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

项目摘要/摘要 随着抗逆转录病毒疗法(ART)的引入，艾滋病毒相关严重症状的流行 神经认知障碍在过去几十年里有所改善。然而，在病毒感染的背景下 抑制，关于持续性认知后遗症的病因出现了新的紧迫问题 在公共卫生研究院发表关于艺术的文章。高达40%的病毒抑制艾滋病毒携带者经历认知障碍 而这些个体神经损伤的潜在机制仍然知之甚少。一个标志性的 艾滋病毒相关神经认知障碍(手)的发现，脑白质损伤，已被初步评估 间接通过神经影像上髓鞘形成的非特异性标记物或病理标记物 动物研究。我们的团队已经开发出一种名为髓鞘水成像的核磁共振序列，可以直接测量髓鞘 内容，白质的一种成分，在体内。我们将应用这个新的序列来纵向评估 与病毒抑制的艾滋病毒(YLWH)携带者相比，年轻成年人的髓鞘形成率降低 人口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，我们还将 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，确定髓鞘丢失是否可能有助于认知发展 青少年儿童的精神障碍。这一应用的前提是基于我们的初步数据，这些数据表明 与病毒抑制的艾滋病毒携带者相比，年轻成年人的全局和局部髓鞘含量降低 年龄和性别与未感染艾滋病毒的对照组相匹配，髓鞘丢失在免疫之间的关系中起中介作用 病毒抑制的艾滋病毒携带者年轻成年人的激活和较低的领域特定认知得分。我们会 将我们评估髓鞘含量的新成像方法与现有的成像技术相结合，如 作为扩散张量成像，纵向获取的认知数据和社会行为的标准化测量 确定我们的病毒队列中潜在认知表型的预测因素的健康决定因素 使用无偏统计建模方法抑制YLWH，基于组的轨迹分析。这个 我们提议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依据 成像作为一种生物标记物来识别所有年龄段有认知障碍风险的PLWH。这项工作可能会为 支持髓鞘保存或髓鞘再分化疗法早期干预试验所需的初步数据 改善更广泛的PLWH人群的认知。

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.