An advanced functional MRI study of frontostriatal injury in adults with HIV

成人 HIV 感染者额纹状体损伤的高级功能 MRI 研究

• 批准号: 10450246
• 负责人: Xiong Jiang
• 金额: $ 58.57万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450246
• 关键词: Adult; Affect; African American; Alcohol abuse; Anterior; Attention; Behavior; Behavioral; Behavioral Paradigm; Biological Markers; Brain Diseases; Brain imaging; Brain region; Cognitive; Corpus striatum structure; Cross-Sectional Studies; Data; Development; Diagnosis; Experimental Designs; Foundations; Functional Magnetic Resonance Imaging; Future; Goals; HIV; HIV-associated neurocognitive disorder; High Prevalence; Hippocampus (Brain); Impairment; Individual; Injury; Learning; Link; Literature; Longitudinal Studies; Machine Learning; Magnetic Resonance Imaging; Measures; Mediating; Memory; Meta-Analysis; Modality; Motor; Neurocognitive; Neurocognitive Deficit; Neurons; Pattern; Performance; Play; Prefrontal Cortex; Prevalence; Process; Recording of previous events; Research; Resistance; Role; Severities; Short-Term Memory; Signal Transduction; Structure; Substance abuse problem; Surrogate Markers; Techniques; Testing; Thalamic structure; Therapeutic Effect; Variant; antiretroviral therapy; base; behavior test; cerebral atrophy; cingulate cortex; clinically relevant; cognitive function; cognitive neuroscience; comorbidity; design; effective therapy; executive function; flexibility; improved; innovation; male; mild neurocognitive impairment; mitochondrial dysfunction; nerve injury; neuroAIDS; neuromechanism; novel; pressure; relating to nervous system; success; tool; treatment response; virology

PROJECT SUMMARY/ABSTRACT In the era of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders, or HAND, remains high in people with HIV (PWH); as a result, there is increasing pressure to identify neural targets for effective therapies. However, to develop effective HAND treatments, there is a strong need for the development of sensitive behavioral tests that can quickly screen and effectively identify probable neurocognitive impairment in PWH and biomarkers that can accurately determine HAND status and evaluate therapeutic effects. This 5-year cross-sectional and longitudinal study is theoretically driven and specifically designed to tackle these challenges. Neural injury to the frontostriatal circuits (plus hippocampus, thalamus, and other associated regions) has long been recognized as a key component in HAND; however, the association between frontostriatal injury and HAND status remains to be elucidated. Recent findings suggest that injury to different key regions in the frontostriatal circuits may play differential roles in HAND status: frontal injury is more prevalent in PWH, but striatal injury better predicts HAND status. This suggests that an accurate assessment of neural injury at different frontostriatal regions (plus other key regions such as hippocampus and thalamus) may have the potential to serve as a biomarker to assist with HAND diagnosis and characterization. To test this hypothesis, we will investigate frontostriatal injury in PWH using two behavioral paradigms that are known to involve distinct frontostriatal regions, along with two advanced functional MRI (fMRI) techniques, fMRI- adaptation (fMRI-A) and multivariate pattern analysis (MVPA). Compared to conventional fMRI techniques, fMRI-A and MVPA techniques can better estimate neural tuning/selectivity that can be directly related to behavioral performance. Briefly, we hypothesize that frontostriatal injury – a central component in HAND – is highly prevalent in PWH and can be assessed behaviorally via two behavioral paradigms (Aim 1), and neurally via fMRI-A & MVPA (Aim 2). The integration of behavioral and fMRI data will help to assess the degree of neural injury at different frontostriatal and associated regions, which in turn may serve as a biomarker for HAND status (Aim 3). The probable impact of common comorbidities (e.g., history of substance and alcohol abuse, etc.) will also be investigated. In summary, this proposal is theoretically driven and highly innovative, with a strong promise for future clinically relevant development. The feasibility of the proposed research is supported by a strong foundation in cognitive neuroscience and neuroHIV, strong preliminary data, and an established research team. The success of this proposed project may help to develop sensitive behavioral tests that can effectively detect mild neurocognitive impairment in PWH, and a biomarker that can assist in determining HAND status/severity.

项目总结/摘要 在联合抗逆转录病毒治疗（cART）时代，HIV相关神经认知功能障碍的患病率 艾滋病病毒感染者（PWH）中的HAND仍然很高;因此， 确定有效治疗的神经靶点。然而，为了开发有效的手部治疗方法， 需要开发敏感的行为测试，可以快速筛选和有效识别 PWH中可能的神经认知障碍和可以准确确定HAND状态的生物标志物， 评价治疗效果。这项为期5年的横向和纵向研究是理论驱动的， 专门为应对这些挑战而设计。 额纹状体回路（加上海马、丘脑和其他相关区域）的神经损伤 长期以来一直被认为是HAND的关键组成部分;然而，额纹状体损伤和 HAND状态仍有待阐明。最近的研究结果表明，损伤不同的关键区域，在 额纹状体回路可能在HAND状态中发挥不同的作用：额部损伤在PWH中更普遍，但 纹状体损伤更能预测HAND状态。这表明，准确评估神经损伤， 不同的额纹状体区域（加上其他关键区域，如海马和丘脑）可能具有 作为生物标志物的潜力，以协助HAND诊断和表征。为了验证这一 假设，我们将调查额纹状体损伤PWH使用两种行为范式，是已知的， 涉及不同的额纹状体区域，沿着两种先进的功能性MRI（fMRI）技术，fMRI- 适应（fMRI-A）和多变量模式分析（MVPA）。与传统的功能磁共振成像技术相比， fMRI-A和MVPA技术可以更好地估计神经调谐/选择性，其可以直接与 行为表现简而言之，我们假设额纹状体损伤--HAND的一个中心组成部分--是 在PWH中非常普遍，可以通过两种行为模式进行行为评估（目标1），以及 通过fMRI-A和MVPA进行神经学研究（Aim 2）。行为和功能磁共振成像数据的整合将有助于评估 不同额纹状体和相关区域的神经损伤程度，这反过来又可以作为一个 HAND状态的生物标志物（目的3）。常见合并症的可能影响（例如，物质史 酗酒等）。也将被调查。 综上所述，该建议是理论驱动和高度创新的，具有很强的前景，为未来的临床 相关发展。所提出的研究的可行性是由一个强大的认知基础的支持 神经科学和神经艾滋病病毒，强大的初步数据和一个成熟的研究团队。的成功 一个拟议的项目可能有助于开发敏感的行为测试，可以有效地检测轻度神经认知障碍。 PWH的损伤，以及可以帮助确定HAND状态/严重程度的生物标志物。