Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis

See Friese (doi: 10.1093/brain/awv349 ) for a scientific commentary on this article. Grey matter pathology has emerged as an important contributor to long-term disability in multiple sclerosis. To better understand where and how neuronal damage in the grey matter is initiated, we used high resolution confocal microscopy of Golgi-Cox impregnated tissue sections and reconstructed single cortical projection neurons in autopsies from eight patients with long-standing relapsing-remitting or secondary progressive multiple sclerosis and eight control patients without neurological disease. Analysis of several hundred individual neurons located in the insular, frontotemporal and occipital lobe revealed a widespread and pronounced loss of dendritic spines in multiple sclerosis cortex that occurs independent of cortical demyelination and axon loss. The presence of a primary synaptic pathology in the normal-appearing cortex of multiple sclerosis patients challenges current disease concepts and has important implications for our understanding of disease progression. See Friese (doi: 10.1093/brain/awv349 ) for a scientific commentary on this article. Neuronal pathology contributes to long-term disability in multiple sclerosis, but where and how this damage is initiated is unclear. Jürgens et al. use high-resolution confocal microscopy to reconstruct single cortical neurons in patients with multiple sclerosis and controls. Results reveal a primary lesion-independent synaptic pathology that challenges current disease concepts.