Aging, Polypharmacy and Neurotoxicity in Adults Living with HIV

摘要 中枢神经系统（CNS）并发症继续发生在成年艾滋病毒感染者中。比如说， 30-50%的HIV感染者（PWH）会出现神经认知障碍。随着年龄的增长，认知和 情绪障碍如抑郁症的频率和严重程度增加。虽然迄今为止的研究集中在 关于与CNS老化相关的生物学机制（例如，淀粉样蛋白相关病理学），很少有研究 关注老龄化，并开出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 认知和抑郁症的ART治疗。老年人抗逆转录病毒药物和处方药物的神经毒性研究 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 短的后续行动。该提案将通过使用近20，000份的数据和标本来解决这些限制 20多年来收集的全面医学和神经行为评估。CNS 并发症，如神经认知障碍和严重抑郁症，是一个关键领域， 艾滋病毒和老龄化的多学科研究，以表征艾滋病毒，共病， 疾病及其治疗，并深入了解这些并发症的发病机制， 治疗学总体假设是，处方药物相关的神经毒性越来越多地有助于 随着年龄的增长，威尔斯亲王医院中枢神经系统并发症的发生率和持续时间。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如何改变 使用纵向数据库研究ART药物与神经认知能力或抑郁症之间的关系 2万多项综合评估和先进的分析方法; 2）确定年龄和 伴随处方的药物改变了ART药物和NC性能之间的剂量-效应关系 和抑郁症使用生理学为基础的药代动力学模型;和3）探索机制， 哪些伴随药物使用新型高通量、诱导型人类多能药物来改变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物相互作用以增加ART神经毒性和CNS风险的有价值数据 并发症这些结果也可能为将来预防和治疗老年人CNS并发症的干预提供信息。 PWH。

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.