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

HIV 和帕金森病导致的衰老过程中认知和运动功能变化的神经功能机制

• 批准号: 10619383
• 负责人: TILMAN SCHULTE
• 金额: $ 82.5万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619383
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Adherence; Affect; Age; Aging; Alcohol consumption; Alcohols; American; Arousal and Regulatory Systems; Basal Ganglia; Behavioral; Bradykinesia; Brain; Brain imaging; CD4 Lymphocyte Count; California; Central Nervous System; Central Nervous System Diseases; Chronic; Cognition; Cognitive; Cognitive deficits; Cohort Studies; Degradation Pathway; Disease; Disease Progression; Elderly; Ethnic Origin; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; General Population; HIV; HIV Infections; HIV-associated neurocognitive disorder; HIV/AIDS; Health; Heterogeneity; Impaired cognition; Impairment; Individual; Injury; Intervention; Life; Life Expectancy; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Medical; Medicine; Memory; Modernization; Morphology; Motor; Movement; National Institute of Mental Health; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurologic; Neuropsychology; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Pattern; Performance; Peripheral; Persons; Physical activity; Population; Preventive therapy; Process; Public Health; Quality of life; Race; Regimen; Reporting; Research; Research Domain Criteria; Research Personnel; Rest; Risk; Risk Factors; Role; Severities; Sleep; Socioeconomic Status; Substance abuse problem; Symptoms; Telephone; Time; United States; Viral; Viral Load result; Visit; Visuospatial; Work; actigraphy; age related neurodegeneration; aged; antiretroviral therapy; biomarker discovery; body system; brain pathway; burden of illness; diagnostic signature; disability; experience; follow-up; frontal lobe; functional independence; human old age (65+); imaging modality; immunosenescence; indexing; information processing; inter-individual variation; middle age; mild cognitive impairment; modifiable risk; mortality; motor deficit; motor impairment; multidisciplinary; neural; neuroimaging; neuroimaging marker; neuropathology; normal aging; novel; organ injury; predictive marker; processing speed; recruit; regional atrophy; resilience; response; sex; sleep quality; sociodemographic factors; substance use

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.

项目概要/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（HIV）以来 （ART），感染艾滋病毒的人现在寿命更长，据估计，在美国，超过一半的人感染艾滋病毒 HIV 感染者，在加利福尼亚州，67% 的 HIV 感染者 (PLWH) 年龄超过 50 岁。 由于美国 HIV 感染者人口结构发生重大变化，正如 PA-20-149 中所述， 迫切需要更好地定义神经系统并发症的潜在病理生理学 老年艾滋病毒感染者的神经认知能力下降。尽管接受了 ART 治疗，但与 HIV 相关的 神经认知障碍（HAND）的发生方式和缺陷严重程度具有高度异质性，特别是 在接受现代 ART 治疗方案的衰老人群中。我们的研究指出神经影像生物标志物可能是 识别诊断特征和了解中枢神经系统疾病的异质性的优势 行为表现，需要进行纵向研究来跟进。精神迟缓是 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，并与运动迟缓有关，运动迟缓是帕金森病与年龄相关的神经变性的主要症状 疾病（PD）。运动迟缓发生在患有更严重认知障碍的感染者身上，可能是 疾病进展涉及更广泛的大脑网络。我们对 fMRI 衍生振幅的新应用 低频波动（ALFF）表明老年人皮质下皮质回路的神经动力学受到破坏 PLWH，与 PD8 的病理生理学有一些重叠。我们的研究指出了个体间的预测因素 与过去 HIV 严重程度（CD4 最低点、艾滋病）、当前 CD4 计数、年龄、酒精相关的损伤特征的变化 物质使用和睡眠质量作为弹性的衡量标准。在这里，我们将这项工作扩展为直接响应 PA-20-149，旨在利用 NIMH 的研究领域纵向研究神经认知概况 用于评估先前确定的认知和运动神经影像生物标志物的标准 (RDoC) 框架 无病毒血症老年感染者接受 ART 治疗的缺陷。我们重点关注精神迟缓和运动迟缓的作用以进行发现 通过遵循我们既定的研究队列和新的研究，研究中枢神经系统疾病进展的神经影像生物标志物 招募老年 PLWH、帕金森病 (PD) 和年龄匹配的健康对照 (HC)。 该提案的具体目标是 目标 1：使用基于领域的方法识别认知恶化的神经影像生物标志物。 目标 2：确定亚临床帕金森病对 PLWH 后期损伤的作用，以及与帕金森病的相似之处。 目标 3：寻找 PLWH 疾病进展的可改变危险因素和调节因素。