Neurofunctional Mechanisms of Changes in Cognition and Motor Function in Aging with HIV and Parkinson's Disease

项目摘要/摘要 自通过抗逆转录病毒疗法成功治疗人类免疫缺陷病毒(HIV)以来 (ART)，感染艾滋病毒的人现在寿命更长，据估计，在美国，超过一半的人 艾滋病毒感染者和加利福尼亚州67%的艾滋病毒携带者(PLWH)年龄在50岁以上。 由于美国艾滋病毒感染人口的这一重大人口结构变化，正如PA-20-149所概述的那样，在那里 迫切需要更好地定义神经并发症的潜在病理生理学和 老龄化的艾滋病毒感染人群的神经认知能力下降。尽管接受了ART治疗，但与艾滋病毒相关的 神经认知障碍(手)在缺陷的模式和严重程度上具有高度的异质性，尤其是 在接受现代艺术养生的老年人中。我们的研究指出，神经成像生物标志物可能是 有助于识别诊断特征和了解中枢神经系统疾病与 行为表现，这需要通过纵向研究来跟进。精神发育迟缓是 提示在其他认知领域表现较差，由基底节-边缘脑通路介导 妥协，并与运动迟缓有关，运动迟缓是帕金森病年龄相关性神经变性的主要症状 疾病(PD)。运动迟缓发生在伴有更严重认知障碍的PLWH中，可能是 疾病的发展涉及到更广泛的大脑网络。我们对功能磁共振波幅的新应用 低频波动(ALF)提示老年人皮质下环路神经动力学紊乱 PLWH，与PD8的病理生理学有一定的重叠。我们的研究指向个体间的预测因素 与过去HIV严重程度(最低的CD4，艾滋病)、当前的CD4计数、年龄较大、饮酒有关的损害特征的变化 和物质使用，以及睡眠质量作为弹性的衡量标准。在这里，我们扩展了这项工作，以直接响应 PA-20-149，旨在利用NIMH的研究领域纵向研究神经认知特征 评估认知和运动神经影像生物标记物的标准(RDoC)框架 抗逆转录病毒治疗的老年PLWH的缺陷。我们将重点放在迟缓和迟缓运动在这一发现中的作用。 通过跟踪我们已建立的研究队列和新的研究，对中枢神经系统疾病进展的神经成像生物标志物进行研究 老年PLWH、帕金森氏病(PD)和年龄匹配的健康对照组(HC)的新兵。 这项建议的具体目的是 目的1：使用基于领域的方法确定认知恶化的神经成像生物标记物。 目的2：确定亚临床帕金森病在PLWH后期损害中的作用，以及与帕金森病的相似性。 目的3：寻找PLWH疾病进展的可改变的危险因素和调节因素。

PROJECT SUMMARY/ABSTRACT Since the introduction of successful treatment for human immunodeficiency virus (HIV) via antiretroviral therapy (ART), individuals infected with HIV are now living longer with estimates that in the United States over half of all HIV infected individuals and in California 67 percent of people living with HIV (PLWH) are over the age of 50. Due to this major demographic shift in the HIV-infected population in the US, and as outlined in PA-20-149, there is an urgent need to better define the underlying pathophysiology of neurological complications and neurocognitive decline in the aging HIV-infected populations. Despite ART treatment, HIV-associated neurocognitive disorders (HAND) occur with high heterogeneity in the pattern and severity of deficits, particularly in people aging on modern ART regimens. Our research points to neuroimaging biomarkers that could be of advantage for identifying diagnostic signatures and understanding the heterogeneity of CNS disease in relation to behavioral manifestations, that would need to be followed up with longitudinal research. Bradyphrenia was indicative of worse performance in other cognitive domains, mediated by basal ganglia-limbic brain pathway compromise, and related to bradykinesia, a main symptom in age-related neurodegeneration in Parkinson's disease (PD). Bradykinesia occurred in PLWH with more severe cognitive impairment and could be a sign of disease progression involving more widespread brain networks. Our novel application of fMRI-derived amplitudes of low frequency fluctuations (ALFF) indicated disrupted neurodynamics in subcortico-cortical circuits in older PLWH, with some overlap with the pathophysiology in PD8. Our research points to predictors of the interindividual variation in impairment profiles related to past HIV severity (nadir CD4, AIDS), current CD4 count, older age, alcohol and substance use, and sleep quality as a measure of resilience. Here, we extend this work in direct response to PA-20-149, aiming to longitudinally investigate the neurocognitive profile using the NIMH's Research Domain Criteria (RDoC) framework to evaluate previously identified neuroimaging biomarkers of cognitive and motor deficits in aviremic older PLWH on ART. We focus on the role of bradyphrenia and bradykinesia for the discovery of neuroimaging biomarkers for CNS disease progression by following our established study cohorts and new recruits of older PLWH, Parkinson's disease (PD), and age-matched healthy controls (HC). The specific aims of this proposal are to Aim 1: Identify neuroimaging biomarkers for worsening in cognition using a domain-based approach. Aim 2: Determine the role of subclinical parkinsonism for later impairment in PLWH, and similarities to PD. Aim 3: Seek modifiable risk factors and moderators for disease progression in PLWH.