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

D Carassiti,N Petrova,B Pakkenberg,D R Altmann,K Schmierer,F Scaravilli

doi:10.1111/nan.12405

Abstract

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. 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 (×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. In MS, the mean number of neurons was 14.9±1.9billion vs. 24.4±2.4billion 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±13% of the MS neocortex and 9±12% of the WM, however, neither correlated with neuronal loss. Only weak association was detected between number of neurons and WM volume. Neocortical neuronal loss in MS is massive and strongly predicted by cortical volume. Cortical volume decline detected invivo 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.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS) usually becoming symptomatic in early adulthood [1, 2]
Given that indices of brain volume have emerged as key outcome measures in natural history studies and treatment trials of new disease modifying agents, establishing the quantitative cellular basis of volumetric changes in the brain is of significant importance [18]
PwMS did not differ from controls with respect to age at death (68 ± 14 years, range: 47-92 years vs 75 ± 18 years, range = 47-92, p = 0.44), post mortem delay (34 ± 12 hours vs 29 ± 19 hours, p = 0.5), and fixation time (59 ± 27 months vs 171 ± 150 months, p = 0.26), the latter was in particular very long for three female controls, this outlier data does not affect our analysis and overall observations

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS) usually becoming symptomatic in early adulthood [1, 2]. Involvement of the grey matter (GM) in MS pathology has been described for well over one century [4,5,6,7,8,9], the past two decades have seen an increased interest in measuring the extent, and identifying the cellular basis, of cortical pathology in people with MS (pwMS), notably demyelination and neuronal loss [10,11,12,13]. Given that indices of brain volume have emerged as key outcome measures in natural history studies and treatment trials of new disease modifying agents, establishing the quantitative cellular basis of volumetric changes in the brain is of significant importance [18]

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Discussion

Conclusion