Review
Gray matter pathology in (chronic) MS: Modern views on an early observation

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Abstract

Involvement of the gray matter (GM) in the pathology of multiple sclerosis (MS) was already recognized in the early days of MS research, but the detection of (cortical) GM lesions under the microscope and with magnetic resonance imaging (MRI) techniques was initially suboptimal and could only recently be enhanced. The visualization of GM lesions in vivo opens new doors for studies focusing on clinical, especially cognitive, effects of GM pathology, as well as for monitoring of neuroprotective treatment. However, so far little is known about what causes GM pathology. In this review, several pathogenetic mechanisms will be discussed, affecting the MS brain both from the ‘outside-in’ and from the ‘inside-out’. Also, the use and reliability of MRI atrophy measures as a monitoring tool for GM damage in the therapeutic setting will be reviewed.

Introduction

“How is it that, one fine morning, Duchenne discovered a disease that probably existed in the time of Hippocrates? Why do we realise things so late, so poorly, with such difficulty?”

This question was pondered by the famous French neurologist Jean-Martin Charcot (1825–1893), in remembrance of his deceased friend Guillaume-Benjamin Duchenne (de Boulogne) who had spent much time and effort on characterizing pseudohypertrophic muscular dystrophy at the end of the 19th century. Charcot's answer to his own question was: “…Because our minds have to take in something that upsets our original set of ideas.” [1]

This, in a slightly different fashion, also applies to the field of multiple sclerosis (MS), where the realization that gray matter (GM) structures are heavily involved in the pathology of the disease has only really sunken in recently, despite early remarks from histology. In 1916, neurohistologist James W. Dawson published a comprehensive overview on the histology of disseminated sclerosis [2], and stated that: “when an area [of demyelination] is confined to the cortex, the changes are, as a rule, not nearly so marked, especially those in the deepest layers. The demyelination may reach from the surface of the convolution to varying depths, even to the border between cortex and white matter. It may lie wholly within the cortex and cut through a portion of the radiation or simply affect Baillarger's stripe. These areas are often in association with a markedly dilated vessel which penetrates from the surface almost to Baillarger's stripe, and a number of dilated changed smaller vessels lie within the area.” Interestingly, noticing the striking lack of glial proliferation, the cellular paucity and the relative preservation of axons within demyelinated GM lesions, Dawson wondered: “Is then, the process that attacks the cortex different in its nature and origin from that which affects the rest of the central nervous system?” These sharp observations and this particular question, stemming from a period well before advanced immunohistochemical staining methods were introduced, have proven to be prophetic to the field.

Section snippets

GM pathology in MS

After the initial casuistic descriptions of demyelination in the GM of MS patients, at the beginning of the 20th century, the subject was long disregarded. This was mainly due to difficulties involved with visualizing cortical GM lesions using conventional histochemical staining procedures, as well as to a predominant attention for the more prominent process of inflammatory demyelination in the white matter (WM). In 1962, the interest in GM lesions in MS was rekindled through a histopathology

Advanced imaging techniques used to visualize GM damage

As mentioned, the problem of low conspicuity of cortical GM lesions on conventional MR images was partly solved by the introduction of the DIR technique (see Fig. 1), which showed a fivefold improvement of cortical lesion detection compared to standard T2-weighted MRI [45]. Furthermore, 3D T1-based imaging [47], and a combination of phase-sensitive inversion recovery and DIR [48], were successfully applied to enhance the visualization of GM lesions in MS. Whether all, or at least most of, the

Pathogenic mechanisms possibly leading to GM damage

Although the exact pathological mechanisms underlying neurodegeneration are presently unknown, it is often considered to be secondary to myelin damage. In this so-called ‘outside-in’ model, damage first occurs to the ‘outer unit’ i.e. oligodendrocyte or the myelin membranes, and as a result of the demyelination, the ‘inside unit’, i.e. the axon, becomes vulnerable and degenerates with time (Fig. 3A).

However, axonal injury may also precede demyelination in MS, in which case neurodegeneration may

Imaging neurodegeneration in a therapeutic setting: do we have a valid technique?

Multi-focal WM lesions, brain atrophy and, to a lesser extent, the more subtle changes in NAWM and NAGM can all be used as MRI outcome measures in MS. However, if we wish to monitor GM damage and the neurodegenerative aspects of MS in a clinical trial setting, measurement of brain atrophy may be the most relevant biomarker [112].

It should be noted that the terms ‘brain atrophy’ and ‘brain volume (BV) loss’ are not clearly distinct in the MS literature. Measured changes in BV in MS can be caused

Conclusions

GM pathology already occurs early in MS and accumulates substantially with progressing disease. What causes GM pathology, and why GM damage accelerates after conversion to the secondary progressive phase, is so far largely unknown. Several pathogenic mechanisms might play a role, and both ‘outside-in’ and ‘inside-out’ types of pathogenesis have been suggested. In the outside-in model, the myelin is primarily affected followed by degeneration of the neuroaxonal structures; in the ‘inside out’

Acknowledgements

JJGG is financially supported by the Dutch MS Research Foundation (grant no. 05-358c). The authors wish to thank Drs. S.D. Roosendaal and E.-J. Kooi for help with Fig. 1, Fig. 2, and Drs. B.D. Trapp and G. Kidd for help with Fig. 3.

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