EVALUATION OF AXONAL INTEGRITY USING DIFFUSION TENSOR IMAGING

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Project Abstract The candidate is an academic neurosurgeon, with a career scientific goal of understanding the mechanisms of axonal degeneration and regeneration following spinal cord and peripheral nerve injury. The candidate has significant prior laboratory experience with a track record of successful published research projects in axonal injury and regeneration. To prepare for the transition to successful independent investigator, the candidate's career development plan includes graduate-level coursework in designing outcomes and clinical research, epidemiology in clinical research, biostatistics, biological imaging technology, and grantsmanship. This will be supplemented with seminars in Neurology, Neurosciences, and the Hope Center for Neurological Disorders, as well as presentation of the candidate's research at major national and international conferences. The proposed career development plan and scientific training will occur at Washington University in St. Louis, an institution with particular strengths in neuroradiology, advanced imaging, and neurobiology, providing the candidate with important intellectual assistance and collaborations. The scientific training will be mentored by Dr. Sheng-Kwei Song, whose laboratory focuses on diffusion tensor imaging (DTI) of the nervous system. His laboratory's expertise in assessing axonal integrity and quantitative methods for determining white matter connectivity as well as his knowledge of cervical spine specific imaging methods will provide the candidate with the research tools needed to succeed as an independent investigator studying axonal injury and white matter integrity in patients with a spinal cord injury. Spinal cord injury is a significant public health problem. A major shortcoming limiting efforts to improve the treatment of patients with spinal cord injuries is the lack of quantifiable metrics on which to base clinical decisions. Advanced MRI techniques, such as DTI have shown tremendous promise as a non-invasive biomarker in traumatic head injury. DTI measures the magnitude, anisotropy, and directionality of water displacement in tissue and provides quantifiable measures of directional diffusivity along white matter tracts. DTI metrics such as fractional anisotropy, axial diffusivity, and radial diffusivity are markers of axonal and myelin damage. In animal studies DTI metrics have been shown to correlate with severity of injury following spinal cord injury. In an animal model we have demonstrated acute DTI measures are predictive of long-term functional outcomes following spinal cord injury. The long-term objective of this proposal is to establish and validate non-invasive imaging biomarkers that are predictors of a patient's clinical course and therapeutic response following a cervical spinal cord injury. The first aim, will determine whether DTI parameters correlate with acute neurologic function following cervical spinal cord injury. This aim will test the hypothesis that primary axonal injury produced by acute spinal cord injury, produces alterations in DTI parameters that correlate with acute neurologic function. The second aim of this proposal, will determine whether spine DTI metrics measured acutely, predict, long-term neurologic outcomes following a cervical spinal cord injury. This aim will test the hypothesis that axonal injury caused by acute spinal cord injury produces a measurable decrease in spinal cord DTI metrics, which are predictive of long-term functional outcomes. The final aim, is to determine the quantitative change in brain and spine corticospinal tract fractional anisotropy, axial diffusivity, and radial diffusivity values in patients with cervical spinal cord injuries. We will test the hypothesis that chronic cervical spinal cord injuries result in predictable changes in both brain and spine DTI metrics that correlate with long-term clinical outcome. The identification and validation of such non-invasive DTI biomarkers will provide guidance on clinical management, long-term prognosis, and family counseling. The validation of a non-invasive biomarker for predicting functional recovery following an acute spinal cord injury would represent a new and substantial advance in prognostication following a cervical spinal cord injury.