Magnetic resonance spectroscopy as a measure of brain damage in multiple sclerosis

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Abstract

Recent MR studies have emphasised the importance of neuronal and axonal damage in multiple sclerosis. In this respect, proton MR spectroscopy (by monitoring levels of N-acetylaspartate, a putative marker of axonal integrity) has been particularly illuminating by showing indirect evidence of neurodegeneration in both lesional and non-lesional brain tissues from the earliest stages of the disease. The importance of these changes to patients’ clinical disability argues for the primary role of neuronal pathology in the pathogenesis of the disease.

Introduction

In the last few years, there has been an appreciation of the apparently primary role of neuronal and axonal injury in the pathogenesis of multiple sclerosis (MS) [1], [2]. This has been driven to a significant degree by results of proton magnetic resonance (MR) spectroscopy (MRS) studies, which have emphasised that substantial neuro-axonal damage occurs inside the demyelinating lesions as well as in the normal-appearing cerebral white matter (WM) and grey matter (GM) of patients with MS [2], [3]. All this has been confirmed pathologically [1], [4], [5] and has led to a reconsideration of the role of axonal damage in MS [6].

Here we review MRS studies assessing in vivo the chemical–pathological changes of MS brains and showing evidence that neuro-axonal injury occurs early, diffusely and perhaps independently of lesion genesis in the brains of patients with MS.

Section snippets

Basics of proton MR spectroscopy

Conventional MRI detects brain abnormalities with great sensitivity, but does not provide specific information about the pathology underlying the detected abnormalities [7]. New MR techniques seem able to overcome some of these limitations [8]. Among these, proton MRS seems to be the most promising as it can complement conventional MRI by defining simultaneously several chemical correlates of the pathological changes occurring within and outside T2-visible lesions.

Resonances in MR spectra are

Proton MRS changes in MRI-visible brain lesions

Proton MRS of acute MS lesions at both short and long echo times reveals increases in Cho and Lac resonance intensities since the early phases of the pathological process [20], [21]. Changes in the resonance intensity of Cho result mainly from increases in the steady state levels of phosphocholine and glycerol–phosphocholine, both membrane phospholipids that are released during active myelin breakdown. Increases in Lac are likely to reflect the metabolism of inflammatory cells. In large, acute

Proton MRS changes in MRI normal appearing brain tissue

Pathologists traditionally have focussed the attention on the plaques of MS. Early single voxel MRS studies also were focussed mainly on MRI-defined lesions [23], [24]. However, more recent studies exploiting the greater coverage and resolution of MRSI have shown that the observed decreases in NAA in MS patients are not restricted to lesions, but are present both adjacent to and distant from the lesions [12], [14], [16], [18], [25], [26]. The extent of this NAA reduction decreases with the

NAA as marker of axonal damage in multiple sclerosis

As mentioned before, NAA is believed to exist in significant quantity essentially in neurons and neuronal processes in mature brains [46], [47]. This has led to the interpretation of NAA decreases as due to significant neuronal and axonal damage or loss.

Recently, concern has been raised about the NAA specificity, as this metabolite has been identified in O2A progenitor cells and oligodendroglial cell cultures [48], [49]. However, earlier observations that antibodies directed against NAA or NAAG

When and how does the axonal damage occur in MS patients?

Several recent studies have emphasized that the diffuse axonal pathology that is found in MS brains occurs in the early stages of the disease [2], [54] and can be evident even before irreversible disability does occur [28]. Even complete clinical recovery from acute attacks in early MS does not mean that axonal pathology has not occurred. Data showing that mild axonal changes can be evident in MS lesions of individuals with no history of neurological symptoms [55] lend support to this

The relationship of NAA decreases to clinical disability

As the pathological changes primarily responsible for disability are logical targets for new therapeutic agents, understanding the changes responsible for functional impairment is a crucial issue. Proton MRS, by providing quantitative tools for non-invasive detection of axonal injury and loss in patients with MS, allows dynamic correlations between such changes and disability in life.

The decreased NAA levels reported by MRS studies have been shown to be closely correlated with increasing

Conclusions

Evidence from proton MRS studies indicates that the progression of axonal injury in MS is diffuse and inexorable and clearly accompanies even the earliest inflammatory changes. More recent evidence of pre-lesional pathology also suggests that this may even precede the recognized focal pathology characteristic of the disease. These results, confirmed by modern histopathology [68], have led to a reconsideration of the importance of neuronal and axonal pathology in this disease.

To the extent that

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