Can Clinical Progression in Multiple Sclerosis Occur Before Axonal Loss?
Can Clinical Progression in Multiple Sclerosis Occur Before Axonal Loss?
Abstract & Commentary
By Susan Gauthier, DO, MS Assistant Professor of Neurology, Weill Medical College of Cornell University Dr. Gauthier reports no financial relationships relevant to this field of study.7/6/2008
Synopsis: The distribution of Na+/K+ ATPase along the internodal axolemma is reduced in chronic demyelinated lesions and can be non-invasively assessed using magnetization transfer ratios (MTR) and T1 contrast ratios during MR imaging.
Source: Young EA, Fowler CD, Kidd GJ, et al. Imaging correlates of decreased axonal Na+/K+ ATPase in chronic multiple sclerosis lesions. Ann Neurol 2008;63:428-435.
Neurodegeneration is widely accepted to be the pivotal factor causing the progressive neurological decline in patients with multiple sclerosis (MS), but key mechanistic factors leading to the axonal loss have yet to be identified. Na+/K+ ATPase is distributed in a uniform pattern along myelinated fibers in the central nervous system and functions to maintain the appropriate ionic gradient by rapidly exchanging axonal Na+ for extracellular K+ in an energy-dependent manner after each depolarization. Alteration in the Na / K balance has been proposed to initiate a cascade of ionic changes that lead to axonal degeneration in chronic demyelinated lesions, specifically causing an increase in Ca+ influx and activation of proteolytic enzymes.1
Young et al studied 13 postmortem brains for which 3 acute and 36 chronic demyelinated lesions were identified. These lesions were compared to white matter from 4 control brains. MRI data were available on a subset of 20 lesions. Lesions were identified as acute, chronic active, or chronic based upon the presence of MHC (major histocompatibility complex) class II cells. Percentages of Na+/K+ ATPase neurofilament-positive axons were quantified through immunoreactivity to the a1, a3, and b1 subunits of Na+/K+ ATPase and Caspr in white matter from control patients, acute demyelinated, and chronic demyelinated lesions as well as normal appearing white matter in the MS brains. As expected, Na+/K+ ATPase immunoreactivity was uniformly distributed along the internodal axolemma with little or no detection at the nodal or paranodal axolemma in control white matter. In acute lesions and normal appearing white matter from MS brains, the Na+/K+ ATPase distribution was similar to that found in control brains. However, in 58% of the chronic lesions, there were 50% less Na+/K+ ATPase positive axons. Correlations between clinical characteristics and the percentage of axonal Na+/K+ ATPase was not assessed, since only a small proportion of the lesion load in each patient was studied. Axon integrity was not reported to be altered, but these patients were quite disabled with a mean EDSS (Expanded Disability Status Score) of 8.0 (restricted to bed or chair) with all but one patient in the progressive stage of the disease.
Previous studies have correlated the extent of demyelination with reduced MTR (magnetization transfer ratio) and axonal loss with a reduced T1 contrast ratio. In the present study, MTR and T1 contrast ratios were compared to the percentage of axons without Na+/K+ ATPase. A normal Na+/K+ ATPase distribution was found in lesions with a MTR greater than 0.8, whereas in lesions with less than 0.7, there was a 20% decrease in axons with Na+/K+ ATPase. T1 contrast ratios revealed a similar relationship; lesions with a ratio of 0.85 or higher had a normal distribution of Na+/K+ ATPase as compared to those with ratios of ess than 0.75, which had a 20% decrease.
Commentary
The key finding from this study is that membrane abnormalities, as demonstrated by the decreased density of Na+/K+ ATPase, can be found in chronically demyelinated lesions without axonal loss. The mechanism responsible for reduced levels of Na+/K+ ATPase along demyelinated fibers, or whether the reduced Na+/K+ ATPase levels are a cause or a result of axonal injury, has yet to be elucidated.2 An important question remains: Could this observation be an independent cause of clinical progression before evidence of axonal loss? Since only a portion of lesions from each brain were studied, this study was unable to accurately address the relationship of Na+/K+ ATPase levels and clinical progression. However, since these patients were quite disabled, one could speculate that Na+/K+ ATPase levels may have been a contributing factor.
Traditional MRI has been extensively used as a marker for disease activity in MS; however, it has been limited by lack of pathological specificity. As non-traditional MRI methods have been applied to MS, specificity has increased and was demonstrated in this study by the identification of chronic lesions with less Na+/K+ ATPase. However, since prior studies have clearly demonstrated the correlation of a reduced T1 contrast ratio with axonal loss,3 how T1 contrast ratio and MTR will distinguish between a decrease in Na+/K+ ATPase and axonal loss has yet to be determined. Most importantly, this study has increased our understanding of membrane dynamics occurring before axonal loss, thus identifying another potential strategy for neuroprotection in MS.
References
1. Dutta R, McDonough J, Yin X, et al. Ann Neurol 2006;59:478-489.
2. Waxman S. Ann Neurol 2008;63:411-413.
3. Van Waesberghe JH, Kamphorst W, De Groot CJ, et al. Ann Neurol 1999;46:747-754.
The distribution of Na+/K+ ATPase along the internodal axolemma is reduced in chronic demyelinated lesions and can be non-invasively assessed using magnetization transfer ratios (MTR) and T1 contrast ratios during MR imaging.Subscribe Now for Access
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