Brain Structural and Functional Connectome in HIV-associated Neuroinflammation

HIV 相关神经炎症中的脑结构和功能连接组

• 批准号: 10614658
• 负责人: GIOVANNI SCHIFITTO
• 金额: $ 55.22万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614658
• 关键词: Address; Affect; Age; Aging; Anti-Retroviral Agents; Behavior; Blood Coagulation Disorders; Brain; Brain region; CD14 gene; Cells; Central Nervous System; Cerebral cortex; Cerebral small vessel disease; Cerebrovascular Disorders; Clinical; Coagulation Process; Cognitive; Corpus striatum structure; Demyelinations; Diffusion; Diffusion Magnetic Resonance Imaging; Evolution; Fibrin fragment D; Funding; Gender; HIV; HIV Infections; HIV Seronegativity; HIV-associated cognitive impairment; Image; Immune; Impaired cognition; Individual; Inflammation; Inflammatory; Injury; Ischemia; Liquid substance; Longitudinal cohort; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mediation; Methodology; Methods; Microcirculation; Monitor; Neurocognitive Deficit; Neurons; Older Population; Participant; Persons; Physiologic pulse; Population; Positioning Attribute; Recovery; Reporting; Reproducibility; Research Proposals; Risk; Role; Structure; Targeted Research; Thick; Thromboplastin; Toxic effect; United States National Institutes of Health; Vascular Diseases; Viral; White Matter Hyperintensity; antiretroviral therapy; attenuation; brain abnormalities; central nervous system injury; clinical imaging; cognitive function; cohort; comorbidity; connectome; cost; follow-up; gray matter; immune activation; improved; monocyte; neuroimaging; neuroinflammation; neuronal circuitry; novel; novel strategies; therapeutic target; vascular risk factor; white matter

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.

抽象的： 随着艾滋病毒衰老的老龄化，消除中枢神经的困难变得越来越困难 由于HIV引起的系统（CNS）损伤，由于合并症，例如血管疾病。之间的共同点 HIV感染和衰老是两者都可以视为炎症状况。因此，艾滋病毒和衰老可以是 预计将对中枢神经系统产生额外的（即使不是协同的负面影响）。艾滋病毒中枢神经系统受伤的驾驶员 联合抗逆转录病毒治疗（CART）的感染者可能是多因素的，可能包括HIV病毒 产品，抗逆转录病毒CNS毒性，传统的血管危险因素和持续的中枢神经系统免疫激活。 促炎单核细胞（例如表达组织因子（TF+））的拟合良好以介导 因此，炎症和凝血病都可能在CNS损伤中发挥作用。 TF+单核细胞增加 艾滋病毒+个人，即使在有效的购物车中也是如此。他们介导炎症和凝结症的能力 可以导致CNS微循环的失调，然后是缺血，然后脱髓鞘。这 在标准临床MRI研究中，最后的效果是白质高强度（WMH），例如天赋 顺序。更先进的脉冲序列（例如扩散加权成像）可以提供定量 即使在天赋上没有可见的WMH时，异常白质微结构完整性的测量也是如此。 预计良好培训的艾滋病毒+个体的神经认知能力下降非常缓慢，也反映了 在小的，神经影像的变化加班。因此，这些成像变化可能需要几年 反映中枢神经系统损伤以通过标准方法进行量化。我们提出了新方法 可重复可重复地构建受试者和人群之间的结构和功能连接，因此 进一步提高了我们对与HIV相关的中枢神经系统损伤进化的理解。这些新颖的方法是 基于严格的统计方法，该方法将提供确定小变化所需的可靠性 随着时间的推移。我们建议在研究TF+单核细胞的作用时实施这些方法，免疫 因此，感染和凝血病十字路口的细胞很可能涉及与HIV相关的中枢神经系统损伤， 特别是在老年人中。下面列出的具体目的将在三年的纵向中进行调查 110名HIV+参与者的队列和110名HIV，性别和血管危险因素与对照相匹配。我们有 选择一个主要由参与者组成的队列≥50岁，因此具有更大的血管疾病风险。 目的1。通过新方法评估大脑结构轨迹的纵向变化 与艾滋病毒的艾滋病毒感染的连接组和功能连通性与艾滋病毒的血清负格个体相比 炎症和凝血病的中间体（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。评估结构连接组，功能连通性和脑皮质的介导效应 特定认知领域的厚度。