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Table 2 Mechanisms and amplification factors for neurodegeneration in progressive multiple sclerosis (PMS)

From: The link of inflammation and neurodegeneration in progressive multiple sclerosis

- Chronic microglial activation and low-grade inflammation: excitotoxicity, and chronic oxidative stress which leads to mitochondrial injury  
- Mitochondrial dysfunction (energy failure; ionic imbalance) that might underlie features of Multiple Sclerosis lesions: demyelination, oligodendrocyte apoptosis and lack of remyelination; and axonal injury  
- Accumulation of lesion burden: retrograde and anterograde degeneration of demyelinated axons due to lack of trophic support and abnormal axonal excitability (altered expression of ion channels) and amplification of microglia activation  
- Mitochondrial DNA deletion over time and with age as in other classical neurodegenerative diseases: increased energy deficiency and amplification of oxidative injury  
- Iron accumulation with ageing in the brain cells and release of iron in demyelinating lesions (more oxidative injury)  
- Progression of age-related neurodegeneration and exhaustion of central nervous system functional reserve capacity