Transentorhinal Region Research Articles

Morphometry of medial temporal lobe subregions using high-resolution T2-weighted MRI in ADNI3: Why, how, and what's next?

This paper for the 20th anniversary of the Alzheimer's Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high-resolution T2-weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface-based tools to characterize MTL neurodegeneration across biomarker-defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high-resolution imaging of the MTL in ADNI Phase 4. HIGHLIGHTS: As of Phase 3, the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) protocol includes a high-resolution T2-weighted MRI scan optimized for imaging hippocampal subfields and medial temporal lobe (MTL) subregions. These scans are processed by the ADNI core to obtain automatic segmentations of MTL subregions and to derive morphologic measurements. More detailed granular examination of MTL neurodegeneration in response to disease progression is achieved by applying surface-based modeling techniques. Surface-based analysis of gray matter loss in MTL subregions reveals increasing and spatially expanding patterns of neurodegeneration with advancing stages of Alzheimer's disease (AD), as defined based on amyloid and tau positron emission tomography biomarkers in accordance with recently proposed criteria. These patterns closely align with post mortem literature on spread of pathological tau in AD, supporting the role of tau pathology in the presence of elevated levels of amyloid beta as the driver of neurodegeneration.

Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer’s disease

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer’s Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

Using an ex vivo MRI atlas of the human medial temporal lobe to characterize the 3D distribution of neurofibrillary tangle burden across histologically defined subregions

AbstractBackgroundAccumulation of tau neurofibrillary tangles (NFT) in the medial temporal lobe (MTL) is an early pathological change associated with neurodegeneration in Alzheimer’s Disease (AD). Current understanding of the spread of NFTs within the MTL is based on 2‐D histological sections sampled at sparse locations. Here, using human MTL specimens from donors with diagnoses spanning the AD continuum, we examine 3‐D quantitative maps of NFT burden derived from serial histology leveraging a high‐resolution, ex vivo MRI atlas, thus enabling more granular analyses.MethodWe combined ex vivo MRI scans (0.2×0.2×0.2mm3, 9.4T) of 55 MTL specimens using a customized registration approach to construct a 3‐D atlas (Ravikumar et al., Acta Neuropathol Comm, 2021). MTL subregions in the atlas were labelled based on cytoarchitecture using serial Nissl histology (n = 17) (Fig.1). For 25 specimens with a primary diagnosis of AD or primary age‐related tauopathy (78.6±10.9 years; 16M/9F), quantitative NFT burden maps were derived from serial anti‐tau immunohistochemistry histology and registered to the atlas for group‐level analysis (Yushkevich et al., Brain, 2021). For quantitative comparisons, we computed the mean NFT burden and cortical thickness within each subregion.ResultFig.2A shows average and summary frequency maps of NFT burden, computed separately for specimens with a low Braak stage (Braak0‐II; n = 11) and high Braak stage (BraakIV‐VI), that reveal a clear anterior‐to‐posterior gradient in NFT burden. At low Braak stages, we observe high levels of NFT burden in cornu ammonis (CA)1, entorhinal cortex (EC), and Brodmann area 35 (BA35;≈transentorhinal region), particularly in the outer cortical layers. CA1 and EC also show higher NFT burden relative to BA35 (Fig.2C). At high Braak stages, overall NFT burden is visibly higher and more widespread, with significant increases found across almost all subregions (Fig.2B). Moreover, significant correlations between NFT burden and cortical thinning were found in the perforant pathway (PP; molecular layer of the subiculum), dentate gyrus, EC and Areas TE, TF and TH (Fig.3).ConclusionBuilding on earlier work, we provide a detailed characterization of the distribution of NFT burden in the MTL. Our findings of specific subregional involvement of early NFT pathology can help inform the development of improved in vivo neuroimaging biomarkers

