Role of Myeloid Cells in Cerebrovascular Permeability and Reactivity in Older HIV Infected Individuals

骨髓细胞在老年 HIV 感染者脑血管通透性和反应性中的作用

基本信息

批准号：
10160749
负责人：
SANJAY B. MAGGIRWAR
金额：
$ 69.64万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160749
关键词：
Address Affect Age Aging Area Arteries Astrocytes Atherosclerosis Attention Blood Blood - brain barrier anatomy Blood Platelets Blood Vessels Blood capillaries Brain CD14 gene Cardiovascular Diseases Cardiovascular system Cell Adhesion Cell Adhesion Molecules Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Chronic Complex Deposition Diagnosis Disease Endothelial Cells Endothelium Evaluation Exposure to Extravasation FCGR3B gene Frequencies Functional Magnetic Resonance Imaging Gender General Population HIV HIV Infections HMGB1 gene Image Imaging Techniques Immune Incidence Individual Infarction Infection Inflammatory Intercellular adhesion molecule 1 Investigation Iron Link Long-Term Effects Longitudinal Studies Measures Mediating Microcirculation Microglia Modeling Myeloid Cells Neopterin Older Population PF4 Gene Pericytes Permeability Persons Phenotype Plasma Platelet Activation Play Population Predisposition Prevention strategy Process Property Proteins Rest Risk Risk Factors Role SIV Spin Labels Subcortical Infarctions Techniques Tissues Tumor necrosis factor receptor 11b Vascular Permeabilities Veins White Matter Hyperintensity activation product antiretroviral therapy arteriole base blood perfusion blood product blood-brain barrier permeabilization brain abnormalities central nervous system injury cerebral atrophy cerebral microbleeds cerebrovascular clinical Diagnosis clinical imaging cognitive performance cohort data modeling endothelial dysfunction imaging biomarker imaging modality immune activation lipoprotein-associated phospholipase A(2)monocyte neuroimaging neurovascular unit quantitative imaging therapeutic target white matter

项目摘要

HIV infected individuals, especially those older, are at increased risk of developing cerebrovascular disease (CBVD). While most of the recent investigations have focused on large vessel disease, cerebral small vessel disease (CSVD) has received much less attention despite its known role and long-term effect on cognitive performance and potentially more direct link to HIV-associated immune dysregulation. CSVD is diagnosed via neuroimaging. Typical findings include small subcortical infarcts, lacunes, white matter hyperintensity, enlarged perivascular spaces, cerebral microbleeds and brain atrophy. Quantitative MR techniques assess indirectly the altered microcirculation and blood brain barrier (BBB) by measuring vascular reactivity, cerebral blood flow, white matter microstructure and tissue susceptibility. Importantly, these quantitative imaging modalities can measure even subtle brain abnormalities that escape the evaluation by standard clinical imaging techniques. CSVD has been associated with markers secreted by myeloid cells. This is particularly relevant to HIV infected individuals. We and others have shown that the aberrant platelet activation during HIV/SIV infection causes an increase in platelet-monocyte complexes (PMCs) that drives monocyte maturation from CD14+/CD16- to the pro-inflammatory CD14(low)/CD16+ phenotype and that the reduced numbers of CD14+/CD16- monocytes are associated with pro-AS changes, BBB permeability and aging. Thus, PMCs could serve as markers and a therapeutic target of CSVD. Based on these observations, we hypothesize that PMCs, by affecting vascular permeability and reactivity, play a crucial role in mediating CSVD, especially in older HIV infected individuals. In a well characterize cohort for CBVD risk factors that includes an older-enriched HIV population (age≥50) and age matched uninfected individuals, we propose to address the following Specific Aims pertinent to CSVD in a 3-year longitudinal study. In Aim 1 we will assess whether changes in vascular reactivity (measured via rs-fMRI) and white matter microstructural integrity (measured via DTI) are associated with levels of PMCs. In Sub-Aim 1 we will determine whether areas with increased tissue susceptibility and decreased vascular reactivity are associated with decreased cerebral blood flow (CBF). In Aim 2 we will determine whether changes vascular reactivity and white matter microstructural integrity are associated with soluble products of pro-inflammatory monocytes (plasma levels of sCD163, neopterin, and HMGB1), platelet activation (platelet factor 4 [PF-4]) and with plasma markers of endothelial dysfunction (intercellular adhesion molecule 1 [sICAM- 1], vascular cellular adhesion molecule-1 [sVCAM-1], osteoprotegerin and lipoprotein-associated phospholipase A2 [Lp-PLA2] mass). In Sub-Aim 2 we will determine whether changes in brain iron deposition are associated with levels of PMCs, PF-4, plasma monocyte and endothelial soluble products. In Aim 3 we will model data generated from the previous aims in the context of cognitive performance.

