Transentorhinal Cortex Research Articles

Targeting the function of the transentorhinal cortex to identify early cognitive markers of Alzheimer's disease.

Initial neuropathology of early Alzheimer's disease accumulates in the transentorhinal cortex. We review empirical data suggesting that tasks assessing cognitive functions supported by the transenthorinal cortex are impaired as early as the preclinical stages of Alzheimer's disease. These tasks span across various domains, including episodic memory, semantic memory, language, and perception. We propose that all tasks sensitive to Alzheimer-related transentorhinal neuropathology commonly rely on representations of entities supporting the processing and discrimination of items having perceptually and conceptually overlapping features. In the future, we suggest a screening tool that is sensitive and specific to very early Alzheimer's disease to probe memory and perceptual discrimination of highly similar entities.

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

Previous research has emphasized the unique impact of Alzheimer’s Disease (AD) pathology on the medial temporal lobe (MTL), a reflection that tau pathology is particularly striking in the entorhinal and transentorhinal cortex (ERC, TEC) early in the course of disease. However, other brain regions are affected by AD pathology during its early phases. Here, we use longitudinal diffeomorphometry to measure the atrophy rate from MRI of the amygdala compared with that in the ERC and TEC in cognitively unimpaired (CU) controls, CU individuals who progressed to mild cognitive impairment (MCI), and individuals with MCI who progressed to dementia of the AD type (DAT), using a dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Our results show significantly higher atrophy rates of the amygdala in both groups of ‘converters’ (CU→MCI, MCI→DAT) compared to controls, with rates of volume loss comparable to rates of thickness loss in the ERC and TEC. We localize atrophy within the amygdala within each of these groups using fixed effects modeling. Controlling for the familywise error rate highlights the medial regions of the amygdala as those with significantly higher atrophy in both groups of converters than in controls. Using our recently developed method, referred to as Projective LDDMM, we map measures of neurofibrillary tau tangles (NFTs) from digital pathology to MRI atlases and reconstruct dense 3D spatial distributions of NFT density within regions of the MTL. The distribution of NFTs is consistent with the spatial distribution of MR measured atrophy rates, revealing high densities (and atrophy) in the amygdala (particularly medial), ERC, and rostral third of the MTL. The similarity of the location of NFTs in AD and shape changes in a well-defined clinical population suggests that amygdalar atrophy rate, as measured through MRI may be a viable biomarker for AD.

The trans‐entorhinal cortex differential depends on retromer‐mediated endosomal recycling

AbstractAnatomical studies have pinpointed the trans‐entorhinal cortex (TEC) as the subregion of the brain selectively vulnerable to Alzheimer’s disease. Additional molecular studies have identified endosomal trafficking defects as a cytopathological driver of the disease. However, whether and how endosomal trafficking is linked to anatomical vulnerability still remains unknown. Here, in addressing these questions, we begin by showing that neurons are enriched with a functional distinct retromer core organized around VPS26b, differentially dedicated to endosomal recycling. Using fMRI imaging, and in contrast to its paralog VPS26a, we further demonstrated that depleting VPS26b in mice caused preferential age‐dependent dysfunction in the trans‐entorhinal cortex, a finding further validated by electrophysiology, immunocytochemistry, and behavior. Surprisingly, repletion of VPS26b, both in vitro and in vivo, rescued all phenotypes seen upon VPS26b depletion. We then turned to humans to find VPS26b highly enriched in the TEC region, where both VPS26b and the retromer‐related receptor SORL1 were found deficient in Alzheimer’s brains. Finally, by regulating glutamate receptor and SORL1 recycling and its levels, VPS26b was shown to mediate regionally‐selective synaptic dysfunction, as well as AD‐associated amyloid‐precursor protein misprocessing and tau secretion. Together with the trans‐entorhinal’s unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD’s regional vulnerability.

Tau antibody 77G7 targeting microtubule binding domain suppresses proteopathic tau to seed tau aggregation.

