This study provides new insights into the mechanisms of SC repair and raises the possibility that increased mitochondrial metabolism is an important component of repair. We found that patients who recovered showed a sustained increase in NAA levels after 1 month, which is in agreement with the findings of studies that have followed up brain lesions in natural history studies,10–12
and brain volumes of interest in patients treated with interferon-beta and glatiramer acetate.13,14
Because NAA concentration reflects both axonal integrity15
and axonal mitochondrial metabolism,16
an increase in NAA levels, occurring in parallel with a decline in cord cross-sectional area that suggests underlying neurodegeneration,4
may be driven by increased axonal mitochondrial metabolism. In addition, there was no correlation between NAA concentration and the SC cross-sectional area at any time point during the study, which not only confirms previous SC17
and brain studies,18,19
but also suggests that these 2 measures reflect, at least in part, independent pathologic mechanisms.
The most striking finding of this study is that this increase in NAA levels from 1 month onward correlates with clinical recovery. In particular, given that NAA is produced by the mitochondria, together with adenosine triphosphate production and oxygen consumption,16
the initial decrease in NAA (during the first month of this study) is in keeping with the decreased mitochondrial activity that has been observed in the presence of inflammatory mediators,20
whereas its subsequent increase may reflect the enhanced mitochondrial activity that is necessary to maintain axonal conduction. The restoration of nerve conduction is considered to be one of the repair mechanisms that spontaneously occurs after an inflammatory demyelinating lesion. The demonstration of an increased number of mitochondria20
and increased mitochondrial mass and complex IV activity within demyelinated axons21
is consistent with the hypothesis that increased mitochondrial activity is an adaptive mechanism in response to demyelination.
There is evidence that points to NAA having a role in the production of the myelin.5
Further, a small concentration of NAA derives from proliferating oligodendrocyte progenitor cells, which, however, reduce significantly over time, and a very low level of NAA immunoreactivity has been detected in oligodendrocytes in adult rats.5
Therefore, it is possible that the observed increase in NAA may relate to ongoing remyelination. However, a significant development of cord atrophy during the follow-up was detected, and this would be inconsistent with remyelination as the main repair mechanism. In fact, it has been suggested that demyelination is the main determinant of cord atrophy.22
Another interesting finding is that the entire patient group, as well as patients who recovered and those who did not, developed a decline in cord area over time. This decline in cord area remained significant not only when we corrected for the presence of cord swelling at baseline (which was seen in 5 of 14 patients), but also when we repeated the analysis with data collected after 1 month. Our additional analysis has shown that, although the presence of swelling at baseline influenced the reduction of cord area occurring during the first month of follow-up, it is unlikely that this alone accounted for the development of cord atrophy between 1 month and 6 months. Therefore, our findings suggest that cord atrophy occurs after acute SC events, mirroring the results of brain and optic nerve longitudinal studies.4,23
Optical coherence tomography studies have proved that a reduction of retinal fiber layer occurs after optic neuritis.24,25
A lack of correlation between decline in cord area and clinical changes confirms results of optic nerve studies of patients with optic neuritis,23,26
suggesting that other mechanisms contribute to clinical outcome despite the loss of optic nerve fibers. However, the effect of cord atrophy on clinical outcome may become evident after a long period of time.
Disease duration was the only significant, independent predictor of recovery. In particular, patients with longer disease duration were less likely to improve clinically, and a longer disease duration was associated with smaller increases in NAA levels after 1 month. These findings suggest that the endogenous repair mechanisms, which are reflected in the increase in NAA levels, become less efficient over time.
A technical limitation of this study is that our spectroscopic voxel encompassed the gray and white matters, and the lesion and the normal-appearing tissues. The SD of the NAA concentration does not seem to be entirely consistent over time, because it slightly increases in patients and decreases in controls, despite the fact that subjects were scanned over the same period. This observation, together with the acquisition of a subject- and position-specific calibration factor at each time point3
and weekly phantom calibration data (results not shown), suggests that the intersubject variability, especially in the patient group, rather than a scanner-dependent factor, is the main reason behind the apparent (and small) changes in reliability of the measure over time.
From a clinical point of view, the number of patients included in this study is small. However, more than 90% of the scans acquired in 27 subjects over the follow-up were included in the analysis, and patients were selected to be representative of patients at the onset of a cervical cord relapse. Further, the longitudinal analyses used here have the advantage of maximizing statistical efficiency by using all available data points.
In the future, it would be interesting to extend SC spectroscopy to patients with a clinically isolated syndrome localized to the cervical cord, to investigate the NAA behavior over time. SC MRS can be further optimized on higher field scanners and may be implemented in treatment trials that aim to enhance SC repair. A better understanding of the mitochondrial mechanisms that contribute to damage and repair may lead to the development of therapies that target mitochondria.27