This study presents a review of the neurogenerative mechanisms in multiple sclerosis.
Multiple sclerosis (MS) is an autoimmune, inflammatory, and neurodegenerative disease of the central nervous system (CNS). The hallmark of MS is inflammatory demyelinating lesions, impaired recovery of which may lead to permanent neurodegeneration and disability. A study in the journal WIREs Mechanisms of Disease reviewed the mechanisms of neurodegeneration in MS.
The most common disease course is relapsing–remitting, characterized by periods of clinical disability and CNS inflammation followed by variable recovery. Some cases can progress to secondary progressive MS with worsening disability. A smaller proportion of patients have primary progressive MS, with disability from the disease onset.
Imaging and Pathology
Magnetic resonance imaging (MRI) is the standard for detecting, diagnosing, and monitoring MS inflammatory activity and neurodegeneration. Oligoclonal immunoglobulin bands in cerebrospinal fluid can aid the diagnosis.
MS lesions differ in their phenotype based on inflammatory characteristics. The resulting heterogeneity of white matter lesions on imaging is used to categorize them as active, chronic active, or chronic inactive.
Markers used to predict and detect progressive disability due to neurodegeneration include MRI quantification of CNS atrophy, retinal thinning on optical coherence tomography, and elevated serum levels of glial fibrillary acidic protein. Spinal cord and thalamic atrophy have been identified as independent predictors of disease progression. A greater burden of cortical lesions is also associated with disability progression, but an accurate determination with MRI is difficult.
Neurodegeneration Mechanisms in MS
Loss of oligodendrocytes and myelin sheath impairs axonal function. Axonal loss is the key contributing factor to progressive neurological disability in MS. Data from animal models have provided insight into mechanisms of neurodegeneration and neuroprotection.
- Axonal Mitochondrial Dysfunction
Demyelination leads to axonal mitochondrial dysfunction. Mitochondrial trafficking, an essential element of neuronal mitostasis, is disrupted in areas of inflammatory lesions. Studies have shown that improving mitochondrial biogenesis and transport in neurons leads to decreased axonal degeneration, suggesting that proper mitochondrial transport is crucial for axonal protection and recovery.
- Synaptic Protein Loss and Chronic Demyelination
A loss of synaptic proteins following demyelination has been observed in post-mortem MS brain studies. Demyelination and axonal injury trigger a complement-mediated response that clears dysfunctional synapses, damaged axons, and dying neurons. Synaptic loss and altered synaptic transmission are implicated in cognitive decline in learning and memory. Research shows improved nerve conduction following remyelination. However, early intervention is necessary within the critical period for remyelination, after which function cannot fully recover. Chronic demyelination damages the axon itself, leading to progressive disability.
- Neuroprotection and Remyelination
Changes in oligodendrocytes and oligodendrocyte progenitor cells in MS lead to inefficient remyelination. Oligodendrocyte protection during inflammation has therefore been shown to reduce axonal injury. Proposed methods include glutamate scavenging and AMPA and NMDA receptor antagonists.
Mey, G. M., Mahajan, K. R., & DeSilva, T. M. (2023). Neurodegeneration in multiple sclerosis. WIREs Mechanisms of Disease, 15(1), e1583. https://doi.org/10.1002/wsbm.1583