Early Visual Biomarkers of Relapse and Rehabilitation in Multiple Sclerosis

多发性硬化症复发和康复的早期视觉生物标志物

• 批准号: 10189737
• 负责人: RANDY H. KARDON
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189737
• 关键词: 4-Aminopyridine; Acceleration; Acute; Address; Affect; Animal Model; Animals; Anterior; Autologous; Axon; Back; Biological Markers; Bone Marrow; Brain; Caring; Cerebrospinal Fluid; Chronic; Clinical; Communities; Contrast Sensitivity; Data; Demyelinations; Detection; Dietary Intervention; Disease; Disease Marker; Early treatment; Echinomycin; Event; Evoked Potentials; Experimental Autoimmune Encephalomyelitis; Flicker Fusion; Frequencies; Functional disorder; Glycolysis; Goals; Human; Individual; Injections; Intervention; Investigational Therapies; Magnetic Resonance Imaging; Measures; Mediating; Mesenchymal Stem Cells; Modeling; Monitor; Motor; Multiple Sclerosis; Mus; Myelin; Nature; Nerve; Nerve Degeneration; Nervous System Physiology; Neural Conduction; Neuraxis; Neurodegenerative Disorders; Neurons; Optic Nerve; Optic Neuritis; Optical Coherence Tomography; Outcome; Outcome Measure; Pathology; Patients; Pharmaceutical Preparations; Phase; Prevention; Preventive; Quality of life; Recovery; Rehabilitation Outcome; Rehabilitation therapy; Relapse; Retina; Retinal Ganglion Cells; Sensory; Signal Transduction; Speed; Stress Tests; Structure; Surrogate Markers; Symptoms; Testing; Therapeutic Effect; Thick; Thinness; Time; Translating; Translations; Veterans; Vision; Visual; Visual Acuity; Visual Pathways; Visual impairment; clinical practice; clinical translation; cognitive function; disability; fatty acid metabolism; functional restoration; immunoregulation; improved; improved functioning; in vivo; individual patient; insight; ketogenic diet; mouse model; multiple sclerosis patient; multiple sclerosis treatment; myelination; nerve stem cell; neuroinflammation; neurological recovery; neuron loss; neuroprotection; novel strategies; novel therapeutics; pre-clinical; preconditioning; preservation; regenerative approach; rehabilitation research; relating to nervous system; remyelination; retinal nerve fiber layer; stem cell therapy; success; tool; treatment effect; treatment response; treatment strategy

Optic neuritis is an associated pathology of MS, and is often the first symptom of the disease. Even in MS patients without any known episodes of optic neuritis, there is evidence that functional and structural manifestations of MS in the anterior visual pathway can be detected and monitored in vivo, reflecting disease activity. These include contrast sensitivity, critical flicker fusion frequency, evoked potentials from the retina and brain, and inner retinal layer thickness using optical coherence tomography (OCT). Our main purpose is to establish sensitive biomarkers of visual function that can be made widely available to veterans suffering from MS for detecting MS relapses, progression and treatment effects. An important secondary rehabilitation goal is to determine which conventional and new experimental treatment could decrease fluctuation in visual and CNS function, which are known to impact quality of life, in preclinical animal models of MS. We will employ two relevant animal models of MS, a MOG-induced experimental autoimmune encephalomyelitis (EAE) model for chronic MS and PLP-induced EAE to mimic the relapsing-remitting form. We will also include a heat-induced stress test to trigger fluctuations in visual and CNS function in EAE mice. We will determine in vivo ocular structural and functional biomarkers and will correlate them with motor- sensory and cognitive function. Data will be related to ex vivo structural manifestations of MS, namely neuron loss and demyelination. We propose that the number of remaining neurons and their myelin integrity will correlate with changes in optic nerve conduction speed, visual acuity and retinal nerve fiber layer thinning. We will then examine if current treatments using Fingolimod, 4-aminopyridine and a ketogenic diet increase neuro- axonal electrical activity and decrease functional fluctuation to favor increased rehabilitation. Newer experimental therapies, derived from compounds hypothesized to mediate the therapeutic effects of mesenchymal stem cell (MSC) therapy, which targeting improved nerve transduction, will also be tested in the chronic and relapsing remitting models of MS. Supported by pilot data results, we will determine with additional rigor that decreased optic nerve conduction velocity precedes motor-sensory and structural deficits in the EAE model and represents an early marker of disease activity. Our expected data will provide insights on how impairment of visual function corresponds to demyelination, retinal thinning and retinal ganglion cell (RGC) loss. We also determine at what time point an earlier treatment intervention will improve long-term functional and structural outcome. We further expect to provide convincing data that improvement of neuro-axonal electrical activity and conduction speed represent promising, new therapeutic avenues with extraordinary clinical impact for restoring function and quality of life. Clinical translation of these results will help predict MS relapses and rehabilitation in MS patients. We will provide strong evidence that testing of visual function can be used as a tool to monitor disease activity in MS, including detection of subclinical episodes of relapse or progression before clinical symptoms develop. In conclusion, we expect to have obtained conclusive data to determine the nature of early visual biomarkers in the EAE model and their value in predicting central nervous system outcome. Translation of such biomarkers to clinical practice would identify veterans with MS in need of further disease modifying agents to optimize recovery and quality of life.

