Rigotti DJ et al.Two-year serial whole-brain N-acetyl-L-aspartate in patients with relapsing-remitting multiple sclerosis.Neurology. 2012 Apr 18. [Epub ahead of print]
OBJECTIVES: To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhibit a quantifiable decline in their whole-brain concentration of the neural marker N-acetyl-l-aspartate (WBNAA), that is 2) more sensitive than clinical changes and 3) may provide a practical outcome measure for proof-of-concept and larger phase III clinical trials.
METHODS: Nineteen patients (5 men and 14 women) with clinically definite RR-MS, who were 33 ± 5 years old (mean ± SD), had a disease duration of 47 ± 28 months, and had a median Expanded Disability Status Scale (EDSS) score of 1.0 (range 0-5.5), underwent MRI and proton magnetic resonance spectroscopy ((1)H-MRS) semiannually for 2 years (5 time points). Eight matched control subjects underwent the protocol annually (3 time points). Their global N-acetyl-l-aspartate (1)H-MRS signal was converted into absolute amounts by phantom replacement and into WBNAA by dividing with the brain parenchymal volume, V(B), from MRI segmentation.
RESULTS: The baseline WBNAA of the patients (10.5 ± 1.7 mM) was significantly lower than that of the controls (12.3 ± 1.3 mM; p < 0.002) and declined significantly (5%/year, p < 0.002) vs that for the controls who did not show a decline (0.4%/year, p > 0.7). Likewise, V(B) values of the patients also declined significantly (0.5%/year, p < 0.0001), whereas those of the controls did not (0.2%/year, p = 0.08). The mean EDSS score of the patients increased insignificantly from 1.0 to 1.5 (range 0-6.0) and did not correlate with V(B) or WBNAA.
CONCLUSIONS: WBNAA of patients with RR-MS declined significantly at both the group and individual levels over a 2-year time period common in clinical trials. Because of the small sample sizes required to establish power, WBNAA can be incorporated into future studies.
N-acetyl-l-aspartate is concentrated in nerves and so loss of N-acetyl-aspartate (NAA) may be equated to nerve loss. This can be seen in images (see above figure) using magnetic resonance spectroscopy. Whilst in some studies there have been reversible metabolic changes associated with NAA levels, which complicates its use as a biomarker, the results of this study indicate that it may be a sensitive marker to monitor nerve loss in MS. This will be of value in monitoring (treatment of) progressive MS.