Long-read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology.

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts - including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 - associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology.

Morphological and Functional Alterations in the CA1 Pyramidal Neurons of the Rat Hippocampus in the Chronic Phase of the Lithium-Pilocarpine Model of Epilepsy.

Epilepsy is known to cause alterations in neural networks. However, many details of these changes remain poorly understood. The objective of this study was to investigate changes in the properties of hippocampal CA1 pyramidal neurons and their synaptic inputs in a rat lithium-pilocarpine model of epilepsy. In the chronic phase of the model, we found a marked loss of pyramidal neurons in the CA1 area. However, the membrane properties of the neurons remained essentially unaltered. The results of the electrophysiological and morphological studies indicate that the direct pathway from the entorhinal cortex to CA1 neurons is reinforced in epileptic animals, whereas the inputs to them from CA3 are either unaltered or even diminished. In particular, the dendritic spine density in the str. lacunosum moleculare, where the direct pathway from the entorhinal cortex terminates, was found to be 2.5 times higher in epileptic rats than in control rats. Furthermore, the summation of responses upon stimulation of the temporoammonic pathway was enhanced by approximately twofold in epileptic rats. This enhancement is believed to be a significant contributing factor to the heightened epileptic activity observed in the entorhinal cortex of epileptic rats using an ex vivo 4-aminopyridine model.

Estimating individual trajectories of structural and cognitive decline in mild cognitive impairment for early prediction of progression to dementia of the Alzheimer's type.

Only a third of individuals with mild cognitive impairment (MCI) progress to dementia of the Alzheimer's type (DAT). Identifying biomarkers that distinguish individuals with MCI who will progress to DAT (MCI-Converters) from those who will not (MCI-Non-Converters) remains a key challenge in the field. In our study, we evaluate whether the individual rates of loss of volumes of the Hippocampus and entorhinal cortex (EC) with age in the MCI stage can predict progression to DAT. Using data from 758 MCI patients in the Alzheimer's Disease Neuroimaging Database, we employ Linear Mixed Effects (LME) models to estimate individual trajectories of regional brain volume loss over 12 years on average. Our approach involves three key analyses: (1) mapping age-related volume loss trajectories in MCI-Converters and Non-Converters, (2) using logistic regression to predict progression to DAT based on individual rates of hippocampal and EC volume loss, and (3) examining the relationship between individual estimates of these volumetric changes and cognitive decline across different cognitive functions-episodic memory, visuospatial processing, and executive function. We find that the loss of Hippocampal volume is significantly more rapid in MCI-Converters than Non-Converters, but find no such difference in EC volumes. We also find that the rate of hippocampal volume loss in the MCI stage is a significant predictor of conversion to DAT, while the rate of volume loss in the EC and other additional regions is not. Finally, individual estimates of rates of regional volume loss in both the Hippocampus and EC, and other additional regions, correlate strongly with individual rates of cognitive decline. Across all analyses, we find significant individual variation in the initial volumes and the rates of changes in volume with age in individuals with MCI. This study highlights the importance of personalized approaches in predicting AD progression, offering insights for future research and intervention strategies.

Entorhinal vessel density correlates with phosphorylated tau and TDP-43 pathology.

INTRODUCTION: The entorhinal cortex (EC) and perirhinal cortex (PC) are vulnerable to Alzheimer's disease. A triggering factor may be the interaction of vascular dysfunction and tau pathology. METHODS: We imaged post mortem human tissue at 100 µm3 with 7 T magnetic resonance imaging and manually labeled individual blood vessels (mean = 270 slices/case). Vessel density was quantified and compared per EC subfield, between EC and PC, and in relation to tau and TAR DNA-binding protein 43 (TDP-43) semiquantitative scores. RESULTS: PC was more vascularized than EC and vessel densities were higher in posterior EC subfields. Tau and TDP-43 strongly correlated with vasculature density and subregions with severe tau at the preclinical stage had significantly greater vessel density than those with low tau burden. DISCUSSION: These data impact cerebrovascular maps, quantification of subfield vasculature, and correlation of vasculature and pathology at early stages. The ordered association of vessel density, and tau or TDP-43 pathology, may be exploited in a predictive context. HIGHLIGHTS: Vessel density correlates with phosphorylated tau (p-tau) burden in entorhinal and perirhinal cortices. Perirhinal area 35 and posterior entorhinal cortex showed greatest p-tau burden but also the highest vessel density in the preclinical phase of Alzheimer's disease. We combined an ex vivo magnetic resonance imaging model and histopathology to demonstrate the 3D reconstruction of intracortical vessels and its spatial relationship to the pathology.

