Neuroinflammation in Cerebral Small Vessel Disease using PET/MR Imaging

使用 PET/MR 成像研究脑小血管疾病的神经炎症

基本信息

批准号：
10467487
负责人：
Hongyu An
金额：
$ 43.09万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467487
关键词：
Affinity Age Alzheimer&apos s Disease Animal Model Astrocytes Atherosclerosis Authorization documentation Autopsy Autoradiography Binding Biological Markers Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Hypoxia-Ischemia C-reactive protein Cells Cerebral small vessel disease Chronic Clinical Dementia Diabetes Mellitus Diagnosis Diffuse Diffusion Magnetic Resonance Imaging Disease Progression Elderly Experimental Autoimmune Encephalomyelitis FDA approved Foundations Functional disorder Future Generations Goals Grant Homeostasis Human Hyperlipidemia Hypertension Image Immunohistochemistry Impaired cognition Impairment Inflammation Inflammatory Injury Institution Lacunar Infarctions Lead Lesion Longitudinal Studies Lymphocyte Magnetic Resonance Imaging Measures Membrane Lipids Metalloproteases Microglia Multiple Sclerosis Neuroglia Participant Pathogenesis Pathology Patient Recruitments Patients Peripheral arterial disease Positron-Emission Tomography Process Proteins Public Health Reactive Oxygen Species Research Research Personnel Risk Rodent Model Safety Sensitivity and Specificity Severity of illness Skeleton Specimen Sphingosine-1-Phosphate Receptor Stroke Testing Time Tissues Vascular Dementia Water White Matter Hyperintensity Width arteriole blood-brain barrier permeabilization burden of illness contrast enhanced cytokine dosimetry gray matter in vivo in vivo imaging injured interest lipid mediator macrophage middle age mouse model neuroinflammation neurological pathology neuropathology novel pathology imaging prevent radioligand radiotracer receptor function recruit sex targeted treatment trafficking uptake vascular cognitive impairment and dementia vascular injury vascular risk factor white matter white matter injury

项目摘要

Project Summary/Abstract Vascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia and a major contributor to Alzheimer’s disease (AD), the leading cause of dementia. VCID is mainly caused by cerebral small vessel disease (CSVD). Thus far, the pathophysiology underlying CSVD has not been well- understood. Vascular risk factors, including hypertension, hyperlipidemia, and diabetes mellitus, may lead to injured arterioles, impaired autoregulation, chronic hypoxia/ischemia, blood brain barrier (BBB) impairment, and neuro-inflammation. Several lines of evidence, including results from animal models, post-mortem human brain neuropathology, and systemic inflammatory biomarkers studies, implicate the independent contribution of neuroinflammation in the pathogenesis of CSVD and resulting VCID. However, direct evidence of neuroinflammation in patients with CSVD is still lacking. Sphingosine-1-phosphate receptor subtype 1 (S1PR1) is involved in cell trafficking and lymphocyte/macrophage recruitment. Previous studies have demonstrated that S1PR1 was highly expressed and colocalized with microglia and astrocytes in a mouse model of multiple sclerosis (MS). The S1P-modulator, FTY720 (fingolimod), approved by the FDA, has been widely used for treating MS due to its ability to antagonize S1P receptors functionality. An 11C-CS1P1 PET radiotracer with high affinity and selectivity for S1P1 has been recently developed and validated in animal models and post-mortem human specimens at our institution. The FDA recently approved an eIND application (IND 146548) for the first human PET imaging of this 11C-CS1P1 radiotracer. We have completed a safety and dosimetry study in normal participants, demonstrating that 11C-CS1P1 PET is safe and ready for patient studies. The goals of this exploratory study are to 1) demonstrate that S1PR1 expression is elevated and colocalize with microglia and astrocytes in post-mortem brain specimens from deceased patients with underlying CSVD. 2) Determine if neuroinflammation measured by 11C-CS1P1 uptake is independently associated with CSVD structural endpoints using in vivo PET/MR imaging. Successful completion of this study will provide both ex vivo and in vivo evidence of neuroinflammation in CSVD. This study will lay the foundation to identify patients who may benefit from therapy targeting neuroinflammation to reduce CSVD injury and dementia in the future.

项目概要/摘要血管对认知障碍和痴呆 (VCID) 的影响是痴呆的第二大原因是阿尔茨海默病 (AD) 的主要致病因素，而 VCID 则是导致痴呆的主要原因。脑小血管病 (CSVD) 迄今为止，CSVD 的病理生理学尚不清楚。了解血管危险因素，包括高血压、高脂血症和糖尿病，可能导致。小动脉受损、自身调节受损、慢性缺氧/缺血、血脑屏障（BBB）受损，以及多种证据，包括动物模型、尸检人脑的结果。神经病理学和全身炎症生物标志物研究表明，然而，神经炎症在 CSVD 发病机制和由此产生的 VCID 中的作用有直接证据。脑小血管病患者的神经炎症仍然缺乏 1-磷酸鞘氨醇受体亚型 1 (S1PR1)。先前的研究表明，参与细胞运输和淋巴细胞/巨噬细胞招募。在多种小鼠模型中，S1PR1 高度表达，并与小胶质细胞和星形胶质细胞共定位。 S1P 调节剂 FTY720（芬戈莫德）已获得 FDA 批准，已广泛用于治疗硬化症 (MS)。由于其能够拮抗 S1P 受体功能而治疗多发性硬化症一种具有高活性的 11C-CS1P1 PET 放射性示踪剂。 S1P1 的亲和力和选择性最近已在动物模型和尸检中得到开发和验证 FDA 最近批准了我们机构的第一个 eIND 申请 (IND 146548)。这种 11C-CS1P1 放射性示踪剂的人体 PET 成像我们已经完成了正常情况下的安全性和剂量测定研究。参与者，证明 11C-CS1P1 PET 是安全的，可以用于患者研究。探索性研究的目的是 1) 证明 S1PR1 表达升高并与小胶质细胞共定位，患有潜在脑小血管病的已故患者的尸检脑标本中的星形胶质细胞 2) 确定是否。通过 11C-CS1P1 摄取测量的神经炎症与 CSVD 结构终点独立相关使用体内 PET/MR 成像的成功完成这项研究将提供离体和体内证据。这项研究将为识别可能从治疗中受益的患者奠定基础。针对神经炎症以减少未来脑小血管病损伤和痴呆症。