Atrophy, hypometabolism and white matter abnormalities in semantic dementia tell a coherent story

Semantic dementia, in which there is progressive deterioration of semantic knowledge, is associated with focal, typically asymmetric, temporal lobe degeneration. The ventrorostral temporal lobe is most severely affected and there is concordance between atrophy and reduced metabolic activity. In this study, we confirmed the veracity of this claim using F-18-fluorodeoxyglucose positron emission tomography and anatomical magnetic resonance images. The principal aim, however, was to understand the impact on neuronal projections from the ventrorostral temporal cortex lesion by studying the full extent of white matter changes, with no a priori assumptions about the nature or spatial location of the tracts involved. Using an unbiased voxel-wise approach known as tract-based spatial statistics, we compared results of whole-brain diffusion tensor imaging-absolute metrics of axial, radial and mean diffusion as well as fractional anisotropy-from 10 patients with mild/moderate semantic dementia and 21 matched controls. Distributions of increased absolute diffusivity and reduced fractional anisotropy for patients with semantic dementia were spatially concordant with each other. Abnormalities in all metrics were highly statistically significant in ventrorostral temporal white matter, more extreme on the left side, thus closely matching results from structural and functional imaging of grey matter. The most sensitive marker of change was radial diffusion. Local white matter tract abnormalities extended rostrally towards the frontal lobe and dorsocaudally towards the superior temporal and supramarginal gyri. To examine more remote changes, we performed a skeletonized probabilistic tractography analysis-'seeding' the rostral temporal voxels identified as abnormal in the patient group-in a healthy control group. Three major neural pathways were found to emanate from this 'seed region': uncinate, arcuate and inferior longitudinal fasciculi. At a less conservative threshold, tensor abnormalities in the semantic dementia group mapped onto the tractographies for the uncinate and arcuate bundles well beyond the rostral temporal lobe; this was not the case for the inferior longitudinal bundle, where abnormalities in semantic dementia did not extend caudal to the atrophic/hypometabolic zone. The results offer direct evidence for how the ventrorostral temporal lesion, proposed to be responsible for deteriorating semantic knowledge in semantic dementia and separate from 'classic' language areas, is associated with degeneration of efferent white matter projections to such language areas.