Neurofibrillary tangle (NFT) of hyperphosphorylated tau is a hallmark of Alzheimer's disease (AD) and related tauopathies. Tau lesion starts in the trans-entorhinal cortex, from where it spreads to limbic regions, followed by neocortical areas. The regional distribution of NFTs associates with the progression of AD. Accumulating evidence suggests that proteopathic tau can seed tau aggregation in a prion-like fashion in vitro and in vivo. Inhibition of tau seeding activity could provide a potential therapeutic opportunity to block the propagation of tau pathology in AD and related tauopathies. In the present study, we investigated the role of 77G7, a monoclonal tau antibody to the microtubule-binding repeats, in repressing the seeding activity of proteopathic tau. We found that 77G7 had a higher affinity toward aggregated pathological tau fractions than un-aggregated tau derived from AD brain. 77G7 inhibited the internalization of tau aggregates by cells, blocked AD O-tau to capture normal tau, and to seed tau aggregation in vitro and in cultured cells. Tau pathology induced by hippocampal injection of AD O-tau in 3xTg-AD mice was suppressed by mixing 77G7 with AD O-tau. Intravenous administration of 77G7 ameliorated site-specific hyperphosphorylation of tau induced by AD O-tau in the hippocampi of Tg/hTau mice. These findings indicate that 77G7 can effectively suppress the seeding activity of AD O-tau and thus could be developed as a potential immunotherapeutic drug to inhibit the propagation of tau pathology in AD and related tauopathies.

Isoform-specific patterns of tau burden and neuronal degeneration in MAPT-associated frontotemporal lobar degeneration

Frontotemporal lobar degeneration with MAPT pathogenic variants (FTLD-MAPT) has heterogeneous tau pathological inclusions postmortem, consisting of three-repeat (3R) or four-repeat (4R) tau isoforms, or a combination (3R + 4R). Here, we studied grey matter tau burden, its relation to neuronal degeneration, and regional patterns of pathology in different isoform groups of FTLD-MAPT. We included 38 FTLD-MAPT autopsy cases with 10 different MAPT pathogenic variants, grouped based on predominant tau isoform(s). In up to eleven regions (ten cortical and one striatal), we quantified grey matter tau burden using digital histopathological analysis and assigned semi-quantitative ratings for neuronal degeneration (i.e. 0–4) and separate burden of glial and neuronal tau inclusions (i.e. 0–3). We used mixed modelling to compare pathology measures (1) across the entire cohort and (2) within isoform groups. In the total cohort, tau burden and neuronal degeneration were positively associated and most severe in the anterior temporal, anterior cingulate and transentorhinal cortices. Isoform groups showed distinctive features of tau burden and neuronal degeneration. Across all regions, the 3R isoform group had lower tau burden compared to the 4R group (p = 0.008), while at the same time showing more severe neuronal degeneration than the 4R group (p = 0.002). The 3R + 4R group had an intermediate profile with relatively high tau burden along with relatively severe neuronal degeneration. Neuronal tau inclusions were most frequent in the 4R group (p < 0.001 vs. 3R), while cortical glial tau inclusions were most frequent in the 3R + 4R and 4R groups (p ≤ 0.009 vs. 3R). Regionally, neuronal degeneration was consistently most severe in the anterior temporal cortex within each isoform group. In contrast, the regions with the highest tau burden differed in isoform groups (3R: striatum; 3R + 4R: striatum, inferior parietal lobule, middle frontal cortex, anterior cingulate cortex; 4R: transentorhinal cortex, anterior temporal cortex, fusiform gyrus). We conclude that FTLD-MAPT isoform groups show distinctive features of overall neuronal degeneration and regional tau burden, but all share pronounced anterior temporal neuronal degeneration. These data suggest that distinct isoform-related mechanisms of genetic tauopathies, with slightly divergent tau distribution, may share similar regional vulnerability to neurodegeneration within the frontotemporal paralimbic networks.

Emerging insights into synapse dysregulation in Alzheimer's disease.

Alzheimer’s disease is the leading cause of dementia and a growing worldwide problem, with its incidence expected to increase in the coming years. Since synapse loss is a major pathology and is correlated with symptoms in Alzheimer’s disease, synapse dysfunction and loss may underlie pathophysiology. In this context, this review focuses on emerging insights into synaptic changes at the ultrastructural level. The three-dimensional electron microscopy technique unequivocally detects all types of synapses, including multi-synapses, which are indicators of synaptic connectivity between neurons. In recent years it has become feasible to perform sophisticated three-dimensional electron microscopy analyses on post-mortem human Alzheimer’s disease brain as tissue preservation and electron microscopy techniques have improved. This ultrastructural analysis found that synapse loss does not always precede neuronal loss, as long believed. For instance, in the transentorhinal cortex and area CA1 of the hippocampus, synapse loss does not precede neuronal loss. However, in the entorhinal cortex, synapse loss precedes neuronal loss. Moreover, the ultrastructural analysis provides details about synapse morphology. For example, changes in excitatory synapses’ post-synaptic densities, with fragmented postsynaptic densities increasing at the expense of perforated synapses, are seen in Alzheimer’s disease brain. Further, multi-synapses also appear to be altered in Alzheimer’s disease by doubling the abundance of multi-innervated spines in the transentorhinal cortex of Alzheimer’s disease brain. Collectively, these recent ultrastructural analyses highlight distinct synaptic phenotypes in different Alzheimer’s disease brain regions and broaden the understanding of synapse alterations, which may unravel some new therapeutic targets.

