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

• Published in: Neuropathology and applied neurobiology Vol. 44; no. 4; pp. 377 - 390
• Main Authors: Carassiti, D., Altmann, D. R., Petrova, N., Pakkenberg, B., Scaravilli, F., Schmierer, K.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.06.2018
• Subjects: Aged; Aged, 80 and over; Brain slice preparation; Cell Count; Clinical trials; Cortex; cortical pathology; Demyelinating Diseases - pathology; Demyelination; Female; Gray Matter - pathology; Humans; Male; Middle Aged; Multiple sclerosis; Multiple Sclerosis - pathology; Myelin; Myelin basic protein; Neocortex - pathology; neuronal loss; Neurons - pathology; Organ Size; progressive multiple sclerosis; Statistical sampling; Substantia alba; Substantia grisea; White Matter - pathology; cortical pathology; neuronal loss; progressive multiple sclerosis
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12405

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 (× 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 ± 1.9 billion vs. 24.4 ± 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 ± 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. 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.