Acute axonal injury in multiple sclerosis - Correlation with demyelinationand inflammation

Damage to axons is taken as a key factor of disability in multiple sclerosi s, but its pathogenesis is largely unknown. Axonal injury is believed to oc cur as a consequence of demyelination and was recently shown to be a featur e even of the early disease stages. The present study was aimed at characte rizing the association of axonal injury and histopathological hallmarks of multiple sclerosis such as demyelination, cellular infiltration and express ion of inflammatory mediators. Therefore, axon reduction and signs of acute axonal damage were quantified in early lesion development of chronic multi ple sclerosis and correlated with demyelinating activity and inflammation. Patients with secondary progressive multiple sclerosis revealed the most pr onounced axonal injury, whereas primary progressive multiple sclerosis pati ents surprisingly showed relatively little acute axonal injury. Acute axona l damage, as defined by the accumulation of amyloid precursor protein (APP) , was found to occur not only in active demyelinating but also in remyelina ting and inactive demyelinated lesions with a large interindividual variabi lity. Only few remyelinating lesions were adjacent to areas of active demye lination, In this minority of lesions, axonal damage may have originated fr om the neighbourhood. APP expression in damaged axons correlated with the n umber of macrophages and CD8-positive T lymphocytes within the lesions, but not with the expression of tumour necrosis factor-alpha (TNF-alpha) or ind ucible nitric oxide synthase (iNOS), Axonal injury is therefore, at least i n part, independent of demyelinating activity, and its pathogenesis may be different from demyelination, This has major implications for therapeutic s trategies, which aim at preventing both demyelination and axonal loss.