Degeneration in Nucleus basalis of Meynert signals earliest stage of Alzheimer's disease progression.

Nucleus Basalis of Meynert (NbM), a crucial source of cholinergic projection to the entorhinal cortex (EC) and hippocampus (HC), has shown sensitivity to neurofibrillary degeneration in the early stages of Alzheimer's Disease. Using deformation-based morphometry (DBM) on up-sampled MRI scans from 1447 Alzheimer's Disease Neuroimaging Initiative participants, we aimed to quantify NbM degeneration along the disease trajectory. Results from cross-sectional analysis revealed significant differences of NbM volume between cognitively normal and early mild cognitive impairment cohorts, confirming recent studies suggesting that NbM degeneration happens before degeneration in the EC or HC. Longitudinal linear mixed-effect models were then used to compare trajectories of volume change after realigning all participants into a common timeline based on their cognitive decline. Results indicated the earliest deviations in NbM volumes from the cognitively healthy trajectory, challenging the prevailing idea that Alzheimer's originates in the EC. Converging evidence from cross-sectional and longitudinal models suggest that the NbM may be a focal target of early AD progression, which is often obscured by normal age-related decline.

Histological and Memory Alterations in an Innovative Alzheimer's Disease Animal Model by Vanadium Pentoxide Inhalation.

Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-ß (Aß) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02 M V2O5 1 h, 3/week for 6 months) groups (n = 10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aß plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.

A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer's disease vulnerable neurons.

Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer's disease. Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease. Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a regulator of tau pathology. We show that epigenetic changes caused by Dek silencing alter activity-induced transcription, with major effects on neuronal excitability. This is accompanied by the gradual accumulation of tau in the somatodendritic compartment of mouse ECII neurons in vivo, reactivity of surrounding microglia, and microglia-mediated neuron loss. These features are all characteristic of early Alzheimer's disease. The existence of a cell-autonomous mechanism linking Alzheimer's disease pathogenic mechanisms in the precise neuron type where the disease starts provides unique evidence that synaptic homeostasis dysregulation is of central importance in the onset of tau pathology in Alzheimer's disease.

Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 µm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.

Entorhinal cortex astrocytic atrophy in human frontotemporal dementia.

The pathophysiology of Fronto Temporal Dementia (FTD) remains poorly understood, specifically the role of astroglia. Our aim was to explore the hypothesis of astrocytic alterations as a component for FTD pathophysiology. We performed an in-depth tri-dimensional (3-D) anatomical and morphometric study of glial fibrillary acidic protein (GFAP)-positive and glutamine synthetase (GS)-positive astrocytes in the human entorhinal cortex (EC) of FTD patients. The studies at this level in the different types of human dementia are scarce. We observed a prominent astrocyte atrophy of GFAP-positive astrocytes and co-expressing GFAP/GS astrocytes, characterised by a decrease in area and volume, whilst minor changes in GS-positive astrocytes in FTD compared to non-dementia controls (ND) samples. This study evidences the importance of astrocyte atrophy and dysfunction in human EC. We hypothesise that FTD is not only a neuropathological disease, but also a gliopathological disease having a major relevance in the understanding the astrocyte role in FTD pathological processes and development.

Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease.

INTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. DISCUSSION: Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

Proteomic analysis identifies HSP90AA1, PTK2B, and ANXA2 in the human entorhinal cortex in Alzheimer's disease: Potential role in synaptic homeostasis and Aß pathology through microglial and astroglial cells.

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder worldwide, is clinically characterized by cognitive deficits. Neuropathologically, AD brains accumulate deposits of amyloid-ß (Aß) and tau proteins. Furthermore, these misfolded proteins can propagate from cell to cell in a prion-like manner and induce native proteins to become pathological. The entorhinal cortex (EC) is among the earliest areas affected by tau accumulation along with volume reduction and neurodegeneration. Neuron-glia interactions have recently come into focus; however, the role of microglia and astroglia in the pathogenesis of AD remains unclear. Proteomic approaches allow the determination of changes in the proteome to better understand the pathology underlying AD. Bioinformatic analysis of proteomic data was performed to compare ECs from AD and non-AD human brain tissue. To validate the proteomic results, western blot, immunofluorescence, and confocal studies were carried out. The findings revealed that the most disturbed signaling pathway was synaptogenesis. Because of their involvement in synapse function, relationship with Aß and tau proteins and interactions in the pathway analysis, three proteins were selected for in-depth study: HSP90AA1, PTK2B, and ANXA2. All these proteins showed colocalization with neurons and/or astroglia and microglia and with pathological Aß and tau proteins. In particular, ANXA2, which is overexpressed in AD, colocalized with amoeboid microglial cells and Aß plaques surrounded by astrocytes. Taken together, the evidence suggests that unbalanced expression of HSP90AA1, PTK2B, and ANXA2 may play a significant role in synaptic homeostasis and Aß pathology through microglial and astroglial cells in the human EC in AD.