Visualizing Braak stages with deformation‐based morphometry in super‐sampled MRI

AbstractBackgroundUnlike MRI data, histological data collected post‐mortem can’t be used to study the longitudinal formation of neurofibrillary tangles (NFT) and corresponding brain changes over time for individuals. Although structural MRI offers the possibility of non‐invasive longitudinal antemortem imaging, its resolution is a limiting factor. Using image processing and super‐sampling techniques, we examined the possibility of employing structural MRI to observe the NFT footprints in the brain.MethodData included baseline MRI scans of 1473 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset including ADNI1, 2, and GO. Voxel size was super‐sampled to 0.5×0.5×0.5mm (Manjón et al. 2010) before non‐linear registration to an ADNI‐based unbiased symmetric MRI template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject as a proxy for local volume. For each subject, the sex‐ and age‐corrected z‐scored Jacobian maps were then calculated and averaged for each diagnostic group: normal subjects(CN), early MCI, late MCI, and AD. The average map for CN group was subtracted from the other average maps to show the AD‐stage differences.ResultThe Braak tau staging pattern (Braak & Braak, 1995) is seen in average Jacobian maps as the disease progresses. Subjects in the MCI groups showed on average more pronounced neurodegeneration in the transentorhinal and entorhinal region (Braak Stages 1‐2), followed by degeneration in the hippocampus (Stages 3‐4). Later on, this neurodegeneration progresses toward the neocortex (Stages 5‐6). Figure 1 illustrates these results: A) the template, B)EMCI vs CN, C) LMCI vs EMCI, D) LMCI vs CN, E) AD vs CN. Red color shows an increase and blue indicates a decrease in local volume.ConclusionUsing novel image processing techniques, we were able to verify the staging of AD‐related neurofibrillary pathology progression in MRI data. This shows that structural MRI data, although limited in resolution, can still offer in‐depth insight into the brain antemortem which will in return allow the longitudinal and possible lifespan studies with an accuracy close to histological data.

MRI deep learning demonstrates featured neuropathological deteriorations in the AD brain

AbstractBackgroundDeep learning (DL) of non‐invasive brain structural magnetic resonance imaging (sMRI) has shown superb performance in differentiating Alzheimer’s disease (AD) from cognitively healthy participants (HC). Attention is needed to tackle AD pathological progression on sMRI using interpretable DL methods. Here, we studied the feasibility of DL in identifying neurodegenerative progression patterns in AD.MethodData applied to the study were from the multi‐centre Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies (OASIS) with 2,369 T1‐weighted brain images of 1,005 subjects. An interpretable DL technique named the ensemble 3‐dimensional convolutional neural network (Ensemble 3DCNN) was used to detect the longitudinal trajectory of sMRI changes during AD progression. The model used multiple 3D convolutional neural networks and a meta‐classifier to assess the degree of brain changes through generating an index score, named P‐score. The score was derived as the outcome of training and verifying the Ensemble 3DCNN model for difference in the whole‐brain sMRI between AD and HC. The predictive P‐scores values were used to analyze the sMRI images for mining neurodegenerative brain regions. In addition, dementia stages, and the temporal and spatial connectivity patterns of neurodegeneration progression were also analyzed.ResultBrain regions showing high P‐scores (> 0.73/1.00) included the amygdala, nucleus accumbens, agranular insular cortex, and the hippocampus, matching the isocortex, basal magnocellular complex, and transentorhinal regions identified in Braak staging. The P‐score increased over time in 82% of the degenerative brain regions. The impaired areas were often spatially connected, consistently across multiple time points in the progression of AD. The trajectory of regional brain changes displayed multiple patterns with complex individual variability.ConclusionThe interpretable 3D DL model demonstrated featured deteriorations on the AD sMRI images. The finding confirmed the neuropathological degeneration of AD and captured additional whole‐brain changes, especially, relating to the heterogeneity of AD expression.

Biochemical analyses of tau and other neuronal markers in the submandibular gland and frontal cortex across stages of Alzheimer disease

Hyperphosphorylation of the microtubule-associated protein tau is hypothesized to lead to the development of neurofibrillary tangles in select brain regions during normal aging and in Alzheimer disease (AD). The distribution of neurofibrillary tangles is staged by its involvement starting in the transentorhinal regions of the brain and in final stages progress to neocortices. However, it has also been determined neurofibrillary tangles can extend into the spinal cord and select tau species are found in peripheral tissues and this may be depended on AD disease stage. To further understand the relationships of peripheral tissues to AD, we utilized biochemical methods to evaluate protein levels of total tau and phosphorylated tau (p-tau) as well as other neuronal proteins (i.e., tyrosine hydroxylase (TH), neurofilament heavy chain (NF-H), and microtubule-associated protein 2 (MAP2)) in the submandibular gland and frontal cortex of human cases across different clinicopathological stages of AD (n = 3 criteria not met or low, n = 6 intermediate, and n = 9 high likelihood that dementia is due to AD based on National Institute on Aging-Reagan criteria). We report differential protein levels based on the stage of AD, anatomic specific tau species, as well as differences in TH and NF-H. In addition, exploratory findings were made of the high molecular weight tau species big tau that is unique to peripheral tissues. Although sample sizes were small, these findings are, to our knowledge, the first comparison of these specific protein changes in these tissues.