Spotlight on the February 15 Issue

#### Notable in Neurology This Week This issue features an article that validates the use of plasma Aβ42/Aβ40 to detect amyloid plaques in patients with Alzheimer disease; another investigates how the age at which children have a stroke affects long-term cognitive outcome. A featured Research Article examines the risk of cerebral venous sinus thrombosis after SARS-CoV-2 vaccination. ### Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract ![Graphic][1]</img> This study found that free water, a marker … [1]: /embed/inline-graphic-1.gif

Volumetric changes within hippocampal subfields in Alzheimer's disease continuum.

Neurodegeneration in Alzheimer's disease continuum (ADC) starts from the transentorhinal cortex and progresses within hippocampal circuitry following the connectivity of its subfields transsynaptically. We aimed to track volumetric changes of the hippocampal subfields by comparing three stages of the ADC. MRI data of 15 patients diagnosed with Alzheimer's disease dementia (ADD), 15 patients with amnestic mild cognitive impairment (MCI), and 15 individuals with subjective cognitive impairment (SCI) were analyzed. The hippocampal formation was subdivided into CA1, CA3, subiculum (SUB), and dentate gyrus (DG) using FreeSurfer and volumetric values were obtained. The volumetric values were analyzed with ANCOVA and intracranial volume was selected as a covariate. ANCOVA results of the hippocampal subfields displayed statistically significant differences among the three groups in bilateral CA1, SUB, and DG volumes (Right CA1: F = 7.316, p = 0.002; left CA1: F = 6.768, p = 0.003; right SUB: F = 9.390, p < 0.001; left SUB: F = 5.925, p = 0.005; right DG: F = 9.469, p < 0.001; left DG: F = 9.354, p < 0.001), while CA3 volumes were not significantly different among the groups. Post hoc comparisons revealed that volume reductions in bilateral CA1, DG, and SUB were present in ADD compared to both MCI and SCI groups. No significant volumetric changes were found between the SCI and MCI groups. While our results are generally consistent with the literature in terms of the CA1 and SUB findings, they additionally point to the importance of the significant volume loss in DG and the resilience of the CA3 sector.

Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract.

The goal of this work was to determine the relationship between diffusion microstructure and early changes in Alzheimer disease (AD) severity as assessed by clinical diagnosis, cognitive performance, dementia severity, and plasma concentrations of neurofilament light chain. Diffusion MRI scans were collected on cognitively normal participants (CN) and patients with early mild cognitive impairment (EMCI), late mild cognitive impairment, and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, 4 magnocellular regions of the basal forebrain (e.g., nucleus basalis of Meynert), entorhinal cortex, and hippocampus. All patients underwent a battery of cognitive assessments; neurofilament light chain levels were measured in plasma samples. FW was significantly higher in patients with EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; p fdr < 0.05). FW was significantly higher in those with AD compared to CN in all the examined regions (mean Cohen d = 1.41; p fdr < 0.01). In addition, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all 5 cognitive impairment metrics and neurofilament light chain levels (mean r 2 = 0.10; p fdr < 0.05). These results show that higher FW is associated with greater clinical diagnosis severity, cognitive impairment, and neurofilament light chain. They also suggest that FW elevation occurs in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus in the transition from CN to EMCI, while other basal forebrain regions and the entorhinal cortex are not affected until a later stage of AD. FW is a clinically relevant and noninvasive early marker of structural changes related to cognitive impairment.

Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling.

