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.

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

“…21 Although subject to short-term fluctuations similar to lesion contrast, MT has been strongly associated with demyelination and axonal loss in histology. 22,23 MT is therefore expected to be more sensitive to the destructive aspects of disease activity, supporting the concept of subacute disease that reaches neither a clinical threshold nor becomes visible as focal MRI changes.…”

Basal forebrain integrity and cognitive memory profile in healthy aging

“…In patients with multiple sclerosis, reductions in MTR can be observed even if other imaging modalities, such as T2-and T1-weighted imaging show no abnormality making it particularly sensitive in detecting early abnormalities of normal appearing tissues including white matter (Audoin et al, 2004;Fernando et al, 2005;Iannucci et al, 2000;Traboulsee et al, 2002) and cortical (Fernando et al, 2005) as well as deep gray matter (Audoin et al, 2004). MTR reductions in normal appearing white matter might be due to astrocytic proliferation, perivascular inflammation, demyelination (Rademacher et al, 1999), and loss of axonal density (van Waesberghe et al, 1999) as well as vascular insults (Fazekas et al, 2005). MTR reductions in normal appearing gray matter could be due to trans-synaptic morphological abnormality secondary to afferent demyelinating lesions (Audoin et al, 2006).…”

Quantitative MRI‐pathology correlations of brain white matter lesions developing in a non‐human primate model of multiple sclerosis

“…Accordingly, the macrophage inflammation marker MF I , which reflects whether macrophages in the lesions express markers of active or inactive lesions, showed the highest correlation with MTR. Both in EAE models and MS patients, the presence of inflammatory cells, and particularly macrophages, has been associated with a reduction in MTR (29,(34)(35)(36), but also with an increase in T 1 relaxation time [or decrease in T 1 -weighted intensity, the so called 'black holes' (35,37,38)] and mainly with the presence of Gd-DTPA enhancement (37)(38)(39)(40)(41)(42)(43). However most studies are descriptive and in only a few studies could quantitative MRI data be correlated with (semi-) quantitative histological data.…”

“…This observation contrasts with several studies in EAE models (35) and patients with MS (36), which reveal significant correlation between axonal density and the same MR characteristics used in our study. Furthermore, axonal density appears to be reduced in black holes compared with normal-appearing tissue in patients with MS (32,36,44). However, this was not observed in all MS studies (45) nor in EAE (35).…”