IMAGING AXONAL DAMAGE OF NORMAL-APPEARING WHITE-MATTER IN MULTIPLE-SCLEROSIS

The current study was designed to determine the relative distribution of decreases of N-acetylaspartate (NAA), a marker of axonal damage, be tween lesions and normal-appearing white matter of patients with estab lished multiple sclerosis and to test for associations between changes in the ratio of NAA to creatine/phosphocreatine (NAA : Cr) in those c ompartments and changes in disability. Data were collected from a 30-m onth longitudinal study of 28 patients with either a relapsing course with partial remissons and no progression between attacks (relapsing/r emitting) (11 patients) or a course of progressively increasing disabi lity, following a period of relapsing/remitting disease (secondary pro gressive) (17 patients). Proton magnetic resonance spectroscopic imagi ng (MRSI) and conventional MRI examinations were performed at 6-8-mont h intervals with concurrent clinical assessments of disability. Genera l linear models were used to test associations between MRSI, MRI, lesi on volume and clinical data. Analysis confirmed that the NAA : Cr rati o is lower in lesions than in the normal-appearing white matter (-15.3 % in relapsing/remitting multiple sclerosis and -8.8% in secondary pro gressive multiple sclerosis). The lower NAA : Cr ratio per unit lesion volume previously observed for secondary progressive relative to rela psing/remitting patients was found to result from a lower ratio (8.2%, P < 0.01) in the normal-appearing white matter rather than from any d ifferences within lesions. The importance of changes in the normal-app earing white matter was emphasized further with the observation that t he NAA : Cr ratio in the normal-appearing white matter accounted for m ost of the observed 15.6% (P < 0.001) decrease in the NAA : Cr ratio i n the brains of relapsing/remitting patients over the period of study. The decrease in the NAA : Cr ratio in normal-appearing white matter c orrelated strongly (P < 0.001) with changes in disability in the relap sing/remitting subgroup. These results add to data suggesting that axo nal damage or loss may be responsible for functional impairments in mu ltiple sclerosis. The accumulation of secondary axonal damage in the n ormal-appearing white matter may be of particular significance for und erstanding chronic disability in this disease.