SUMMARYWhether and how the pathogenic disruptions in endosomal trafficking observed in Alzheimer’s disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion—a finding validated by electrophysiology, immunocytochemistry, and behavior. VPS26b was then found enriched in the trans-entorhinal cortex of human brains, where both VPS26b and the retromer-related receptor SORL1 were found deficient in AD. Finally, by regulating glutamate receptor and SORL1 recycling, we show that VPS26b can mediate regionally selective synaptic dysfunction and SORL1 deficiency. Together with the trans-entorhinal’s unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD’s regional vulnerability.

Microglial activation and tau propagate jointly across Braak stages

AbstractBackgroundCompelling experimental evidence suggests that microglial activation is involved in the spread of tau neurofibrillary tangles over the neocortex in Alzheimer’s disease (AD). Here, we tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak‐like pattern in the human brain.MethodWe studied 130 subjects (86 cognitively unimpaired and 44 cognitively impairment elderly) with microglia activation [11C]PBR28 PET, Amyloid [18F]NAV4694 PET, cognitive tests, magnetic resonance imaging, and cerebrospinal fluid (CSF) biomarkers. Participants also had baseline and follow‐up tau [18F]MK6240 PET scans. We used linear regressions and partial correlations to estimate the association between topographical distributions of microglial activation and tau accumulation.Result(A)Microglial activation (MA) connectivity analysis between regions comprising Braak histopathological stages (Braak I‐VI) across our population demonstrated that MA regions correlated hierarchically with each other, where a Braak‐like stage region only correlates with the previous and subsequent stage. (B)Tau tangles connectivity analysis between regions that comprise Braak stages (Braak I‐VI) across our population demonstrated that tau regions correlated hierarchically with each other, where a Braak stage only correlates with the previous/subsequent stage (C)The scatterplot shows that the elements of the MA‐MA matrix and tau‐tau matrix were highly positively correlated with each other, reinforcing the notion of a joint topographic propagation of MA and tau tangles through Braak stages. (D) Rates of tau propagation over 1‐year hierarchically correlated in Braak stages. (E)Significant Pearson correlation between longitudinal tau propagation and baseline tau network. (F)Significant Pearson correlation between longitudinal tau propagation and baseline microglia network. (G)Partial residuals plots show the results of regression between network of tau propagation over 1‐year and both baseline topographic circuits, MA‐MA and tau‐tau networks. The model suggests that the pathways of longitudinal tau propagation depended on underlying microglia, rather than tau circuits. (H)The figure shows thatmicroglial activation levels in the transentorhinal cortex predicted longitudinal tau spread over the neocortex.ConclusionOur results support a model in which an interaction between amyloid load and activated microglia set the pace for tau spread across Braak stages, while the simultaneous cerebral presence of these pathologies potentiates the development of dementia.

Systematic Review of Different Neuroimaging Correlates in Mild Cognitive Impairment and Alzheimer's Disease.

Alzheimer's disease (AD) is aheterogeneous progressive neurocognitive disorder. Although different neuroimaging modalities have been used for the identification of early diagnostic and prognostic factors of AD, there is no consolidated view of the findings from the literature. Here, we aim to provide acomprehensive account of different neural correlates of cognitive dysfunction via magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), functional MRI (fMRI) (resting-state and task-related), positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) modalities across the cognitive groups i.e., normalcognition, mild cognitive impairment (MCI), and AD. A total of 46 meta-analyses met the inclusion criteria, including relevance to MCI, and/or AD along with neuroimaging modality used with quantitative and/or functional data. Volumetric MRI identified early anatomical changes involving transentorhinal cortex, Brodmann area28, followed by the hippocampus, which differentiated early AD from healthy subjects. Aconsistent pattern of disruption in the bilateral precuneus along with the medial temporal lobe and limbic systemwas observed in fMRI, while DTI substantiated the observed atrophic alterations in the corpus callosum among MCI and AD cases. Default mode network hypoconnectivity in bilateral precuneus (PCu)/posterior cingulate cortices (PCC) and hypometabolism/hypoperfusion in inferior parietal lobules and left PCC/PCu was evident. Molecular imaging revealed variable metabolite concentrations in PCC. In conclusion, the use of different neuroimaging modalities together may lead to identification of an early diagnostic and/or prognostic biomarker for AD.

