Frontotemporal lobar degeneration proteinopathies have disparate microscopic patterns of white and grey matter pathology

Lucia A A Giannini,John Q Trojanowski,David J Irwin,Katya Raskovsky,Corey T Mcmillan,David A Wolk,Vivianna M Van Deerlin,Sharon X Xie,Daniel Ohm,Lauren Massimo,Eunrah Suh,Claire Peterson,Murray Grossman,Edward B Lee

doi:10.1186/s40478-021-01129-2

Lucia A A Giannini, John Q Trojanowski + Show 12 more

Open Access

https://doi.org/10.1186/s40478-021-01129-2

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Abstract

Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau) or TDP-43 inclusions (FTLD-TDP) are associated with clinically similar phenotypes. However, these disparate proteinopathies likely differ in cellular severity and regional distribution of inclusions in white matter (WM) and adjacent grey matter (GM), which have been understudied. We performed a neuropathological study of subcortical WM and adjacent GM in a large autopsy cohort (n = 92; FTLD-Tau = 37, FTLD-TDP = 55) using a validated digital image approach. The antemortem clinical phenotype was behavioral-variant frontotemporal dementia (bvFTD) in 23 patients with FTLD-Tau and 42 with FTLD-TDP, and primary progressive aphasia (PPA) in 14 patients with FTLD-Tau and 13 with FTLD-TDP. We used linear mixed-effects models to: (1) compare WM pathology burden between proteinopathies; (2) investigate the relationship between WM pathology burden and WM degeneration using luxol fast blue (LFB) myelin staining; (3) study regional patterns of pathology burden in clinico-pathological groups. WM pathology burden was greater in FTLD-Tau compared to FTLD-TDP across regions (beta = 4.21, SE = 0.34, p < 0.001), and correlated with the degree of WM degeneration in both FTLD-Tau (beta = 0.32, SE = 0.10, p = 0.002) and FTLD-TDP (beta = 0.40, SE = 0.08, p < 0.001). WM degeneration was greater in FTLD-Tau than FTLD-TDP particularly in middle-frontal and anterior cingulate regions (p < 0.05). Distinct regional patterns of WM and GM inclusions characterized FTLD-Tau and FTLD-TDP proteinopathies, and associated in part with clinical phenotype. In FTLD-Tau, WM pathology was particularly severe in the dorsolateral frontal cortex in nonfluent-variant PPA, and GM pathology in dorsolateral and paralimbic frontal regions with some variation across tauopathies. Differently, FTLD-TDP had little WM regional variability, but showed severe GM pathology burden in ventromedial prefrontal regions in both bvFTD and PPA. To conclude, FTLD-Tau and FTLD-TDP proteinopathies have distinct severity and regional distribution of WM and GM pathology, which may impact their clinical presentation, with overall greater severity of WM pathology as a distinguishing feature of tauopathies.

Highlights

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that are currently classified based on the main protein constituents of intracellular aggregations detectable at autopsy
We report a large-scale digital histopathological study in a well-characterized autopsy cohort of behavioral-variant frontotemporal dementia (FTD) (bvFTD) and progressive aphasia (PPA) patients to address this knowledge gap and test the following hypotheses: (1) there is greater white matter (WM) pathologic burden across regions in FTLD-Tau subtypes compared to subtypes of FTLD-TDP; (2) WM pathology burden is related to greater WM degeneration in FTLDTau compared to FTLD-TDP; and (3) there are distinct regional patterns of WM and grey matter (GM) pathology in FTLDTau and FTLD-TDP proteinopathies and their subtypes, which are in part related to clinical phenotype
In bvFTD with FTLD-TDP, INS had similar GM and WM pathology burden to OFC (p > 0.9), and had greater burden than superior parietal lobe (SPL) in both GM (p = 0.026) and WM (p = 0.002). In this large-scale digital histopathological comparative study of WM and adjacent GM pathology in a clinically well-defined FTLD autopsy cohort, we find that greater WM pathology burden and WM degeneration is a consistent neuropathological feature of tauopathies compared to TDP-43 proteinopathies (Figs. 1, 2; Table 3)

Summary

Introduction

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that are currently classified based on the main protein constituents of intracellular aggregations detectable at autopsy. Antemortem neuroimaging patterns of regional atrophy in living patients with clinical PPA and bvFTD suggest that regional patterns of neurodegeneration in interconnected brain regions comprising functional cognitive networks are influential for clinical symptomology in FTD [64] It remains unclear how disparate FTLD proteinopathies cause somewhat similar clinical FTD phenotypes. No study far has rigorously quantified the severity of WM pathology in a large autopsy cohort of FTLD-Tau and FTLD-TDP, and few have examined whether the differential severity of pathology or the regional anatomic distribution of WM pathology contributes to specific FTD clinical phenotypes [23, 58] Examination of both WM and GM pathology is critical in clinicopathologic studies given current neurocognitive models of largescale network degradation in neurodegenerative disease [61]

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