Imaging retinal leukocyte-endothelial interaction as a diagnostic marker for multiple sclerosis

视网膜白细胞-内皮相互作用成像作为多发性硬化症的诊断标志物

• 批准号: 9383166
• 负责人: Clemens Alt
• 金额: $ 41.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383166
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Area; Axon; Blood Vessels; Brain; Caliber; Cell Adhesion Molecules; Cells; Cerebrospinal Fluid; Clinical; Custom; Data; Detection; Development; Diagnosis; Diagnostic Imaging; Disease; Disease Progression; Encephalitis; Endotoxins; Experimental Autoimmune Encephalomyelitis; Eye; Feedback; Frequencies; Human; Image; Imaging Techniques; Immune; Incidence; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injectable; Injection of therapeutic agent; Interleukin-1 beta; Interleukin-17; Interleukin-6; Knowledge; Label; Lasers; Lesion; Leukocyte Rolling; Leukocytes; Lipopolysaccharides; Location; Magnetic Resonance Imaging; Measures; Methods; Monitor; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Neoadjuvant Therapy; Neuraxis; Neurologic Symptoms; Newly Diagnosed; Ophthalmoscopes; Optic Chiasm; Optic Disk; Optic Nerve; Optic Neuritis; Optics; Patients; Pilot Projects; Pupil; Recurrent disease; Relapse; Relapsing-Remitting Multiple Sclerosis; Reporting; Residual state; Resolution; Retina; Retinal; Rodent Model; Scanning; Severities; Speed; Spinal Cord; Steroids; Subarachnoid Space; Symptoms; TNF gene; Testing; Therapeutic Intervention; Time; Tracer; Translating; Update; Vascular Endothelial Cell; Vascular Endothelium; adaptive optics; adaptive optics scanning laser ophthalmoscopy; base; brain parenchyma; clinical predictors; cytokine; diagnostic biomarker; disability; experience; experimental study; imaging modality; improved; instrument; intravital imaging; mouse model; multiple sclerosis patient; nervous system disorder; neuroinflammation; optical imaging; relapse prediction; response; treatment response

PROJECT SUMMARY In multiple sclerosis (MS), the most common neurological disease in the working young, inflammatory cells infiltrate the central nervous system (CNS) and attack the myelin-producing cells that are crucial for function and survival of axons. Most patients experience a relapsing-remitting disease course with ever worsening neurological symptoms and, ultimately, disability. Current diagnostic imaging techniques cannot predict relapses because they cannot detect the active leukocyte infiltration into the CNS that leads to clinical disease symptoms downstream. This proposal intends to provide a method that enables non-invasive assessment of this asymptomatic disease activity based on the detection of leukocyte-endothelial interaction (LEI) in the retina by live imaging, which will allow prediction of MS relapses and rapid feedback on treatment response and disease progression. Thus, retinal LEI detection could help transform therapeutic intervention in MS and mitigate the development and severity of disability in MS. LEI, the rolling of white blood cells that is a requirement for leukocyte infiltration, is absent in healthy CNS and considered a hallmark of inflammation. We hypothesize that retinal LEI near the optic nerve head (ONH) indicates active leukocyte infiltration into the CNS that precedes MRI detectable lesions and clinical disease symptoms. The retina is an optically accessible compartment of the CNS that lends itself to optical, intravital imaging through the pupil of the eye. With a scanning laser ophthalmoscope (SLO), custom built for mouse retinal imaging, retinal LEI was detected in early stages of experimental autoimmune encephalomyelitis (EAE), an accepted rodent model of MS, prior to clinical symptoms. Our preliminary data further demonstrated, that pro-inflammatory messengers can reach the retina via transport of cerebrospinal fluid (CSF) and cause retinal LEI, although the retina and optic nerve themselves are not inflamed. In aim 1, we will characterize retinal LEI in EAE and compare its time course to that of leukocyte infiltration into the CNS, as assessed by flow cytometric analysis, and to development of CNS lesions by MRI. Treatment will be administered upon LEI detection and the disease time course compared with untreated controls. In aim 2, we will assess the sensitivity of retinal LEI to remotely detect CNS inflammation. We determine if the location of an inflammatory brain lesion affects the frequency of retinal LEI. Furthermore, MS-relevant cytokines will be injected directly into the CSF to test their ability to elicit retinal LEI. In aim 3, we will develop an adaptive optics (AO) SLO that is specialized for the detection of retinal LEI. Using high-speed scanning and a woofer-tweeter AO architecture, the instrument will generate a field of view that probes the area in and near the optic nerve head, where most LEI would be expected. This cutting-edge instrument will be used in a pilot study to assess retinal LEI in MS patients.

项目摘要 在多发性硬化症（MS），最常见的神经系统疾病，在工作的年轻，炎症细胞 渗透到中枢神经系统（CNS）并攻击对功能至关重要的髓鞘生成细胞 和轴突的存活大多数患者经历复发缓解型病程， 神经系统症状最终导致残疾目前的诊断成像技术无法预测 因为他们不能检测到导致临床疾病的活跃的白细胞浸润到CNS中 下游症状该提案旨在提供一种方法，使非侵入性评估 这种无症状的疾病活动基于视网膜中白细胞-内皮细胞相互作用（LEI）的检测 通过实时成像，这将允许预测MS复发和快速反馈治疗反应， 疾病进展。因此，视网膜LEI检测可以帮助改变MS的治疗干预， 减轻MS残疾的发展和严重程度。 LEI，即白细胞浸润所需的白色血细胞的滚动，在健康的CNS中不存在， 被认为是炎症的标志我们假设视神经乳头（ONH）附近的视网膜LEI 表明活动性白细胞浸润到CNS中，先于MRI可检测的病变和临床 疾病症状。视网膜是中枢神经系统的光学可达区室， 通过眼睛瞳孔的活体成像。使用扫描激光检眼镜（SLO）， 小鼠视网膜成像，在实验性自身免疫性脑脊髓炎的早期阶段检测视网膜LEI (EAE)在出现临床症状之前，是公认的MS啮齿动物模型。我们的初步数据进一步表明， 促炎信使可以通过脑脊液（CSF）的运输到达视网膜， 视网膜LEI，尽管视网膜和视神经本身没有发炎。 在目的1中，我们将描述EAE中视网膜LEI的特征，并将其时间过程与白细胞浸润的时间过程进行比较。 通过流式细胞术分析评估的CNS，以及通过MRI评估的CNS病变的发展。治疗将 与未治疗的对照相比，在LEI检测和疾病时程时施用。 在目标2中，我们将评估视网膜LEI远程检测CNS炎症的灵敏度。我们确定如果 炎性脑损伤的位置影响视网膜LEI的频率。此外，MS相关 将细胞因子直接注射到CSF中以测试它们引起视网膜LEI的能力。 在目标3中，我们将开发一种专门用于检测视网膜LEI的自适应光学（AO）SLO。使用 高速扫描和低音-高音AO架构，该仪器将产生一个视场， 探测视神经头内和附近的区域，大多数LEI将被预期。这项尖端 仪器将用于试点研究，以评估MS患者的视网膜LEI。