Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis

Abstract

Magnetic resonance (MR) techniques are of value in following the pathological process of multiple sclerosis in vivo. They are widely applied to monitor the disease natural history and its modification by treatment. However, serial studies of lesion measures have yielded generally disappointing correlations with the development of clinical disability. A potential explanation for this is the presence of abnormalities, beyond the visible lesions, in the normal appearing white matter (NAWM) and grey matter (NAGM). Quantitative structural MR techniques, including measures of magnetisation transfer, diffusion, relaxation times and spectroscopic metabolite concentrations, reveal that there are abnormalities in NAWM and NAGM. These are present from clinical onset and become more pronounced with clinical progression, increasing disability and increasing lesion load. Furthermore, functional MRI (fMRI) studies of motor and visual paradigms has identified a range of responses suggesting that cortical plasticity exists; such modified responses are seen in the earliest stages of disease and in the absence of visible lesions, but are more pronounced with disease progression and increasing lesion load and abnormality in the NAWM. Limited reproducibility and sensitivity to change can pose methodological limitations for MR studies of NAWM and NAGM, especially when follow up intervals are relatively short. Whilst existing quantitative MR measures from normal appearing tissues provide valuable information to understand the natural history and monitor treatment effects in MS, none of them fully or even predominantly accounts for the patient's functional state nor can be relied on as a definitive surrogate measure of treatment effect. Better resolution of the abnormalities is needed especially in grey matter where pathological foci are known to be abundant. Studies correlating structural MR and fMRI parameters with measures of function in well defined anatomical pathways should further elucidate the pathogenic role of abnormality in the normal appearing tissues. In future, new imaging modalities are needed that provide a more specific measure of histopathological and cellular aspects of the disease process in vivo.

Classifying minimally disabled multiple sclerosis patients from resting state functional connectivity

“…Our results do not only confirm that functional changes affecting widespread (cortical and subcortical) networks are a prominent feature of MS brain pathology (Miller et al, 2003) but also show that these alterations can be reliably and sensitively measured using functional MRI of resting state, and furthermore be used to classify disease state in individual subjects. Our method is based on an established technique of brain decoding using wavelet decomposition of resting state time courses (Richiardi et al, 2011;Eryilmaz et al, 2011), previously applied to study cognitive and emotional states in normal conditions, but adapted here to assess pathological states.…”

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

“…99,100 However, these subtle MR changes are pathologically nonspecific and could potentially represent the effects of inflammation, gliosis, or axonal loss, all of which occur in NAWM. 4,101 Although they may be valuable for monitoring clinically relevant disease progression they should not be considered as specific markers of neurodegeneration. Another abnormality reported in MS is a decrease in signal on T2-weighted images of deep gray matter structures, 102 which probably reflects increased iron deposition; whether or not this correlates with neuronal loss is unclear.…”

High field MRI in the diagnosis of multiple sclerosis: high field–high yield?

“…The lack of correlation between conventional MRI findings in terms of T2 lesion load and clinical outcome measures, the so-called clinico-radiological dissociation has urged the development of several quantitative MRI methods including MR spectroscopy, diffusion tensor imaging, and magnetization transfer imaging [54][55][56]. Of special interest are these methods in quantifying disease burden in the normal-appearing brain tissue, particularly in CIS patients in order to get additional prognostic information [54,57,58].…”

“…Of special interest are these methods in quantifying disease burden in the normal-appearing brain tissue, particularly in CIS patients in order to get additional prognostic information [54,57,58].…”

“…1 H-MR spectroscopy 1 H-MR spectroscopy ( 1 H-MRS) is one of the best established quantitative MRI methods allowing the assessment and quantification of metabolic changes in lesions and the normal-appearing brain tissue (normal-appearing white matter; normal-appearing gray matter) of patients with CIS or definite MS [54]. In MS, two major metabolites are of special interest: the first one, the N-acetyl moiety (tNAA), a maker of neuronal viability.…”