18F]MK‐6240 depicts early and late Braak stages of neurofibrillary tangles in preclinical and symptomatic subjects

AbstractBackgroundPostmortem Braak staging provides an index of disease stage and has therefore been incorporated as a core neuropathological criterion for the diagnosis of Alzheimer’s disease (AD). Recent in vivo studies using the tau positron emission tomography agent [18F]flortaucipir have shown low sensitivity to detect tau pathology in early Braak stages. These studies report Braak I‐II or greater in ∼20% of cognitively unimpaired elderly, in contrast to the ∼70‐90% of non‐zero Braak stage reported in postmortem studies. Here, we tested whether the novel high‐affinity tau tangles tracer [18F]MK‐6240 (6 fold &gt; [18F]flortaucipir)can better identify individuals in the early stages of tau accumulation.MethodTo this end, we studied 301 individuals (30 young adults, 138 cognitively unimpaired (CU) elderly, 67 mild cognitive impairment (MCI), 54 AD dementia, and 12 frontotemporal dementia (FTD)) with amyloid‐b[18F]NAV4694, tau [18F]MK‐6240, magnetic resonance imaging, and clinical assessments.Results[18F]MK‐6240 discriminated AD from FTD dementia as well as predicted amyloid‐b positivity with the highest area under the curve in Braak I‐II region (=∼95‐100%)(Fig.1 and 2). [18F]MK‐6240 accumulation hierarchically followed the 6 Braak stages (Fig.3)in 98% of our population (Fig.4).91% of the elderly amyloid‐b positive and 46% of the elderly amyloid‐b negative displayed tau deposition, at least in the transentorhinal cortex (Braak I)(Fig.4). Cognition and amyloid‐b status explained most of the Braak stages variance (P&lt;0.0001, R2=0.75). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid‐b, neurodegeneration, and cognitive impairment (P&lt;0.0001). No single region‐of‐interest accurately segregated individuals into the 6 Braak stages (Fig.5). However, classification decision tree analysis suggested that a composite of transentorhinal, entorhinal, and hippocampal cortices(Braak I‐II) was the region‐of‐interest that best represented [18F]MK‐6240Braak stages (capacity of a region’ SUVR cutoff segregating individuals in 7 levels (Braak 0‐VI)) (accuracy=86.2%)(Fig.6).ConclusionOur results highlight that the hierarchical 6‐stage Braak model using [18F]MK‐6240 provides a robust index of early and late tau accumulation as well as disease stages in preclinical and symptomatic individuals. Tau positron emission tomography Braak staging using high‐affinity tracers has the potential to be incorporated in the diagnosis of living patients with AD.

The locus coeruleus: In‐vivo characterization with advanced MRI methods and associations with memory in older adults at risk for Alzheimer’s disease

AbstractBackgroundThe locus coeruleus (LC) is the brain’s main source of norepinephrine and plays a key role in modulating attention and memory processes. In Alzheimer’s disease (AD), the LC has been identified as an early site of tau accumulation and this tau pathology may spread via its connections to the transentorhinal cortex (TEC). Historically, this region has been nearly impossible to study in vivo. However, recent advances in structural magnetic resonance imaging (MRI) have provided opportunities to capture the integrity of LC neurons and their projections. We utilized a combination of neuromelanin‐sensitive and diffusion tensor MRI to examine LC integrity and its role in memory.Method31 older adults (26 cognitively normal; 5 MCI) underwent T1 fast spin echo and diffusion MRI scans as well as neuropsychological testing. Bilateral LC contrast ratios (CRs) were calculated as neuromelanin‐related signal intensities relative to a reference region. In a subset of participants (n=12; 10 cognitively normal, 2 MCI) LC‐TEC white matter pathways were reconstructed using probabilistic tractography in FSL and average fractional anisotropy (FA) was extracted. Logical Memory and CVLT‐2 were used to assess verbal learning and memory.ResultResults revealed lower bilateral LC‐CRs was associated with poorer performance on measures of story learning (LMI; r=0.425, p=.045) and word‐list recall (CVLT‐2 Short Delay Recall: r=.481, p=.006; CVLT‐2 Long Delay Recall: r=.375, p=.038). Tractography analyses indicated that higher FA of the left LC‐TEC tract was associated with poorer story learning (LM1: r=‐.651, p=.02), whereas higher FA of the right LC‐TEC tract was associated with poorer word‐list recall (CVLT‐2 Short Delay Recall: r=‐.599, p=.039; CVLT‐2 Short Delay Cued Recall, r=‐.705, p=.01).ConclusionPreliminary results indicate that neuromelanin and tractography MRI methods can be utilized for in vivo characterization of the human LC. Lower neuromelanin signal, but higher FA is associated with poorer memory performance in a sample of cognitively normal and MCI adults. Greater tau pathology may alter the LC signal and encroaching tau accumulation in the LC‐TEC pathway may initiate neuroinflammatory processes reflected by increased FA. Future work is needed to understand the temporal course and nature of LC changes across the aging‐MCI‐AD continuum.

