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，它可能会与 老化的影响。这种相互作用的结果可能是导致血管高发的原因。 在老年艾滋病毒感染者中观察到的疾病，包括脑部小血管疾病(CSVD)。这个 通过标准的临床MR脉冲序列对CVSD进行定性评估，提供一个肤浅的评估 大脑微结构的损伤。更重要的是，它没有提供对 中枢神经系统损伤的病理机制。在这方面，我们建议综合两位先生提供的资料。 评估组织微结构、磁共振弹性成像(MRE)和轴突定向的方法- 弥散密度成像(NODI)。我们假设这些模式的组合可以帮助我们 了解免疫激活如何影响细胞内和细胞外神经元隔膜(NODI) 以及组织粘弹性特性(MRE)的相关变化。我们还将能够量化评估 这些影像指标与外周血液免疫激活标志物和神经元的关系 和神经胶质细胞功能障碍。此外，我们将能够评估细胞内和细胞外的变化 神经元的隔间和大脑粘弹性特性的变化会影响认知能力。 一些神经退行性疾病和神经炎性疾病的MRE指标已经被证明是改变的 多发性硬化症等疾病。然而，没有关于它在艾滋病毒感染方面的用处的数据。 也没有包含MRE、NODI、免疫激活标记物、神经元和神经胶质细胞的数据 功能障碍和认知表现，提供了神经炎症是如何联系在一起的全面图景 导致中枢神经系统损伤和认知能力下降。由于缺乏知识，我们提交了这份报告 求婚。据我们所知，这项研究是第一次应用大脑MRE来评估整体 假设艾滋病毒相关的免疫激活影响大脑的粘弹性特性，导致认知 功能障碍。为了最大限度地减少成本和提高效率，我们建议解决下列具体目标 一项横断面研究，将联合招募60名参与者(30名HIV+和30名HIV-)参加我们正在进行的纵向研究 HIV相关性CSVD的研究(RO1 AG054328)。CSVD队列已经登记了预计220人中的140人 参与者(110名HIV阳性者，110名HIV-者)。这项研究的目标是在2019年夏天完成招生。 在目标1中，我们将评估艾滋病毒感染是否影响大脑的粘弹性特性，以及这些特性是否 变化与免疫激活的系统标志物(可溶性CD14和CD163，D-二聚体， 可溶性组织因子和转铁蛋白+单核细胞)。在目标2中，我们将研究脑与脑之间的关系 粘弹性、轴突(轴突和树突)形态及这些成像指标的相关性 到血浆神经元和星形胶质细胞功能障碍的标志物水平。在目标3中，我们将确定MRE和 扩散磁共振指标与认知表现相关。