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

Llamas‐Rodríguez, Josue; Oltmer, Jan; Greve, Douglas N.; Williams, Emily; Slepneva, Natalya; Wang, Ruopeng; Champion, Samantha N; Lang‐Orsini, Melanie; Fischl, Bruce; Frosch, Matthew P.; Kouwe, André van der; Augustinack, Jean C.

doi:10.3233/jad-215567

Cited by 20 publications

(63 citation statements)

References 85 publications

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“…Within the EC, posterior‐lateral subfields ECL, ELc, and ECs Lat , respectively, showed the highest semi‐quantitative pTDP‐43 density scores, while EO had the lowest (Figure 3A). Our finding of a posterior‐lateral EC vulnerability to pTDP‐43 complements molecular characterizations of vulnerable caudal EC neurons [42], PET imaging observations [43], the p‐tau gradient in subfields [32], and the use of lateral EC atrophy as a potential biomarker of preclinical AD [44, 45]. Two reports support a prion‐like seeding mechanism involved in TDP‐43 spread [46, 47], and recent hippocampal data from FTD patients suggest that TDP‐43 pathology spreads along trans‐synaptic connections [48].…”

Section: Discussionsupporting

confidence: 72%

TDP‐43 and tau concurrence in the entorhinal subfields in primary age‐related tauopathy and preclinical Alzheimer's disease

et al. 2023

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Phosphorylated tau (p‐tau) pathology correlates strongly with cognitive decline and is a pathological hallmark of Alzheimer's Disease (AD). In recent years, phosphorylated transactive response DNA‐binding protein (pTDP‐43) has emerged as a common comorbidity, found in up to 70% of all AD cases (Josephs et al., Acta Neuropathol, 131(4), 571–585; Josephs, Whitwell, et al., Acta Neuropathol, 127(6), 811–824). Current staging schemes for pTDP‐43 in AD and primary age‐related tauopathy (PART) track its progression throughout the brain, but the distribution of pTDP‐43 within the entorhinal cortex (EC) at the earliest stages has not been studied. Moreover, the exact nature of p‐tau and pTDP‐43 co‐localization is debated. We investigated the selective vulnerability of the entorhinal subfields to phosphorylated pTDP‐43 pathology in preclinical AD and PART postmortem tissue. Within the EC, posterior‐lateral subfields showed the highest semi‐quantitative pTDP‐43 density scores, while the anterior‐medial subfields had the lowest. On the rostrocaudal axis, pTDP‐43 scores were higher posteriorly than anteriorly (p < 0.010), peaking at the posterior‐most level (p < 0.050). Further, we showed the relationship between pTDP‐43 and p‐tau in these regions at pathology‐positive but clinically silent stages. P‐tau and pTDP‐43 presented a similar pattern of affected subregions (p < 0.0001) but differed in density magnitude (p < 0.0001). P‐tau burden was consistently higher than pTDP‐43 at every anterior–posterior level and in most EC subfields. These findings highlight pTDP‐43 burden heterogeneity within the EC and the posterior‐lateral subfields as the most vulnerable regions within stage II of the current pTDP‐43 staging schemes for AD and PART. The EC is a point of convergence for p‐tau and pTDP‐43 and identifying its most vulnerable neuronal populations will prove key for early diagnosis and disease intervention.

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Section: Discussionsupporting

confidence: 72%

TDP‐43 and tau concurrence in the entorhinal subfields in primary age‐related tauopathy and preclinical Alzheimer's disease

et al. 2023

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“…Second, these results demonstrate concordance between patterns of microscopic NFT pathology, specific to pathologically confirmed AD, and macroscopic ex vivo measures of atrophy through reconstruction of microscopic measures in the dense, submillimeter metric of high field MRI. Previous studies have shown correlation between single time point ex vivo measures of thickness and levels of NFT and TDP-43 pathology, particularly in the areas of ERC and hippocampus ( Ravikumar et al, 2021 , Llamas-Rodríguez et al, 2022 ). Here, we show significant atrophy rates measured longitudinally in vivo in both the ERC and amygdala, which are correspondingly supported by our observation of highest densities of NFTs in our postmortem specimens not only in the ERC, but also in the amygdala.…”

