOLD-fMRI studies by employing a battery of attentional, memory and motor tasks. We hypothesize that the extent and/or magnitude of activation will decrease for attentional and motor tasks but increase for two memory tasks. Fourth, we will examine the effects of acute and chronic administration of tetrahydrocannabinol (THC) and other CB1 agonists, and of THC withdrawal, on responses to forepaw sensory in the rat brain, using a high-field animal imaging system. The combination of TMS/fMRI in [unreadable] [unreadable] humans and fMRI in an animal model will allow us to understand how attentional, motor, memory and motor systems may be dysregulated in active frequent cannabis users, giving rise to functional changes. As cannabis is widely used in the United States and elsewhere, and has potential medical benefits for some populations (e.g. glaucoma, HIV, cancer), it is a matter of utmost concern to public health to determine the consequences of frequent cannabis use for the brain. We thus envisage that this project will inform issues of public policy. [unreadable] [unreadable] [unreadable]

0-11 years old; AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Acquired brain injury; Adolescent; Adolescent Youth; Aging; Algorithms; Amentia; Applications Grants; Applied Research; Applied Science; Area; Benzeneethanamine, N,alpha-dimethyl-, (S)-; Brain; Brain Diseases; Brain Disorders; Brain Injuries; CRISP; Categories; Child; Child Youth; Children (0-21); Clinical; Clinical Research; Clinical Study; Clinical assessments; Computer Retrieval of Information on Scientific Projects Database; Crystal Meth; Dementia; Deoxyephedrine; Desoxyephedrine; Development; Drugs; Dysfunction; Encephalon; Encephalon Diseases; Encephalons; Fostering; Functional disorder; Funding; Future; Goals; Grant; Grant Proposals; Grants, Applications; HIV; HTLV-III; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human, Child; Individual; Institution; Intracranial CNS Disorders; Intracranial Central Nervous System Disorders; Investigators; LAV-HTLV-III; Lead; Lymphadenopathy-Associated Virus; MR Imaging; MR Tomography; MRI; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Marihuana; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medical center; Medication; Methamphetamine; Methods; Methods and Techniques; Methods, Other; Methylamphetamine; N-Methylamphetamine; NIH; NMR Imaging; NMR Tomography; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Nuclear Magnetic Resonance Imaging; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiopathology; Pilot Projects; Programs (PT); Programs [Publication Type]; Protocol; Protocols documentation; R01 Mechanism; R01 Program; RPG; Research; Research Activity; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Research Resources; Researchers; Resources; Senescence; Source; Substance abuse problem; Techniques; Training; Training of Investigators; Translational Research; Translational Research Enterprise; Translational Science; United States National Institutes of Health; Virus-HIV; Visit; Zeugmatography; abuse of substances; base; brain damage; brain lesion (from injury); children; design; designing; drug/agent; heavy metal Pb; heavy metal lead; image processing; improved; interdisciplinary collaboration; interest; investigator training; juvenile; juvenile human; new technology; normal aging; pathophysiology; pilot study; programs; senescent; substance abuse; translation research enterprise; youngster

DESCRIPTION (provided by applicant): This application is submitted by a group of investigators at 9 sites distributed throughout the U.S. where there are active developmental research programs involving substantial numbers of typically developing children, and neuroimaging investigators with experience in multi-site imaging initiatives. We propose to join forces to leverage these ongoing pediatric studies to assemble, over a period of 2 years, a large, cross- sectional imaging-genomics dataset to be used as a shared resource. The major aim of our proposal is to create a database that will include genome-wide association results for a large number of neural architectural phenotypes obtained using multimodal structural imaging. We propose to offer this database - essentially a map depicting the genomic landscape of the developing human brain - as a resource to the scientific community. Across the sites, investigators will administer the brief NIH Neuroscience Blueprint Toolbox Cognitive assessment;acquire standardized structural and diffusion images, and collect DNA samples in 1575 children and adolescents who are participants in their ongoing studies. The DNA samples will be shipped to a central Genetics Core for analysis, the imaging data will be uploaded for quality control and computational morphometry by the Imaging Core, and other data will be uploaded to the Coordinating Core, where an aggregate database of demographic, behavioral, imaging, and genomics deliverables will be compiled from 1400 individuals and maintained for shared access. A large, cross-sectional pediatric dataset would fill a significant gap that currently prevents description of gene and gene-by-age effects on neural architecture in children (i.e., main effects of genetic variation and gene effects on developmental trajectories) that are likely to be relevant to variability in behavioral and neuropsychiatric outcomes. Preliminary results of analyses of large adult cohorts suggest that common genetic variation accounts for substantial variability in brain morphology. The age-span of participants in these studies has made it possible to detect gene-by-age interactions relevant to variability in brain aging. Unfortunately because there are no well-powered studies with data from individuals spanning the childhood and adolescent age range, it is not known whether these neural phenotypes are present in children;and if they are, whether they can be observed early in development or evolve as ongoing remodeling of neural structures proceeds during childhood. This project would address the discrepancy between currently available imaging-genetics data in children of different ages and those available in adults. In addition to providing an informative data resource, the project would create a collaborative hub of investigators prepared to participate in an imaging- genomics adjunct study of the National Children's Study, which is in the early planning stages at this time. PUBLIC HEALTH RELEVANCE: The aim of this project is to assemble, over a period of 2 years, a large, cross-sectional imaging-genomics dataset to be used as a shared resource for investigations of genetic bases of neural phenotypes and age-by- genotype interactions that may represent genetically-mediated differences in developmental trajectories.

