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.

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.