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

项目总结/摘要 随着抗逆转录病毒疗法的采用，艾滋病毒相关的严重表现的流行率下降， 神经认知障碍在过去的几十年里得到了改善。然而，在病毒的背景下， 抑制，新的紧迫的问题已经出现了关于病因的持续认知后遗症 高达40%的病毒抑制HIV感染者经历认知障碍 并且这些个体中神经损伤的潜在机制仍然知之甚少。一个标志 HIV相关的神经认知障碍（HAND），即白色物质损伤的发现，已被初步评估 间接地通过PLWH神经影像学上的髓鞘形成的非特异性标志物或PLWH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，直接测量髓磷脂 内容物，一种体内白色物质的成分。我们将应用这种新的序列来纵向评估， 髓鞘形成率降低发生在病毒抑制型HIV（YLWH）感染的年轻人中， 人口统计学和抗逆转录病毒治疗风险因素匹配，HIV未感染的对照。此外，我们将 评估髓鞘含量变化与认知轨迹之间的独立相关性， 对于健康的社会决定因素，以确定髓磷脂的损失是否可能有助于认知功能的发展， YLWH中的疾病。本申请的前提是基于我们的初步数据，这些数据表明 与对照组相比， 年龄和性别匹配的未感染HIV的对照组，髓磷脂丢失介导了免疫功能之间的关系， 激活和较低的领域特异性认知得分与病毒抑制的艾滋病病毒感染的年轻人。我们将 联合收割机将我们评估髓磷脂含量的新成像方法学与已建立的成像技术相结合， 作为弥散张量成像，纵向获得的认知数据和社会行为的标准化测量 健康的决定因素，以确定我们的病毒感染者队列中潜在认知表型的预测因素。 使用无偏的统计建模方法，基于组的轨迹分析抑制YLWH。的 我们所提出的研究提供的信息不仅将提高我们对髓鞘变化的理解， YLWH中的含量与认知结果有关，但也为评估髓鞘水提供了基础 成像作为生物标志物，以识别所有年龄段的PLWH认知障碍风险。这项工作可以提供 支持髓鞘保存或髓鞘再生疗法的早期干预试验所需的初步数据， 改善更广泛PLWH人群的认知能力。

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.