Do tau-synaptic long-term depression interactions in the hippocampus play a pivotal role in the progression of Alzheimer's disease?

Cognitive decline in Alzheimer's disease correlates with the extent of tau pathology, in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus. Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-β or long-term depression, a form of synaptic weakening involved in learning and memory, share similar mechanisms. Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging. Conversely, certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau, in particular, phosphorylation at residue Ser396. Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau (hyper)phosphorylation. We first summarize experimental evidence regarding tau-long-term depression interactions, followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer's disease. Finally, we conclude with some thoughts and perspectives on future research about these interactions.

CSF tau368/total-tau ratio reflects cognitive performance and neocortical tau better compared to p-tau181 and p-tau217 in cognitively impaired individuals

IntroductionCerebrospinal fluid (CSF) tau biomarkers are reliable diagnostic markers for Alzheimer’s disease (AD). However, their strong association with amyloid pathology may limit their reliability as specific markers of tau neurofibrillary tangles. A recent study showed evidence that a ratio of CSF C-terminally truncated tau (tau368, a tangle-enriched tau species), especially in ratio with total tau (t-tau), correlates strongly with tau PET tracer uptake. In this study, we set to evaluate the performance of the tau368/t-tau ratio in capturing tangle pathology, as indexed by a high-affinity tau PET tracer, as well as its association with severity of clinical symptoms.MethodsIn total, 125 participants were evaluated cross-sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (21 young, 60 cognitively unimpaired [CU] elderly [15 Aβ+], 10 Aβ+ with mild cognitive impairment [MCI], 14 AD dementia patients, and 20 Aβ− individuals with non-AD cognitive disorders). All participants underwent amyloid and tau PET scanning, with [18F]-AZD4694 and [18F]-MK6240, respectively, and had CSF measurements of p-tau181, p-tau217, and t-tau. CSF concentrations of tau368 were quantified in all individuals with an in-house single molecule array assay.ResultsCSF tau368 concentration was not significantly different across the diagnostic groups, although a modest increase was observed in all groups as compared with healthy young individuals (all P < 0.01). In contrast, the CSF tau368/t-tau ratio was the lowest in AD dementia, being significantly lower than in CU individuals (Aβ−, P < 0.001; Aβ+, P < 0.01), as well as compared to those with non-AD cognitive disorders (P < 0.001). Notably, in individuals with symptomatic AD, tau368/t-tau correlated more strongly with [18F]-MK6240 PET SUVR as compared to the other CSF tau biomarkers, with increasing associations being seen in brain regions associated with more advanced disease (isocortical regions > limbic regions > transentorhinal regions). Importantly, linear regression models indicated that these associations were not confounded by Aβ PET SUVr. CSF tau368/t-tau also tended to continue to become more abnormal with higher tau burden, whereas the other biomarkers plateaued after the limbic stage. Finally, the tau368/t-tau ratio correlated more strongly with cognitive performance in individuals with symptomatic AD as compared to t-tau, p-tau217 and p-tau181.ConclusionThe tau368/t-tau ratio captures novel aspects of AD pathophysiology and disease severity in comparison to established CSF tau biomarkers, as it is more closely related to tau PET SUVR and cognitive performance in the symptomatic phase of the disease.

