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.
Highlights
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, 55, 56]
We found widespread associations of medial temporal lobe (MTL) TAR DNA-binding protein 43 (TDP-43) score with almost all MTL subregional thickness measures, whereas MTL tau score showed a more circumscribed pattern involving regions affected early in Braak stageing
Our results showing widespread MTL atrophy related to MTL TDP-43 score agree with two previous studies using antemortem MRI [3, 15]
Summary
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, 55, 56]. In the presence of neurodegenerative disorders, such as pathologically confirmed Alzheimer’s disease (AD), other pathologies such as α-synuclein and TAR DNA-binding protein 43 (TDP-43) co-occur frequently [31, 55, 56] These common neurodegenerative pathologies show a characteristic pattern of progression throughout the brain, where the medial temporal lobe (MTL) is frequently an early nidus [5, 7, 27, 46, 59], making the MTL an important region in which to study polypathology. Studies with both antemortem MRI and autopsy data have started to shed light on how different neurodegenerative pathologies are associated with different atrophy patterns in the brain and the MTL [3, 15, 28, 29, 40, 46, 52, 66]. Such patterns could provide early AD imaging biomarkers for neurodegeneration that are more specific to Alzheimer’s Disease Neuropathological Change (ADNC) and less confounded by comorbid pathologies than current commonly used MRI biomarkers of neurodegeneration (e.g. whole hippocampal atrophy)
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