Contribution of the medial entorhinal cortex to performance on the Traveling Salesperson Problem in rats.

In order to successfully navigate through space, animals must rely on multiple cognitive processes, including orientation in space, memory of object locations, and navigational decisions based on that information. Although highly-controlled behavioral tasks are valuable for isolating and targeting specific processes, they risk producing a narrow understanding of complex behavior in natural contexts. The Traveling Salesperson Problem (TSP) is an optimization problem that can be used to study naturalistic foraging behaviors, in which subjects select routes between multiple baited targets. Foraging is a spontaneous, yet complex, behavior, involving decision-making, attention, course planning, and memory. Previous research found that hippocampal lesions in rats impaired TSP task performance, particularly on measures of spatial memory. Although traditional laboratory tests have shown the medial entorhinal cortex (MEC) to play an important role in spatial memory, if and how the MEC is involved in finding efficient solutions to the TSP remains unknown. In the current study, rats were trained on the TSP, learning to retrieve bait from targets in a variety of spatial configurations. After recovering from either an MEC lesion or control sham surgery, the rats were tested on eight new configurations. Our results showed that, similar to rats with hippocampal lesions, MEC-lesioned rats were impaired on measures of spatial memory, but not spatial decision-making, with greatest impairments on configurations requiring a global navigational strategy for selecting the optimal route. These findings suggest that the MEC is important for effective spatial navigation, especially when global cue processing is required.

Astrocyte S100ß expression and selective differentiation to GFAP and GS in the entorhinal cortex during ageing in the 3xTg-Alzheimer's disease mouse model.

The study of astrocytes and its role in the development and evolution of neurodegenerative diseases, including Alzheimer's disease (AD) is essential to fully understand their aetiology. The aim if this study is to deepen into the concept of the heterogeneity of astrocyte subpopulations in the EC and in particular the identification of differentially functioning astrocyte subpopulations that respond differently to AD progression. S100ß protein belongs to group of small calcium regulators of cell membrane channels and pumps that are expressed by astrocytes and is hypothesised to play and have a relevant role in AD development. We analysed the selective differentiation of S100ß-positive astrocytes into Glutamine synthetase (GS) and Glial fibrillary acidic protein (GFAP)-positive sub-groups in the entorhinal cortex (EC) of AD triple transgenic animal model (3xTg-AD). EC is the brain region earliest affected in humans AD but also in this closest animal model regarding their pathology and time course. We observed no changes in the number of S100ß-positive astrocytes between 1 and 18 months of age in the EC of 3xTg-AD mice. However, we identified relevant morphological changes in S100ß/GFAP positive astrocytes showing a significant reduction in their surface and volume whilst an increase in number and percentage. Furthermore, the percentage of S100ß/GS positive astrocyte population was also increased in 18 months old 3xTg-AD mice compared to the non-Tg mice. Our findings reveal the presence of differentially controlled astrocyte populations that respond differently to AD progression in the EC of 3xTg-AD mice. These results highpoints the major astrocytic role together with its early and marked affection in AD and arguing in favour of its importance in neurogenerative diseases and potential target for new therapeutic approaches.

Comparison of Quantitative Hippocampal Volumes and Structured Scoring Scales in Predicting Alzheimer Disease Diagnosis.

