Brain aging and cognitive impairment in persons with HIV

项目总结/摘要 虽然联合抗逆转录病毒疗法提高了艾滋病毒感染者的预期寿命， 至少有30%的人仍然存在这种缺陷。然而，目前还不清楚大脑老化是否是 加速，即PWH是否具有类似于老年未感染（HIV-）对照的神经表型。也是 目前尚不清楚脑结构和功能老化与PWH患者认知功能下降或保留的关系。 为了使申请人能够解决这些问题，本修订提案包括一个培训计划， 在艾滋病毒临床问题和实践，传染病生物学，数据分析， 科学专业发展。该计划包括指导学习，临床跟踪，教学 课程，并与经验丰富的，多学科的辅导团队不断参与。的 申请人的长期目标是更好地表征脑老化中的结构-功能关系， 神经系统感染性疾病，作为独立研究者进行临床相关的神经影像学检查。 在研究策略中，提出了一种多模态MRI方法，将大脑结构和 功能这种方法将集中在两个关键的神经生物标志物：白色物质健康和网络连接。 白色物质完整性将通过弥散加权MRI（DW-MRI）从一大组去识别的 PWH（n=440）和HIV-对照（n=255）。将使用静息状态功能性MRI分析大脑连接 （rs-fMRI）。DW-MRI和rs-fMRI将用于生成大脑预测年龄，这是一个代表 系统性退化或功能障碍。大脑预测的年龄将使用机器学习回归计算 模型，经过训练可以从MRI中预测参与者的年龄。脑年龄差距（BAG），预测的 和实际年龄，将获得所有参与者。 核心假设是大脑老化，包括结构完整性和网络连接的丧失， 在PWH中加速，表现为老年PWH与HIV对照组相比BAG升高。目标1将测试 年龄样白色变性在PWH中增加，而Aim 2将研究网络功能是否正常 连通性下降。由于该人群的两种临床合并症风险升高， 心血管疾病和可能经历的社会经济劣势，这是至关重要的量化 这些因素对大脑衰老的影响。艾滋病毒携带者的衰老是异质性的，许多人表现为 典型的甚至是弹性的认知，因此预测成功的大脑老化的因素也应该被确定，特别是 可变因素探索性目标3将对PWH中脑老化的变异性进行建模，作为临床 变量、人口统计和社会经济因素以及神经心理学表现。 这项研究计划将深入了解艾滋病毒相关的神经认知障碍的起源， 这是一个严重的临床问题，降低了数百万威尔斯亲王医院的生活质量。连同拟议的培训目标， 它将使申请人获得技能和知识的重要性，为一个独立的神经影像学研究的职业生涯。

PROJECT SUMMARY/ABSTRACT While combination antiretroviral therapy has improved life expectancy for persons with HIV (PWH), cognitive impairment persists in at least 30% of this population. However, it remains unclear whether brain aging is accelerated, i.e. whether PWH have neurophenotypes resembling older uninfected (HIV-) controls. It is also unclear how structural and functional brain aging relate to cognitive decline or preservation in PWH. To enable the applicant to address these questions, this revised proposal includes a training plan focused on further education in HIV clinical problems and practices, infectious disease biology, data analytics, and scientific professional development. This plan includes mentored learning, clinical shadowing, didactic coursework, and continuous engagement with an experienced, multi-disciplinary mentorship team. The applicant’s long-term goals are to better characterize structure-function relationships in brain aging and neurological infectious disease as an independent investigator performing clinically relevant neuroimaging. In the Research Strategy, a multimodal MRI approach is proposed, incorporating both brain structure and function. This approach will focus on two key neural biomarkers: white matter health and network connectivity. White matter integrity will be measured with diffusion-weighted MRI (DW-MRI) from a large group of de-identified PWH (n=440) and HIV- controls (n=255). Brain connectivity will be profiled using resting-state functional MRI (rs-fMRI). DW-MRI and rs-fMRI will be used to generate brain-predicted age, a summary metric representing systemic degeneration or dysfunction. Brain-predicted age will be calculated using machine learning regression models, trained to predict participant ages from MRI. Brain-age gap (BAG), the difference between predicted and chronological age, will be obtained for all participants. The central hypothesis is that brain aging, including loss of structural integrity and network connectivity, is accelerated in PWH, represented by elevated BAG among older PWH vs. HIV- controls. Aim 1 will test whether age-like white matter degeneration is increased in PWH, while Aim 2 will investigate whether network functional connectivity is decreased. As this population is at elevated risk for both clinical co-morbidities such as cardiovascular disease and likely to experience socioeconomic disadvantages, it is critical to quantify the contribution of such factors to brain aging. Aging with HIV is heterogenous, and many individuals present with typical or even resilient cognition, so factors predicting successful brain aging should also be identified, especially modifiable factors. Exploratory Aim 3 will model variability in brain aging among PWH as a function of clinical variables, demographic and socioeconomic factors, and neuropsychological performance. This research plan will provide insights into the origins of HIV-associated neurocognitive impairment, a major clinical problem that reduces quality-of-life for millions of PWH. Together with the proposed training goals, it will enable the applicant to obtain skills and knowledge vital for an independent neuroimaging research career.