Signature laminar distributions of pathology in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregional laminar pathology display patterns unique to proteinopathy or clinical syndrome. We hypothesized that FTLD-tau and FTLD-TDP accumulate pathology in relatively distinct cortical layers independent of clinical syndrome, with greater involvement of lower layers in FTLD-tau. The current study examined 170 patients with either FTLD-tau (n = 73) or FTLD-TDP (n = 97) spanning dementia and motor phenotypes in the FTD spectrum. We digitally measured the percent area occupied by tau and TDP-43 pathology in upper layers (I-III), lower layers (IV-VI), and juxtacortical white matter (WM) from isocortical regions in both hemispheres where available. Linear mixed-effects models compared ratios of upper to lower layer pathology between FTLD groups and investigated relationships with regions, WM pathology, and global cognitive impairment while adjusting for demographics. We found lower ratios of layer pathology in FTLD-tau and higher ratios of layer pathology in FTLD-TDP, reflecting lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology, respectively (p < 0.001). FTLD-tau displayed lower ratios of layer pathology related to greater WM tau pathology (p = 0.002) and to earlier involved/severe pathology regions (p = 0.007). In contrast, FTLD-TDP displayed higher ratios of layer pathology not related to either WM pathology or regional severity. Greater cognitive impairment was associated with higher ratios of layer pathology in FTLD-tau (p = 0.018), but was not related to ratios of layer pathology in FTLD-TDP. Lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology are proteinopathy-specific, regardless of clinical syndromes or regional networks that define these syndromes. Thus, patterns of laminar change may provide a useful anatomical framework for investigating how degeneration of select cells and corresponding laminar circuits influence large-scale networks and clinical symptomology in FTLD.

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

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.