Combined Pathologies in FTLD-TDP Types A and C

Abstract

This study investigated the presence of combined pathologies in a large cohort of autopsies that show a primary pathologic diagnosis of phosphorylated 43-kDa TAR DNA-binding protein (FTLD-TDP), the majority of which portrayed clinical phenotypes consistent with primary progressive aphasia or behavioral variant frontotemporal dementia (bvFTD). Thirty-eight cases with FTLD-TDP (30 type-A and 8 type-C) were identified to determine characteristic differences between cases with and without combined pathologies. Findings indicated that combined pathologies co-occur with FTLD-TDP type-A at a high frequency (50%)-greater than when compared to FTLD-TDP type-C cases (12.5%). Those with FTLD-TDP type-A and combined pathologies showed significantly longer lifespans (p < 0.05), and longer disease durations (p < 0.05), than those with only FTLD-TDP type-A. Cases with FTLD-TDP type-A and known genetic mutations tended not to show combined pathology. Those with the GRN mutation and FTLD-TDP type-A showed a significantly younger age of onset (p < 0.05) and younger age at death (p < 0.01) compared to noncarriers. In 1 bvFTD case, we highlight the rare presence of "triple" FTLD-TDP type-A, FTLD-tau, and Alzheimer pathology. The ante- and post-mortem features associated with combined pathologies in FTLD-related disorders are of useful consideration in the stratification of patients to drug trials, and in the development of therapeutic targets for FTLD.

FIGURE 1.

MRI and FDG-PET images from patient with “triple” neuropathologic diagnoses 6 years prior to death. (A) Brain MRI showed bilateral perisylvian atrophy, greater in left-hemisphere (L) compared to right (R). (B) FDG-PET showed bilateral frontal and anterior temporal hypometabolism (L > R), with additional posterior parietal hypometabolism (L > R).

FIGURE 2.

Gross findings from patient with “triple” neuropathologic diagnoses. Coronal autopsied sections showed severe frontotemporal atrophy (L > R) including temporal pole, and moderate atrophy of parietal and occipital cortex. There is severe ventricular dilatation and moderate atrophy of the caudate and hippocampus.

FIGURE 3.

Pathologic findings from patient with “triple” neuropathologic diagnoses. (A, B) Thioflavin-S-positive AD pathology (high Alzheimer disease neuropathologic change score = A3, B3, C3) in parietal cortex was found in relatively equal distribution in both left and right hemispheres. Magnification: 100×. (C, D) FTLD-TDP pathology in temporal cortex was found in greater distribution in left hemisphere compared to right. Magnification: 200×.

FIGURE 4.

Pathologic findings from patient with “triple” neuropathologic diagnoses (continued). FTLD-tau pathology consistent with PSP was apparent in subcortical areas (A, subthalamic nucleus at 100× magnification), cerebellum (B, dentate nucleus at 400× magnification), and brainstem (C, substantia nigra; D, red nucleus; both at 200× magnification).