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Page 62 Griffiths et al. Neuroimmunol Neuroinflammation 2020;7:51-67 I http://dx.doi.org/10.20517/2347-8659.2019.21

Substantial subpial cortical grey matter demyelination defines a subset of progressive MS
cases
Quantitative image analysis of whole coronal macrosections revealed the proportion of demyelinated cortical
grey matter to be almost twice that of the proportion of demyelinated white matter. In those cases, with the
greatest cortical pathology, labelled as cortical GML High MS, there was a near four-fold increase in relative
[25]
area of cortical GML compared to WML. These data are in accordance with the work of Carassiti et al.
and are supportive of an MS post-mortem cohort characterised by a dominant neocortical demyelinating
[26]
pathology . Amongst our samples, we observed instances of hugely divergent grey over white matter
pathology (for example, Case MS214 WML accounted for 3.2% of total WM, whilst cortical GML area
was 43.4% of total cortex; Case MS217 WML area was 3.1% and cortical GML was 59.6%). Cortical GML
pathology was overwhelmingly subpial in location, with an average of 90.9% of total cortical GML being
characterised as subpial (Type III/IV) in distribution. Such extensive and disproportionate demyelination
exceeds that previously reported by ourselves and others and highlights the benefit of working with whole
coronal macrosection preparations [2,12,18] to better understand MS pathology.

We have previously noted associations between lymphoid-like structure status and clinical disease measures,
such as age of onset, age at progression and age at death [13,18] . Our cortical GML High and Low MS cases
had a similar age of onset to that seen in our earlier studies (median age at onset of 27 and 35 years,
respectively) but this did not represent a significant difference in our relatively small study. No other
clinical-pathological correlation was noted, which in part reflects the complex and highly variable
pathology of this disease, whereby synaptic, neuritic and neuronal loss, alongside demyelination and
gliosis, variable impact on disease outcome.

Demyelinating pathology at subpial and subependymal territories
The correlation between the extent of demyelination of the hippocampus and deep grey (including
the caudate, putamen, pallidum and thalamus) with that of subpial cortical GML suggests, at least in
part, a shared pathological mechanism of lesion formation and/or expansion between these regions
lining superficial surfaces of the pia and ventricles. Subpial demyelinating lesions are a pathological
[27]
hallmark of MS and clinical imaging shows that the thalamus of children with MS, a structure which
is severely affected in progressive MS , displays a specific imaging abnormality as a surface-in gradient
[28]
[29]
pattern from the ventricular margin . Adult MS patients also display a gradient of magnetisation
transfer ratio signal change from the superficial surfaces of the brain: a gradient of signal change,
declining with distance across the white matter [30,31] when measured from the ventricular surface, and
across the neocortex from the pial surface, which are most altered in progressive MS [32,33] . A magnetic
resonance imaging (MRI) signature of gadolinium leptomeningeal enhancement, which may partly
reflect inflammation of meninges , relates to the number and volume of cortical and thalamic
[34]
[35]
lesions . These imaging studies support the concepts of meningeal inflammation and outside-in
CSF factor(s) in lesion genesis. Numerous post-mortem studies have demonstrated a topographical
association between the extent of immune cell infiltration of the leptomeninges with cortical GM
demyelination [13,23,36-40] , which is also true for subpial tissue of the cerebellar cortex and spinal cord [41-44] .
This subpial demyelinating pathology of the neocortex is associated with microglia activation, a gradient of
tissue injury and disruption of the pial glial limiting membrane [16,45] . Therefore, the pattern of neocortical
lesion location and deep GM pathology is suggestive, at least in part, of an effect of soluble cytotoxic
mediators from the overlying CSF-filled spaces that contributes to the underlying disease process.

Soluble mediators of subpial lesions
Recently, we have demonstrated the overexpression of RNA transcripts associated with pleiotropic
chemokines and cytokines in the isolated meningeal tissue from cases characterised by extensive
leptomeningeal inflammation and subpial demyelination [46,47] . The profile of elevated mediators, many