Neuronal loss, demyelination and volume change in the multiple sclerosis neocortex

Abstract

(2017) Neuropathology and Applied Neurobiology Neuronal loss, demyelination and volume change in the multiple sclerosis neocortex Aims: Indices of brain volume [grey matter, white matter (WM), lesions] are being used as outcomes in clinical trials of patients with multiple sclerosis (MS). We investigated the relationship between cortical volume, the number of neocortical neurons estimated using stereology and demyelination. Methods: Nine MS and seven control hemispheres were dissected into coronal slices. On sections stained for Giemsa, the cortex was outlined and optical disectors applied using systematic uniform random sampling. Neurons were counted using an oil immersion objective (9 60) following stereological principles. Grey and WM demyelination was outlined on myelin basic protein immunostained sections, and expressed as percentages of cortex and WM respectively. Results: In MS, the mean number of neurons was 14.9 AE 1.9 billion vs. 24.4 AE 2.4 billion in controls (P < 0.011), a 39% difference. The density of neurons was smaller by 28% (P < 0.001) and cortical volume by 26% (P = 0.1). Strong association was detected between number of neurons and cortical volume (P < 0.0001). Demyelination affected 40 AE 13% of the MS neocortex and 9 AE 12% of the WM, however, neither correlated with neuronal loss. Only weak association was detected between number of neurons and WM volume. Conclusion: Neocortical neuronal loss in MS is massive and strongly predicted by cortical volume. Cortical volume decline detected in vivo may be similarly indicative of neuronal loss. Lack of association between neuronal density and demyelination suggests these features are partially independent, at least in chronic MS.

Synaptic Loss in Multiple Sclerosis Spinal Cord

“…Neuronal damage and loss in pwMS can be extensive 11 . In a recent stereological study, we reported that after nearly 30 years disease duration, pwMS will have lost almost 40% of their neocortical neurons irrespective of the presence of demyelination 18 . The degree of neuronal loss in the current study (47%) is higher than previously reported, 19 perhaps reflecting differences in disease duration and/or severity between studies.…”

Meningeal inflammation and cortical demyelination in acute multiple sclerosis

“…In agreement with this, we noted extensive neuron loss in acute MS GM lesions and normal GM in comparison to matched non‐diseased controls. The extent of neuron loss was comparable to that seen in the progressive MS cortex, and of a similar magnitude as other GM structures . The significant neurodegeneration in acute MS is supported by evidence that the majority of neuron loss in the spinal cord occurs early in disease and that in progressive MS the greatest neuronal loss is seen in those who experienced the shortest disease duration .…”

Application of mechanistic methods to clinical trials in multiple sclerosis: the simvastatin case

“…The slower than expected rate of atrophy in the deep grey matter suggests a flooreffect at which the decline of these structure may slow down. Our results are in line with pathological observations that generalised neurodegeneration may dominate long-standing secondary progressive MS (Frischer et al, 2009;Hawker et al, 2009;Carassiti et al, 2017), while a more selective pattern is seen in earlier MS alongside focal inflammation that responds to immunomodulation (Frischer et al, 2009;Montalban et al, 2017). Although there was a general reduction in several regions in the simvastatin group, only the treatment effect on the transverse temporal gyrus was significant, which also had the highest rate of volume loss in the grey matter.…”