视神经炎是多发性硬化症的相关病理，并且通常是该疾病的首发症状。即使在多发性硬化症中 没有任何已知的视神经炎发作的患者，有证据表明功能和结构 可以在体内检测和监测 MS 在前视觉通路中的表现，从而反映疾病 活动。这些包括对比敏感度、临界闪烁融合频率、视网膜诱发电位 使用光学相干断层扫描 (OCT) 测量大脑和视网膜内层厚度。我们的主要目的是 建立视觉功能的敏感生物标志物，可以广泛提供给患有以下疾病的退伍军人 MS 用于检测 MS 复发、进展和治疗效果。一个重要的次要康复目标是 确定哪种传统和新的实验治疗可以减少视觉和中枢神经系统的波动 在多发性硬化症临床前动物模型中，已知这些功能会影响生活质量。 我们将采用两种相关的 MS 动物模型，一种 MOG 诱导的实验性自身免疫模型 慢性 MS 和 PLP 诱导的 EAE 脑脊髓炎 (EAE) 模型模拟复发缓解型。 我们还将进行热诱导压力测试，以引发 EAE 小鼠视觉和中枢神经系统功能的波动。 我们将确定体内眼部结构和功能生物标志物，并将它们与运动相关联。 感觉和认知功能。数据将与 MS 的离体结构表现相关，即神经元 丧失和脱髓鞘。我们建议剩余神经元的数量及其髓磷脂的完整性将 与视神经传导速度、视力和视网膜神经纤维层变薄的变化相关。我们 然后将检查目前使用芬戈莫德、4-氨基吡啶和生酮饮食的治疗是否会增加神经功能 轴突电活动并减少功能波动，有利于增强康复能力。较新 实验疗法，源自假设介导治疗效果的化合物 针对改善神经转导的间充质干细胞（MSC）疗法也将在 MS 的慢性和复发缓解模型。 在试验数据结果的支持下，我们将更加严格地确定减少视神经传导的因素 在 EAE 模型中，速度先于运动感觉和结构缺陷，并代表了早期的标志 疾病活动。我们的预期数据将提供关于视觉功能损伤如何对应的见解 脱髓鞘、视网膜变薄和视网膜神经节细胞（RGC）损失。我们还确定在什么时间点 早期治疗干预将改善长期功能和结构结果。我们进一步期望 提供令人信服的数据，表明神经轴突电活动和传导速度的改善 前景光明的新治疗途径，对恢复功能和生活质量具有非凡的临床影响。 这些结果的临床转化将有助于预测多发性硬化症患者的复发和康复。我们将 提供强有力的证据表明视觉功能测试可以用作监测多发性硬化症疾病活动的工具， 包括在出现临床症状之前检测复发或进展的亚临床发作。 总之，我们期望获得结论性数据来确定早期视觉生物标志物的性质 EAE 模型及其在预测中枢神经系统结果中的价值。此类生物标志物的翻译 临床实践将确定患有多发性硬化症的退伍军人需要进一步的疾病调节剂来优化 康复和生活质量。