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.

项目摘要/摘要 由于通过抗逆转录病毒疗法引入了成功治疗人类免疫缺陷病毒（HIV） （艺术），感染艾滋病毒的人现在寿命更长，估计在美国一半以上 艾滋病毒感染的人和加利福尼亚州有67％的艾滋病毒（PLWH）年龄超过50岁。 由于美国感染了艾滋病毒的人群的这种重大人口转变，并在PA-20-149中概述 迫切需要更好地定义神经系统并发症和 衰老的HIV感染人群的神经认知能力下降。尽管有艺术治疗，但与HIV相关 神经认知障碍（手）出现在缺陷的模式和严重程度上，特别是 在现代艺术方案中老化的人。我们的研究指出了可能是神经影像的生物标志物 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。脑脑是 表明其他认知领域的表现较差，由基底神经节limbic脑途径介导 妥协，并且与Bradykinesia有关，Bradykinesia是帕金森氏症年龄相关的神经变性的主要症状 疾病（PD）。 Bradykinesia在PLWH中发生，具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。我们新颖的fmri衍生幅度应用 低频波动（ALFF）表明在较老的亚皮层皮层电路中神经动力学破坏 PLWH，与PD8中的病理生理学重叠。我们的研究指出了个体的预测指标 与过去的HIV严重程度（Nadir CD4，AIDS），当前CD4计数，年龄较大，酒精有关的损伤概况的变化 和药物使用，并睡眠质量作为弹性的衡量。在这里，我们将这项工作直接响应扩展到 PA-20-149，旨在使用NIMH的研究领域纵向研究神经认知谱 标准（RDOC）框架评估先前确定的认知和运动的神经影像生物标志物 Art上的Aviromical PLWH的缺陷。我们专注于脑肌动症和胸肌的作用 通过遵循我们既定的研究队列和新的新的CNS疾病进展生物标志物的神经影像标志物 较老的PLWH，帕金森氏病（PD）和年龄匹配的健康对照（HC）的新兵。 该提议的具体目的是 目标1：确定使用基于域的方法在认知中恶化的神经影像标志物。 AIM 2：确定亚临床帕金森氏症在PLWH中的损害和与PD的相似之处的作用。 AIM 3：寻求可修改的危险因素和调节剂，以了解PLWH中的疾病进展。