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Aging, Polypharmacy and Neurotoxicity in Adults Living with HIV

成人艾滋病毒感染者的衰老、多药治疗和神经毒性

基本信息

批准号：
10013739
负责人：
Scott L Letendre
金额：
$ 82.23万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10013739
关键词：
Address Adult Affect Age Aging Amyloid Anti-Cholinergics Area Astrocytes Benzodiazepines Biological Blood Categories Cell Culture Techniques Clinical Treatment Clonazepam Coculture Techniques Cognition Cognition Disorders Cognitive Data Data Analyses Data Sources Databases Disease Dose Drug Combinations Drug Kinetics Drug Prescriptions Drug usage Early Intervention Early treatment Elderly Frequencies Future HIV HIV antiretroviral HIV therapy Human Incidence Intervention Knowledge Major Depressive Disorder Masks Measures Medical Mental Depression Mental Health Methods Mitochondria Modeling Molecular Mood Disorders Moods National NeuroAids Tissue Consortium Neuraxis Neurites Neurocognitive Neurocognitive Deficit Neuronal Injury Neurons Opioid Participant Pathogenesis Pathology Performance Persons Pharmaceutical Preparations Pharmacology Physiological Physiology Pluripotent Stem Cells Polypharmacy Renal function Research Risk Sample Size Severities Source Specimen System Therapeutic Time Toxic effect Validation advanced analytics analytical method antiretroviral therapy base clinical translation cohort comorbidity drug distribution drug metabolism experimental study extracellular vesicles follow-up human pluripotent stem cell improved insight longitudinal database multidisciplinary multiple drug use neuroAIDS neurobehavioral neurotoxic neurotoxicity novel pharmacokinetic model prevent public health relevance sex therapy adverse effect treatment optimization

项目摘要

ABSTRACT Central nervous system (CNS) complications continue to occur among adults aging with HIV. For example, neurocognitive impairment occurs in 30-50% of persons with HIV (PWH). With advancing age, cognitive and mood disorders such as depression increase in frequency and in severity. While research to date has focused on the biological mechanisms associated with the aging of the CNS (e.g., amyloid-related pathology), few studies have focused on aging and prescribed, potentially neurotoxic drugs influence the effects of HIV and antiretroviral therapy (ART) on cognition and depression. Studies of neurotoxicity of ART drugs and prescribed drugs in older PWH have largely been limited by small sample sizes, suboptimal neurocognitive characterization, and relatively short follow-up. This proposal will address these limitations by using data and specimens from nearly 20,000 comprehensive medical and neurobehavioral assessments collected over more than 20 years. CNS complications, such as neurocognitive impairment and major depression disorder, are a key area for multidisciplinary studies of HIV and aging in order to characterize the interactions between HIV, comorbid diseases, and their treatment and to gain insights into the pathogenesis of these complications that may inform therapeutics. The overarching hypothesis is that prescribed drug-related neurotoxicity increasingly contributes to the incidence and persistence of CNS complications in PWH as they age. To address this, the proposed project is organized into three aims: 1) Determine how age and concomitantly prescribed drugs modify the relationships between ART drugs and neurocognitive performance or depression using a longitudinal database of more than 20,000 comprehensive assessments and advanced analytical methods; 2) Determine how age and concomitantly prescribed drugs modify the dose-effect relationships between ART drugs and NC performance and depression using physiologically-based pharmacokinetic modeling; and 3) Explore the mechanisms by which concomitant drugs modify ART neurotoxicity using a novel high-throughput, inducible human pluripotent stem cell culture method and extracellular vesicle characterization. The completion of this proposal will provide valuable data on how aging interacts with prescribed drugs to increase the risk of ART neurotoxicity and CNS complications. The results may also inform future interventions to prevent and treat CNS complications in older PWH.

摘要