Brain, Vol. 126, No. 2, 433-437,
February 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg038
Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis
1 Neuroimaging Research Unit, Department of Neuroscience 2 Departments of Neurology and 3 Neuroradiology, Scientific Institute and University Ospedale San Raffaele, Milan 4 Multiple Sclerosis Center, Ospedale di Gallarate, Gallarate, Italy and 5 Department of Radiology, New York University School of Medicine, New York, NY, USA
Correspondence to: Dr Massimo Filippi, Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute and University, Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy E-mail: m.filippi{at}hsr.it
Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4–6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.
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|
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|
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|
|
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|
|
|
|
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 A. Chaudhuri and P. O Behan Shared scheme for assessing drugs for multiple sclerosis: Why are eyes tightly shut to considering causes other than autoimmunity? BMJ, May 29, 2003; 326(7400): 1213 - 1213. [Full Text]
|
|