Rostrocaudal analysis of corpus callosum demyelination and axon damage across disease stages refines diffusion tensor imaging correlations with pathological features.
Noninvasive assessment of the progression of axon damage is important for evaluating disease progression and developing neuroprotective interventions in multiple sclerosis patients. We examined the cellular responses correlated with diffusion tensor imaging-derived axial (lambda(parallel)) and radial (lambda(perpendicular)) diffusivity values throughout acute (4 weeks) and chronic (12 weeks) stages of demyelination and after 6 weeks of recovery using the cuprizone demyelination of the corpus callosum model in C57BL/6 and Thy1-YFP-16 mice. The rostrocaudal progression of pathological alterations in the corpus callosum enabled spatially and temporally defined correlations of pathological features with diffusion tensor imaging measurements. During acute demyelination, microglial/macrophage activation was most extensive and axons exhibited swellings, neurofilament dephosphorylation, and reduced diameters. Axial diffusivity values decreased in the acute phase but did not correlate with axonal atrophy during chronic demyelination. In contrast, radial diffusivity increased with the progression of demyelination but did not correlate with myelin loss or astrogliosis. Unlike other animal models with progressive neurodegeneration and axon loss, the acute axon damage did not progress to discontinuity or loss of axons even after a period of chronic demyelination. Correlations of reversible axon pathology, demyelination, microglia/macrophage activation, and astrogliosis with regional axial and radial diffusivity measurements will facilitate the clinical application of diffusion tensor imaging in multiple sclerosis patients.
Department of Radiology, Washington University School of Medicine, St Louis, Missouri, USA.
Mingqiang
M
Xie
Jennifer E
JE
Tobin
Matthew D
MD
Budde
Chin-I
CI
Chen
Kathryn
K
Trinkaus
Anne H
AH
Cross
Dennis P
DP
McDaniel
Sheng-Kwei
SK
Song
Regina C
RC
Armstrong
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D003337:Corpus Callosum / Q000473:pathology* / Q000648:ultrastructure; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000150:complications / Q000473:pathology*; D020833:Diffuse Axonal Injury / Q000209:etiology* / Q000473:pathology; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D004195:Disease Models, Animal; D018450:Disease Progression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007211:Indoles; D008164:Luminescent Proteins / Q000235:genetics; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D046529:Microscopy, Electron, Transmission; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D016900:Neurofilament Proteins / Q000378:metabolism; D013223:Statistics as Topic; D013997:Time Factors
D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D008164:Luminescent Proteins; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D016900:Neurofilament Proteins; C051774:neurofilament protein H; C007293:DAPI; D003471:Cuprizone