Section: Discussionmentioning

confidence: 96%

“…Regarding ex vivo analysis, other efforts to reconstruct distributions of tau pathology in 3D include efforts to analyze concordance of distributions between subjects in early AD ( Ravikumar et al, 2021 , Yushkevich et al, 2021 , Llamas-Rodríguez et al, 2022 ) and to develop validation measures for in vivo molecular imaging ( Ushizima et al, 2022 ). These studies harbor advantages in terms of number of samples ( Ravikumar et al, 2021 , Yushkevich et al, 2021 , Llamas-Rodríguez et al, 2022 ) and scope of brain region (e.g. whole brain) ( Ushizima et al, 2022 ) analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we present ex vivo 3D reconstructions of MTL NFT pathology from only two brain samples. Other studies have reconstructed distributions of pathology amidst larger cohorts, which has enabled the use of statistical methods to extract patterns in distributions across subjects ( Yushkevich et al, 2021 ) and correlate these patterns with other measures such as cortical thickness ( Ravikumar et al, 2021 , Llamas-Rodríguez et al, 2022 ). However, these cohorts have increased the heterogeneity in diagnosis and both stage and type of pathology observed.…”

Section: Discussionmentioning

confidence: 99%

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Early amygdala and ERC atrophy linked to 3D reconstruction of rostral neurofibrillary tau tangle pathology in Alzheimer’s disease

Stouffer

Chen

Kulason

et al. 2023

NeuroImage: Clinical

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“…All cases were assessed with gross tissue inspection and Luxol fast blue as well as Hematoxylin & Eosin staining were applied to rule out vascular disease and stroke. Immunohistochemistry for phosphorylated tau was used and all cases were staged for Braak & Braak (MPF, JCA) [41][42][43] . Subsequently, one case was diagnosed as normal control, three as Braak and Braak I, and three as Braak and Braak II.…”

Section: Methodsmentioning

confidence: 99%

Stereology neuron counts correlate with deep learning estimates in the human hippocampal subregions

Oltmer

Rosenblum

Williams

et al. 2023

Sci Rep

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Hippocampal subregions differ in specialization and vulnerability to cell death. Neuron death and hippocampal atrophy have been a marker for the progression of Alzheimer’s disease. Relatively few studies have examined neuronal loss in the human brain using stereology. We characterize an automated high-throughput deep learning pipeline to segment hippocampal pyramidal neurons, generate pyramidal neuron estimates within the human hippocampal subfields, and relate our results to stereology neuron counts. Based on seven cases and 168 partitions, we vet deep learning parameters to segment hippocampal pyramidal neurons from the background using the open-source CellPose algorithm, and show the automated removal of false-positive segmentations. There was no difference in Dice scores between neurons segmented by the deep learning pipeline and manual segmentations (Independent Samples t-Test: t(28) = 0.33, p = 0.742). Deep-learning neuron estimates strongly correlate with manual stereological counts per subregion (Spearman’s correlation (n = 9): r(7) = 0.97, p < 0.001), and for each partition individually (Spearman’s correlation (n = 168): r(166) = 0.90, p <0 .001). The high-throughput deep-learning pipeline provides validation to existing standards. This deep learning approach may benefit future studies in tracking baseline and resilient healthy aging to the earliest disease progression.

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

Cited by 20 publications

References 85 publications

TDP‐43 and tau concurrence in the entorhinal subfields in primary age‐related tauopathy and preclinical Alzheimer's disease

TDP‐43 and tau concurrence in the entorhinal subfields in primary age‐related tauopathy and preclinical Alzheimer's disease

Early amygdala and ERC atrophy linked to 3D reconstruction of rostral neurofibrillary tau tangle pathology in Alzheimer’s disease

Stereology neuron counts correlate with deep learning estimates in the human hippocampal subregions

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