Combining high‐resolution ex vivo MRI and histopathology to identify medial temporal lobe atrophy patterns specific to tau pathology in Alzheimer’s Disease

AbstractBackgroundTau pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is an early pathological change associated with Alzheimer’s disease (AD). MRI measures of MTL neurodegeneration have proven to be sensitive to change during preclinical AD. Current measures are confounded by the presence of non‐AD pathologies (e.g., TDP‐43, ageing). Here, we combine ex vivo imaging with histopathological ratings of tau and TDP‐43 to identify fine‐grained MTL atrophy patterns specific to tau. Such an analysis could be used to define MTL “hotspots” where in vivo measures of neurodegeneration are expected to be strongly associated with tau, potentially enabling the development of biomarkers that are more effective during early AD clinical trials.MethodEx vivo MRI scans (0.2x0.2x0.2mm3, 9.4T) of human MTL specimens were combined using a customized registration approach to construct a 3D atlas. Using serial histology available in a subset of specimens (n = 11), MTL subregions in the atlas were labelled based on cytoarchitecture (Ravikumar et al., 2021) (Figure 1A). To perform thickness analysis, 29 specimens containing a primary diagnosis of AD or primary age‐related tauopathy were registered to the atlas (13 specimens were registered to the atlas during atlas construction, and 16 were registered to the atlas after it was constructed) (Figure 1B, Table 1). Using histopathology measures of tau and TDP‐43 pathology (based on contralateral sampling), we investigated the association between tau and thickness by fitting a linear model (with age/TDP‐43 as covariates) at each point along the MTL and SRLM surface.ResultPointwise thickness analysis reveals significant atrophy patterns in the transentorhinal region and SRLM. When excluding age from the model, stronger tau associations are observed in the SRLM, entorhinal cortex, and extending further towards Brodmann Area 35 (Figure 2).ConclusionOur findings are consistent with early Braak stages but suggest that covarying for age may be obscuring some associations due to tau since age and tau burden have a highly correlated relationship (Figure 3). In future work, quantitative maps of NFT burden will be mapped from serial pathology images into atlas space, allowing us to characterize NFT distribution in 3D (Yushkevich et al., 2021).

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

AbstractBackgroundIn 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.MethodWe 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.ResultFirst, 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 (see Figure 1). 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.ConclusionIn 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.

Very high interrater reliability for manual segmentation of the medial perirhinal cortex

AbstractBackgroundIntracellular neurofibrillary tangles (NFT) belong to the main characteristics of Alzheimer’s disease (AD) pathology and occur first in the medial perirhinal cortex (mPRC; also referred to as “transentorhinal region”). Adjacent regions such as lateral perirhinal cortex (lPRC), entorhinal cortex (ERC), and hippocampus are affected at a later stage of NFT progression. Therefore, mPRC integrity potentially serves as a promising imaging biomarker in early AD. Due to the high anatomic variability of the collateral sulcus, which defines mPRC boundaries, it is important to evaluate the interrater reliability of manual segmentation. Today, automated segmentation protocols only exist for the whole PRC (i.e. mPRC and lPRC together). However, discrete analysis of mPRC integrity is crucial to detect AD related pathology as early as possible.MethodForty‐four adults (20 men; mean age = 69.2 ± 10.4 years) from different diagnostic groups (e.g. normal controls, mild cognitive impairment, Alzheimer's dementia or major depression) were included in the analyses. All subjects received structural magnetic resonance imaging in a 3‐Tesla scanner (MAGNETOM Verio, Siemens). Regions of interest (mPRC, lPRC, and ERC) were drawn by‐hand by two raters (SK, NAH) blinded for diagnoses. Bilateral cortical thickness estimates were extracted using FreeSurfer. Intraclass correlation coefficients (ICC) were calculated in SPSS based on a single‐rating, absolute‐agreement, 2‐way mixed‐effects model.ResultA high degree of reliability was found between both raters with an average measure ICC of .876 for the left mPRC (F[43,43]=14.954, p&lt;.001, 95% confidence interval [CI] =.784 ‐ .930) and .873 for the right mPRC (F[43,43]=14.472, p&lt;.001, 95% CI=.779 ‐ .929). Similar results were found for lPRC (left: ICC=.984; F[43,43]=118.834, p&lt;.001, 95% CI=.970 ‐ .991; right: ICC=.953; F[43,43]=40.344, p&lt;.001, 95% CI=.915 ‐ .974) and ERC (left: ICC=.969; F[43,43]=62.657, p&lt;.001, 95% CI=.944 ‐ .983; right: ICC=.961; F[43,43]=49.390, p&lt;.001, 95% CI=.930 ‐ .979).ConclusionThe ICC analysis showed a very high interrater reliability for manual mPRC segmentation as well as for lPRC and ERC. These results indicate that the applied segmentation protocol, which considers collateral sulcus variability, allows different raters to achieve highly similar results and may serve as a reference to establish future automated segmentation protocols.

