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：
10577736
负责人：
Scott L Letendre
金额：
$ 78.34万
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/10577736
关键词：
Address Adult Adverse effects Affect Age Aging Amyloid Anti-Cholinergics Area Astrocytes Benzodiazepines Biological Blood Categories Cell Culture Techniques Central Nervous System Clinical 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 General Population HIV HIV antiretroviral 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 Neurites Neurocognitive Neurocognitive Deficit Neuronal Injury Opioid Participant Pathogenesis Pathology Performance Persons Pharmaceutical Preparations Physiological Physiology Polypharmacy Renal function Research Risk Sample Size Severities Source Specimen System Therapeutic Toxic effect Validation advanced analytics analytical method antiretroviral therapy clinical translation cohort comorbidity drug distribution drug metabolism experimental study extracellular vesicles follow-up human pluripotent stem cell improved induced pluripotent stem cell insight longitudinal analysis longitudinal database multidisciplinary multiple drug use nerve stem cell neuroAIDS neurobehavioral neuroprotection neurotoxic neurotoxicity novel pharmacokinetic model pharmacologic prevent public health relevance sex 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.

抽象的患有艾滋病毒衰老的成年人中，中枢神经系统（CNS）并发症继续发生。例如，神经认知障碍发生在30-50％的HIV患者（PWH）中。随着年龄的发展，认知和情绪障碍（例如抑郁症）的频率和严重程度增加。迄今为止的研究集中关于与CNS衰老相关的生物学机制（例如，淀粉样蛋白相关病理），很少有研究专注于衰老和处方，潜在的神经毒性药物会影响HIV和抗逆转录病毒的作用认知和抑郁症的治疗（艺术）。对年龄较大的艺术药物和处方药的神经毒性的研究 PWH在很大程度上受到了小样本量的限制，次优神经认知的表征和相对随访短。该建议将通过使用近20,000的数据和标本来解决这些限制全面的医学和神经行为评估已有20多年的时间。 CNS 并发症，例如神经认知障碍和严重抑郁症，是艾滋病毒和衰老的多学科研究，以表征艾滋病毒，合并症之间的相互作用疾病及其治疗，并了解可能告知这些并发症的发病机理疗法。总体假设是规定的与药物相关的神经毒性越来越多地贡献随着年龄的增长，CNS并发症的发生率和持久性。为了解决这个问题，提议项目分为三个目标：1）确定年龄和同时处方药如何修改使用纵向数据库的艺术药物与神经认知表现或抑郁症之间的关系超过20,000种综合评估和高级分析方法； 2）确定年龄和同时规定的药物修改了艺术药物与NC性能之间的剂量效应关系使用基于生理的药代动力学建模的抑郁； 3）通过伴随的药物使用新型的高通量，可诱导的人类多能修改ART神经毒性干细胞培养方法和细胞外囊泡表征。该提案的完成将提供关于衰老如何与处方药相互作用以增加艺术神经毒性和CNS的风险的宝贵数据并发症。结果还可能为未来的干预措施提供信息，以预防和治疗较老的中枢神经系统并发症 PWH。