DESCRIPTION (provided by applicant): This application is submitted in response to PAR-09-011 Diversity-promoting Institutions Drug Abuse Research Program (DIDARP) requested by the National Institute on Drug Abuse (NIDA). This proposed research program is timely since it focuses on two ofthe major health disparity issues in Hawaii, namely, methamphetamine abuse and HIV infection. Recent surveys indicate that Native Hawaiians or other Pacific islanders have the highest rate of methamphetamine use among persons aged 12 or older in the United States. Although HIV/AIDS infection rate is relatively low in Hawaii compared to other major metropolis, the rates are increasing among Hawaiians. This DIDARP will include two primary and one pilot research projects that will focus on mechanisms and factors that might enhance neurotoxicity associated with methamphetamine of HIV. We aim to enhance the capacity for drug abuse research at UH by creating this small translational research team. This group will take advantage and build on the expertise of the few but outstanding existing clinical drug abuse and HIV researchers and basic scientists. We aim to enable UH to develop a strong clinical and translational drug abuse research program. To complement these projects, we additionally propose training and career development activities that wil offer exciting opportunities for DIDARP investigators and others at UH through the Administrative and Training Core. The Faculty in the Core will provide guidance and mentorship for these junior faculty and graduate students, through infrastructure support, educational courses, seminars, and a dedicated DIDARP website, We have obtained institutional support for two additional graduate students for the program. We also have recruited 4 distinguished External Advisory Committee members with expertise related to the proposed research; each has enthusiastically agreed to provide their advice and letter of support for the development of this DIDARP at UH. PUBLIC HEALTH RELEVANCE (See instructions); The current proposal attempts to strengthen drug abuse and HIV research capacity by developing translational research teams at the University of Hawaii, and to train junior investigators and students in drug abuse and HIV research.

DESCRIPTION (provided by applicant): Despite the wide availability of potent antiretroviral therapy, up to 50% of HIV-infected individuals continue to demonstrate milder forms of HIV-associated neurocognitive disorders (HAND). With the increasing aging population of HIV-infected patients who are at greater risk for developing HAND, the cost of care may nearly double in the next two decades. Co-morbid issues such as alcohol, marijuana or psychostimulant abuse, which occur at much higher prevalence amongst HIV patients, can further exacerbate their cognitive deficits. Since effective treatment and preventions for HAND are still lacking, developing effective treatments or adjunctive therapy for these patients are critical. Working memory (WM) and attention deficits are common and may underlie cognitive deficits that lead to HAND. Therefore, we propose to evaluate the efficacy of an adaptive WM computer based training program called Cogmed. Effectiveness of adaptive WM training was shown in children with attention deficit and hyperactivity disorder (ADHD), and in adults with other neurological disorders, but has not been evaluated in HIV-positive subjects. WM deficits also may be related to neuroinflammation, frontal lobe dysfunction or decreased dopaminergic function. Therefore, the aims of this proposal are: 1) To perform a double blind placebo-controlled study using Cogmed to determine whether the intensive adaptive WM training will lead to greater improvement (gain) on WM and other cognitive functions (transfer of gain) in HIV-infected individuals and in HIV-seronegative (SN) controls than fixed low level (placebo) training, at one-month and at six months after training (maintenance of gain). 2) To assess the neural correlates of WM training: Whether brain activation will improve, at 1-month and 6-months after the training, on BOLD-fMRI during WM and attention. 3) Since individuals with the AA genotype for the SNP (rs4657412) for LMX1A showed greater magnitudes of training-related gains in verbal WM in a prior study, we will assess our subjects for this allelic variation on thei training effects (gain and maintenance). Lastly, we will assess changes in neuroinflammatory markers and monoamine metabolites in the CSF of those who consent to lumbar punctures before and 6 months after training, and evaluate the relationships between these CSF makers, cognitive performance and training effects, as well as brain activation fMRI. Although Cogmed is not a cure for HAND, this research project may identify a new and effective adjunctive therapy to improve cognitive function and hence these patients' activities of daily living and functioning. Our genetic study may identify individuals who might benefit the most from the WM training, and therefore help to guide future treatment plans for HIV-infected individuals. Finally, we will also learn how brain activation, neuroinflammation and CSF monoamine levels might relate to WM function before and after the training.

