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

Acta Neuropathologica Communications

Sharon X. Xie¹  Katya Raskovsky²  Corey T. McMillan²  Lauren Massimo²  Murray Grossman²  David A. Wolk³  Edward B. Lee⁴  EunRah Suh⁵  Vivianna M. Van Deerlin⁵  John Q. Trojanowski⁶  Claire Peterson⁷  David J. Irwin⁷  Daniel Ohm⁷  Lucia A. A. Giannini⁸ 

[1] Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Neurology, Perelman School of Medicine, Penn Frontotemporal Degeneration Center (FTDC), Hospital of the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA;Department of Pathology and Laboratory Medicine, Alzheimer’s Disease Center, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Pathology and Laboratory Medicine, Alzheimer’s Disease Center, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Pathology and Laboratory Medicine, Alzheimer’s Disease Center, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Neurology, Perelman School of Medicine, Penn Frontotemporal Degeneration Center (FTDC), Hospital of the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA;Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Neurology, Perelman School of Medicine, Penn Frontotemporal Degeneration Center (FTDC), Hospital of the University of Pennsylvania, 3600 Spruce Street, 19104, Philadelphia, PA, USA;Department of Neurology, Alzheimer Center, Erasmus University Medical Center, Rotterdam, The Netherlands;

关键词: Tau;    TDP-43;    Frontotemporal dementia;    Primary progressive aphasia;    Neuropathology;   

DOI  :  10.1186/s40478-021-01129-2

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY