Gray matter imaging in multiple sclerosis: what have we learned?

Abstract

At the early onset of the 20th century, several studies already reported that the gray matter was implicated in the histopathology of multiple sclerosis (MS). However, as white matter pathology long received predominant attention in this disease, and histological staining techniques for detecting myelin in the gray matter were suboptimal, it was not until the beginning of the 21st century that the true extent and importance of gray matter pathology in MS was finally recognized. Gray matter damage was shown to be frequent and extensive, and more pronounced in the progressive disease phases. Several studies subsequently demonstrated that the histopathology of gray matter lesions differs from that of white matter lesions. Unfortunately, imaging of pathology in gray matter structures proved to be difficult, especially when using conventional magnetic resonance imaging (MRI) techniques. However, with the recent introduction of several more advanced MRI techniques, the detection of cortical and subcortical damage in MS has considerably improved. This has important consequences for studying the clinical correlates of gray matter damage. In this review, we provide an overview of what has been learned about imaging of gray matter damage in MS, and offer a brief perspective with regards to future developments in this field.

Figure 1

Timeline of GM imaging in MS. A schematic overview of developments in the field of GM imaging in MS from the beginning of the 20^th century until now. A, B, D) Reproduced from Kidd et al. [7], Kutzelnigg et al. [19], and Schmierer et al. [88] respectively, all with permission from Oxford University Press. C) Reproduced from Cifelli et al. [100] with permission from John Wiley and Sons. E, F) Reproduced from Geurts et al. [69] and Roosendaal et al. [126] respectively, both with permission of the Radiological Society of North America.

Figure 2

Pathological classification system of GM lesions in MS. GM lesion classification system as proposed by Bo et al,. 2003. Type 1 lesions (A) extend through both white and gray matter. Type 2 lesions (B) are intracortical, having no contact with white matter or with the surface of the brain. Type 3 lesions (C) extend inward from the surface of the brain. Type 4 lesions (D) extend through the whole width of the cortex without reaching into white matter. Reproduced from Geurts and Barkhof [131] with permission from Elsevier.

Figure 3

Subcortical GM damage in MS. Subcortical atrophy, measured using FIRST (part of FSL 4.1: http://www.fmrib.ox.ac.uk/fsl/). Above: Effect sizes of subcortical atrophy in a cohort of 120 early RRMS patients, six years post-diagnosis. Below: Two examples of segmented subcortical structures in a healthy control (HC, above) and an age-matched RRMS patient (MS, below).

Figure 4

Non-neocortical GM damage: the hippocampus. A) Extensive hippocampal demyelination observed in post-mortem material. Reproduced from Geurts et al. [95] with permission from the American Association of Neuropathologists Inc. B) In vivo detection of hippocampal lesions using DIR imaging. Reproduced from Roosendaal et al. [116] with permission from John Wiley and Sons. C) Hippocampal atrophy on high field MRI provides detailed information on the specific location in the hippocampus where atrophy is present. Reproduced from Sicotte et al. [118] with permission from Oxford University Press. D) Anno 2011 it is besides structural changes also possible to study functional changes in the hippocampus; the blue areas indicates reduced hippocampal activity in cognitively impaired MS patients compared to healthy controls. Reproduced from Hulst et al. [127] with permission from John Wiley and Sons.