MR Spectroscopy AAcetyl Aspartate AAA

The main peak in the proton MR spectrum from human adult CNS is ^-acetyl aspartate (NAA), an amino acid contained almost exclusively in neurones and axons. A reduction in NAA provides evidence of axonal dysfunction or loss and has been consistently reported in MS lesions and NAWM (Fu et al., 1998). Neuroaxonal loss per se is not a sufficient explanation for all instances where a decrease in NAA is observed. In acute gadolinium enhancing lesions, decreased NAA is consistently present during the acute phase but frequently increases with follow-up in subsequent months (Davie et al., 1994). This suggests that there is a partly reversible element to the decrease indicating dysfunction but not death of neurones and axons. A possible mechanism is mitochondrial dysfunction during acute inflammation, which reduces the normal production and metabolism of NAA (that is closely linked to mitochondrial function). There is evidence from a study of acute experimental allergic encephalomyelitis that decreased NAA and ultrastructural mitochondrial abnormalities occur in the absence of axonal loss (Brenner et al., 1993). Follow-up of acute MS lesions has nevertheless revealed that the recovery of NAA is incomplete; persistent decrease in postinflammatory lesions would be consistent with axonal loss, although a persistent disturbance of mitochondrial function in the presence of demyelination may also be a possible explanation.

Two approaches have been used to measure NAA: (i) an absolute measure of concentration and using an external standard reference of known concentration and (ii) a ratio of NAA/Cr which assumes that Cr (creatine/phosphocrea-tine) remains stable in pathological situations. Although both approaches have produced robust evidence that NAA is reduced in MS lesions and normal appearing tissues, abnormalities of Cr may also occur (Fernando et al., 2004). Therefore absolute measures are preferable. A methodological approach of recent interest is the quantitation of whole brain NAA (Gonen et al., 2000). As a global marker of the progressive neurodegenerative process in MS it appears promising, although any changes observed are not anatomically localized and could represent abnormality in lesions,

NAWM, or gray matter. The resonance for whole brain NAA is broad and requires manual delineation for quantification—its analysis is potentially subject to bias and poor reproducibility. The narrow NAA resonances from small voxels—obtained as a single region or as part of a spectroscopic imaging slice—can be automatically identified and quantified with a model that uses as reference a solution with a known concentration of NAA (Provencher, 1993).

There have been several studies of NAA in cohorts with CIS or early relapsing remitting MS, which are of interest in understanding when neuroaxonal dysfunction or loss begins. Tourbah and colleagues (1999) reported a normal NAA/Cr ratio from the NAWM in a group of patients with isolated optic neuritis compared with controls. Recently, Fernando et al. (2004) have investigated NAWM NAA in 96 patients within 6 months of a CIS; compared to 44 healthy controls they reported a mean -2.2% decrease in NAA but this difference was not significant. Another recent study—in patients with clinically definite relapsing-remitting MS and a disease duration less than 3 years—reported that compared to controls, there was a significant reduction in MS NAWM NAA (mean -5%; Chard et al., 2002b). Taking these findings together suggests that axonal loss or dysfunction in NAWM is minimal at MS onset with a CIS but becomes apparent within a few years.

These findings of limited or no abnormality of NAWM NAA contrasts with another recent study of CIS patients, which reported a -22.3% decrease in whole brain NAA of patients versus controls (Filippi et al., 2003). The difference in findings may have several explanations: (i) the whole brain study included lesions and gray matter as well as white matter; (ii) the cohort studied was smaller and restricted to those with evidence fulfilling the McDonald criteria of dissemination in space; (iii) there are fundamental differences in the methodologies used. Based on evidence from a cross-sectional study of patients with relapsing-remitting MS compared with controls that the extent of decrease in whole brain NAA is greater than that of brain atrophy, it has been suggested that neuronal/axonal dysfunction (decrease in NAA) precedes parenchymal tissue loss (atrophy) (Ge et al., 2004). Further studies are needed that specifically explore disease effects upon gray matter and white matter metabolite profiles in patients with CIS.

