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: 10228819
• 负责人: GIOVANNI SCHIFITTO
• 金额: $ 27.94万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228819
• 关键词: Address; Affect; Age; Aging; Anti-Retroviral Agents; Behavior; Blood Coagulation Disorders; Brain; Brain region; CD14 gene; Cells; Cerebral small vessel disease; Cerebrovascular Disorders; Cerebrum; Clinical; Coagulation Process; Cognitive; Corpus striatum structure; Demyelinations; Diffuse; 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; Lead; Liquid substance; Longitudinal cohort; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mediation; Methodology; Methods; Microcirculation; Monitor; Neuraxis; Neurocognitive Deficit; Neurons; Older Population; Participant; Physiologic pulse; Play; Population; Positioning Attribute; Recovery; Reporting; 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; base; brain abnormalities; central nervous system injury; clinical imaging; 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： 随着艾滋病毒人口老龄化，解开中枢神经系统变得越来越困难 HIV 引起的中枢神经系统损伤与血管疾病等合并症引起的损伤之间存在共同点。 HIV感染和衰老都可以被认为是炎症性疾病；因此HIV和衰老可以是炎症性疾病； 预计会对中枢神经系统产生累加（如果不是协同）负面影响艾滋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、抗逆转录病毒药物中枢神经系统毒性、传统血管危险因素和持续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+) 的单核细胞，能够很好地介导 炎症和凝血障碍，因此可能在中枢神经系统损伤中发挥作用，TF+单核细胞增加。 HIV+ 个体，即使是那些接受有效 cART 的个体，也具有介导炎症和凝血障碍的能力。 可导致中枢神经系统微循环失调，继而出现缺血，然后导致脱髓鞘。 在标准临床 MRI 研究中，最后一个效应表现为白质高信号 (WMH)，例如 FLAIR 更先进的脉冲序列，例如扩散加权成像，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观结构的完整性。 接受良好治疗的艾滋病毒+个体预计神经认知能力下降非常缓慢，这也反映在 随着时间的推移，神经影像学会发生微小的变化，因此，这些影像学变化可能需要几年的时间。 我们提出了可以用标准方法量化的反映中枢神经系统损伤的新方法。 跨受试者和人群之间可重复地构建结构和功能连接体，从而 这些新方法进一步提高了我们对 HIV 相关中枢神经系统损伤演变的理解。 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 我们建议在研究 TF+ 单核细胞、免疫的作用时实施这些方法。 细胞处于炎症和凝血病的十字路口，因此可能参与艾滋病毒相关的中枢神经系统损伤， 特别是在老年人口中，将在三年的纵向中调查下面列出的具体目标。 我们有 110 名 HIV+ 参与者和 110 名 HIV- 年龄、性别和血管危险因素匹配的对照组。 选择了一个主要由年龄≥50岁的参与者组成的队列，因此患血管疾病的风险更大。 目标 1. 通过新颖的方法评估大脑结构轨迹的纵向变化 与艾滋病毒血清阴性个体相比，艾滋病毒感染者的连接组和功能连接 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）。 目标 2. 评估结构连接体、功能连接和大脑皮质的中介作用 特定认知领域的厚度。