MRI Studies

MRI reveals that axonal loss in MS lesions correlates with the presence of permanent Tl-weighted "black holes'' on MRI (87-90), a reduction in N-acetyl aspartate (NAA) on magnetic resonance spectroscopy (MRS) (91,92) and the extent of CNS atrophy in the spinal cord (93). Since these imaging parameters correlate with clinical disability, axonal damage likely contributes to irreversible clinical disability in MS.

New Gd enhancing lesions mainly occur during the early relapsing phase of the disease, whereas Gd-enhancing lesions occur less frequently during the slowly progressive phase of the disease, characteristic of PPMS and SPMS without relapses (94). There are also progressive signal abnormalities in the so-called "normal appearing'' white matter of MS patients. MRS reveals reduced NAA and elevated creatine levels in the NAWM of primary progressive MS (95,96), and magnetic transfer ratios are reduced in the NAWM of chronic versus relapsing disease (97). These changes have been interpreted as evidence of axonal destruction in the white matter plaques leading to secondary (Wallerian) degeneration (92,98,99). However, brain atrophy in MS is, in part, independent of T2 lesion load, suggesting that NAWM pathology not only reflects Wallerian degeneration of axons traversing macroscopic lesions, but also reflects microscopic or diffuse lesions not detected by MRI (100). Diffuse white matter damage and axonal loss can be severe despite very few white matter lesions (101,102), again highlighting the dissociation between inflammatory demyelination and neurodegeneration in MS. The focus on focal white matter pathology in MS represented by enhancing and nonenhancing lesions on MRI may have missed potential pathological differences between relapsing and progressive MS. Defining these pathologic differences may help better understand the dissociation between inflammatory demyelination (relapses/MRI activity) and neurodegeneration (gradual disease progression) in MS.

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