行为变异额颞叶痴呆(bvFTD)是一种临床综合征,主要由tau(bvFTD-tau)或TDP-43(bvFTD-TDP)蛋白病引起。我们以前发现较低的皮质层和背外侧区域积累的tau比TDP-43病理更大;然而,bvFTD中跨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沿皮质梯度具有不同的锥体神经变性层状分布,基于增加的锥体密度和层状分化的细胞结构子区域的拓扑顺序。这里,我们在由五种细胞结构类型组成的额叶皮质梯度中检验了这一假设(即,周围皮质,球状中皮层,颗粒异常的中皮层,乌拉胺酸盐-I异皮质,eulaminate-II等皮质)跨越前扣带,模拟,眶额,bvFTD-tau中的中额回(n=27),bvFTD-TDP(n=47),和健康对照(HC;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)进行了免疫染色,并在颗粒上II-III中进行了数字定量的NeuN免疫反应性(ir)和SMI32-ir,颗粒下V-VI,以及每种细胞结构类型的所有I-VI层。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各组之间的SMI32-ir,并检查与皮质梯度的关系。远程路径,和临床症状。我们发现了预计HC的SMI32-ir的区域和层状分布,在皮质梯度框架内验证我们的度量。虽然在bvFTD-TDP中SMI32-ir的损失沿皮质梯度相对均匀,SMI32-ir沿bvFTD-tau的皮质梯度逐渐降低,并且与bvFTD-TDP相比,bvFTD-TDP的颗粒上乌拉胺酸II异皮质中的SMI32-ir损失更大(p=0.039)。使用SMI32-ir的比率来模拟小脑膜中皮层和小脑膜上等皮层之间已知的远程连接,我们发现bvFTD-tau与bvFTD-TDP的层流比较大(p=0.019),提示选择长投射途径可能导致bvFTD-tau的等皮质优势变性。在最高NeuN-ir的细胞结构类型中,我们发现bvFTD-tau与bvFTD-TDP中的SMI32-ir较低(p=0.047),提示锥体神经变性可能发生在bvFTD-tau早期。最后,我们发现SMI32-ir的降低与行为严重程度和额叶介导的字母流利度有关,不是以时间为媒介的对抗命名,证明额锥体神经变性与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丢失是bvFTD的临床相关特征,它沿bvFTD-tau的额叶皮质梯度选择性恶化,不是bvFTD-TDP。因此,tau介导的变性可能优先涉及富含锥体的层,这些层连接了更远的细胞结构类型。此外,细胞结构沿皮质梯度的分层排列可能是一个重要的神经解剖学框架,用于确定哪些类型的细胞和通路在蛋白质病之间有差异.
Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic 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, eulaminate-II isocortex) spanning anterior cingulate, paracingulate, orbitofrontal, and mid-frontal gyri in bvFTD-tau (n=27), bvFTD-TDP (n=47), and healthy controls (HC; 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 biologic 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 HC, validating our measures within the cortical gradient framework. While SMI32-ir loss was relatively uniform along the cortical gradient in bvFTD-TDP, SMI32-ir progressively decreased 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 select long-projecting pathways may 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 pyramidal neurodegeneration may occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir related to behavioral 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 loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that selectively worsens along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration may preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients may be an important neuroanatomical framework for identifying which types of cells and pathways are differentially involved between proteinopathies.