Although magnetic resonance (MR) imaging is valuable in clinical and experimental evaluation of spinal cord injury (SCI), its potential for defining the nature and severity of axonal damage in SC trauma has not been realized. Research in SCI suggests that it may be possible to: a) limit axonal deterioration, b) encourage repair and c) promote axon regeneration. Application of these remedies will require early and accurate identification of interrupted axons and the ability to follow axonal regeneration. Our goal is to develop analysis tools which will permit the use of MR to monitor axonal degeneration and regeneration. In the normal SC, diffusion is anisotropic, with higher apparent diffusion coefficients (ADC) parallel than perpendicular to the long axis on the cord. Previously, we have shown that SC injury reduces diffusional anisotropy. Current models of the diffusion process suggest that anisotropy is a consequence of diffusion barriers posed by the axon surface membrane and myelin sheath and that the diameter of the axons is an important parameter in determining white matter (WM) ADC. The magnetization transfer ratio (MTR) is a function of the interaction of water with macromolecules. In our earlier work, we found that the MTR correlated with the severity of damage to both myelin and neurofilaments (NF). These concepts of the determinants of ADC and MTR have been tested only for a limited range of axonal pathology, and their predictive value with regard to SCI are still unknown. We wish to determine the roles of these factors in generating the changes in ADC and MTR that are observed after SCI. We propose to compare the effects of post-traumatic axonal degeneration and regeneration on ADC and MTR in 2 animal models.: 1) The sea I lamprey, which lacks myelin, contains a very broad range of spinal cord axon diameters (some as large as 50 microns) and shows robust spontaneous regeneration; and 2) The rat, which contains myelin, has a narrower range of axon diameters, similar to that of humans, and does not normally show spontaneous axonal regeneration in the cord. In the rat, we will induce regeneration through transplantation of fibroblasts genetically modified to express brain derived neurotrophic factor (BDNF), which promotes regeneration and retards degeneration of injured axons. By correlating the MR measures and functional outcomes with I histopathologic evidence of axonal injury in these animal models, we will develop methods for using MRI to predict the location, nature and severity of axonal damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041380-03
Application #
6639749
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Kleitman, Naomi
Project Start
2001-05-01
Project End
2006-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
3
Fiscal Year
2003
Total Cost
$563,793
Indirect Cost
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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