Behavioural variant frontotemporal dementia (bvFTD) is a clinical syndrome caused primarily by either tau (bvFTD-tau) or transactive response DNA-binding protein of 43 kDa (TDP-43) (bvFTD-TDP) proteinopathies. We previously found that lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, the patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD are understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topological order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e. periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex and eulaminate-II isocortex) spanning the anterior cingulate, paracingulate, orbitofrontal and mid-frontal gyri in bvFTD-tau (n = 27), bvFTD-TDP (n = 47) and healthy controls (n = 32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II–III, infragranular V–VI and all I–VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biological variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for healthy controls, validating our measures within the cortical gradient framework. The SMI32-ir loss was relatively uniform along the cortical gradient in bvFTD-TDP, whereas SMI32-ir decreased progressively along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau versus bvFTD-TDP (P = 0.039). Using a ratio of SMI32-ir to model known long-range connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio in bvFTD-tau versus bvFTD-TDP (P = 0.019), suggesting that select long-projecting pathways might contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau versus bvFTD-TDP (P = 0.047), suggesting that pyramidal neurodegeneration might occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir was related to behavioural severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest that loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that worsens selectively along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration might preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients might be an important neuroanatomical framework for identifying which types of cells and pathways are involved differentially between proteinopathies.

中文翻译：

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行为变异额颞叶痴呆中椎板变性的细胞结构梯度


行为变异额颞叶痴呆 （bvFTD） 是一种主要由 tau （bvFTD-tau） 或反式反应 43 kDa 的 DNA 结合蛋白 （TDP-43） （bvFTD-TDP） 蛋白病引起的临床综合征。我们之前发现，下皮质层和背外侧区域积累的 tau 比 TDP-43 病理更大;然而，bvFTD 中不同细胞结构的层状神经变性模式研究不足。我们假设 bvFTD-tau 和 bvFTD-TDP 沿皮层梯度具有明显的锥体神经变性层状分布，这是基于锥体密度增加和层状分化的细胞结构亚区的拓扑顺序。在这里，我们在由五种细胞结构类型组成的额叶皮层梯度中测试了这一假设（即 外层皮层、无颗粒中皮层、颗粒状中皮层、Eulaminate-I 等皮层和 Eulaminate-II 等皮层）跨越前扣带回、腭层、眶额叶和额中回在 bvFTD-tau （n = 27）、bvFTD-TDP （n = 47） 和健康对照 （n = 32）。我们对所有组织的总神经元 （NeuN;神经元核蛋白） 和锥体神经元 （SMI32;非磷酸化神经丝） 进行免疫染色，并数字量化了颗粒上 II-III、下颗粒 V-VI 和每种细胞结构类型中的所有 I-VI 层中的 NeuN-免疫反应性 （ir） 和 SMI32-ir。我们使用针对人口统计学和生物学变量进行调整的线性混合效应模型来比较组间 SMI32-ir，并检查与皮质梯度、长程通路和临床症状的关系。我们发现健康对照预期的 SMI32-ir 的区域和层状分布，验证了我们在皮质梯度框架内的措施。 在 bvFTD-TDP 中，SMI32-ir 损失沿皮层梯度相对均匀，而 SMI32-ir 沿 bvFTD-tau 的皮层梯度逐渐减少，并且与 bvFTD-TDP 相比，bvFTD-tau 中颗粒上层层 II 等皮层中 SMI32-ir 损失更大 （P = 0.039）。使用 SMI32-ir 的比率来模拟下颗粒中皮层和颗粒上等皮层之间已知的长距离连接，我们发现 bvFTD-tau 与 bvFTD-TDP 的层流比更大 （P = 0.019），表明选定的长投射途径可能有助于 bvFTD-tau 中等皮层为主的变性。在具有最高 NeuN-ir 的细胞结构类型中，我们发现 bvFTD-tau 的 SMI32-ir 低于 bvFTD-TDP （P = 0.047），这表明锥体神经变性可能在 bvFTD-tau 中发生得更早。最后，我们发现 SMI32-ir 降低与行为严重程度和额叶介导的字母流畅性有关，而不是时间介导的对抗命名，证明了额叶锥体神经变性与 bvFTD 相关症状的临床相关性和特异性。我们的数据表明，富含神经丝的锥体神经元的缺失是 bvFTD 的一个临床相关特征，它在 bvFTD-tau 中沿着额叶皮层梯度选择性恶化，而不是 bvFTD-TDP。因此，tau 介导的变性可能优先涉及连接更远的细胞结构类型的富含金字塔的层。此外，沿皮质梯度的细胞结构分层排列可能是一个重要的神经解剖学框架，用于识别哪些类型的细胞和通路在蛋白质病之间差异参与。