Neuroinflammation in Cerebral Small Vessel Disease using PET/MR Imaging

项目总结/摘要 血管对认知障碍和痴呆的贡献（VCID）是痴呆的第二大原因 也是阿尔茨海默病（AD）的主要原因，AD是痴呆症的主要原因。VCID主要由以下原因引起： 脑小血管病（CSVD）。到目前为止，CSVD的病理生理学基础还不清楚- 明白血管危险因素，包括高血压、高脂血症和糖尿病，可能导致 损伤的小动脉、受损的自动调节、慢性缺氧/缺血、血脑屏障（BBB）损伤，以及 神经炎症几条证据，包括动物模型的结果，死后的人脑 神经病理学和全身炎症生物标志物的研究，涉及独立的贡献， 神经炎症在CSVD和导致的VCID的发病机制中的作用。然而，直接证据表明， CSVD患者的神经炎症仍然缺乏。1-磷酸鞘氨醇受体亚型1（S1 PR 1） 参与细胞运输和淋巴细胞/巨噬细胞募集。先前的研究表明， 在多发性骨髓瘤小鼠模型中，S1 PR 1高表达并与小胶质细胞和星形胶质细胞共定位。 硬化症（MS）。FDA批准的S1 P调节剂FTY 720（芬戈莫德）已广泛用于 由于其拮抗S1 P受体功能的能力而治疗MS。一种11 C-CS 1 P1 PET放射性示踪剂， 对S1 P1的亲和性和选择性最近已经被开发出来，并在动物模型和尸检中得到了验证。 我们机构的人体标本FDA最近批准了一项eIND申请（IND 146548）， 这种11 C-CS 1 P1放射性示踪剂的人PET成像。我们已经完成了一项安全性和剂量学研究， 参与者，证明11 C-CS 1 P1 PET是安全的，并准备用于患者研究。这个的目标 探索性研究是为了1）证明S1 PR 1表达升高并与小胶质细胞共定位， 星形胶质细胞在尸检脑标本与潜在的CSVD患者。2)确定是否 通过11 C-CS 1 P1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。本研究的成功完成将提供离体和体内证据 CSVD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 靶向神经炎症，以减少CSVD损伤和痴呆症的未来。

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.