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

项目总结/摘要 自从通过抗逆转录病毒疗法成功治疗人类免疫缺陷病毒以来， (ART)据估计，在美国， 艾滋病毒感染者和加州67%的艾滋病毒感染者（PLWH）年龄超过50岁。 由于美国HIV感染人群的这一重大人口统计学变化，如PA-20-149所述， 迫切需要更好地定义神经系统并发症的潜在病理生理学， 神经认知能力的下降。尽管接受了抗逆转录病毒治疗， 神经认知障碍（HAND）的发生在缺陷的模式和严重程度上具有高度异质性，特别是 在接受现代抗逆转录病毒疗法的老年人中。我们的研究指出了可能的神经成像生物标志物 有利于识别诊断特征和了解CNS疾病的异质性， 行为表现，这将需要后续的纵向研究。智力迟钝是 表明其他认知领域的表现较差，由基底神经节-边缘脑通路介导 妥协，并与运动迟缓，在帕金森氏症的年龄相关的神经退行性病变的主要症状 疾病（PD）。运动迟缓发生在PLWH中，伴有更严重的认知障碍，可能是 疾病进展涉及更广泛的大脑网络。我们的新应用fMRI衍生的振幅 低频波动（ALFF）表明老年人皮质下-皮质回路的神经动力学紊乱， PLWH，与PD 8的病理生理学有一些重叠。我们的研究指出， 与既往HIV严重程度（CD 4最低值、AIDS）、当前CD 4计数、老年、酒精相关的损伤特征变异 以及物质使用和睡眠质量作为恢复力的衡量标准。在这里，我们将这项工作扩展到直接响应 PA-20-149，旨在使用NIMH的研究领域纵向研究神经认知特征 标准（RDoC）框架，以评价先前确定的认知和运动神经影像学生物标志物 无尿症老年PLWH对ART的缺陷。我们重点关注智力迟钝和运动迟缓在这一发现中的作用 CNS疾病进展的神经影像学生物标志物，通过我们建立的研究队列和新的 招募老年PLWH，帕金森病（PD）和年龄匹配的健康对照（HC）。 这项建议的具体目标是 目的1：使用基于领域的方法确定认知恶化的神经影像学生物标志物。 目的2：确定亚临床帕金森综合征在PLWH后期损害中的作用，以及与PD的相似性。 目的3：寻找PLWH疾病进展的可改变的风险因素和调节因子。

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.