艾滋病毒感染的个体，尤其是年龄较大的人，患有脑血管疾病的风险增加（CBVD）。尽管最近的大多数调查都集中在大型血管疾病上，但脑小血管疾病（CSVD）尽管已知的作用和对认知的长期影响，但受到了较少的关注性能，并有可能与HIV相关的免疫失调的更直接联系。 CSVD通过神经影像学。典型的发现包括皮层下小，拉加尼斯，白质超强度，扩大血管周空间，脑微孔和脑萎缩。定量MR技术间接评估通过测量血管反应性，脑血流量，改变微循环和血脑屏障（BBB），白质微观结构和组织敏感性。重要的是，这些定量成像方式可以测量通过标准临床成像技术逃脱评估的微妙脑异常。 CSVD与髓样细胞分泌的标记有关。这与艾滋病毒特别相关受感染的人。我们和其他人表明，HIV/SIV感染期间的异常血小板激活导致血小板单细胞复合物（PMC）增加，从而使单核细胞成熟 CD14+/CD16-至促炎CD14（低）/CD16+表型，并减少了数量 CD14+/CD16-单核细胞与Pro-As变化，BBB渗透性和衰老有关。那，PMC 可以用作CSVD的标记和治疗靶标。基于这些观察，我们假设 PMC通过影响血管通透性和反应性，在中介CSVD中起着至关重要的作用，尤其是在年龄较大的艾滋病毒感染了个体。在良好的特征中，包括富含较老的HIV人群的CBVD风险因素的队列（年龄≥50）和年龄符合未感染的人，我们建议解决与CSVD有关的以下特定目标在一项为期3年的纵向研究中。在AIM 1中，我们将评估血管反应性的变化（通过 RS-FMRI）和白质微结构完整性（通过DTI测量）与PMC水平有关。在 Sub-aim 1我们将确定组织易感性增加和血管降低的区域是否反应性与脑血流降低有关（CBF）。在AIM 2中，我们将确定是否变化血管反应性和白质微结构完整性与固体产品有关促炎单核细胞（SCD163的血浆水平，Neopterin和HMGB1），血小板激活（血小板因子4 [PF-4]）和内皮功能障碍的血浆标记（细胞间粘合分子1 [SICAM-- 1]，血管细胞粘合分子-1 [SVCAM-1]，骨蛋白蛋白蛋白蛋白和脂蛋白相关磷脂酶A2 [LP-PLA2]质量）。在Sub-aim 2中，我们将确定脑铁沉积的变化是否变化与PMC，PF-4，血浆单核细胞和内皮固体产物的水平有关。在AIM 3中，我们将在认知性能的背景下对从以前的目标产生的数据进行建模。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Artificial intelligence for diffusion MRI-based tissue microstructure estimation in the human brain: an overview.

DOI：
10.3389/fneur.2023.1168833
发表时间：
2023
期刊：
Frontiers in neurology
影响因子：
3.4
作者：
通讯作者：

Brain lesions disrupting addiction map to a common human brain circuit.

DOI：
10.1038/s41591-022-01834-y
发表时间：
2022-06
期刊：
NATURE MEDICINE
影响因子：
82.9
作者：
Joutsa, Juho;Moussawi, Khaled;Siddiqi, Shan H.;Abdolahi, Amir;Drew, William;Cohen, Alexander L.;Ross, Thomas J.;Deshpande, Harshawardhan U.;Wang, Henry Z.;Bruss, Joel;Stein, Elliot A.;Volkow, Nora D.;Grafman, Jordan H.;van Wijngaarden, Edwin;Boes, Aaron D.;Fox, Michael D.
通讯作者：
Fox, Michael D.

A longitudinal analysis of brain extracellular free water in HIV infected individuals.

DOI：
10.1038/s41598-021-87801-y
发表时间：
2021-04-15
期刊：
Scientific reports
影响因子：
4.6
作者：
Uddin MN;Faiyaz A;Wang L;Zhuang Y;Murray KD;Descoteaux M;Tivarus ME;Weber MT;Zhong J;Qiu X;Schifitto G
通讯作者：
Schifitto G

Validation of deep learning techniques for quality augmentation in diffusion MRI for clinical studies.

DOI：
10.1016/j.nicl.2023.103483
发表时间：
2023
期刊：
NEUROIMAGE-CLINICAL
影响因子：
4.2
作者：
Aja-Fernandez, Santiago;Martin-Martin, Carmen;Planchuelo-Gomez, Alvaro;Faiyaz, Abrar;Uddin, Md Nasir;Schifitto, Giovanni;Tiwari, Abhishek;Shigwan, Saurabh J.;Singh, Rajeev Kumar;Zheng, Tianshu;Cao, Zuozhen;Wu, Dan;Blumberg, Stefano B.;Sen, Snigdha;Goodwin-Allcock, Tobias;Slator, Paddy J.;Avci, Mehmet Yigit;Li, Zihan;Bilgic, Berkin;Tian, Qiyuan;Wang, Xinyi;Tang, Zihao;Cabezas, Mariano;Rauland, Amelie;Merhof, Dorit;Maria, Renata Manzano;Campos, Vinicius Paraniba;Santini, Tales;Vieira, Marcelo Andrade da Costa;Hashemizadehkolowri, Seyyedkazem;Dibella, Edward;Peng, Chenxu;Shen, Zhimin;Chen, Zan;Ullah, Irfan;Mani, Merry;Abdolmotalleby, Hesam;Eckstrom, Samuel;Baete, Steven H.;Filipiak, Patryk;Dong, Tanxin;Fan, Qiuyun;de Luis-Garcia, Rodrigo;Tristan-Vega, Antonio;Pieciak, Tomasz
通讯作者：
Pieciak, Tomasz

Surface-Based Connectivity Integration: An atlas-free approach to jointly study functional and structural connectivity.