Brain Structural and Functional Connectome in HIV-associated Neuroinflammation

摘要： 随着艾滋病毒人口的老龄化，将中枢神经分离变得越来越困难。 艾滋病毒引起的系统(CNS)损伤是由于血管疾病等共病引起的。两国之间的共同点 艾滋病毒感染和衰老都可以被认为是炎症状态；因此艾滋病毒和衰老可以 预计会对中枢神经系统产生相加的负面影响，如果不是协同的话。人类免疫缺陷病毒中枢神经系统损伤的驱动因素 接受联合抗逆转录病毒疗法(CART)的感染者可能是多因素的，可能包括艾滋病毒病毒 产品、抗逆转录病毒药物、中枢神经系统毒性、传统血管风险因子和持久中枢神经系统免疫激活。 促炎单核细胞，如那些表达组织因子(TF+)的单核细胞，处于很好的中介地位 炎症和凝血障碍，可能在中枢神经系统损伤中发挥作用。Tf+单核细胞增多 HIV+个体，即使在那些有效的购物车上也是如此。它们同时调节炎症和凝血障碍的能力 可导致中枢神经系统微循环失调，随后是缺血，然后是脱髓鞘。这 最后一种影响在标准的临床磁共振成像研究中表现为白质高信号(Wmh)，例如FLAIR。 序列。更先进的脉冲序列，如扩散加权成像，可以提供定量 即使FLAIR上没有可见的WMH，也可以测量异常白质微结构的完整性。 经过良好治疗的HIV+患者的神经认知能力下降非常缓慢，这也反映在 在小的情况下，随着时间的推移，神经成像会发生变化。因此，这些成像变化可能需要几年时间 用标准方法反映中枢神经系统损伤成为可量化的。我们提出了新的方法， 可重复地构建跨对象和人群之间的结构和功能连接，从而 进一步提高对HIV相关中枢神经系统损伤演变的认识。这些新方法是 基于严格的统计方法，该方法将提供确定微小变化所需的可靠性 加班。我们建议在研究Tf+单核细胞免疫功能的同时实施这些方法 处于炎症和凝血障碍的十字路口的细胞，因此可能参与艾滋病毒相关的中枢神经系统损伤， 尤其是在老年人口中。以下列出的具体目标将进行为期三年的纵向调查 110名HIV+参与者和110名HIV-年龄、性别和血管危险因素的队列与对照组匹配。我们有 选择了一个主要由年龄为≥50岁的参与者组成的队列，因此患血管疾病的风险更大。 目的1.通过新的方法评估大脑结构轨迹的纵向变化 HIV感染者与HIV血清阴性者的连接组和功能连接性 炎症和凝血障碍的中间体(可溶性CD14和CD163、D-二聚体、可溶性组织因子 和Tf+单核细胞)。 目的2.评估结构连接体、功能连接性和大脑皮层的中介作用 在特定认知域上的厚度。

Abstract: With an aging HIV population, it is becoming increasingly difficult to disentangle central nervous system (CNS) injury due to HIV from that due to comorbidities such as vascular disease. A commonality between HIV infection and aging is that both can be considered inflammatory conditions; thus HIV and aging can be expected to have an additive, if not synergistic, negative effect on the CNS. The driver of CNS injury in HIV infected individuals on combination antiretroviral therapy (cART) is likely multifactorial, and may include HIV viral products, antiretrovirals CNS toxicity, traditional vascular risk factors and persistent CNS immune activation. Pro-inflammatory monocytes, such as those expressing tissue factor (TF+), are well-positioned to mediate both inflammation and coagulopathy, thus likely to play a role in CNS injury. TF+ monocytes are increased in HIV+ individuals, even in those on effective cART. Their ability to mediate both inflammation and coagulopathy can lead to dysregulation of the CNS microcirculation, followed by ischemia, and then to demyelination. This last effect is visible as white matter hyperintensities (WMH) in standard clinical MRI studies, for example FLAIR sequence. More advanced pulse sequences, such as diffusion weighted imaging, can provide quantitative measurements of abnormal white matter microstructure integrity even when there is no visible WMH on FLAIR. Well-treated HIV+ individuals are expected to have a very slow neurocognitive decline which is also reflected in small, neuroimaging changes overtime. Therefore, it may take several years for those imaging changes reflecting CNS injury to become quantifiable with standard methodology. We propose novel methodologies that reproducibly construct structural and functional connectomes across subjects and between populations, thus further improving our understanding in the evolution of HIV-associated CNS injury. These novel methods are based on a rigorous statistical approach which will provide the reliability needed to ascertain small changes overtime. We propose to implement these methodologies while investigating the role of TF+ monocytes, immune cells at the crossroad of inflammation and coagulopathy, thus likely involved in HIV-associated CNS injury, especially in an older population. The specific aims listed below will be investigated in a three-year longitudinal cohort of 110 HIV+ participants and 110 HIV- age, gender and vascular risk factors matched controls. We have chosen a cohort that is primarily composed of participants age ≥50 thus at greater risk of vascular disease. Aim 1. To assess via novel methodologies the longitudinal changes in the trajectory of brain structural connectome and functional connectivity in HIV infected compared to HIV seronegative individuals in the context of intermediaries of inflammation and coagulopathy (soluble CD14 and CD163, D-dimer, soluble tissue factor and TF+ monocytes). Aim 2. To assess the mediation effect of structural connectome, functional connectivity and cerebral cortical thickness on specific cognitive domains.