Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations

Abstract

Neural network breakdown is a key issue in neurodegenerative disease, but the mechanisms are poorly understood. Here we investigated patterns of brain atrophy produced by defined molecular lesions in the two common forms of genetically mediated frontotemporal lobar degeneration (FTLD). Nine patients with progranulin (GRN) mutations and eleven patients with microtubule-associated protein tau (MAPT) mutations had T1 MR brain imaging. Brain volumetry and grey and white matter voxel-based morphometry (VBM) were used to assess patterns of cross-sectional atrophy in the two groups. In a subset of patients with longitudinal MRI rates of whole-brain atrophy were derived using the brain-boundary-shift integral and a VBM-like analysis of voxel-wise longitudinal volume change was performed. The GRN mutation group showed asymmetrical atrophy whereas the MAPT group showed symmetrical atrophy. Brain volumes were smaller in the GRN group with a faster rate of whole-brain atrophy. VBM delineated a common anterior cingulate-prefrontal-insular pattern of atrophy in both disease groups. Additional disease-specific profiles of grey and white matter loss were identified on both cross-sectional and longitudinal imaging: GRN mutations were associated with asymmetrical inferior frontal, temporal and inferior parietal lobe grey matter atrophy and involvement of long intrahemispheric association white matter tracts, whereas MAPT mutations were associated with symmetrical anteromedial temporal lobe and orbitofrontal grey matter atrophy and fornix involvement. The findings suggest that the effects of GRN and MAPT mutations are expressed in partly overlapping but distinct anatomical networks that link specific molecular dysfunction with clinical phenotype.

Fig. 1

Annualized rates of whole-brain atrophy (as measured using the boundary shift integral) in the MAPT mutation (diamonds) and GRN mutation (triangles) groups as well as the controls (circles).

Fig. 2

Left/right hemisphere volume ratio in the three groups (A) and in patients with longitudinal imaging as a function of disease duration i.e. time from symptom onset (B).

Fig. 3

VBM analysis on grey matter (GM) and white matter (WM) regions in GRN- and MAPT-associated FTLD relative to healthy controls. Statistical parametric maps (SPMs) have been thresholded at p < 0.001 after false discovery rate correction over the whole-brain volume and rendered on a study-specific average group T1-weighted MRI template image in DARTEL space. The colour bar (lower right) indicates the t score. Left (L) and right (R) markers are shown for ease of reference however this analysis was performed on flipped images (see text). GM panels show the same series of coronal MR sections in the GRN and MAPT cases; WM panels show coronal (above) and sagittal (below) sections based on zones of maximal white matter loss in each disease group.

Fig. 4

VBM analysis comparing grey matter (GM) and white matter (WM) atrophy between GRN- and MAPT-associated FTLD groups. Left-hand panels show regions where tissue intensity was reduced in the GRN group relative to the MAPT group (GRNp < 0.001 (uncorrected) and rendered on the same template used in Fig. 3. The colour bar (lower right) indicates the t score. Left (L) and right (R) markers are shown for ease of reference however this analysis was performed on flipped images (see text). Sections shown are based on zones of maximal grey and white matter loss in each disease group.

Fig. 5

Longitudinal voxel compression map analysis showing comparison between GRN- and MAPT-associated FTLD groups. Red indicates more severe longitudinal atrophy in the MAPT group, and blue greater in GRN. Top panel shows grey matter (GM) maps and bottom panel shows white matter (WM) maps, which are overlaid on the same average template used in Fig. 3. Because of the very small groups, we present only unthresholded maps of the group-difference, rather than thresholded t-maps, which show only a few isolated peaks at an uncorrected 0.001 level. These unthresholded maps of effect–size show the character, but not the significance, of the group differences.