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cART时代的一个关键问题，并且它可能与抗逆转录病毒药物协同作用。 老化的影响。这种相互作用的结果可能导致血管性高患病率， 疾病，包括脑小血管疾病（CSVD），在老年HIV感染者中观察到。的 通过标准临床MR脉冲序列对CVSD进行定性评估， 大脑微结构损伤的证据更重要的是，它没有提供一个完整的理解， CNS损伤的病理机制。在这方面，我们建议将两位议员提供的资料联合收割机合并 评估组织微结构完整性、MR弹性成像（MRE）和神经突定位的模式- 弥散密度成像（NODDI）。我们假设这些方法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（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志物之间的关系 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 神经元隔室和脑粘弹性的变化影响认知表现。 MRE指标已被证明在几种神经退行性疾病和神经炎性疾病中改变。 例如多发性硬化症。然而，没有数据表明它在艾滋病毒感染方面的效用。 也没有数据包括MRE，NODDI，免疫激活，神经元和神经胶质细胞的制造商 功能障碍和认知表现，提供了一个全面的图片如何神经炎症是联系在一起的 中枢神经系统损伤和认知能力下降。知识的缺乏促使我们提交这份 提议据我们所知，这项研究代表了脑MRE的第一个应用，以评估整体 假设HIV相关的免疫激活影响大脑的粘弹性，导致认知 功能障碍为减低成本和提高效率，我们建议达致以下的具体目标， 一项横断面研究，将在我们正在进行的纵向研究中共招募60名参与者（30名HIV+和30名HIV-）， HIV相关CSVD研究（RO 1 AG 054328）。CSVD队列已入组预期220例中的140例 受试者（110例HIV+，110例HIV-）。该研究的目标是在2019年夏季完成招募。 在目标1中，我们将评估HIV感染是否会影响脑粘弹性，以及这些粘弹性是否会影响脑组织的粘弹性。 这些变化与免疫活化的系统性标志物（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）。在目标2中，我们将研究大脑与 粘弹性、神经突（轴突和树突）形态以及这些成像指标的相关性 神经元和星形胶质细胞功能障碍的标记物的血浆水平。在目标3中，我们将确定地雷危险教育和 扩散MR指标与认知表现相关。