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

• 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
• 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' 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

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 也是导致痴呆症的主要原因阿尔茨海默病 (AD) 的主要原因。 VCID主要是由 脑小血管疾病（CSVD）。迄今为止，小脑小血管病的病理生理学尚未得到很好的阐明。 明白了。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 神经炎症。多方面的证据，包括动物模型、死后人类大脑的结果 神经病理学和全身炎症生物标志物研究表明， 脑小血管病 (CSVD) 发病机制中的神经炎症及其导致的 VCID。然而，直接证据表明 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) 参与细胞运输和淋巴细胞/巨噬细胞招募。先前的研究表明 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。 硬化症（MS）。 S1P调节剂FTY720（芬戈莫德）已获得FDA批准，已广泛用于 由于其拮抗 S1P 受体功能的能力而治疗多发性硬化症。 11C-CS1P1 PET 放射性示踪剂，具有高 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 我们机构的人体标本。 FDA 最近批准了第一个 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。本次活动的目标 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。这项研究的成功完成将提供离体和体内证据 脑小血管病 (CSVD) 中的神经炎症。这项研究将为确定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。