Staging tau pathology with tau PET in Alzheimer\u2019s disease: a longitudinal study

A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer’s disease could be illustrated with biomarker measurement under NIA–AA framework. Clinical–neuroimaging–neuropathological studies in other cohorts are needed to validate these findings.

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

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, range 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 tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found 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.

Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer\u2019s disease

BackgroundMitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF.MethodsThirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed.ResultsThe [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR.ConclusionsOur results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

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

In Alzheimer’s disease, post-mortem 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 Brodmann 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 amyloid-β− cognitively unimpaired, 81 amyloid-β+ cognitively unimpaired and 87 amyloid-β+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-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 Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann 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, Brodmann 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.

Molecular alterations of protein tau in the cingulate cortex of human brain with Alzheimer’s disease

AbstractBackgroundAlzheimer's disease (AD) brain tissue at different stages were examined to compare the events of protein tau hiperphosphorilation and its assemble into Neurofibrillary tangles (NFT) in the hippocampus and the cingulate cortex and how this may be involved in the appearance of the Behavioral and Psychological Symptoms of Dementia (BPSD).MethodBrain tissue previously fixed with 4% paraformaldehyde from 7 patients with different stages of AD were examined in this study. Sections were blocked with 0.2% IgG free albumin and the primary antibody (Table 1) was incubated overnight. Secondary antibody HRP was incubated considering the specie and isotype. Finally, the reaction was revealed with 0.0006% 3´3´diaminobenzidine and 0.006% H2O2 ResultThe cases with early stages of AD are morphologically characterized by diffuse and granular deposits of tau aggregate in a non‐fibrillar state in the transentorhinal region of the hippocampus and to a lesser extent in the cingulate cortex. Following this pattern, in cases with mild stage was found in less proportion extracellular NFT (E‐NFT) in CA1 region of the hippocampus, in contrast, there was a major labelling for this antibody in the cingulate cortex but for intracellular NFT. Finally, in moderate AD cases was found E‐NFT both in the cingulate cortex and hippocampus, being the latter where it was observed to a greater extent.ConclusionThere is a direct relationship in the processes of NFT formation and subsequent disease progression between the cingulate cortex and the hippocampus, having its origin in the latter.

Relationship between neuropsychiatric symptoms and Alzheimer's disease pathology: An in vivo positron emission tomography study.

To investigate the relationship between amyloid-β- and tau-based Alzheimer's disease (AD) pathologies assessed using positron emission tomography imaging and neuropsychiatric symptoms (NPS) in a sample of AD continuum including clinically normal subjects and patients with mild cognitive impairment or AD. We analyzed datasets of the Alzheimer's disease Neuroimaging Initiative and included amyloid-positive subjects who underwent an AV-45 scan within 1 year of an AV-1451 scan (n = 99). Correlation between standardized uptake value ratio (SUVR) of AV-45 and AV-1451 and the Neuropsychiatric Inventory (NPI) score (and its four domain subscores for hyperactivity, psychosis, affective, and apathy) was evaluated. Stepwise logistic regression analysis was used to examine the influence of SUVRs on the presence of NPS. SUVRs were also tested for their ability to discriminate the group with NPS using receiver operating characteristic (ROC) curve analyses. Significant positive relationships were found between the total NPI score and affective symptoms and Braak 1&2 (transentorhinal region) AV-1451 SUVR. Stepwise logistic regression analysis identified tau accumulation in the area of Braak 1&2 as a significant covariate discriminating the presence of affective symptoms. The area under the ROC curve analysis showed that subjects with affective symptoms were discriminated by AV-1451 SUVR with an accuracy of 77.7%. Tau aggregation in the transentorhinal region, where neurodegeneration affected by tau pathology was seen in the early stage of AD, correlated with more severe NPS, especially affective symptoms. Therefore, tau pathology in the transentorhinal cortex might be associated with affective symptoms in the early stage of AD.

From the Entorhinal Region via the Prosubiculum to the Dentate Fascia: Alzheimer Disease-Related Neurofibrillary Changes in the Temporal Allocortex.

