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

• 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
• 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

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 中枢神经系统（CNS）并发症在感染艾滋病毒的成年人中继续发生。例如， 30-50% 的 HIV 感染者 (PWH) 出现神经认知障碍。随着年龄的增长，认知能力和 抑郁等情绪障碍的频率和严重程度都会增加。虽然迄今为止的研究主要集中在 关于与中枢神经系统衰老相关的生物学机制（例如淀粉样蛋白相关病理学），很少有研究 重点关注衰老问题，并且处方的潜在神经毒性药物会影响艾滋病毒和抗逆转录病毒的作用 认知和抑郁治疗（ART）。 ART 药物和处方药物对老年人的神经毒性研究 PWH 在很大程度上受到小样本量、次优神经认知特征以及相对 简短的后续行动。该提案将通过使用来自近 20,000 个样本的数据和样本来解决这些限制 20 多年来收集的综合医学和神经行为评估。中枢神经系统 神经认知障碍和重度抑郁症等并发症是治疗的关键领域 对艾滋病毒和衰老进行多学科研究，以描述艾滋病毒、合并症之间的相互作用 疾病及其治疗，并深入了解这些并发症的发病机制，这可能会提供信息 疗法。总体假设是，处方药物相关的神经毒性越来越多地导致 随着年龄的增长，PWH 中枢神经系统并发症的发生率和持续性。为了解决这个问题，建议 该项目分为三个目标：1）确定年龄和伴随处方药物如何改变 使用纵向数据库研究 ART 药物与神经认知表现或抑郁症之间的关系 超过20,000项综合评估和先进的分析方法； 2) 确定年龄和 伴随处方药物改变 ART 药物与 NC 表现之间的剂量效应关系 使用基于生理学的药代动力学模型来治疗抑郁症； 3）探索机制 哪些伴随药物使用新型高通量、可诱导的人类多能性来改变 ART 神经毒性 干细胞培养方法和细胞外​​囊泡表征。本提案的完成将提供 关于衰老如何与处方药物相互作用以增加 ART 神经毒性和中枢神经系统风险的宝贵数据 并发症。研究结果还可能为未来预防和治疗老年人中枢神经系统并发症的干预措施提供信息。 王后。