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

AbstractTau 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.

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Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01225-3 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

L. E. M. Wisse ◽

S. Ravikumar ◽

R. Ittyerah ◽

S. Lim ◽

J. Lane ◽

...

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Strong Association ◽

Amyloid Β ◽

Stratum Radiatum ◽

Post Mortem ◽

Age Related ◽

Important Region ◽

Cornu Ammonis ◽

Mri Scans

AbstractThe 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.

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3D Mapping of Neurofibrillary Tangle Burden in the Human Medial Temporal Lobe

10.1101/2021.01.15.421909 ◽

2021 ◽

Author(s):

Paul A Yushkevich ◽

Mónica Muñoz López ◽

Maria Mercedes Iñiguez de Onzoño Martin ◽

Ranjit Ittyerah ◽

Sydney Lim ◽

...

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Ex Vivo ◽

Neurofibrillary Tangle ◽

Imaging Biomarkers ◽

Synaptic Loss ◽

The Brain ◽

Transentorhinal Region ◽

Anterior Posterior

Abstract Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on conventional 2D 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 (MTL) specimens were used to construct 3D quantitative maps of NFT burden in the MTL at individual and group levels. These maps reveal significant variation in NFT burden along the anterior-posterior axis. While early NFT pathology is thought to be confined to the transentorhinal region, we find similar levels of NFT burden in this region and other MTL subregions, including amygdala, temporopolar cortex, and subiculum/CA1.

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Early stages of tau pathology and its associations with functional connectivity, atrophy and memory

Brain ◽

10.1093/brain/awab114 ◽

2021 ◽

Author(s):

David Berron ◽

Jacob W Vogel ◽

Philip S Insel ◽

Joana B Pereira ◽

Long Xie ◽

...

Keyword(s):

Functional Connectivity ◽

Entorhinal Cortex ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Memory Impairment ◽

Memory Performance ◽

Hippocampal Atrophy ◽

Tau Pathology ◽

Β Amyloid ◽

With Memory

Abstract In Alzheimer’s disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 β-amyloid negative cognitively unimpaired, 81 β-amyloid positive cognitively unimpaired and 87 β-amyloid positive individuals with mild cognitive impairment, who each underwent [18]F-RO948 tau and [18]F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease-stage specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.

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Unfolding the Medial Temporal Lobe Cortex to Characterize Neurodegeneration Due to Alzheimer’s Disease Pathology Using Ex vivo Imaging

10.1007/978-3-030-87586-2_1 ◽

2021 ◽

pp. 3-12

Author(s):

Sadhana Ravikumar ◽

Laura Wisse ◽

Sydney Lim ◽

David Irwin ◽

Ranjit Ittyerah ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Ex Vivo ◽

Ex Vivo Imaging

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Novel ex vivo MRI atlas of the medial temporal lobe can be used to characterize structural changes due to Alzheimer’s disease pathology

Alzheimer s & Dementia ◽

10.1002/alz.041279 ◽

2020 ◽

Vol 16 (S4) ◽

Author(s):

Sadhana Ravikumar ◽

Laura Wisse ◽

Long Xie ◽

Ranjit Ittyerah ◽

Sandhitsu R. Das ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Structural Changes ◽

Ex Vivo

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History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease

Neurology ◽

10.1212/01.wnl.0000308937.30473.d1 ◽

2008 ◽

Vol 70 (15) ◽

pp. 1258-1264 ◽

Cited By ~ 133

Author(s):

M. I. Geerlings ◽

T. den Heijer ◽

P. J. Koudstaal ◽

A. Hofman ◽

M.M.B. Breteler

Keyword(s):

Depressive Symptoms ◽

Alzheimer Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Medial Temporal Lobe Atrophy ◽

History Of ◽

History Of Depression ◽

Lobe Atrophy

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Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0861-9 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 3

Author(s):

Christy M. Kelley ◽

Sylvia E. Perez ◽

Elliott J. Mufson

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Chronic Traumatic Encephalopathy ◽

