Biopsychosocial Phenotypes and Potential Mechanisms in CHARTER

项目总结 艾滋病毒携带者(PWH)经历一系列不同的中枢神经系统并发症，包括认知和情绪 精神错乱。即使在接受抗逆转录病毒治疗(ART)的个体中也可能发生中枢神经系统并发症 此外，最近的研究表明，艾滋病毒感染可能会加速PWH的衰老。然而， 加速衰老没有在大脑结构的背景下仔细检查，可能会因 PWH患者中枢神经系统并发症的差异性。基于磁共振成像(MRI)的研究表明 加速生物衰老与加速脑萎缩的关系。拟议的研究旨在 计算“脑年龄”，这是根据结构神经成像变量估计的生物老化的标志， 包括皮质厚度和皮质下体积。被发现的估计大脑年龄大于 个人的实际年龄被认为反映了大脑与年龄相关的变化的积累。至 更好地描述艾滋病毒(PWH)患者中枢神经系统(CNS)生物型的机制， 拟议补充内容旨在提取来自磁共振成像的皮质厚度和皮质下体积测量 扫描以将估计的脑年龄与实际年龄、端粒长度和线粒体DNA拷贝进行比较 数字(衰老的生物标志物)。该项目通过父建议书(R01MH12520- 02)，它将使用聚类方法来评估威尔斯亲王医院的中枢神经系统生物型。补充的具体目标1是 使用皮质厚度和皮质下体积的综合测量来估计队列中的大脑年龄 将其与时序年龄和生物衰老的生物标记物进行比较。我们建议使用最小绝对值 收缩和选择运算符(套索)回归计算脑年龄，这是一种与 样本量有限。我们假设PWH患者的大脑皮质会变薄(与大脑年龄的增长一致)。 与PWH参照组相比，谁有不利的CNS生物型，后者在 对认知、情绪和日常功能的评估。补充的具体目标2是确定大脑如何 年龄与机器学习在母项目中识别的不同中枢神经系统生物类型有关，以及大脑年龄是如何 与既往艾滋病毒相关神经认知障碍的诊断有关。我们将包括与健康相关的 变量作为模型中的协变量，因为它们与认知能力下降和大脑老化有关。为 例如，心血管风险因素、高酒精摄入量和中风风险评分与 大脑老化。我们还假设，CNS不良的PWH患者的估计脑年龄将会加快 与PWH参照组的生物学类型进行比较。解开艾滋病毒对人类认知和生物的影响 老年人及其与心理健康的关系将通过告知我们对艾滋病毒的理解来推动艾滋病毒领域的发展 艾滋病病毒携带者的心理健康状况。这项拟议的多样性补充将提供 接受过神经成像、机器学习、端粒和线粒体DNA计数方面重要培训的申请者 研究，这将拓宽她的研究技能和对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.