Biopsychosocial Phenotypes and Potential Mechanisms in CHARTER

项目摘要 HIV感染者（PWH）经历了一系列不同的CNS并发症，包括认知和情绪 紊乱CNS并发症甚至可能发生在接受抗逆转录病毒治疗（ART）以抑制 此外，最近的研究表明，HIV感染可能会加速PWH的衰老。然而，在这方面， 加速老化尚未在大脑结构的背景下仔细研究，可能会因 威尔斯亲王医院中枢神经系统并发症的多样性。基于磁共振成像（MRI）的研究显示， 加速生物老化和加速脑萎缩之间的关系。拟议的研究旨在 计算“大脑年龄”，这是一个生物老化的标志，从结构神经成像变量估计， 包括皮质厚度和皮质下体积。据估计，大脑年龄大于 一个人的实际年龄被认为反映了大脑中与年龄相关的变化的积累。到 更好地描述中枢神经系统（CNS）生物型在艾滋病毒感染者（PWH）中的机制， 建议的补充旨在提取来自MRI的皮质厚度和皮质下体积测量 扫描以比较估计的大脑年龄与实际年龄、端粒长度和线粒体DNA拷贝 数字（老化的生物标志物）。该项目通过母提案（R 01 MH 12520- 02），将使用聚类方法来评估PWH中的CNS生物型。补充具体目标1是 使用皮质厚度和皮质下体积的复合测量来估计队列中的脑年龄， 将其与实际年龄和生物衰老的生物标志物进行比较。我们建议使用最小绝对值 收缩和选择算子（LASSO）回归来推导大脑年龄，这是一种与 样本量有限。我们假设PWH患者的大脑皮层会更薄（与大脑年龄的增长一致）， 与威尔斯亲王医院的参照组相比， 认知、情绪和日常功能的评估。补充具体目标2是确定如何大脑 年龄与在父项目中通过机器学习识别的不同CNS生物型以及大脑如何老化有关 与HIV相关神经认知障碍的历史诊断有关。我们将包括与健康有关的 这些变量在模型中作为协变量，因为它们与认知能力下降和大脑年龄增大有关。为 例如，心血管风险因素、高水平的酒精摄入和中风风险评分与 大脑老化我们还假设，估计脑年龄将加速PWH与不利的中枢神经系统 生物型与PWH的参考组相比。解开艾滋病毒对人类的认知和生物学影响 老年人及其与心理健康的关系将通过告知我们的理解来推进艾滋病毒领域 艾滋病毒感染者的心理健康状况。这项拟议的多样性补充将提供 申请人在神经成像，机器学习，端粒和线粒体DNA计数方面接受过重要培训 研究，这将扩大她的研究技能和神经生物学机制的理解。

PROJECT SUMMARY People with HIV (PWH) experience a diverse set of CNS complications including cognitive and mood disorders. CNS complications may occur even in individuals taking antiretroviral therapy (ART) to suppress HIV RNA, moreover, recent studies suggest HIV infection may accelerate aging among PWH. However, accelerated aging has not been carefully examined in the context of brain structure and may be complicated by the diversity in CNS complications among PWH. Studies based on magnetic resonance imaging (MRI) show a relationship between accelerated biological aging and accelerated brain atrophy. The proposed study aims to calculate “brain age”, which is a marker of biological aging estimated from structural neuroimaging variables, including cortical thickness and subcortical volume. Estimated brain age found to be greater than an individual’s chronological age is thought to reflect an accumulation of age-related changes to the brain. To better characterize the mechanisms of central nervous system (CNS) biotypes in people with HIV (PWH), the proposed supplement aims to extract cortical thickness and subcortical volume measures derived from MRI scans to compare estimated brain age to chronological age, telomere length and mitochondrial DNA copy numbers (biological markers of aging). The project is leveraged through the parent proposal (R01MH12520- 02), which will use clustering methods to assess CNS biotypes in PWH. Supplement Specific Aim 1 is to estimate brain age in the cohort using a composite measure of cortical thickness and subcortical volume to compare it to chronological age and biomarkers of biological aging. We propose to use a Least Absolute Shrinkage and Selection Operator (LASSO) regression to derive brain age, a method that works well with limited sample sizes. We hypothesize that cortices will be thinner (consistent with older brain age) among PWH who have adverse CNS biotypes when compared to the reference group of PWH who perform as expected on assessments of cognition, mood, and daily functioning. Supplement Specific Aim 2 is to determine how brain age relates to different CNS biotypes identified by machine learning in the parent project and how brain age relates to historical HIV-Associated Neurocognitive Disorders diagnosis. We will include health-related variables as covariates in the model, since they are associated with cognitive decline and older brain age. For example, cardiovascular risk factors, high levels of alcohol intake, and stroke risk score are associated with brain aging. We also hypothesize that estimated brain age will be accelerated among PWH with adverse CNS biotypes compared to the reference group of PWH. Disentangling the cognitive and biological effects of HIV in older adults and their relation to mental health will advance the HIV field through informing our understanding of mental health conditions among people with HIV. This proposed diversity supplement will provide the applicant with critical training in neuroimaging, machine learning, telomere and mitochondrial DNA count research, which will broaden her research skillset and understanding of neurobiological mechanisms.