Cortical axonal loss is associated with both gray matter demyelination and white matter tract pathology in progressive multiple sclerosis: Evidence from a combined MRI-histopathology study.
BACKGROUND
Neuroaxonal degeneration is one of the hallmarks of clinical deterioration in progressive multiple sclerosis (PMS).


OBJECTIVE
To elucidate the association between neuroaxonal degeneration and both local cortical and connected white matter (WM) tract pathology in PMS.


METHODS
Post-mortem in situ 3T magnetic resonance imaging (MRI) and cortical tissue blocks were collected from 16 PMS donors and 10 controls. Cortical neuroaxonal, myelin, and microglia densities were quantified histopathologically. From diffusion tensor MRI, fractional anisotropy, axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were quantified in normal-appearing white matter (NAWM) and white matter lesions (WML) of WM tracts connected to dissected cortical regions. Between-group differences and within-group associations were investigated through linear mixed models.


RESULTS
The PMS donors displayed significant axonal loss in both demyelinated and normal-appearing (NA) cortices (p < 0.001 and p = 0.02) compared with controls. In PMS, cortical axonal density was associated with WML MD and AD (p = 0.003; p = 0.02, respectively), and NAWM MD and AD (p = 0.04; p = 0.049, respectively). NAWM AD and WML AD explained 12.6% and 22.6%, respectively, of axonal density variance in NA cortex. Additional axonal loss in demyelinated cortex was associated with cortical demyelination severity (p = 0.002), explaining 34.4% of axonal loss variance.


CONCLUSION
Reduced integrity of connected WM tracts and cortical demyelination both contribute to cortical axonal loss in PMS.
['Kiljan|Svenja|S|', 'Preziosa|Paolo|P|', 'Jonkman|Laura E|LE|', 'van de Berg|Wilma Dj|WD|', 'Twisk|Jos|J|', 'Pouwels|Petra Jw|PJ|', 'Schenk|Geert J|GJ|', 'Rocca|Maria A|MA|', 'Filippi|Massimo|M|', 'Geurts|Jeroen Jg|JJ|', 'Steenwijk|Martijn D|MD|']
D056324:Diffusion Tensor Imaging D066128:Gray Matter D006801:Humans D008279:Magnetic Resonance Imaging D009103:Multiple Sclerosis D066127:White Matter
axonal loss progressive Multiple sclerosis magnetic resonance imaging histopathology post mortem