Structural Neuroimaging Markers in Primary HIV Infection

描述（由申请人提供）：由于有效的抗逆转录病毒治疗（ART），人类免疫缺陷病毒（HIV）感染患者现在的寿命更长。尽管ART对系统性病毒抑制有效，但高达一半的慢性HIV感染（HIV+）个体将发展为HIV相关的神经认知障碍（HAND）。越来越多的努力集中在了解原发性HIV感染（PHI，定义为HIV传播后的第一年）期间开始的中枢神经系统（CNS）内的早期病理生理变化。目前尚不清楚在PHI期间早期开始ART是否可以降低未来发生HAND的发生率。 为了了解可能影响CNS损伤轨迹的关键早期事件的机制，必须开发早期生物标志物（包括脑脊液（CSF）和神经影像学）。既往的PHI研究主要是横断面研究，主要集中在通过单一方式评估的有限数量的PHI参与者上。我们提出了一项纵向研究，以评估PHI和早期ART对脑结构的影响，该研究将结构神经影像学分析与血液和CSF感染，炎症和神经变性的测量以及临床数据（包括暴露于滥用兴奋剂药物）相结合，以研究在PHI期间开始脑损伤的可能机制。具体而言，本研究将采用结构神经成像方法（扩散张量成像（DTI）和脑容量）来研究CNS中PHI自然史的CNS机制以及在感染早期开始ART的影响。基于我们初步的横断面分析，我们假设结构神经成像（DTI和脑容量）将揭示在ART之前的早期感染期间脑中的进行性损伤，这可能在血清转换后不久开始ART的受试者中停止。使用甲基苯丙胺的受试者可能会增加对HIV相关结构损伤的脆弱性，这与大脑中的炎症有关。这项建议将：（目的1）通过将结构成像异常的出现与实验室生物标志物和神经心理学表现在时间上相关联来研究ART之前PHI中CNS损伤的机制。此外（目的2），我们将探讨早期ART的CNS效应的机制，通过评估白色物质的完整性和脑容量随着时间的推移，在受试者开始ART之前和之后。我们的长期目标是提供证据的适当时机ART启动和评估可能的定制的连续性神经保护治疗，以防止手的基本原理。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infected patients are now living longer due to potent antiretroviral therapy (ART). Despite the effectiveness of ART for systemic viral suppression, up to half of chronically HIV infected (HIV+) individuals will develop HIV associated neurocognitive disorders (HAND). Increasing efforts have focused on understanding the early pathophysiologic changes within the central nervous system (CNS) initiated during primary HIV infection (PHI, defined as the first year after HIV transmission). It remains unknown if early initiation of ART during PHI could reduce the future incidence of developing HAND. It is imperative that early biomarkers (including cerebrospinal fluid (CSF) and neuroimaging) are developed for understanding the mechanisms of crucial early events that may influence the trajectory of damage in the CNS. Previous studies of PHI have primarily been cross sectional and have focused on a limited number of PHI participants assessed by single modality. We propose a longitudinal study to assess the effects of PHI and early ART on brain structure which integrates structural neuroimaging analyses with blood and CSF measures of infection, inflammation and neurodenegeration, as well as clinical data including exposure to stimulant drugs of abuse to investigate possible mechanisms of brain injury beginning during PHI. Specifically, this study will employ structural neuroimaging methods (diffusion tensor imaging (DTI) and brain volumetrics) to study the CNS mechanisms that underlie the natural history of PHI in the CNS as well as the effects of starting ART in the early stages of infection. Based on our preliminary cross sectional analyses, we hypothesize that structural neuroimaging (DTI and brain volumetrics) will reveal progressive injury in the brain during early infection prior to ART which may be halted in subjects that initiate ART soon after seroconversion. Subjects using methamphetamine may have increased vulnerability to HIV-associated structural injury, tied to inflammation in the brain. This proposal will: (Aim 1) investigate the mechanisms of CNS injury in PHI prior to ART by temporally associating the emergence of abnormalities in structural imaging with laboratory biomarkers and neuropsychological performance. Additionally (Aim 2) we will explore the mechanisms of early ART effects in the CNS through assessment of white matter integrity and brain volumetrics over time in subjects both before and after starting ART. Our long term goal is to provide evidence for the appropriate timing of ART initiation and to evaluate the rationale of possible tailored adjunctive neuroprotective therapies to prevent HAND.