Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis

Abstract

Diffusion MRI and magnetic resonance spectroscopic measurements of selectively neuronally localised N-acetylaspartate (NAA) both have been used widely to assess white matter integrity and axonal loss. We have tested directly the relationship between changes in diffusion MRI parameters and NAA concentrations in the corpus callosum (CC) in an in vivo study of patients with MS. Fifteen MS patients (median EDSS 2.5, range 1–4) were studied with T1 anatomical, T2-weighted, and diffusion-sensitised MRI and PRESS single-voxel MRS. A recently described method, tract-based spatial statistics (TBSS) [Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E. et al., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487–1505] also was used to perform exploratory voxelwise whole-brain analysis of white matter diffusion fractional anisotropy (FA). We found a strong correlation between callosal size and both mean FA (r=0.68, p<0.005) (related specifically to changes in the radial tensor component) and mean inter-hemispheric motor tract connectivity probability (r=0.74, p<0.001). TBSS confirmed that the diffusion anisotropies of white matter voxels specifically within the callosum were correlated with the callosal size. Individual patient global T2 lesion volumes were correlated with both the probability of callosal connectivity (r=−0.69, p<0.005) and fractional anisotropy across the callosum (r=−0.76, p<0.001). However, absolute concentrations of NAA from the voxel showed no correlation with callosal cross-sectional area, mean connectivity or fractional anisotropy within the callosal pathway. We conclude that diffusion MRI shows changes consistent with sensitivity to axonal loss, but that relative NAA changes are not necessarily related directly to this. Axonal metabolic function, independent of structural integrity, may be a major determinant of NAA measures in MS.