Comparison of histological delineation of the entorhinal, perirhinal, ectorhinal, and parahippocampal cortices by different neuroanatomy laboratories

Abstract Background The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and a hotspot of neurodegenerative processes (e.g., accumulation of tau tangles or TDP‐43). Importantly, the MTL cortex comprises several subregions with distinct functional, cytoarchitectonic, and macro‐anatomical features (Fig. 1). In vivo imaging studies measuring atrophy or aggregates of pathologies in these subregions rely on various segmentation protocols. Comparability of these imaging studies is limited as segmentation protocols differ, which results from different macro‐anatomical parcellations and cytoarchitectonic definitions of MTL subregions. Thus, it must be clarified to which extent definitions of MTL subregions overlap between neuroanatomists, to establish a harmonized MTL magnetic resonance imaging (MRI) segmentation protocol. We give an overview of cytoarchitectonic definitions of MTL cortex subregions provided by four neuroanatomists from independent laboratories. Method Four neuroanatomists performed annotations of the entorhinal cortex, Brodmann area (BA) 35, BA36, and the parahippocampal cortex on digital histology images. Nissl‐stained series were acquired in three specimens (Fig. 2). Slices (50µm thick) were prepared perpendicular to the anterior commissure‐posterior comimssure line spanning the entire longitudinal extent of the MTL cortex. Neuroanatomists annotated MTL cortex subdivisions on digitized (20X resolution) slices with 5mm spacing. Parcellations, terminology, and delineations were compared between neuroanatomists. Result Cytoarchitectonic features of the MTL cortex subregions are described in detail. Overall, we observed higher agreement in the definition of the entorhinal cortex and BA35, while definitions of BA36 and the parahippocampal cortex exhibited less overlap between neuroanatomists (Fig. 2). The degree of overlap of cytoarchitectonic definitions was reflected in the neuroanatomists’ agreement on the respective delineations. Lower agreement on annotations was observed for transitional zones where gradual changes from one subregion to another occur (Fig. 3). Due to the gradual transition of features from, for example, proisocortex to periallocortex, border placement is difficult to determine according to the neuroanatomists. Conclusion The results highlight that definitions and parcellations of the MTL cortex are variable but increase understanding of why these differences arise. This sets a crucial foundation for a harmonized in vivo MRI segmentation protocol for cortical MTL subregions and the study of these regions in the context of dementia.

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