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.

摘要： 随着艾滋病毒感染者的老龄化， 由HIV引起中枢神经系统（CNS）损伤与由血管疾病等合并症引起的CNS损伤之间的差异。之间的共性 艾滋病毒感染和衰老是，两者都可以被认为是炎症条件;因此，艾滋病毒和衰老可以是 如果不是协同作用，则预期对CNS具有累加的负面作用。HIV中CNS损伤的驱动因素 接受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、抗逆转录病毒药物CNS毒性、传统血管危险因素和持续CNS免疫激活。 促炎性单核细胞，如表达组织因子（TF+）的单核细胞， 炎症和凝血病，因此可能在CNS损伤中起作用。TF+单核细胞增加， 艾滋病毒阳性个体，即使是在那些有效的cART。它们调节炎症和凝血功能障碍的能力 可导致中枢神经系统微循环失调，接着是局部缺血，然后是脱髓鞘。这 在标准临床MRI研究（例如FLAIR）中，最后一个效应作为白色高信号（WMH）可见 顺序更先进的脉冲序列，如扩散加权成像，可以提供定量的 测量异常白色物质的微观结构完整性，即使在FLAIR上没有可见的WMH。 治疗良好的HIV+个体预计会有非常缓慢的神经认知下降，这也反映在 在小的神经影像学改变中因此，可能需要几年的时间才能实现这些成像变化 反映CNS损伤可通过标准方法量化。我们提出了新的方法， 可重复地构建跨受试者和群体之间的结构和功能连接体， 进一步提高我们对HIV相关CNS损伤演变的理解。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 加班我们建议实施这些方法，同时研究TF+单核细胞，免疫调节剂和免疫调节剂的作用。 细胞处于炎症和凝血病的交叉点，因此可能参与HIV相关的CNS损伤， 尤其是在老年人中。将对下列具体目标进行为期三年的纵向调查， 110名HIV阳性参与者和110名HIV-年龄、性别和血管危险因素匹配的对照组。我们有 选择了一个主要由年龄≥50岁的参与者组成的队列，因此血管疾病的风险更大。 目标1.通过新的方法评估脑结构轨迹的纵向变化， HIV感染者与HIV血清阴性个体的连接体和功能连接 炎症和凝血障碍的中间体（可溶性CD 14和CD 163，D-二聚体，可溶性组织因子 和TF+单核细胞）。 目标2.评估结构连接体、功能连接和大脑皮层的中介作用 特定认知领域的厚度。