HIV neuroinflammation alters brain microstructure and viscoelastic properties

HIV 神经炎症改变大脑微观结构和粘弹性特性

• 批准号: 9981823
• 负责人: Marvin M Doyley
• 金额: $ 19.91万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981823
• 关键词: Address; Affect; Age; Aging; Astrocytes; Axon; Biological Markers; Blood Coagulation Disorders; Brain; Brain Injuries; CD14 gene; Cellularity; Cerebral small vessel disease; Chronic; Clinical; Cross-Sectional Studies; Data; Demyelinations; Dendrites; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Enrollment; Environment; Event; Fibrin fragment D; Functional disorder; Glial Fibrillary Acidic Protein; Gliosis; Goals; HIV; HIV Infections; High Prevalence; Image; Immunologic Markers; Impaired cognition; Individual; Inflammation; Inflammatory; Knowledge; Lacunar Infarctions; Lead; Light; Link; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Mediating; Modality; Morphology; Multiple Sclerosis; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroglia; Neurons; Participant; Peripheral; Physiologic pulse; Plasma; Play; Population; Positioning Attribute; Process; Property; Recovery; Role; Structure; Techniques; Thromboplastin; Tissues; Vascular Diseases; White Matter Hyperintensity; age effect; antiretroviral therapy; attenuation; base; brain tissue; central nervous system injury; cognitive performance; cohort; cost; density; elastography; extracellular; imaging modality; immune activation; indexing; mechanical properties; monocyte; neurofilament; neuroinflammation; neurovascular unit; novel; peripheral blood; tau Proteins; ubiquitin C-terminal hydrolase; vibration; virology; viscoelasticity; white matter

Persistent immune activation remains a key concern in the cART era and it is likely to synergize with the effects of aging. The results of this interaction are likely contributing to the high prevalence of vascular disease, including cerebral small vessel disease (CSVD), observed in older HIV infected individuals. The qualitative assessment of CVSD via standard clinical MR pulse sequences, provides a superficial assessment of the brain microstructure damage. More importantly, it does not offer a full understanding of pathomechanisms of CNS injury. In this regard, we propose to combine the information provided by two MR modalities that assess the integrity of tissue microstructure, MR elastography (MRE) and neurite-orientation- dispersion density imaging (NODDI). We hypothesize that the combination of these modalities can help us understand how immune activation affects the intracellular and extracellular neuronal compartments (NODDI) and associated changes in tissue viscoelastic properties (MRE). We will also be able to assess quantitatively the relationship among these imaging metrics and peripheral blood markers of immune activation and neuronal and glia dysfunction. Furthermore, we will be able to assess how changes in intracellular and extracellular neuronal compartments and changes in brain viscoelastic properties affect cognitive performance. MRE metrics have been shown to be altered in several neurodegenerative disorders and neuroinflammatory disorders such as multiple sclerosis. However, there is no data on its usefulness in the context of HIV infection. Neither are there data that incorporate MRE, NODDI, makers of immune activation, neuronal and glia dysfunction and cognitive performance, providing a comprehensive picture of how neuroinflammation is linked to CNS injury and decreased cognitive performance. The lack of knowledge has prompted us to submit this proposal. To our knowledge, this study represents the first application of brain MRE to assess the overall hypothesis that HIV-associated immune activation affects the brain viscoelastic properties, leading to cognitive dysfunction. To minimize cost and increase efficiency, we propose to address the specific aims listed below in a cross-sectional study that will co-enroll 60 participants (30 HIV+ and 30 HIV-) in our ongoing longitudinal study of HIV-associated CSVD (RO1 AG054328). The CSVD cohort has enrolled 140 of the expected 220 participants (110 HIV+, 110 HIV-). The study is on target to complete the enrolment by the summer of 2019. In Aim 1, we will assess whether HIV infection influences brain viscoelastic properties and whether these changes are associated with systemic markers of immune activation (soluble CD14 and CD163, D-dimer, soluble tissue factor and TF+ monocytes). In Aim 2, we will investigate the relationship between brain viscoelastic properties, neurites (axons and dendrites) morphology and the correlation of these imaging metrics to plasma levels of markers of neuronal and astrocyte dysfunction. In Aim 3, we will determine if MRE and diffusion MR metrics are associated with cognitive performance.

持续的免疫激活仍然是购物车时代的关键问题，它很可能与 衰老的影响。这种相互作用的结果可能导致血管的高流行率 疾病，包括大脑小血管疾病（CSVD），在年龄较大的HIV感染个体中观察到。这 通过标准临床MR脉冲序列对CVSD进行定性评估，提供了表面评估 大脑微观结构损害的损害。更重要的是，它没有完全理解 中枢神经系统损伤的病理机理。在这方面，我们建议将两个MR提供的信息结合在一起 评估组织微观结构，MR弹性图（MRE）和神经突取向的完整性的方式 色散密度成像（NODDI）。我们假设这些方式的结合可以帮助我们 了解免疫激活如何影响细胞内和细胞外神经元区室（NODDI） 以及组织粘弹性特性（MRE）的相关变化。我们还将能够定量评估 这些成像指标与免疫激活和神经元的外周血标记之间的关系 和神经胶质功能障碍。此外，我们将能够评估细胞内和细胞外的变化 神经元区室和大脑粘弹性特性的变化会影响认知性能。 已显示MRE指标在几种神经退行性疾病和神经炎症性中发生了改变 诸如多发性硬化症之类的疾病。但是，在艾滋病毒感染的背景下，没有关于其有用性的数据。 没有任何数据包含MRE，NODDI，免疫激活，神经元和神经胶质的制造商 功能障碍和认知表现，提供了有关神经炎症如何联系的全面图片 CNS损伤和认知表现降低。缺乏知识促使我们提交了 提议。据我们所知，这项研究代表了大脑MRE评估整体的首次应用 HIV相关免疫激活影响脑粘弹性的假设，导致认知 功能障碍。为了最大程度地降低成本并提高效率，我们建议解决以下列出的具体目标 一项横断面研究，将在我们正在进行的纵向中共同注册60名参与者（30 HIV+和30 HIV-） HIV相关CSVD的研究（RO1 AG054328）。 CSVD队列已招募了预期220的140个 参与者（110 HIV+，110 HIV-）。这项研究的目标是在2019年夏季完成入学率。 在AIM 1中，我们将评估艾滋病毒感染是否影响脑粘弹性的特性以及它们是否影响 变化与免疫激活的全身标记有关（可溶性CD14和CD163，d-dimer， 可溶性组织因子和TF+单核细胞）。在AIM 2中，我们将研究大脑之间的关系 粘弹性特性，神经突（轴突和树突）形态和这些成像指标的相关性 到神经元和星形胶质细胞功能障碍的等离子水平。在AIM 3中，我们将确定MRE和是否是否 扩散MR指标与认知性能有关。