Progressive logopenic/phonological aphasia: erosion of the language network

Abstract

The primary progressive aphasias (PPA) are paradigmatic disorders of language network breakdown associated with focal degeneration of the left cerebral hemisphere. Here we addressed brain correlates of PPA in a detailed neuroanatomical analysis of the third canonical syndrome of PPA, logopenic/phonological aphasia (LPA), in relation to the more widely studied clinico-anatomical syndromes of semantic dementia (SD) and progressive nonfluent aphasia (PNFA). 32 PPA patients (9 SD, 14 PNFA, 9 LPA) and 18 cognitively normal controls had volumetric brain MRI with regional volumetry, cortical thickness, grey and white matter voxel-based morphometry analyses. Five of nine patients with LPA had cerebrospinal fluid biomarkers consistent with Alzheimer (AD) pathology (AD-PPA) and 2/9 patients had progranulin (GRN) mutations (GRN-PPA). The LPA group had tissue loss in a widespread left hemisphere network. Compared with PNFA and SD, the LPA group had more extensive involvement of grey matter in posterior temporal and parietal cortices and long association white matter tracts. Overlapping but distinct networks were involved in the AD-PPA and GRN-PPA subgroups, with more anterior temporal lobe involvement in GRN-PPA. The importance of these findings is threefold: firstly, the clinico-anatomical entity of LPA has a profile of brain damage that is complementary to the network-based disorders of SD and PNFA; secondly, the core phonological processing deficit in LPA is likely to arise from temporo-parietal junction damage but disease spread occurs through the dorsal language network (and in GRN-PPA, also the ventral language network); and finally, GRN mutations provide a specific molecular substrate for language network dysfunction.

Fig. 1

Cortical thickness maps showing patterns of cortical thinning in disease groups compared to healthy controls. For each disease panel, left hemisphere sections are shown above and right hemisphere sections below. Maps are thresholded at p < 0.001 after FDR correction over the whole brain volume. The colored bar represents FDR corrected p-values. Within the LPA group, the composite map “AD/GRN overlap” codes areas in which cortical thinning was observed only in the AD-PPA group (green), only in the GRN-PPA group (blue) or in both groups (orange) relative to healthy controls at the prescribed threshold.

Fig. 2

Cortical thickness maps showing patterns of cortical thinning in between disease-group differences. For each disease panel, left hemisphere sections are shown on the left and right hemisphere sections on the right. Maps are thresholded at p < 0.05 after FDR correction over the whole brain volume. The colored bar represents FDR corrected p-values.

Fig. 3

VBM analysis on grey matter regions in PPA groups relative to healthy controls. For each axial section, the left hemisphere is shown on the left; sagittal sections are through the left hemisphere. Maps are thresholded at p < 0.05 after FDR correction over the whole brain volume. Grey matter differences are color coded (red-yellow) in terms of t-score as indicated on the color bar (right).

Fig. 4

VBM analysis on grey matter regions in disease group comparisons. For each axial section, the left hemisphere is shown on the left. Maps are thresholded at p < 0.001 uncorrected. Grey matter differences are color coded (red-yellow) in terms of t-score as indicated on the color bar (lower right).

Fig. 5

VBM analysis on white matter regions in PPA subgroups relative to healthy controls and (bottom row) in the GRN-PPA subgroup relative to other disease groups. For each axial section, the left hemisphere is shown on the left; sagittal sections are through the left hemisphere. For control comparisons, maps are thresholded at p < 0.05 after FDR correction over the whole brain volume; for disease group comparisons, maps are thresholded at p < 0.001 uncorrected. White matter differences are color coded (red-yellow) in terms of t-score as indicated on the color bar (right).The AD-PPA subgroup showed no significant areas of white matter loss relative to other disease groups at the prescribed threshold.