Imaging correlates of decreased axonal Na+/K+ ATPase in chronic multiple sclerosis lesions.
OBJECTIVE
Degeneration of chronically demyelinated axons is a major cause of irreversible neurological decline in the human central nervous system disease, multiple sclerosis (MS). Although the molecular mechanisms responsible for this axonal degeneration remain to be elucidated, dysfunction of axonal Na+/K+ ATPase is thought to be central. To date, however, the distribution of Na+/K+ ATPase has not been studied in MS lesions.


METHODS
The percentage of axons with detectable Na+/K+ ATPase was determined in 3 acute and 36 chronically demyelinated lesions from 13 MS brains. In addition, we investigated whether postmortem magnetic resonance imaging profiles could predict Na+/K+ ATPase immunostaining in a subset (20) of the chronic lesions.


RESULTS
Na+/K+ ATPase subunits alpha1, alpha3, and beta1 were detected in the internodal axolemma of myelinated fibers in both control and MS brains. In acutely demyelinated lesions, Na+/K+ ATPase was detectable on demyelinated axolemma. In contrast, 21 of the 36 chronic lesions (58%) contained less than 50% Na+/K+ ATPase-positive demyelinated axons. In addition, magnetic resonance imaging-pathology correlations of 20 chronic lesions identified a linear decrease in the percentage of Na+/K+ ATPase-positive axons and magnetization transfer ratios (p < 0.0001) and T1 contrast ratios (p < 0.0006).


CONCLUSIONS
Chronically demyelinated axons that lack Na+/K+ ATPase cannot exchange axoplasmic Na+ for K+ and are incapable of nerve transmission. Loss of axonal Na+/K+ ATPase is likely to be a major contributor to continuous neurological decline in chronic stages of MS, and quantitative magnetization transfer ratios and T1 contrast ratios may provide a noninvasive surrogate marker for monitoring this loss in MS patients.
Young
Elizabeth A
EA
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Fowler
Christie D
CD
Kidd
Grahame J
GJ
Chang
Ansi
A
Rudick
Richard
R
Fisher
Elizabeth
E
Trapp
Bruce D
BD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001369:Axons / Q000201:enzymology* / Q000473:pathology* / Q000502:physiology; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D009413:Nerve Fibers, Myelinated / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D021122:Protein Subunits / Q000172:deficiency / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000172:deficiency* / Q000378:metabolism* / Q000502:physiology
D021122:Protein Subunits; D000254:Sodium-Potassium-Exchanging ATPase