Axonal loss in the multiple sclerosis spinal cord revisited

Abstract

Preventing chronic disease deterioration is an unmet need in people with multiple sclerosis, where axonal loss is considered a key substrate of disability. Clinically, chronic multiple sclerosis often presents as progressive myelopathy. Spinal cord cross-sectional area (CSA) assessed using MRI predicts increasing disability and has, by inference, been proposed as an indirect index of axonal degeneration. However, the association between CSA and axonal loss, and their correlation with demyelination, have never been systematically investigated using human post mortem tissue. We extensively sampled spinal cords of seven women and six men with multiple sclerosis (mean disease duration5 29 years) and five healthy controls to quantify axonal density and its association with demyelination and CSA. 396 tissue blocks were embedded in paraffin and immuno-stained for myelin basic protein and phosphorylated neurofilaments. Measurements included total CSA, areas of (i) lateral cortico-spinal tracts, (ii) gray matter, (iii) white matter, (iv) demyelination, and the number of axons within the lateral cortico-spinal tracts. Linear mixed models were used to analyze relationships. In multiple sclerosis CSA reduction at cervical, thoracic and lumbar levels ranged between 19 and 24% with white (19-24%) and gray (17-21%) matter atrophy contributing equally across levels. Axonal density in multiple sclerosis was lower by 57-62% across all levels and affected all fibers regardless of diameter. Demyelination affected 24-48% of the gray matter, most extensively at the thoracic level, and 11-13% of the white matter, with no significant differences across levels. Disease duration was associated with reduced axonal density, however not with any area index. Significant association was detected between focal demyelination and decreased axonal density. In conclusion, over nearly 30 years multiple sclerosis reduces axonal density by 60% throughout the spinal cord. Spinal cord cross sectional area, reduced by about 20%, appears to be a poor predictor of axonal density. AbbreviationsaCST 5 cortico-spinal tract area; CDD 5 chronic disease deterioration; CoV 5 coefficient of variation; CSA 5 cross sectional area; CST 5 Lateral corticospinal tract; EDSS 5 expanded disability status scale; GM 5 gray matter; MBP 5 myelin basic protein; WM 5 white matter.

Magnetic resonance imaging correlates of neuro‐axonal pathology in the MS spinal cord

“…Significant axonal loss takes place in the MS spinal cord, degree of which appears most strongly associated with the duration of the disease. A recent study reported reduction of axonal density in the cortico‐spinal tracts by 57%–62% across all cord levels after a mean disease duration of 29 years , confirming earlier studies using tissue from pwMS with similar disease duration , while studies of material with shorter disease duration reported less pronounced axonal loss . In line with this observation, axonal loss [be it within or beyond the margins of MS lesions ] is considered a major contributor to the relentless accrual of disability in pwMS over time.…”

“…However, compared to controls axonal density was reduced by 57%-62%. And while disease duration was a predictor of reduced axonal density, CSA was not, and neither were separate indices of proportional gray or white matter area (55).…”

“…While in 2001 Nijeholt and co-workers highlighted the close relationship between areas of high signal on T 2 W MRI with the extent of demyelination (53), a subsequent study by the same group described considerable T 2 W MRI signal abnormalities in cord tissue not affected by lesions (nonlesional cord tissue) yet significant-and seemingly lesionindependent-axonal loss (4). Of note, the authors did not control for remote effects on axonal loss of lesions along the pathway examined, which have been shown to be of importance when examining the relationship between inflammation, demyelination, and axonal loss (55).…”

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

“…The lack of correlation in chronic MS between neocortical demyelination and neuronal loss is also strikingly similar to the lack of such association between the total amount of demyelination and axonal loss in the chronic MS spinal cord . It will be of interest to investigate these relationships using post mortem tissue of the entire neuraxis, which to our knowledge has only been performed once in a relatively limited sample .…”

Heat shock proteins are differentially expressed in brain and spinal cord: implications for multiple sclerosis

“…The comparative pathology studies demonstrate that, similar to the brain, MS spinal cord is affected by focal demyelination in white and grey matter, microglial proliferation, macrophage and T cell infiltration, astrogliosis, axon degeneration and neuronal loss [11][12][13][14][15][16]. In MS spinal cord, the extent of white as well as grey matter demyelination is high compared to brain regions [17].…”