Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias

Abstract

Pick's disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.

Keywords: Behavioral variant frontotemporal dementia; Frontotemporal lobar degeneration; Pick’s disease; Primary progressive aphasia; Stereology; Tau.

Fig. 1

Bilateral and mean total (L + R) neocortical densities of Pick bodies in bvFTD and PPA. Bars represent mean density per cubic millimeter of Pick bodies in neocortical regions in bvFTD (N = 9) and PPA cases (N = 9). Neocortical regions include bilateral middle frontal, superior temporal, and inferior parietal gyri. Error bars represent standard errors of mean (SEM). A Bar graphs demonstrate hemispheric differences in mean neocortical density of Pick bodies, highlighting that right hemispheric neocortex in PPA has significantly fewer Pick bodies than the left hemisphere (p < 0.01). B Bar graphs show the mean overall (L + R) cortical regions in bvFTD vs PPA with error bars representing SEMs. Across the three neocortical regions, bvFTD has significantly greater overall mean density of PiD pathology (M = 25,240.24, SD = 11,431.51) compared to PPA (M = 20,260.76, SD = 11,816.51) (p < 0.01), driven by the leftward asymmetry seen in PPA, as shown in A. **p < 0.01

Fig. 2

Neocortical distribution of Pick bodies in bvFTD vs PPA. Height of bars represent mean density per cubic millimeter of Pick bodies in neocortical regions in bvFTD (N = 9) and PPA (N = 9) cases. Error bars represent standard errors of mean (SEM). Pick body density was highest in MFG in bvFTD and ATL in PPA, and OCC showed no Pick bodies in bvFTD and PPA. bvFTD displayed generally bilateral distribution of PiD pathology, except for STG which showed rightward asymmetry (p < 0.05). In PPA, regions were generally leftward asymmetric, which reached significance in STG (p < 0.01). ATL showed slight rightward predilection in PPA. MFG = Middle frontal gyrus; STG = Superior temporal gyrus; IPL = Inferior parietal lobule; ATL = Anterior temporal lobe; OCC = Occipital cortex. *p < 0.05; **p < 0.01

Fig. 3

Laterality of Pick bodies in Right/Left Neocortex. A Ratios of Pick body density counts per millimeter cubed in individual right/left neocortical regions were transformed logarithmically (base 10) to illustrate hemispheric differences in PiD pathology in bvFTD (N = 9) and PPA (N = 9). In STG, right-to-left ratio was significantly different between PPA, which showed significant leftward asymmetry, and bvFTD, which showed slight rightward asymmetry (p < 0.001). The IPL ratio for Case 14 was excluded because the right IPL showed no pathology, so the right/left ratio equaled zero and thus could not be logarithmically transformed. The MFG ratio for Case 15 was excluded as an outlier (M ±  ≥ 2 SD). MFG = Middle frontal gyrus; STG = Superior temporal gyrus; IPL = inferior parietal lobule; R = Right; L = Left. ***p < 0.001. B Opposite laterality of Pick bodies in STG of PPA vs bvFTD. Photomicrographs (i) & (ii) were obtained from Case 5, an 82-year-old female with a 12-year history of bvFTD and (iii) and (iv) were obtained from Case 12, a 65-year-old male with a 12-year history of PPA-G; images highlight significant leftward asymmetry in PiD in STG, while bvFTD cases showed slight rightward predominance. Brown appearance in i and ii are due to DAB, and red appearance in (iii) and (iv) are due to Vector NovaRed substrate. Scale bar = 100 µm in (iv), and also applies to (i–iii)

Fig. 4

Abundant hippocampal pathologic burden is a universal substrate of Pick’s Disease (PiD). A Height of bars represent mean density per cubic millimeter of Pick bodies in anatomic regions in bvFTD (N = 9) and PPA cases (N = 9). Error bars represent standard errors of mean (SEM). Dotted line indicates the highest mean neocortical Pick body density from Fig. 2 for the PPA group, which was right ATL at 34,473 inclusions per mm³. Dashed line indicates the highest mean neocortical Pick body density from Fig. 2 for the bvFTD group, which was right MFG at 29,157 inclusions per mm³. bvFTD cases had slightly greater mean DG and CA1 densities compared to PPA cases, which did not reach significance. Burden was symmetric for both phenotypes. Photomicrographs (B & C) illustrate the substantial neuropathologic burden throughout the entire hippocampus in both the behavioral and aphasic phenotypes; B was obtained from Case 5, an 82-year-old female with a 12-year history of bvFTD and C was obtained from Case 12, a 65-year-old male with a 12-year history of PPA-G. Inset highlights the granule cells of the dentate gyrus, which were most affected by Pick bodies in both bvFTD and PPA cohorts. Images were taken at 1 × magnification, and insets were taken at 20X. DG = Dentate gyrus; CA1 = Cornu Ammonis field 1

Fig. 5

Pick body packing density in hippocampus versus neocortex. A and B show density of tau pathology staining using immunohistochemistry with AT8 antibody in relation to neuronal density. A illustrates the high degree of pathology in the dentate gyrus (DG) of the hippocampus, which also holds a high density of neurons, in Case 13, a 75-year-old male with a 9-year history of PPA. B shows relative density of tau pathology in the left middle frontal gyrus (MFG), a neocortical region with relatively abundant Pick disease pathology, in Case 18, a 71-year-old female with a 14-year history of PPA. Photographs were taken at the same magnification. Inclusion-to-neuron analyses in a subset of cases show that despite differences in neuronal packing density, hippocampal cells, particularly granule cells in the DG, contain significantly more inclusions per neuron (p < 0.05). Bar indicates 100 µm