Pyramidal neurodegeneration is linked to select cytoarchitecture and cognitive impairment in behavioral variant frontotemporal dementia with tau or TDP‐43 pathology
Authors: Ohm Daniel T , Bahena Alejandra , Arezoumandan Sanaz , Cousins Katheryn A Q , Phillips Jeffrey S , Capp Noah , Trotman Winifred , Xie Emily , Wolk David A. , McMillan Corey T , Trojanowski John Q , Lee Eddie B , Grossman Murray , Irwin David J. 
Published: December 2023

Background

The behavioral variant of frontotemporal dementia (bvFTD) is primarily caused by either tauopathies (bvFTD‐tau) or TDP‐43 (bvFTD‐TDP) proteinopathies. Frontal cortices are often the earliest sites of degeneration in bvFTD, and previous studies suggest bvFTD‐tau and bvFTD‐TDP share similar patterns of pyramidal neurodegeneration in infragranular layers of agranular cortices. However, neurodegeneration in other cortical layers in more laminated (dysgranular‐to‐granular) cytoarchitecture in bvFTD remain poorly understood. We recently reported that infragranular layers throughout agranular‐to‐granular regions accumulate more protein inclusions in bvFTD‐tau than bvFTD‐TDP. Thus, the current study tested the hypothesis that pyramidal neurodegeneration is greater in more laminated regions of bvFTD‐tau than bvFTD‐TDP and relates to frontal‐mediated cognitive impairment.

Methods

In 49 bvFTD‐TDP, 28 bvFTD‐tau, and 33 cognitively normal (CN) participants, we examined 11 subregions of anterior cingulate, medial orbitofrontal, and mid‐frontal cortices representing a cytoarchitectonic gradient of agranular‐to‐dysgranular‐to‐granular cortex (i.e., Brodmann areas 33, 24, 32, 14, 11, 46). We immunostained 6µm‐thick serial sections of each region using antibodies to total (NeuN) and pyramidal (SMI‐32) neurons, and digitally quantified immunoreactivity of each antibody per subregion. We z‐scored measures in bvFTD using the CN group, producing neurodegeneration metrics analyzed in linear mixed‐effect models adjusted for demographics and biological variables. Exploratory analyses compared region‐specific neurodegeneration to letter fluency performance (an executive functioning test) available within five years from symptom‐onset (n = 23).

Results

While total (NeuN) neurodegeneration in each type of cortex was similar between bvFTD‐TDP and bvFTD‐tau, pyramidal (SMI‐32) neurodegeneration in granular cortex (not agranular or dysgranular cortex) was greater in bvFTD‐tau than bvFTD‐TDP (beta = ‐0.946, SE = 0.306, p = 0.003). Pyramidal neurodegeneration progressively worsened across the agranular‐to‐granular arrangement of six Brodmann areas sampled in bvFTD‐TDP (beta = ‐0.104, SE = 0.032, p = 0.001) and bvFTD‐tau (beta = ‐0.191, SE = 0.04, p<0.001). Executive dysfunction worsened with greater pyramidal neurodegeneration in dysgranular/granular cortex (beta = 0.105, SE = 0.044, p = 0.042), not agranular cortex (p = 0.449).

Conclusions

In clinically similar bvFTD participants, we find greater pyramidal neurodegeneration in more laminated (granular) cytoarchitecture that is more prominent in bvFTD‐tau than bvFTD‐TDP. Furthermore, selective pyramidal neurodegeneration in more laminated cytoarchitecture may differentially contribute to early executive dysfunction characteristic of bvFTD, suggesting tauopathies may have a clinically relevant and distinctive neurodegenerative pattern in the bvFTD spectrum.