Cytoarchitectonic gradients of laminar degeneration in behavioural variant frontotemporal dementia

Behavioural variant frontotemporal dementia (bvFTD) is a clinical syndrome caused primarily by either tau (bvFTD-tau) or transactive response DNA-binding protein of 43kDa (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.