Pathological abnormalities in the normal-appearing white matter in multiple sclerosis

In established cases of multiple sclerosis (MS), the normal-appearing white matter (NAWM), as defined for magnetic resonance imaging (MRI), is abnorma l in the majority of cases. The clinical significance of these NAWM abnorma lities is the subject of debate, but there is strong correlation with degre e and progression of disability. New lesions form in NAWM before blood-brai n barrier breakdown, as evidenced by gadolinium enhancement. The pathologic al basis of these neuroimaging abnormalities is largely unknown. Definitive pathological studies on the NAWM are few and are often based on small numb ers of samples and of cases. Despite a variety of MS NAWM pathological stud ies, major research questions, of importance to our understanding of basic pathogenetic mechanisms and consequent rational therapies, remain unanswere d. These relate to the frequency and extent of oligodendrocyte/myelin and a xonal abnormalities in MS NAWM, and to the cellular basis of very early MS lesions detected by neuroimaging. In a pilot study of MS NAWM, microglial a ctivation was demonstrated in 9 of 10 MS cases. We are currently testing th e hypothesis that microglial activation, as defined by altered phenotype an d HLA-DR positivity, will act as a marker for oligodendrocyte/myelin and ax onal pathology in MS NAWM.