TDP-43 subtypes are associated with distinct atrophy patterns in frontotemporal dementia

Abstract

Background: We sought to describe the antemortem clinical and neuroimaging features among patients with frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP).

Methods: Subjects were recruited from a consecutive series of patients with a primary neuropathologic diagnosis of FTLD-TDP and antemortem MRI. Twenty-eight patients met entry criteria: 9 with type 1, 5 with type 2, and 10 with type 3 FTLD-TDP. Four patients had too sparse FTLD-TDP pathology to be subtyped. Clinical, neuropsychological, and neuroimaging features of these cases were reviewed. Voxel-based morphometry was used to assess regional gray matter atrophy in relation to a group of 50 cognitively normal control subjects.

Results: Clinical diagnosis varied between the groups: semantic dementia was only associated with type 1 pathology, whereas progressive nonfluent aphasia and corticobasal syndrome were only associated with type 3. Behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease were seen in type 2 or type 3 pathology. The neuroimaging analysis revealed distinct patterns of atrophy between the pathologic subtypes: type 1 was associated with asymmetric anterior temporal lobe atrophy (either left- or right-predominant) with involvement also of the orbitofrontal lobes and insulae; type 2 with relatively symmetric atrophy of the medial temporal, medial prefrontal, and orbitofrontal-insular cortices; and type 3 with asymmetric atrophy (either left- or right-predominant) involving more dorsal areas including frontal, temporal, and inferior parietal cortices as well as striatum and thalamus. No significant atrophy was seen among patients with too sparse pathology to be subtyped.

Conclusions: FTLD-TDP subtypes have distinct clinical and neuroimaging features, highlighting the relevance of FTLD-TDP subtyping to clinicopathologic correlation.

Figure 1 Voxel-based morphometry analysis on gray matter regions in the type 1 group relative to healthy controls (A) and in the type 1 subgroups with left- and right-sided predominant atrophy (B) Statistical parametric maps 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 color bar (left) indicates the t score. The left hemisphere is shown on the left of each figure.

Figure 2 Voxel-based morphometry analysis on gray matter regions in the type 2 group relative to healthy controls Statistical parametric maps 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 color bar (left) indicates the t score. The left hemisphere is shown on the left of each figure.

Figure 3 Voxel-based morphometry analysis on gray matter regions in the type 3 group relative to healthy controls (A) and in the type 3 subgroups with right- and left-sided predominant atrophy (B) Statistical parametric maps 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 color bar (left) indicates the t score. The left hemisphere is shown on the left of each figure.