Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe

Abstract

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer’s disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangle was measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden reveal significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we find similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu Ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer’s disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

Structural progression of Alzheimer’s disease over decades: the MRI staging scheme

“…A recent 3D mapping of human tau pathology suggests, for instance, a more widespread distribution of NFT at the early stages of Alzheimer’s disease: similar levels of tau burden were found in entorhinal areas and the amygdala, the hippocampus, and the temporopolar cortex, supporting our MRI findings. 26 …”

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

“…Furthermore, we note that the cases with primary FTLD-Tau/AGD are evenly distributed between cases with high and low thickness, particularly in the SUB and SRLM hotspots, suggesting that FTLD-associated tau is unlikely to be driving the tau-structure associations in these regions. To further examine the contribution of NFTs to neurodegeneration in the hotspots, we performed a preliminary analysis in a subset of fifteen specimens for which 3D quantitative maps of NFT burden derived from dense serial histology are available [ 29 ]. These NFT density maps are generated using a weakly supervised deep learning algorithm, trained to specifically detect tangles and pre-tangles on AT8-stained sections and have been shown to correlate strongly with manual NFT counts [ 29 ].…”

“…To further examine the contribution of NFTs to neurodegeneration in the hotspots, we performed a preliminary analysis in a subset of fifteen specimens for which 3D quantitative maps of NFT burden derived from dense serial histology are available [ 29 ]. These NFT density maps are generated using a weakly supervised deep learning algorithm, trained to specifically detect tangles and pre-tangles on AT8-stained sections and have been shown to correlate strongly with manual NFT counts [ 29 ]. Three cases with a primary FTLD-Tau or AGD diagnosis (CNDR01, CNDR06 and CNDR07) were excluded from the analysis since they likely contain 4R-tau inclusions which can be difficult to distinguish from AD-related NFTs.…”

“…Perhaps future analyses leveraging this technology in a patient cohort more consistent with the one we would expect to encounter in an AD clinical trial would result in hotspots that are more sensitive to longitudinal change in the presence of NFT pathology, potentially enabling the development of neurodegeneration biomarkers which are more effective during early AD clinical trials. Furthermore, in future work, 3D quantitative maps of NFT density derived from serial histology imaging will be mapped into ex vivo atlas space to generate a comprehensive probabilistic description of the progression of NFT pathology at each Braak stage [ 29 , 48 , 49 ]. This will allow us to describe NFT topography during the different stages of AD in more detail than current descriptions, which are in 2D and based on selective sampling of the MTL [ 1 , 2 ].…”

“…For each block, the scanned sections were reconstructed into a 3D volume and aligned to MRI space using a custom deformable 3D registration pipeline. Further details of the histology protocol and the approach for 3D reconstruction and matching of histology to MRI are provided in Yushkevich et al [ 29 ].…”