A greater reduction of NAWM NAA is observed in secondary progressive than in relapsing-remitting MS (Fu et al., 1998), and disability has been correlated with reduced NAA in both cerebral (Sarchielli et al., 1999) and cerebellar white matter (Davie et al., 1995) NAWM (Fig. 5). The observation that there is a significant correlation between increasing atrophy and decreasing NAA in both cerebral hemispheres (Coles

The study compared 11 ataxic MS patients vs 11 non ataxic MS and 11 healthy controls. Reduced cerebellar white matter [NAA] was seen in ataxic patients only mean concentration Ataxic MS 6.7mM p=0.0002

Ataxic MS Nonataxic MS Healthy controls

9.7mM NS

(a) Region where spectra acquired

(b) Reduced NAA peak in ataxic patient

(c) Normal NAA peak in non ataxic patient

From Davie et al Brain 1995

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Figure 5 MR spectroscopy evidence of cerebellar white matter axonal loss and disability in MS. (From Davie et al. (1995), Brain 118, 1583-1592.)

et al., 1999) and cerebellum (Davie et al., 1995) supports their role as measures of axonal loss. Decreased NAA has also been observed in cortical gray matter in early relapsing-remitting MS (-7%) suggesting that early neuronal cell body damage is occurring (Chard et al., 2002b). It is reduced by ~20% in thalamic gray matter in secondary progressive MS and in a postmortem study, the decrease in NAA (accompanied by atrophy) was associated with decreased numbers of neurones (Cifelli et al., 2002). In primary progressive MS, NAWM NAA is decreased (Leary et al., 1999) and reduction of NAA and atrophy appear to be relatively independent of T2-lesion load (Pelletier et al., 2003).

Additional studies comparing relapsing-remitting versus secondary progressive MS have yielded valuable information. A cross-sectional analysis using a large single slab of tissue acquired through the cerebral hemispheres above the level of the lateral ventricles reported a similar reduction in the NAA/Cr ratio in both subgroups although a larger proportion of the region of interest was occupied by lesions in the relapsing-remitting group (Matthews et al., 1996). Subsequent investigation using single-slice spectroscopic imaging revealed that NAWM NAA was reduced in both groups but more so in those with secondary progressive MS (Fu et al., 1998). The reduction in NAWM NAA was not as great as that seen in lesions (Fu et al., 1998), but is potentially of more functional importance since the NAWM constitutes a much larger proportion of the CNS. A follow-up study after an interval of two years reported a further reduction of NAWN NAA/Cr in the relapsing remitting but not secondary progressive cohort (Fu et al., 1998). Taken together, these studies point to a dynamic process of progressive axonal dysfunction or loss in cerebral NAWM that contributes to disease progression, although its contribution may diminish with increasing disease duration.

A lower level of cerebral hemisphere NAA was recently reported in a subgroup of 19/72 MS patients who had the epsilon4 allele of apolipoprotein E (Enzinger et al., 2003). Among 44 patients followed up for an average of 34 months, there was a greater ongoing decline in NAA in epsilon4 carriers. This study points to the potential for genetic factors to influence the susceptibility to axonal loss and, by implication, the clinical prognosis.

A limitation of spectroscopy is the low signal-to-noise ratio and modest reproducibility of the measured metabolite concentrations. For this reason, it has been little used in multi-center therapeutic trials. Two small single-center studies of patients treated with beta interferon have produced conflicting results. One study showed an increase in NAA suggesting a therapy-induced reversal of axonal dysfunction (Narayanan et al., 2001). The other showed a decrease in NAA suggesting that progressive axonal loss continues in spite of treatment (Parry et al., 2003). In spite of methodological difficulties, more vigorous efforts to investigate NAA as a surrogate outcome in trials of neuro-

protection in MS would seem warranted, given that this metabolite provides specific information on axonal survival and function.

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