Brain Atrophy

The progressive development of brain atrophy is a well-known feature of patients with MS (Miller et al., 2002) (Fig. 1). As a consequence, measurement of brain atrophy is viewed as a potentially useful marker of destructive and irreversible MS tissue damage.

Considering that axons represent a large proportion of white matter, axonal loss is likely to be an important contributor to atrophy in MS. Plaques in MS are not limited to the white matter, but they are also located, diffusely, in the cortical (Lumdsen, 1970; Kidd et al., 1999; Peterson et al., 2001) and deep (Cifelli et al., 2002) gray matter, whose neurons might also be affected by retrograde and trans-synaptic degeneration secondary to white matter damage. Therefore, loss of myelin and axons in these lesions might also contribute to brain atrophy in MS. An additional and compelling in vivo evidence that brain atrophy might reflect irreversible axonal loss derives from multiparametric MRI studies (Coles et al., 1999; Sailer et al., 2001) that have demonstrated a strong correlation between measures of brain atrophy and (1) the reduction of the level of N-acetylaspartate (NAA) (Coles et al., 1999), a metabolite that is considered a marker of axonal/neuronal loss/dysfunction (Simmons et al., 1991); and (2) the amount of T1-hypointense lesions (Sailer et al., 2001), which are characterized pathologically by marked axonal loss (van Walderveen et al., 1998). Nevertheless, it is likely that other pathological substrates, such as myelin loss, astrocytosis and inflammation can influence brain volume measures. Therefore, caution should be taken when considering this metric as a measure of axonal/neuronal damage in MS.

Several cross-sectional and longitudinal MRI studies have investigated the magnitude of the correlation between brain volume decrease and clinical findings in MS. The main results of these studies can be summarized as follows:

1. Brain atrophy can develop in the early, relapsing-remitting (RR) phase of MS (Simon et al., 1999; Ge et al., 2000; Chard et al., 2002a), as well as in patients with

Figure I Axial Tj-weighted magnetic resonance (MR) images of the brain from a normal control (A) and from a patient with secondary progressive multiple sclerosis (MS) (B). In the patient with MS, an enlargement of the lateral ventricles and of the brain sulci is evident.

clinically isolated syndromes (CIS) suggestive of MS (Dalton et al., 2002; Filippi et al., 2003b)

2. The amount of tissue loss increases with increasing disability and disease duration (Losseff et al., 1996; Stevenson et al., 1999; Kalkers et al., 2001)

3. Brain volume measurements correlate better with clinical disability than other cMRI metrics, particularly in patients with the progressive phenotypes of the disease (Kalkers et al., 2002; Miller et al., 2002)

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