Imaging Marker for Monitoring Myelin Pathology After Spinal Cord Injury
Abstract
Spinal cord injury (SCI) is a life-altering event that usually results in permanent neurological disability. While it is difficult to estimate the world-wide incidence of SCI, recent meta-analysis suggests anywhere from 3.6 to 195 patients per million persons have SCI. The incidence in the United States is estimated at 54 cases per million persons with 17,500 new cases per year. SCI is one of the medical conditions with high impact on the US armed forces. Recent studies by U.S. Army Medical Research and Development Command (USAMDMC) suggested that the incidence rates of SCI have risen sharply among U.S. military Service members deployed to battlefields such as Iraq and Afghanistan. Despite the relatively lower incidence compared to chronic diseases and conditions, the economic burden of SCI is substantial. The cost of hospital charges alone in the United States was estimated to be $1.69 billion in 2009 and did not include cost of lost productivity or non-hospital expenses. In the Department of Veterans Affairs (VA) system, it has been shown that the annual cost of caring for a Veteran with SCI exceeds that of caring for a person with any other chronic disease. The significance of these data is made more salient given the complete absence of treatments to enhance neurological recovery and mitigate disability after SCI. Even though it has been demonstrated that rehabilitative efforts can extend life and improve the quality of life for persons with SCI, there are no diagnostic tests that can be utilized to provide prognosis, direct rehabilitation intervention or identify appropriate patients for clinical trials. The overarching goal of our work is to develop a non-invasive imaging technique that provides prognostic information to direct rehabilitation efforts as well as identify the most appropriate persons for clinical trials based on the pathophysiology of their injury. SCI often leads to programmed death of oligodendrocyte cells, which causes damage to myelin membranes of axonal tracts and compromises axonal propagation of action potential and signal transduction along the spinal cord. Thus, a major challenge facing the diagnosis and prognosis of SCI is to quantitatively monitor the pattern and degree of myelin damage and repair after SCI, which so far has remained a matter of speculation. This is primarily due to the lack of an in vivo imaging technique that can be used to specifically detect myelin changes. Currently, magnetic resonance imaging (MRI) is used as the primary imaging modality to detect lesions in the spinal cord. However, use of MRI as an imaging marker has some severe limitations such as the non-specific nature of white matter changes and low sensitivity as well as limited quantification capability, which combine to lead to a clinico-radiological paradox: a weak association between MRI lesion load and myelin pathology. This is caused by the fact that MRI signals reflect mostly changes of tissue water content, which are not specific for myelin. For this reason, we have set out to develop a novel imaging technique based on positron emission tomography (PET), a clinical imaging modality that is highly specific and sensitive when used with myelintargeting molecular probes. We have developed and tested a wide array of these probes that readily enter the brain and spinal cord and bind to myelin with high affinity and specificity. We have demonstrated the ability of these agents, when labeled with positron-emitting C-11, to image static myelin and dynamic myelin loss and repair in non-human primates as well as in various animal models in a longitudinal fashion. Several of the myelin-imaging agents we developed have become standard tools for other investigators worldwide to study myelin-related neurological diseases. For spinal cord imaging, we have identified [N-methyl-11C]-4,4’-diaminostilbene ([11C]MeDAS) as our lead radiotracer for PET as an imaging endpoint for disease stratification and for monitoring trea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910823
Entities
People
- Yanming Wang
Organizations
- Case Western Reserve University
- United States Army