Ohm Daniel T, Xie Sharon X, Capp Noah, Arezoumandan Sanaz, Cousins Katheryn A Q, Rascovsky Katya, Wolk David A, Van Deerlin Vivianna M, Lee Edward B, McMillan Corey T, Irwin David J
Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Brain. 2025 Jan 7;148(1):102-118. doi: 10.1093/brain/awae263.
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.
行为变异型额颞叶痴呆（bvFTD）是一种主要由tau蛋白病（bvFTD-tau）或43 kDa的反式激活反应DNA结合蛋白（TDP-43）蛋白病（bvFTD-TDP）引起的临床综合征。我们之前发现，与TDP-43病理相比，皮质浅层和背外侧区域积累了更多的tau病理；然而，bvFTD中不同细胞结构的层状神经退行性变模式尚未得到充分研究。我们假设，bvFTD-tau和bvFTD-TDP在皮质梯度上的锥体神经退行性变具有不同的层状分布，这是一种基于锥体密度增加和层状分化的细胞结构亚区域的拓扑顺序。在此，我们在一个由五种细胞结构类型（即周边异皮质、无颗粒中间皮质、颗粒减少的中间皮质、I型均质同皮质和II型均质同皮质）组成的额叶皮质梯度中检验了这一假设，该梯度跨越bvFTD-tau（n = 27）、bvFTD-TDP（n = 47）和健康对照（n = 32）的前扣带回、旁扣带回、眶额回和额中回。我们对所有组织进行全神经元（NeuN；神经元核蛋白）和锥体神经元（SMI32；非磷酸化神经丝）免疫染色，并对每种细胞结构类型的颗粒上层II-III、颗粒下层V-VI和所有I-VI层中的NeuN免疫反应性（ir）和SMI32-ir进行数字量化。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的SMI32-ir，并检查其与皮质梯度、长程通路和临床症状的关系。我们发现了健康对照预期的SMI32-ir的区域和层状分布，验证了我们在皮质梯度框架内的测量方法。在bvFTD-TDP中，SMI32-ir损失沿皮质梯度相对均匀，而在bvFTD-tau中，SMI32-ir沿皮质梯度逐渐下降，且与bvFTD-TDP相比，bvFTD-tau的颗粒上层II型均质同皮质中SMI32-ir损失更大（P = 0.039）。使用SMI32-ir与模型已知的颗粒下中间皮质和颗粒上同皮质之间的长程连接性的比值，我们发现bvFTD-tau与bvFTD-TDP相比，层状比值更大（P = 0.019），这表明特定的长投射通路可能导致bvFTD-tau中以同皮质为主的变性。在NeuN-ir最高的细胞结构类型中，我们发现bvFTD-tau与bvFTD-TDP相比，SMI32-ir更低（P = 0.047），这表明锥体神经退行性变可能在bvFTD-tau中更早发生。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相关，而与颞叶介导的对质命名无关，这证明了额叶锥体神经退行性变与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丧失是bvFTD的一个临床相关特征，在bvFTD-tau中沿额叶皮质梯度选择性恶化，而在bvFTD-TDP中则不然。因此，tau介导的变性可能优先累及连接更远细胞结构类型的富含锥体的层。此外，沿皮质梯度的细胞结构层次排列可能是一个重要的神经解剖框架，用于确定在蛋白病之间哪些类型的细胞和通路存在差异参与。
