In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living with HIV.

项目摘要 在美国，老年艾滋病毒感染者（PWH）是一个迅速扩大的群体， 抑郁症和认知障碍，尽管病毒学抑制。虽然重度抑郁症是一种 生活质量下降的关键因素，目前影响20-40%的PWH，没有有效的 诊断和有限的治疗，以预测疾病和降低发病率的PWH抗逆转录病毒治疗。 随着越来越多的艾滋病毒诊所提供者照顾艾滋病毒感染者的老龄化人口，我们认识到需要提供 诊断，以评估临床环境和介入研究中的神经病理学。我们还认识到 在开始有效的抗抑郁药物之前，需要考虑老年艾滋病病毒感染者特有的抑郁亚型 治疗磁共振成像（MRI）技术的最新进展允许低磁场 强度成像（LF-MRI）的成本是传统高场MRI的十分之一，并且可以在 磁共振室的受控访问环境这将使便携式LF- MRI成为 神经病学诊所和神经精神病学临床试验设计中的诊断工具的临床剧目 疾病评估该床旁神经成像工具的诊断性能， 抑郁症和认知功能障碍在接受抗逆转录病毒治疗的老年威尔斯亲王医院队列中至关重要。在 母公司R 01（MH 131194）、PI（Shibani Mukerji博士）和研究团队详细介绍了评价 与神经活性类固醇有关的抑郁症的生物亚型， 艾滋病毒抗逆转录病毒治疗。这项研究是一项随机、安慰剂对照的临床试验， 艾滋病毒感染者和抑郁症患者（SOOTHE; NCT 05570812）。在这份行政补充报告中， 团队将重点关注患有抑郁症的老年PWH（55岁及以上），利用SOOTHE基础设施 研究老年PWH常见的抑郁和神经病理学之间的关系（萎缩和 脑小血管疾病）。这些神经影像学标记物在 一项关于无艾滋病毒老年人痴呆症发病率下降的调查。 从该提案中产生的数据将用于扩展SOOTHE模型，以评估 抑郁症适合神经活性类固醇，并确定在试验设计中使用LF-MRI治疗 艾滋病病毒感染者的疗效。

PROJECT SUMMARY Older people with HIV (PWH) in the United States are a rapidly expanding group and are at increased risk for depression and cognitive impairment despite virologic suppression. While major depressive disorder is a critical contributor to reduced quality of life and currently affects 20-40% of PWH, there are no effective diagnostics and limited therapeutics to predict disease and mitigate morbidity in PWH on antiretroviral therapy. As more providers in HIV clinics care for an aging population with HIV, we recognize the need for accessible diagnostics to assess neuropathology in clinical settings and interventional studies. We also recognize the need to consider depression subtypes unique to older people with HIV before initiating effective antidepression therapies. Recent advances in magnetic resonance imaging (MRI) technology allow for low magnetic field strength imaging (LF-MRI) at 1/10th the cost of conventional, high-field MRI, and can be performed outside of the controlled access environments of an MRI suite. This will enable portable LF- MRI to become part of a clinical repertoire of diagnostic tools in neurology clinics and in clinical trial design for neuropsychiatric diseases. Assessing the diagnostic performance of this point-of-care neuroimaging tool for evaluating depression and cognitive impairment in cohorts of older PWH on antiretroviral therapy is critically important. In the parent R01 (MH131194), the PI (Dr. Shibani Mukerji) and research team detailed methods for evaluating a biological subtype of depression related to neuroactive steroids, a cholesterol-derived hormone in people with HIV on antiretroviral therapy. The study is a randomized, placebo-controlled clinical trial of pregnenolone in people with HIV and depression (SOOTHE; NCT05570812). In this administrative supplement, the research team will focus on older PWH (age 55 years and over) with depression, leveraging the SOOTHE infrastructure to investigate the relationship between depression and neuropathology common to older PWH (atrophy and cerebral small vessel disease) using portable LF-MRI. These neuroimaging markers are actively under investigation for age-associated dementia decline in older people without HIV presenting to memory clinics. Data generated from this proposal will be used to expand the SOOTHE model in assessing subtypes of depression amenable to neuroactive steroids and determine the use of LF-MRI in trial design for therapeutic efficacy among people aging with HIV.