Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration

Abstract

Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.

Figure 1

Cerebral interhemispheric asymmetry in FTLD pathological groups and in healthy controls. For display purposes, hemispheric asymmetry is here expressed as the ratio of left/right hemisphere volumes for each subject. Horizontal lines indicate healthy control range aFTLDU = atypical FTLDU; CBD = corticobasal degeneration; NIFID = neuronal intermediate filament inclusion disease.

Figure 2

Voxel-based morphometry analysis on grey matter regions in FTLD pathological groups relative to healthy controls. Statistical parametric maps have been thresholded at P < 0.01 after false discovery rate correction over the whole-brain volume and rendered on axial (left) and coronal (right) sections of a study-specific average group T₁-weighted MRI template image in DARTEL space. The colour bar (lower right) indicates the t-score. This analysis was performed on flipped images (see text). For ease of comparison, the same brain template sections are shown for each pathological group; co-ordinates (mm) for the plane of each section are indicated below. aFTLDU = atypical FTLDU; CBD = corticobasal degeneration.

Figure 3

Voxel-based morphometry analysis on white matter regions in FTLD pathological groups relative to healthy controls. Statistical parametric maps have been thresholded at P < 0.01 after false discovery rate correction over the whole-brain volume and rendered on axial (left) and coronal (right) sections of a study-specific average group T₁-weighted MRI template image in DARTEL space. The colour bar (lower right) indicates the t-score. This analysis was performed on flipped images (see text). For ease of comparison, the same brain template sections are shown for each pathological group; co-ordinates (mm) for the plane of each section are indicated below. CBD = corticobasal degeneration.

Figure 4

Cluster analyses of the FTLD cohort. Cluster analyses are shown for pathological (right-hand text column for each panel) and clinical syndromic diagnoses, according to frontotemporal, intertemporal and interfrontal volumetric difference measures (see text). Cluster dendrograms use average linkage between groups. Each cluster dendrogram demonstrates separation of the entire FTLD group into two subgroups based on the corresponding difference measure; together, the measures partition the cohort into at least four pathological subgroups (Pick’s, MAPT, TDP-C, corticobasal degeneration/FUS; Fig. 5). bvFTD = behavioural variant FTD; CBD = corticobasal degeneration; PSPS = progressive supranuclear palsy syndrome; SD = semantic dementia.

Figure 5

Diagrammatic summary of neuroanatomical features associated with pathological diagnosis in this FTLD cohort. The figure is based on volumetric, voxel-based morphometry and cluster analyses of the present neuroimaging data. Diseases can in general be classified according to whether they produced relatively focal temporal lobe atrophy (TL) or atrophy predominantly involving extratemporal (extra-TL; e.g. frontal lobe) regions; and according to whether they produced relatively symmetric or strongly asymmetric atrophy. Pick’s disease was associated with an asymmetric atrophy profile variably involving temporal or extra temporal regions. TDP-A was associated with strongly asymmetric atrophy (especially in association with GRN mutations) but with wide individual variability. CBD = corticobasal degeneration.