Tau acetylation at K280 is critical for propagation and an antibody targeting it prevents in vivo tau propagation

AbstractBackgroundThe spread of tau pathology from the transentorhinal cortex to the hippocampus and neocortex in Alzheimer’s disease (AD) is explained by the prion‐like cell‐to‐cell seeding and propagation of misfolded tau aggregates. Hence, it is important to define the seeding‐ and propagation‐competent tau species and to develop targeted therapeutic antibodies.MethodVarious methods like thioflavin‐T, FRET, FACS, and in vivo stereotaxic injection of AD‐derived tau aggregate fractions were used to evaluate tau aggregation, propagation, and the efficacy of an antibody to inhibit these processes.ResultAcetylation of tau at K280 is critical for the successive tau propagation processes, including secretion, aggregation, and seeding. An antibody targeting acetylated tau at K280 effectively prevented AD‐derived insoluble tau aggregates‐induced proteopathic seeding and propagation in in vitro assays and in vivo mouse brains.ConclusionAcetylated tau at K280 is a core species of seeding and propagation, which could be a therapeutic target for AD and other tauopathies.

Medial temporal neuroinflammation unleashes tau spreading over the neocortex

AbstractBackgroundTransentorhinal tau neurofibrillary tangles deposition is a typical finding in cognitively unimpaired (CU) elderly. Thus, how tau tangle spreads over the neocortex, leading to disease progression, is a pressing issue in Alzheimer's disease (AD). Although amyloid is postulated to trigger this spread, the fact that amyloid deposition is present in low concentrations in temporal structures challenges this framework. Here, we tested the hypothesis that brain amyloid burden interacts with medial temporal neuroinflammation unleashing tau spread over the neocortex. To assess neuroinflammation, we used [11C]PBR28 PET, a ligand that binds to the 18‐kDa translocator protein(TSPO), considerate a proxy of inflammation.MethodsTSPO polymorphism (rs6971) was genotyped in 678 participants from the Montreal catchment area (48% presented rs6971 polymorphism of high TSPO binders). Following inclusion/exclusion criteria, we studied 131 high TSPO binders (22 CU young, 63 CU elderly, 28 MCI, 18 AD). All individuals had PET; amyloid [18F]NAV4694, tau [18F]MK6240, and [11C]PBR28,as well as MRI, cognitive and genetic assessments. Structural equation modeling (SEM) tested associations between markers.Results[11C]PBR28 uptake was progressively higher from CU to AD(Fig.1). [18F]NAV4694,[18F]MK6240, and [11C]PBR28 were correlated (Fig.2); however, analysis of variance suggested that an interaction between [18F]NAV4694and[11C]PBR28 on [18F]MK6240 best explain the association between these markers(P&lt;0.0001). Voxel‐wise analysis, taking into consideration global and local tracer effects, suggests an interaction between global [18F]NAV4694 and medial temporal [11C]PBR28 on medial temporal [18F]MK6240(Fig.3). Stratified analysis revealed that individuals with abnormal amyloid, tau, and neuroinflammation (A+/T+/NI+) had elevated cognitive impairment and hippocampus atrophy(Fig.4). SEM suggests that global amyloid interacts with transentorhinal inflammation leading to tau spread over Braak II‐III(Fig.5). Subsequently, tau hierarchically spread from Braak III to VI. Models inverting the variables mentioned above or the order of Braak regions did not fit the data. Accumulation of tau only in Braak IV‐VI was associated with cognitive symptoms (Fig.6).ConclusionOur results suggest that an interaction between global amyloid and medial temporal neuroinflammation triggers tau spread over the neocortex. Global amyloid may represent distant amyloid load or amyloid oligomers. Our results suggest individuals with tau deposition confined to transentorhinal cortex as targets for the use of anti‐inflammatory drugs in AD.

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.

Distribution of tau hyperphosphorylation in canine dementia resembles early Alzheimer's disease and other tauopathies.

