The blood–brain barrier in multiple sclerosis

Abstract

Perivascular inflammation and blood–brain barrier (BBB) leakage marks a key stage in the development of the typical scattered demyelinated lesions in multiple sclerosis (MS). Immunocytochemistry and confocal laser microscopy were used to analyse the status of inter-endothelial BBB tight junctions (TJ) in MS lesional and normal-appearing white matter (NAWM) and in control white matter. The results revealed TJ abnormalities which, though most common in active lesions (42% of vessels affected), were also present in inactive lesions (23%), in MS NAWM (13%) and in neurological control white matter (8%). The observed baseline for normal controls was 3.7%. Vessels of all sizes were affected equally and TJ abnormality was associated with serum protein leakage (extravascular fibrinogen immunoreactivity). Tight junctional abnormalities seen included discontinuities in fluorescent signal, redistribution of signal from membranes to cytoplasm and apparent separation of junctions. These findings taken with the results of previous studies, which showed cytoplasmic alterations in MS microvessels consistent with increased transcellular transport, point to a partial loss of BBB phenotype and to possible mechanisms of leakage. The resultant increased vascular permeability in many parts of the lesional and non-lesional white matter is likely to impair homeostasis and may affect both disease progression and drug delivery.