Myelin Content and Cognitive Trajectories in Young Adults Living with Virally Suppressed HIV

感染病毒抑制的艾滋病毒的年轻人的髓磷脂含量和认知轨迹

• 批准号: 10759305
• 负责人: Payal Patel
• 金额: $ 65.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759305
• 关键词: Accounting; Address; Adult; Affect; Age; Age Years; Animals; Attenuated; Biological Markers; Blood; Blood Vessels; Brain; Brain Injuries; Cerebrum; Clinical Trials; Cognition; Cognition Disorders; Cognitive; Cross-Sectional Studies; Data; Demyelinations; Development; Diffusion Magnetic Resonance Imaging; Early intervention trials; Educational Status; Etiology; Exclusion; Executive Dysfunction; HIV; HIV Infections; HIV-associated neurocognitive disorder; Health; Image; Imaging Techniques; Impaired cognition; Impairment; Incidence; Individual; Infection; Knowledge; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Mental Health; Methodology; Multiple Sclerosis; Myelin; Myelin Water Imaging; Nervous System Trauma; Neurobehavioral Manifestations; Neurologic; Opportunistic Infections; Outcome; Participant; Pathologic; Pathology; Perinatal; Persons; Phenotype; Plasma; Population; Prevalence; Publishing; Questionnaires; Recording of previous events; Recovery; Research; Risk; Risk Assessment; Risk Factors; Socioeconomic Status; Standardization; Statistical Models; Time; Trauma; Viral; Work; adverse childhood events; age group; antiretroviral therapy; axon injury; biopsychosocial; biopsychosocial factor; cognitive performance; cognitive testing; cohort; comorbidity; daily functioning; executive function; experience; follow-up; high risk; immune activation; improved; in vivo; inflammatory marker; injured; monocyte; myelination; neuroimaging; novel; pharmacologic; pre-exposure prophylaxis; preservation; prospective; remyelination; sex; social health determinants; social stigma; standardize measure; therapeutic target; white matter; white matter change; white matter injury; young adult

Project Summary/Abstract With the introduction of antiretroviral therapy (ART), the prevalence of severe manifestations of HIV-associated neurocognitive disorders has improved over the past few decades. However, in the context of viral suppression, new pressing questions have emerged regarding the etiology of the persistent cognitive sequalae in PLWH on ART. Up to 40% of individuals living with virally suppressed HIV experience cognitive impairment and the mechanisms underlying neurologic injury in these individuals remain poorly understood. A hallmark finding of HIV associated neurocognitive disorder (HAND), white matter injury, has primarily been evaluated indirectly through non-specific markers of myelination on neuroimaging in PLWH or pathologic markers in animal studies. Our team has developed an MRI sequence, myelin water imaging, to directly measure myelin content, a component of white matter, in vivo. We will apply this novel sequence to longitudinally evaluate if reduced myelination rates occur in young adults living with virally suppressed HIV (YLWH) compared to demographic and antiretroviral therapy risk factor matched, HIV-uninfected controls. Additionally, we will evaluate the independent correlation between changes in myelin content and cognitive trajectories, accounting for social determinants of health, to determine if loss of myelin may contribute to the development of cognitive disorders in YLWH. The premise of this application is based on our preliminary data, which demonstrate decreased global and regional myelin content in young adults living with virally suppressed HIV compared to age and sex matched HIV-uninfected controls and that myelin loss mediates the relationship between immune activation and lower domain specific cognitive scores in young adults living with virally suppressed HIV. We will combine our novel imaging methodology assessing myelin content with established imaging techniques, such as diffusion tensor imaging, longitudinally acquired cognitive data and standardized measures of social determinants of health to determine predictors of the latent cognitive phenotypes within our cohort of virally suppressed YLWH using an unbiased statistical modeling approach, group-based trajectory analyses. The information provided by our proposed study will not only improve our understanding of changes in myelin content in YLWH in relation to cognitive outcomes, but also provide the basis for evaluating myelin water imaging as a biomarker to identify PLWH of all ages at risk for cognitive impairment. This work may provide the preliminary data needed to support early intervention trials of myelin preservation or remyelination therapies to improve cognition in a broader population of PLWH.

项目概要/摘要 随着抗逆转录病毒疗法（ART）的引入，艾滋病毒相关的严重症状的流行 神经认知障碍在过去几十年中得到了改善。然而，在病毒式传播的背景下 抑制，关于持续性认知后遗症的病因学出现了新的紧迫问题 在 ART 的 PLWH 中。高达 40% 的 HIV 病毒感染者会出现认知障碍 对于这些个体神经损伤的机制仍知之甚少。一个标志 HIV 相关神经认知障碍 (HAND)、白质损伤的发现已得到初步评估 间接通过 PLWH 神经影像上的髓鞘形成非特异性标志物或 PLWH 中的病理标志物 动物研究。我们的团队开发了一种 MRI 序列——髓磷脂水成像，可以直接测量髓磷脂 含量，体内白质的组成部分。我们将应用这个新颖的序列来纵向评估是否 与相比，感染病毒抑制型艾滋病毒 (YLWH) 的年轻人的髓鞘形成率降低 人口统计学和抗逆转录病毒治疗危险因素匹配，未感染艾滋病毒的对照。此外，我们将 评估髓磷脂含量变化与认知轨迹、会计之间的独立相关性 对于健康的社会决定因素，确定髓鞘质的丧失是否可能有助于认知能力的发展 YLWH 疾病。该应用的前提是基于我们的初步数据，这些数据表明 与相比，感染病毒抑制的艾滋病毒的年轻人的整体和区域髓磷脂含量降低 年龄和性别与未感染艾滋病毒的对照相匹配，髓鞘质损失介导了免疫之间的关系 感染病毒抑制的艾滋病毒的年轻人的激活和较低的特定领域认知得分。我们将 将我们评估髓磷脂含量的新颖成像方法与现有的成像技术相结合，例如 作为扩散张量成像、纵向获取的认知数据和社会的标准化测量 健康的决定因素，以确定我们病毒队列中潜在认知表型的预测因素 使用无偏统计建模方法、基于组的轨迹分析来抑制 YLWH。这 我们拟议的研究提供的信息不仅会提高我们对髓磷脂变化的理解 YLWH 中的含量与认知结果相关，同时也为评估髓磷脂水提供基础 成像作为生物标志物来识别所有年龄段有认知障碍风险的感染者。这项工作可能会提供 支持髓磷脂保存或髓鞘再生疗法的早期干预试验所需的初步数据 提高更广泛的感染者和艾滋病患者的认知能力。