Ex vivo MRI atlas of the human medial temporal lobe: characterizing neurodegeneration due to tau pathology

Abstract

Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.

Entorhinal Subfield Vulnerability to Neurofibrillary Tangles in Aging and the Preclinical Stage of Alzheimer’s Disease

“…3 i). These data corroborate findings from a recent report by Ravikumar et al, which correlated atrophy in the EC with tau scores in 3D [ 31 ]. Our results extend the cortical thickness measures to the subfields, which is more sensitive and specific.…”

“…The Yushkevich paper evaluated the entirety of the MTL, which extends posterior beyond the end of the EC, but notably, our findings corroborate their average NFT burden when considering the boundaries of EC. The Ravikumar study builds on the Yushkevich study, by combining and registering mapping to construct a 3D probabilistic atlas of MTL tau [ 31 ]. While their preliminary scores were performed on AT8-stained tissue [ 30 ], the latter slides on which the atlas was based on were immunostained with PHF-1 [ 31 ].…”

“…The Ravikumar study builds on the Yushkevich study, by combining and registering mapping to construct a 3D probabilistic atlas of MTL tau [ 31 ]. While their preliminary scores were performed on AT8-stained tissue [ 30 ], the latter slides on which the atlas was based on were immunostained with PHF-1 [ 31 ]. In our report we used CP13 (shared epitope with AT8), which is an antibody most commonly used for Braak staging for its robust immunoreactivity, lack of cross-reactivity with other tau epitopes, and reliability irrespective of fixation time in formaldehyde [ 4 ].…”

“…Initial ex vivo MRI investigations have undertaken three-dimensional mappings of NFTs in the medial temporal lobe regions including the entorhinal, hippocampus, amygdala, and temporal pole areas [ 30–33 ]. Based on these initial scores, subsequent mappings have been combined to construct a 3D probabilistic atlas of medial temporal lobe (MTL) pathology [ 31 ]. Previous ex vivo reports, however, have lacked entorhinal subdivision specificity and histopathology validation approaches.…”

Imaging crossing fibers in mouse, pig, monkey, and human brain using small-angle X-ray scattering

“…In vivo MRI studies have been able to segment the hippocampal subfields [57], and show the main and even microscopic fiber pathways [58], [59]. Ex vivo , high-resolution MRI has been commonly used to study hippocampal connectivity in excised specimens; early high-resolution anatomical and diffusion tensor imaging scanning could delineate the different laminae [60], while modern scanners and approaches combining scanning with histology allow detailed subfield segmentation and studies in the context of neurodegenerative diseases [61], [62]. In addition, micrometer-resolution scanning using polarized light imaging has allowed unprecedented insights into the hippocampal connectivity [15].…”