Axonal loss in the multiple sclerosis spinal cord revisited

Area of Science:

• Neuroscience
• Pathology
• Neurology

Background:

• Chronic disease progression in multiple sclerosis (MS) is a significant clinical challenge.
• Axonal loss is a primary driver of disability in MS, often presenting as progressive myelopathy.
• Spinal cord cross-sectional area (CSA) is an MRI-based measure linked to disability, but its direct correlation with axonal loss and demyelination is unconfirmed.

Purpose of the Study:

• To systematically investigate the relationship between spinal cord cross-sectional area (CSA), axonal density, and demyelination in post-mortem human tissue from multiple sclerosis patients.
• To quantify axonal loss and demyelination across different spinal cord levels and correlate these with disease duration.

Main Methods:

• Post-mortem spinal cord tissue from 13 multiple sclerosis patients and 5 healthy controls was sampled.
• Tissue blocks were stained for myelin basic protein and phosphorylated neurofilaments to assess demyelination and axonal density.
• Measurements included total CSA, regional areas (lateral cortico-spinal tracts, gray matter, white matter), and axonal counts, analyzed using linear mixed models.

Main Results:

• Multiple sclerosis patients exhibited a 19-24% reduction in spinal cord CSA, with equal contributions from gray and white matter atrophy.
• Axonal density was significantly reduced by 57-62% across all spinal cord levels in MS patients, irrespective of fiber diameter.
• Demyelination affected 24-48% of gray matter and 11-13% of white matter; focal demyelination correlated with reduced axonal density.
• Longer disease duration was associated with lower axonal density but not with CSA changes.

Conclusions:

• Multiple sclerosis leads to profound and widespread axonal loss (approximately 60%) throughout the spinal cord over decades.
• Spinal cord cross-sectional area reduction (around 20%) is a poor predictor of the actual axonal density loss in multiple sclerosis.
• Understanding the direct relationship between demyelination and axonal loss is crucial for developing strategies to prevent disability progression in MS.