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

Lucia Giannini, C Peterson, D Ohm, SX Xie, CT McMillan, K Raskovsky, L Massimo, ER Suh, VM Van Deerlin, DA Wolk, JQ Trojanowski, EB Lee, M Grossman, DJ Irwin

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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.

Original languageEnglish
Article number30
JournalActa neuropathologica communications
Issue number1
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
This study was funded by NIH grants NS109260, AG017586, AG038490, AG052943, AG054519, AG010124, AG043503, AG066597, the Penn Institute on Aging, an anonymous donor, and the Wyncote Foundation.

Funding Information:
We thank the patients and their families for their participation in medical research; M. Neumann and E. Kremmer for providing the phosphorylation-specific TDP-43 antibody p409/410; M. Leonard for her assistance in the creation of Figures and . We thank Alzheimer Nederland, the Royal Netherlands’ Academy of Arts and Sciences (Van Walree Grant) and the Society for Neuroscience (Trainee Professional Development Award) for supporting author L.A.A.G. with student travel funding.

Publisher Copyright:
© 2021, The Author(s).


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