Aging, Polypharmacy and Neurotoxicity in Adults Living with HIV

摘要 中枢神经系统(CNS)并发症在成年艾滋病毒携带者中继续发生。例如, 30%-50%的艾滋病毒感染者(PWH)会出现神经认知障碍。随着年龄的增长，认知能力和 情绪障碍，如抑郁症，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 关于中枢神经系统衰老的生物学机制(例如，淀粉样蛋白相关的病理)，很少有研究 专注于衰老和处方，潜在的神经毒性药物影响艾滋病毒和抗逆转录病毒的效果 认知和抑郁的治疗(ART)。抗逆转录病毒药物和处方药对老年人的神经毒性研究 PWH在很大程度上受到样本量小、神经认知特征不佳以及相对 短期的跟踪调查。这项提案将通过使用近20,000份数据和样本来解决这些限制 20多年来收集的全面医学和神经行为评估。氯化萘 并发症，如神经认知障碍和严重的抑郁症，是 艾滋病毒与老龄化的多学科研究，以表征艾滋病毒与老龄化之间的相互作用 疾病及其治疗，并深入了解这些并发症的发病机制，可能有助于 治疗学。最重要的假设是，处方药相关的神经毒性越来越大。 随着年龄的增长，PWH患者中枢神经系统并发症的发生率和持久性。为解决这一问题，拟议的 该项目组织为三个目标：1)确定年龄和伴随开出的药物如何改变 应用纵向数据库研究抗逆转录病毒药物与神经认知功能或抑郁的关系 20,000多项综合评估和先进的分析方法；2)确定年龄和 同时开出的药物改变了ART药物与NC表现之间的量效关系 使用基于生理的药代动力学模型研究抑郁症；以及3)通过 哪些伴随药物使用一种新的高通量、可诱导的人类多能性来改变ART神经毒性 干细胞培养方法和胞外囊泡特性。这项提案的完成将提供 关于衰老如何与处方药相互作用增加ART神经毒性和中枢神经系统风险的宝贵数据 并发症。这一结果也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参考 威尔斯亲王医院。

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.