Discussion

Human NAA-synthesis has been observed directly in vivo, by means of 13C MRS. As expected the rate is very low, suggesting that NAA, in contrast with NAAG, is most unlikely to fulfill any function as a neurotransmitter. In human Canavan's Disease where NAA accumulates in the brain as the direct result of reduction in NAA-deacylase activity, NAA synthesis appears to be strongly inhibited. This appears to be an adaptive process, the result of either end-product inhibition or substrate limited enzyme synthesis. Nevertheless, it could be of importance as effective gene replacement therapy is achieved. Will detection of falling [NAA] be the best measure of success, or will a new equilibrium arise, where high [NAA] is maintained despite recovery from the primary enzyme defect? In neurodegenerative disease, as well as in schizophrenia where neuronal loss has been observed, it might be hypothesized that NAA synthesis would fall. The present results appear to contradict such a hypothesis. With the caveat mentioned, it appears that NAA synthesis rate may be elevated, rather than reduced in one neurodegenerative disease and one psychiatric disease. If so, there is an adaptive metabolic process which may be 'protective' against the neurodegenerative process(es).

The data is sufficiently surprising to suggest the study be repeated under the ideal conditions used to establish the rate of NAA synthesis in Canavan's Disease patients. This means a more costly and lengthier protocol with infusion of sufficient 1-13C glucose to raise the fractional enrichment of aspartate and to maintain a steady state during the entire period of observation of NAA enrichment - as much as 180 minutes.

Figure 5. Impact of Canavan disease (aspartoacylase deficiency) on fractional enrichment ENAA2 (%).

NAA2/Asp2 0.7

Figure 6. Impact of neurodegenerative and psychiatric deceases (schizophrenia) on cerebral NAA synthesis. Note: Apparent rate of synthesis was derived from fractional enrichment of NAA/Asp and plotted against a *H MRS measures of normal number (NAA/Cr).

NAA/Cr

Figure 6. Impact of neurodegenerative and psychiatric deceases (schizophrenia) on cerebral NAA synthesis. Note: Apparent rate of synthesis was derived from fractional enrichment of NAA/Asp and plotted against a *H MRS measures of normal number (NAA/Cr).

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