Axonal loss in multiple sclerosis lesions: Magnetic resonance imaging insights into substrates of disability

Magnetic resonance imaging (MRT) monitoring of disease progression in multi ple sclerosis is limited by the lack of correlation of abnormalities seen o n T2-weighted imaging, and disability. We studied the histopathology of mul tiple sclerosis lesions, as depicted by MRI, in a large postmortem sample, focusing on axonal loss. Tissue samples from 17 patients were selected imme diately postmortem for histopathological analysis on the basis of T2-weight ed imaging, including normal appearing white matter and T1 hypointense lesi ons. In each region, we measured magnetization transfer ratios (MTR), T1 co ntrast ratio, myelin, and axonal density. T2 lesions (109 samples) mere het erogeneous with regard to MRI appearance on T1 and MTR, whereas axonal dens ity ranged from 0% (no residual axons) to 100% (normal axonal density). Of 64 T2 lesions, 17 were reactive (mild perivascular inflammation only), 21 a ctive, 15 chronically active, and 11 chronically inactive. MTR and T1 contr ast ratio correlated strongly with axonal density. Also in normal appearing white matter (24 samples), MTR correlated with axonal density. In conclusi on, postmortem tissue sampling by using MRI revealed a range of pathology, illustrating the high sensitivity and low specificity of T2-weighted imagin g. T1 hypointensity and MTR were strongly associated with axonal density, e mphasizing their role in monitoring progression in multiple sclerosis.