Some aged community dogs acquire a degenerative syndrome termed Canine Cognitive Dysfunction (CCD) that resembles human dementia because of Alzheimer’s Disease (AD), with comparable cognitive and behavioral deficits. Dogs also have similar neuroanatomy, share our domestic environment and develop amyloid‐β plaques, making them likely a valuable ecological model of AD. However, prior investigations have demonstrated a lack of neurofibrillary tau pathology in aged dogs, an important hallmark of AD, though elevated phosphorylated tau (p‐tau) at the Serine 396 (S396) epitope has been reported in CCD. Here using enhanced immunohistochemical methods, we investigated p‐tau in six CCD brains and six controls using the AT8 antibody (later stage neurofibrillary pathology), and an antibody against S396 p‐tau (earlier stage tau dysfunction). For the first time, we systematically assessed the Papez circuit and regions associated with Braak staging and found that all CCD dogs displayed elevated S396 p‐tau labeling throughout the circuit. The limbic thalamus was particularly implicated, with a similar labeling pattern to that reported for AD neurofibrillary pathology, especially the anterior nuclei, while the hippocampus exhibited dysfunction confined to synaptic layers and efferent pathways. The cingulate and temporal lobes displayed significantly greater tauopathy than the frontal and occipital cortices, also reflective of early Braak staging patterns in AD. Immunofluorescence confirmed that S396 was accumulating within neuronal axons, somata and oligodendrocytes. We also observed AT8 labeling in one CCD brain, near the transentorhinal cortex in layer II neurons, one of the first regions to be affected in AD. Together, these data demonstrate a concordance in regional distribution of tauopathy between CCD and AD, most evident in the limbic thalamus, an important step in further validating CCD as a translational model for human AD and understanding early AD pathogenic mechanisms.

A probabilistic atlas of locus coeruleus pathways to transentorhinal cortex for connectome imaging in Alzheimer's disease

According to the latest Braak staging of Alzheimer's disease (AD), tau pathology occurs earliest in the brain in the locus coeruleus (LC) of the brainstem, then propagates to the transentorhinal cortex (TEC), and later to other neocortical regions. Recent animal and in vivo human brain imaging research also support the trans-axonal propagation of tau pathology. In addition, neurochemical studies link norepinephrine to behavioral symptoms in AD. It is thus critical to examine the integrity of the LC-TEC pathway in studying the early development of the disease, but there has been limited work in this direction. By leveraging the high-resolution and multi-shell diffusion MRI data from the Human Connectome Project (HCP), in this work we develop a novel method for the reconstruction of the LC-TEC pathway in a cohort of 40 HCP subjects carefully selected based on rigorous quality control of the residual distortion artifacts in the brainstem. A probabilistic atlas of the LC-TEC pathway of both hemispheres is then developed in the MNI152 space and distributed publicly on the NITRC website. To apply our atlas on clinical imaging data, we develop an automated approach to calculate the medial core of the LC-TEC pathway for localized analysis of connectivity changes. In a cohort of 138 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we demonstrate the detection of the decreased fiber integrity in the LC-TEC pathways with increasing disease severity.

Entorhinal and Transentorhinal Atrophy in Preclinical Alzheimer's Disease.

This study examines the atrophy patterns in the entorhinal and transentorhinal cortices of subjects that converted from normal cognition to mild cognitive impairment. The regions were manually segmented from 3T MRI, then corrected for variability in boundary definition over time using an automated approach called longitudinal diffeomorphometry. Cortical thickness was calculated by deforming the gray matter-white matter boundary surface to the pial surface using an approach called normal geodesic flow. The surface was parcellated based on four atlases using large deformation diffeomorphic metric mapping. Average cortical thickness was calculated for (1) manually-defined entorhinal cortex, and (2) manually-defined transentorhinal cortex. Group-wise difference analysis was applied to determine where atrophy occurred, and change point analysis was applied to determine when atrophy started to occur. The results showed that by the time a diagnosis of mild cognitive impairment is made, the transentorhinal cortex and entorhinal cortex was up to 0.6 mm thinner than a control with normal cognition. A change point in atrophy rate was detected in the transentorhinal cortex 9–14 years prior to a diagnosis of mild cognitive impairment, and in the entorhinal cortex 8–11 years prior. The findings are consistent with autopsy findings that demonstrate neuronal changes in the transentorhinal cortex before the entorhinal cortex.