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

Abstract

Magnetic resonance imaging (MRI) monitoring of disease progression in multiple sclerosis is limited by the lack of correlation of abnormalities seen on T2-weighted imaging, and disability. We studied the histopathology of multiple sclerosis lesions, as depicted by MRI, in a large postmortem sample, focusing on axonal loss. Tissue samples from 17 patients were selected immediately postmortem for histopathological analysis on the basis of T2-weighted imaging, including normal appearing white matter and T1 hypointense lesions. In each region, we measured magnetization transfer ratios (MTR), T1 contrast ratio, myelin, and axonal density. T2 lesions (109 samples) were heterogeneous with regard to MRI appearance on T1 and MTR, whereas axonal density ranged from 0% (no residual axons) to 100% (normal axonal density). Of 64 T2 lesions, 17 were reactive (mild perivascular inflammation only), 21 active, 15 chronically active, and 11 chronically inactive. MTR and T1 contrast ratio correlated strongly with axonal density. Also in normal appearing white matter (24 samples), MTR correlated with axonal density. In conclusion, postmortem tissue sampling by using MRI revealed a range of pathology, illustrating the high sensitivity and low specificity of T2-weighted imaging. T1 hypointensity and MTR were strongly associated with axonal density, emphasizing their role in monitoring progression in multiple sclerosis.

Lesion heterogeneity in multiple sclerosis: a study of the relations between appearances on T1 weighted images, T1 relaxation times, and metabolite concentrations

“…Interestingly, several reports have correlated reduced lesion MTR with reduced NAA34 35 and with prolonged T1, the last either measured directly17 or inferred from the appearance of T1 hypointensity 1516 36 …”

“…Histopathological studies from both biopsy13 and postmortem14 15 brain tissue provide further evidence that hypointense T1 lesions are indeed associated with more severe tissue damage including axonal loss, and also with increased extracellular fluid. The severity of the tissue damage seems to be reflected by the degree of the hypointensity, determined semiquantitatively,14-17 and with the T1 relaxation time 17…”

The Effect of Three Times a Week Glatiramer Acetate on Cerebral T1 Hypointense Lesions in Relapsing‐Remitting Multiple Sclerosis

“…Measurement of T1H black holes may capture various aspects of lesion evolution, such as demyelination and axonal loss 4, 5, 8…”

“…On T1‐weighted pre‐contrast scans, focal areas appearing hypointense compared with surrounding, normal‐appearing white matter are termed T1 hypointense (T1H) lesions 3. T1H lesions appearing on pre‐contrast T1‐weighted images (WI) may capture various pathologic hallmarks of lesion evolution, including demyelination, axonal loss, and tissue loss, and have been termed “black holes.”3 In subjects with relapsing‐remitting MS (RRMS), the formation of new T1H black holes can yield important information with regard to areas of matrix destruction, and their presence has been associated with MS‐related disability 4, 5…”

Cerebral Blindness due to Acute Disseminated Encephalomyelitis

“…Repeat imaging, three months after discharge, showed no new lesions, although many of the existing lesions, particularly those in the right optic radiation, had become hypointense on the T1-weighted imaging (Figure 4), appearances suggestive of tissue destruction. 2 One year later her …”