? DESCRIPTION (provided by applicant): This cooperative agreement (U01) application responds to NIH RFA-DA-15-015, Adolescent Brain Cognitive Development (ABCD) study. The University of Hawaii (UH) is #2 of 9 Research Sites of the Prospective Research in Studies of Maturation (PRISM) Consortium. The Consortium's objective is to establish a national, multisite, longitudinal cohort to prospectively examine the neurodevelopmental and behavioral effects of substance use (SU) from early adolescence through the period of risk for SU and SU disorders. This 10-year longitudinal study of 11,000 children will measure brain development, SU, cognition, emotion, executive function, mental health, physical health, environment, and collect biospecimens for future genetic and epigenetic studies. The Consortium has an optimized research protocol and 4 specific aims: 1) Using advanced multi-modal neuroimaging to evaluate premorbid factors and the impact associated with diverse patterns of SU on structure and function of the developing brain. 2) Disentangle the predictors and consequences of diverse patterns of SU on physical health, psychosocial and cognitive development, academic achievement, motivation and emotional regulation. 3) Examine how the quantity and combination of substances used affect the expression of psychopathology and, conversely, how the emergence of psychopathology influences SU. 4) Assess how each substance used contributes to the use of other substances (gateway interactions). To further evaluate neurochemical and neurophysiological changes in these youth, we will additionally perform 1H MR spectroscopy (MRS), perfusion MRI (using arterial spin labeling or ASL), and quantitative susceptibility mapping (QSM), in approximately half of our volunteers, in collaboration with PRISM sites at Penn, UCLA, Utah, Hawaii, JHU, and Baylor. We are proposing a multi-PI leadership approach for our site. The PIs have complementary and inter- disciplinary expertise that encompasses all areas required to manage this comprehensive project. We have expertise in SUD research, clinical assessments, subject sampling and recruitment, and MR methodology. Additional unique qualifications of our site are: 1) we have access to a racially diverse population (including Native Hawaiians and Pacific Islanders) that is disproportionately affected by SUD, 2) we have a strong track record of MR research in SUD and at risk populations, such as adolescents, and 3) we have participated in and led several multi-center research studies that involve complex multi-modal MR outcome measures and subject assessments. Therefore, we have all the necessary resources, experience and expertise to conduct the proposed research, and our effort will complement that of other outstanding research sites to collectively achieve the overall goals of the PRISM Consortium.

? DESCRIPTION (provided by applicant): Body fatness contributes to a substantial proportion of the premature deaths in the U.S., including 15-20% of cancer mortality. The impact is greater among ethnic minorities because they tend to accumulate more visceral fat that bears a higher metabolic risk. The unabated obesity epidemic and lack of sustainable weight control interventions may improve if we understand obesity better as a brain disease and a dysregulation of the brain-gut-adiposity axis. The brain is long known to regulate energy homeostasis based on fuel availability signals originating from the gut and adipose tissue but appears to be altered structurally and metabolically in obesity, which may perpetuate the positive energy balance. Obesity has been associated with a smaller brain volume, deleterious neurochemical imbalance, and cognitive impairment. Obesity-prone eating behaviors and anabolic dietary composition have been similarly associated with brain alterations. Also, the colonic microbiota has recently been shown to be associated with brain chemistry, anxiety behaviors and adiposity. Leveraging recent advances in brain and body composition imaging and in molecular technology, we propose to investigate the brain-gut-adiposity axis for novel inter-relationships across brain imaging characteristics, gut microbial profiles and visceral fat content. We will add a brain MRI study to an ongoing Program Project grant, where we are assessing visceral and hepatic fat with whole-body DXA and abdominal MRI in 2,000 women and men of five ethnic groups from the Multiethnic Cohort Study to examine the relationship of visceral/liver fat to gut microbiota phylogeny based on 16S rRNA gene sequencing and to habitual dietary intakes using eating behavior and food frequency questionnaires. We will conduct brain MR imaging (MRI) and proton MR spectroscopy (1H MRS) to assess brain imaging characteristics (macro- and micro-structural morphology, neurometabolite levels) in a subgroup of 100 program project participants from three ethnic groups (Japanese American, Native Hawaiian, white) in Hawaii. Our specific aims are to determine the association of these structural and neurochemical brain traits with (1) visceral and hepatic fat content, (2) eating behaviors and dietary composition, and (3) gut microbial community profiles. We hypothesize that lower total and regional brain volumes, higher levels of glial metabolite myoinositol, indicative of inflammation, and lower neuronal metabolite N-acetylaspartate will be associated with greater amounts of visceral and liver fat, a higher tendency for obesity-prone eating behaviors (external, emotional, routinely restrained eating) and anabolic dietary composition (high in refined carbohydrates, saturated fat), and altered and less diverse gut microbial profiles Cognitive functions will be assessed with the NIH Toolbox and correlated to brain MRI, dietary intake, and gut bacteria measurements. This innovative line of research has a great potential to lead to more effective and better targeted obesity intervention strategies.