Stage Iv ◽

Perirhinal Cortex ◽

Stage Ii ◽

Stage Iii ◽

Dystrophic Neurites ◽

Tau Pathology ◽

African American Athletes

AbstractChronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropathological diagnosis defined as stage II, III, or IV. Sections were immunolabeled using an early (AT8) or a late (TauC3) marker for pathological tau and for amyloid beta (Aβ) species (6E10, Aβ1–42 and thioflavin S). Stereological analysis revealed that stage III had significantly less AT8-positive neurons and dystrophic neurites than stage IV in all MTL regions except hippocampal subfield CA3, whereas significantly more AT8-positive neurons, dystrophic neurites, and neurite clusters were found in the perirhinal cortex, entorhinal cortex, hippocampal CA1, and subiculum of CTE stage III compared with stage II. TauC3-positive pathology was significantly higher in the perirhinal and subicular cortex of stage IV compared to stage III and the perirhinal cortex of stage III compared to stage II. AT8-positive neurite clusters were observed in stages III and IV, but virtually absent in stage II. When observed, Aβ pathology appeared as amyloid precursor protein (APP)/Aβ (6E10)-positive diffuse plaques independent of region. Thioflavine S labeling, did not reveal evidence for fibril or neuritic pathology associated with plaques, confirming a diffuse, non-cored plaque phenotype in CTE. Total number of AT8-positive profiles correlated with age at death, age at symptom onset, and time from retirement to death. There was no association between AT8-positive tau pathology and age sport began, years played, or retirement age, and no difference between CTE stage and the highest level of sport played. In summary, our findings demonstrate different tau profiles in the MTL across CTE stages, proffering CA3 tau pathology and MTL dystrophic neurite clusters as possible markers for the transition between early (II) and late (III/IV) stages, while highlighting CTE as a progressive noncommunicative tauopathy.

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White-matter markers for psychosis in a prospective ultra-high-risk cohort

Psychological Medicine ◽

10.1017/s0033291709991711 ◽

2009 ◽

Vol 40 (8) ◽

pp. 1297-1304 ◽

Cited By ~ 94

Author(s):

O. J. N. Bloemen ◽

M. B. de Koning ◽

N. Schmitz ◽

D. H. Nieman ◽

H. E. Becker ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Healthy Controls ◽

Syndrome Scale ◽

Ultra High Risk ◽

Mri Scans ◽

Magnetic Resonance Imaging Mri ◽

The Right

BackgroundSubjects at ‘ultra high risk’ (UHR) for developing psychosis have differences in white matter (WM) compared with healthy controls. WM integrity has not yet been investigated in UHR subjects in relation to the development of subsequent psychosis. Hence, we investigated a prospective cohort of UHR subjects comparing whole brain fractional anisotropy (FA) of those later developing psychosis (UHR-P) to those who did not (UHR-NP).MethodWe recruited 37 subjects fulfilling UHR criteria and 10 healthy controls. Baseline 3 Tesla magnetic resonance imaging (MRI) scans and Positive and Negative Syndrome Scale (PANSS) ratings were obtained. UHR subjects were assessed at 9, 18 and 24 months for development of frank psychosis. We compared baseline FA of UHR-P to controls and UHR-NP subjects. Furthermore, we related clinical data to MRI outcome in the patient population.ResultsOf the 37 UHR subjects, 10 had transition to psychosis. UHR-P subjects showed significantly lower FA values than control subjects in medial frontal lobes bilaterally. UHR-P subjects had lower FA values than UHR-NP subjects, lateral to the right putamen and in the left superior temporal lobe. UHR-P subjects showed higher FA values, compared with UHR-NP, in the left medial temporal lobe. In UHR-P, positive PANSS negatively correlated to FA in the left middle temporal lobe. In the total UHR group positive PANSS negatively correlated to FA in the right superior temporal lobe.ConclusionsUHR subjects who later develop psychosis have differences in WM integrity, compared with UHR subjects who do not develop psychosis and to healthy controls, in brain areas associated with schizophrenia.

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