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.

具有 tau (FTLD-tau) 或 TDP-43 (FTLD-TDP) 包涵体的额颞叶变性 (FTLD) 是不同的蛋白质病，经常引起类似的额颞叶痴呆 (FTD) 临床综合征。FTD 综合征通常在区域和网络水平上显示神经变性的宏观特征，但尚不清楚亚区域层状病理学是否显示蛋白质病或临床综合征特有的模式。我们假设 FTLD-tau 和 FTLD-TDP 在独立于临床综合征的相对不同的皮质层中积累病理，FTLD-tau 中下层的参与更多。目前的研究检查了 170 名患有 FTLD-tau ( n  = 73) 或 FTLD-TDP ( n = 97) 跨越 FTD 谱中的痴呆和运动表型。我们以数字方式测量了 tau 和 TDP-43 病变在上层 (I-III)、下层 (IV-VI) 和两个半球等皮质区域的近皮质白质 (WM) 中所占的面积百分比（如果可用）。线性混合效应模型比较了 FTLD 组之间上下层病理学的比率，并研究了与区域、WM 病理学和整体认知障碍的关系，同时针对人口统计学进行了调整。我们在 FTLD-tau 中发现层病理学的比率较低，在 FTLD-TDP 中发现层病理学的比率较高，分别反映了下层为主的 tau 病理学和上层为主的 TDP-43 病理学（p < 0.001)。FTLD-tau 显示与更大的 WM tau 病理学 ( p  = 0.002) 和早期受累/严重病理学区域 ( p  = 0.007)相关的层病理学比率较低。相比之下，FTLD-TDP 显示与 WM 病理学或区域严重性无关的层病理学比率较高。更大的认知障碍与 FTLD-tau 中更高的层病理学比率相关（p = 0.018)，但与 FTLD-TDP 中层病理学的比率无关。下层为主的 tau 病理学和上层为主的 TDP-43 病理学是蛋白质病特异性的，无论定义这些综合征的临床综合征或区域网络如何。因此，层流变化模式可能提供有用的解剖学框架，用于研究选定细胞和相应层流回路的退化如何影响 FTLD 中的大规模网络和临床症状。