This R21 application responds to RFA-MH-18-611 ?Altered neuronal circuits, receptors and networks in HIV-induced Central Nervous System (CNS) dysfunction (R21)?. Despite effective viral suppression from combined antiretroviral therapy, up to 50% of the patients continue to have HIV-associated neurocognitive disorders (HAND). The cognitive deficits or impairment in HIV patients may be due to legacy effects from early stages of the infection, residual viral reservoirs with ongoing neuroinflammation, and potential neurotoxicity from some of the antiretroviral medications. Furthermore, co-morbid disorders associated with the aging HIV+ population, the high prevalence of substance use, and host characteristics, may further increase the risk and exacerbate the severity of HAND. Optimal care for patients with HAND requires efficient and appropriate diagnosis that can guide effective treatments. However, the current diagnostic approach for HAND requires lengthy and specialized cognitive tests and involves subjective components. Our overall goal is to develop an unsupervised machine learning (ML) algorithm to assess brain pathology, using objective measures such as alterations in structural connectivity on DTI, augmented with other neuroimaging and clinical variables. Ultimately, this may lead to a robust approach to classify subtypes and to quantify brain injury in HIV-infected individuals. This exploratory project has three specific aims (SA): SA1: Employ an automated unsupervised ML algorithm to detect subgroups of HIV-infected subjects, based solely on DTI tractography (structural connectivity). SA2: Add objective demographic, genetic, clinical, and non-DTI MR variables to the training DTI tractography data set, and determine their effects on predicting HAND and cognitive performance. SA3: Evaluate the optimized model for stability to undersampling, and determine whether it can be generalized to other data sets, including those from multi-center studies (i.e. Multicenter AIDS Cohort Study). Our optimized ML model has the potential to provide efficient, objective and reproducible biomarkers to identify individuals with or at risk for HAND, to guide prevention and treatment for HAND, and thereby ameliorate the burden of HIV infection and dementias.

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA-DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, with 607 being followed in Baltimore, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child's changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.

Project Summary: This DP1 application responds to PAR-20-221 ?NIDA Avant-Garde Award Program for HIV/AIDS and Substance Use Disorder Research?. The PI, Linda Chang, proposes to tackle a major challenge in the treatment or cure for HIV, namely, the inability of current treatment regimens to eradicate the viral reservoirs, especially those that are protected by the blood brain barrier (BBB) in the central nervous system (CNS). HIV-infected persons who have substance use disorders (SUDs) often have even higher viral loads and suffer from greater severity of HIV- associated neurocognitive disorders (HAND). She proposes to use the emerging technology of MR-guided focused ultrasound (MRgFUS) to safely and transiently open the BBB in order to maximize the delivery of long-acting slow release antiretroviral therapy (LASER ART), and to provide targeted delivery of CRISPR-Cas9 to eliminate the integrated HIV proviral DNA in the CNS viral reservoirs. The combined approach of LASER ART, followed by AAV-CRISPR-Cas9 has shown early successes in subgroups of rodent models, but further optimal delivery of these agents to the CNS is needed. First, HIV-humanized rodent models will be used to demonstrate markedly improved delivery of these agents into the CNS, and the efficacy of eliminating the virus without rebounds. Furthermore, since the same FUS energy and pulse patterns used for BBB opening can also induce neurogenesis and activate microglia, these secondary effects will be evaluated as well. Lastly, due to compelling early preclinical findings with neuromodulation by others, low-intensity MRgFUS as a potential treatment for addiction will also be explored in drug self-administration rodent models. The PI has assembled an outstanding team of collaborators who are experts in each of the techniques and approaches required to ensure the success of the proposed research. Furthermore, since MRgFUS, at higher intensities, is currently being used in the clinical settings to successfully treat patients with essential tremors or Parkinson?s disease, and at different parameters (e.g., pulsed high intensity, low intensity, etc.) and hardware configurations in clinical trials of other neurological disorders, the proposed research has a high potential for clinical translation. Given the available resources and expertise at the University of Maryland, pilot clinical trials may start in years 3-5. In summary, the proposed research to use MRgFUS to maximize the delivery of HIV elimination agents may ultimately eradicate the HIV viral reservoirs, especially those in the CNS, and halt the progression or prevent the development of HAND, particularly for those with SUDs.