The pathological process underlying Alzheimer disease (AD) unfolds predominantly in the cerebral cortex with the gradual appearance and regional progression of abnormal tau. Intraneuronal tau pathology progresses from the temporal transentorhinal and entorhinal regions into neocortical fields/areas of the temporal allocortex. Here, based on 95 cases staged for AD-related neurofibrillary changes, we propose an ordered progression of abnormal tau in the temporal allocortex. Initially, abnormal tau was limited to distal dendritic segments followed by tau in cell bodies of projection neurons of the transentorhinal/entorhinal layer pre-α. Next, abnormal distal dendrites accumulated in the prosubiculum and extended into the CA1 stratum oriens and lacunosum. Subsequently, altered dendrites developed in the CA2/CA3 stratum oriens and stratum lacunosum-moleculare, combined with tau-positive thorny excrescences of CA3/CA4 mossy cells. Finally, granule cells of the dentate fascia became involved. Such a progression might recapitulate a sequence of transsynaptic spreading of abnormal tau from 1 projection neuron to the next: From pre-α cells to distal dendrites in the prosubiculum and CA1; then, from CA1 or prosubicular pyramids to CA2 principal cells and CA3/CA4 mossy cells; finally, from CA4 mossy cells to dentate granule cells. The lesions are additive: Those from the previous steps persist.

Top-Down Projections Direct the Gradual Progression of Alzheimer-Related Tau Pathology Throughout the Neocortex.

In sporadic Alzheimer's disease (sAD), tau pathology gradually but relentlessly progresses from the transentorhinal region of the temporal lobe into both the allocortex and temporal high order association areas of the neocortex. From there, it ultimately reaches the primary sensory and motor fields of the neocortex. The brunt of the changes seen during neurofibrillary stages (NFT) I-VI is borne by top-down projection neurons that contribute to cortico-cortical connectivities between different neocortical fields. Very early changes develop in isolated pyramidal cells in layers III and V, and these cells are targets of top-down projections terminating in association areas of the first temporal gyrus or in peristriate regions of the occipital lobe. Neurofibrillary pathology in these regions is routinely associated with late NFT stages. Sequential changes occur in different cell compartments (dendritic, somatic, axonal) of these early-involved neurons. Tau pathology first develops in distal segments of basal dendrites, then in proximal dendrites, the soma, and, finally, in the axon of affected pyramidal neurons. This sequence of abnormal changes supports the concept that axons of cortico-cortical top-down neurons may carry and spread abnormal tau seeds in a focused manner (transsynaptically) into the distal dendritic segments of nerve cells directly following in the neuronal chain, thereby sustaining tau-seeded templating in sAD.

Phosphorylation of different tau sites during progression of Alzheimer\u2019s disease

Alzheimer’s disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of this site is used to assign Braak stage based on occurrence of neurofibrillary tangles. Only little is known about the spatial and temporal phosphorylation profile of other phosphorylated tau (ptau) sites. Here, we investigate total tau and ptau at residues Tyr18, Ser199, Ser202/Thr205, Thr231, Ser262, Ser396, Ser422 as well as amyloid-β plaques in human brain tissue of AD patients and controls. Allo- and isocortical brain regions were evaluated applying rater-independent automated quantification based on digital image analysis. We found that the level of ptau at several residues, like Ser199, Ser202/Thr205, and Ser422 was similar in healthy controls and Braak stages I to IV but was increased in Braak stage V/VI throughout the entire isocortex and transentorhinal cortex. Quantification of ThioS-stained plaques showed a similar pattern. Only tau phosphorylation at Tyr18 and Thr231 was already significantly increased in the transentorhinal region at Braak stage III/IV and hence showed a progressive increase with increasing Braak stages. Additionally, the increase in phosphorylation relative to controls was highest at Tyr18, Thr231 and Ser199. By contrast, Ser396 tau and Ser262 tau showed only a weak phosphorylation in all analyzed brain regions and only minor progression. Our results suggest that the ptau burden in the isocortex is comparable between all analyzed ptau sites when using a quantitative approach while levels of ptau at Tyr18 or Thr231 in the transentorhinal region are different between all Braak stages. Hence these sites could be crucial in the pathogenesis of AD already at early stages and therefore represent putative novel therapeutic targets.