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. 2021 Oct 24;9(1):173.
doi: 10.1186/s40478-021-01275-7.

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

Sadhana Ravikumar  1   2 , Laura E M Wisse  3   4   5 , Sydney Lim  3 , Ranjit Ittyerah  3 , Long Xie  3 , Madigan L Bedard  3 , Sandhitsu R Das  4 , Edward B Lee  6 , M Dylan Tisdall  3 , Karthik Prabhakaran  3 , Jacqueline Lane  4 , John A Detre  4 , Gabor Mizsei  3 , John Q Trojanowski  6 , John L Robinson  6 , Theresa Schuck  6 , Murray Grossman  4 , Emilio Artacho-Pérula  7 , Maria Mercedes Iñiguez de Onzoño Martin  7 , María Del Mar Arroyo Jiménez  7 , Monica Muñoz  7 , Francisco Javier Molina Romero  7 , Maria Del Pilar Marcos Rabal  7 , Sandra Cebada Sánchez  7 , José Carlos Delgado González  7 , Carlos de la Rosa Prieto  7 , Marta Córcoles Parada  7 , David J Irwin  4 , David A Wolk  4 , Ricardo Insausti  7 , Paul A Yushkevich  8   3
Affiliations

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

Sadhana Ravikumar et al. Acta Neuropathol Commun. .

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.

Keywords: Alzheimer’s disease; Biomarkers; Co-morbidities; Ex vivo MRI; Neurodegeneration; Neurofibrillary tangles.

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Conflict of interest statement

D.A.W has received grant support from Merck, Biogen, and Eli Lilly/Avid. D.A.W received consultation fees from Neuronix and is on the DSMB for a clinical trial run by Functional Neuromodulation. L.X. received personal consultation fees from Galileo CDS, Inc. J.Q.T. may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is co-Inventor and he received revenue from the sale of Avid to Eli Lily as co-inventor on imaging related patents submitted by the University of Pennsylvania.

Figures

Fig. 1
Fig. 1
Demographic and diagnostic summaries for the twenty-nine brain donors. The tau and TDP-43 pathology ratings refer to the average rating computed from measurements sampled at three medial temporal lobe locations (entorhinal cortex at the mid-level of the amygdala and subiculum/cornu ammonis and dentate gyrus at the mid-level of the hippocampus). Dashed lines are used to indicate the mean value across specimens
Fig. 2
Fig. 2
Computational atlas of the medial temporal lobe (MTL) constructed by groupwise registration of the magnetic resonance image (MRI) scans of twenty-nine ex vivo specimens. Three coronal sections are shown ordered from anterior (ant) to posterior (post), indicated as I, II and III, as well as a sagittal and axial section through the MTL. For each section, the “average” MRI is shown with and without the consensus MTL subregion segmentation derived from serial histology in eleven specimens. In the top right, a 3D reconstruction of the MTL atlas is shown along with a 3D brain rendering indicating the location of the MTL within the brain. (med medial, lat lateral, sup superior, inf inferior, SUB subiculum, SRLM stratum radiatum lacunosum moleculare, CA cornu ammonis, DG dentate gyrus, HATA hippocampal amygdala transition area, ERC entorhinal cortex, BA Brodmann Area)
Fig. 3
Fig. 3
Coronal view of the MRI scans of each of the twenty-nine specimens warped into the space of the MRI atlas. The corresponding atlas image is outlined in blue, in the bottom-right corner. The more similar the warped images are, the better the atlas quality. The dashed blue circles point out examples where the perirhinal cortex (region surrounding the collateral sulcus) was particularly challenging to register due to significant variability in cortical folding patterns. The color bar at the bottom of each image indicates the average neurofibrillary tangle (NFT) rating for that specimen. Yellow represents a rating of 0 (no/rare pathology) and red represents a rating of 3 (severe Alzheimer’s disease)
Fig. 4
Fig. 4
Statistical map of the correlation between cortical thickness and the severity of tau pathology. These analyses were performed in the subset of specimens age 59 years and older. The covariates used in each analysis are provided in parentheses. The clusters outlined in black indicate regions where a significant correlation was observed after correction for multiple hypothesis testing (corrected p < 0.05). The clusters outlined in blue indicate regions where a trend level correlation was observed (corrected p < 0.10). (SUB subiculum, SRLM stratum radiatum lacunosum moleculare, CA cornu ammonis, DG dentate gyrus, HATA hippocampal amygdala transition area, ERC entorhinal cortex, BA Brodmann Area)
Fig. 5
Fig. 5
Bland–Altman plots showing the level of agreement between average ipsilateral and contralateral ratings of tau and TDP-43 pathology. The dashed red lines indicate the mean of the differences and the dashed gray lines indicate two standard deviations above and below that. A different color is used to indicate cases with frontotemporal lobar degeneration (FTLD) neuropathology. The raw ipsilateral and contralateral ratings for tau and TDP-43 pathology in each specimen are plotted in Additional file 1: Fig. S8. (SUB subiculum, SRLM stratum radiatum lacunosum moleculare, CA cornu ammonis, DG dentate gyrus, HATA hippocampal amygdala transition area, ERC entorhinal cortex, BA Brodmann Area)
Fig. 6
Fig. 6
Location of medial temporal lobe (MTL) subregion, Brodmann Area 35 (BA35), defined histologically in eleven specimens and mapped into the space of the MRI atlas. Different color labels are used to indicate the type of sulcal pattern each speciemen has: type 1, deep continuous sulcus; type 2, discontinuous sulcus with shallower anterior branch. Panels A and B each show a cross-sectional view through the MTL at an anterior and more posterior level respectively. Each panel includes a heat map (top-left corner) showing the degree of overlap across the different specimens. The bottom row demonstrates the variability in the location of specific anatomical bondaries between different specimens. Note that boundaries in which a background label is adjacent to a non-background label are not considered, i.e. in some cases, the ERC label is adjacent to the background instead of the para-subiculum. (ERC entorhinal cortex, ParaSUB para-subiculum, BA Brodmann Area)
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References

    1. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–259. doi: 10.1007/bf00308809. - DOI - PubMed
    1. Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging. 1995;16:271–278. doi: 10.1016/0197-4580(95)00021-6. - DOI - PubMed
    1. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ. National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s Dement. 2012;8:1–13. doi: 10.1016/j.jalz.2011.10.007. - DOI - PMC - PubMed
    1. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R, Elliott C, Masliah E, Ryan L, Silverberg N. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement. 2018;14:535–562. doi: 10.1016/j.jalz.2018.02.018. - DOI - PMC - PubMed
    1. Bobinski M, Wegiel J, Tarnawski M, Bobinksi M, Reisberg B, De Leon MJ, Miller DC, Wisniewski HM. Relationships between regional neuronal loss and neurofibrillary changes in the hippocampal formation and duration and severity of Alzheimer disease. J Neuropathol Exp Neurol. 1997;56:414–420. doi: 10.1097/00005072-199704000-00010. - DOI - PubMed

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