Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions

Abstract

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-β and α-synuclein pathology were rated on a scale of 0 (absent)—3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm³ post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman’s rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r =  − 0.27 to r =  − 0.46), and (2) tau with BA35 (r =  − 0.31) and SRLM thickness (r =  − 0.33). In amyloid-β and TDP-43 negative cases, we found strong significant associations of tau with ERC (r =  − 0.40), BA35 (r =  − 0.55), subiculum (r =  − 0.42) and CA1 thickness (r =  − 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-β suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

Introduction

It has become increasingly evident that multiple neurodegenerative pathologies often co-occur in the brains of older adults and contribute to cognitive decline [31, 41, 4]. We hypothesize that TDP-43 pathology score will be associated with ERC and subiculum thickness [47]. We do not expect strong associations with MTL thickness measures for amyloid-β plaques [18, 19, 21] and α-synuclein pathology [8, 9, 14, 4] and has been shown to be thinner in clinical AD [

Fig. 1

Method for obtaining thickness measures from high-resolution post-mortem MRI in medial temporal lobe subregions. For each anatomical location (indicated by a dot; first row), cortical thickness was measured by using semi-automated active contour segmentation in ITK-SNAP (with possible manual correction) to segment a portion of the surrounding gray matter extending ~ 5–10 mm from the dot in all directions (second and third row). Thickness at each location was measured as the diameter of the sphere overlap** the dot, fully contained in the gray matter segmentation, and having maximum possible radius (fourth row). Segmentations and fitted spheres were visually inspected for quality assurance. See supplementary Methods for details. Note that we only show three examples in this figure. For this study we performed thickness measurements for seven subregions and averaged thickness measurements over two locations for each subregion, see Additional file 1: Fig. 1. ERC = entorhinal cortex; SRLM = stratum radiatum lacunosum moleculare; PHC = parahippocampal cortex

Note that we performed the thickness measurements in raw reconstructed MRI scans, in contrast to our previous paper [68] which in the future will allow for more fine-grained analyses or analyses in subgroups such as the recently introduced Limbic Age-related TDP-43 Encephalopathy, or LATE [46].

The atrophy pattern associated with tau pathology was more specifically restricted to regions affected early in Braak stageing: BA35, ERC (trend) and SRLM. Braak et al. identified BA35 (referred to as transentorhinal region in their report) and the lateral aspect of ERC as the earliest cortical site of tau NFT pathology [5]. Relatively early impact of NFT pathology in SRLM of CA, a region consisting of the apical dendrites [17], has also been reported [6]. Moreover, NFT pathology has long been associated with neuron loss in BA35 and ERC and neuropil loss in SRLM in multiple ex vivo studies [68]. This will allow for the creation of 3D neurodegenerative pathology maps which can be directly linked to local neurodegeneration. Moreover, as this dataset continues to grow, we will be able to further tease apart the effects of different neurodegenerative pathologies on MTL structure.