BACKGROUND AND PURPOSE: Brain imaging plays an important role in investigating patients with cognitive decline and ruling out secondary causes of dementia. This study compares the diagnostic value of quantitative hippocampal volumes derived from automated volumetric software and structured scoring scales in differentiating Alzheimer disease, mild cognitive impairment, and subjective cognitive decline. MATERIALS AND METHODS: Retrospectively, we reviewed images and medical records of adult patients who underwent MR imaging with a dementia protocol (2018-2021). Patients with postscanning diagnoses of Alzheimer disease, mild cognitive impairment, and subjective cognitive decline based on the International Statistical Classification of Diseases and Related Health Problems, 10th revision, were included. Diagnostic performances of automated normalized total hippocampal volume and structured manually assigned medial temporal atrophy and entorhinal cortical atrophy scores were assessed using multivariate logistic regression and receiver operating characteristic curve analysis. RESULTS: We evaluated 328 patients (Alzheimer disease, n = 118; mild cognitive impairment, n = 172; subjective cognitive decline, n = 38). Patients with Alzheimer disease had lower normalized total hippocampal volume (median, 0.35%), higher medial temporal atrophy (median, 3), and higher entorhinal cortical atrophy (median, 2) scores than those with subjective cognitive decline (P < .001) and mild cognitive impairment (P < .001). For discriminating Alzheimer disease from subjective cognitive decline, an entorhinal cortical atrophy cutoff value of 2 had a higher specificity (87%) compared with normalized total hippocampal volume (74%) and medial temporal atrophy (66%), but a lower sensitivity (69%) than normalized total hippocampal volume (84%) and medial temporal atrophy (84%). In discriminating Alzheimer disease from mild cognitive impairment, an entorhinal cortical atrophy cutoff value of 3 had a specificity (66%), similar to that of normalized total hippocampal volume (67%) but higher than medial temporal atrophy (54%), and its sensitivity (69%) was also similar to that of normalized total hippocampal volume (71%) but lower than that of medial temporal atrophy (84%). CONCLUSIONS: Entorhinal cortical atrophy and medial temporal atrophy may be useful adjuncts in discriminating Alzheimer disease from subjective cognitive decline, with reduced cost and implementation challenges compared with automated volumetric software.

Associations of olfactory function with brain structural and functional outcomes. A systematic review.

In aging, olfactory deficits have been associated with lower cognition and motor function. Olfactory dysfunction is also one of the earliest features of neurodegenerative disease. A comprehensive review of the neural correlates of olfactive function may reveal mechanisms underlying the associations among olfaction, cognition, motor function, and neurodegenerative diseases. Here, we summarize existing knowledge on the relationship between brain structural and functional measures and olfaction in older adults without and with cognitive impairment, including Alzheimer's disease. We identified 33 eligible studies (30 MRI/DTI,3 fMRI); 31 were cross-sectional, most assessed odor identification, and few examined multiple brain areas. Lower olfactory function was associated with smaller volumes in the temporal lobe (hippocampus,parahippocampal gyrus,fusiform gyrus), olfactory-related regions (piriform cortex,amygdala,entorhinal cortex), pre- and postcentral gyri, and globus pallidus. During aging, olfactory impairment may be associated with pathology in brain areas important for motor function and cognition, especially memory. Future longitudinal studies that include neuroimaging across different brain areas are warranted to determine the neurobiological changes underlying olfactory changes in the aging brain and the progression of neurodegeneration.

Localization of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer's disease.

Alzheimer's disease cortical tau pathology initiates in the layer II cell clusters of entorhinal cortex, but it is not known why these specific neurons are so vulnerable. Aging macaques exhibit the same qualitative pattern of tau pathology as humans, including initial pathology in layer II entorhinal cortex clusters, and thus can inform etiological factors driving selective vulnerability. Macaque data have already shown that susceptible neurons in dorsolateral prefrontal cortex express a "signature of flexibility" near glutamate synapses on spines, where cAMP-PKA magnification of calcium signaling opens nearby potassium and hyperpolarization-activated cyclic nucleotide-gated channels to dynamically alter synapse strength. This process is regulated by PDE4A/D, mGluR3, and calbindin, to prevent toxic calcium actions; regulatory actions that are lost with age/inflammation, leading to tau phosphorylation. The current study examined whether a similar "signature of flexibility" expresses in layer II entorhinal cortex, investigating the localization of PDE4D, mGluR3, and HCN1 channels. Results showed a similar pattern to dorsolateral prefrontal cortex, with PDE4D and mGluR3 positioned to regulate internal calcium release near glutamate synapses, and HCN1 channels concentrated on spines. As layer II entorhinal cortex stellate cells do not express calbindin, even when young, they may be particularly vulnerable to magnified calcium actions and ensuing tau pathology.

Prominent and conspicuous astrocyte atrophy in human sporadic and familial Alzheimer's disease.

Pathophysiology of sporadic Alzheimer's disease (SAD) and familial Alzheimer's disease (FAD) remains poorly known, including the exact role of neuroglia and specifically astroglia, in part because studies of astrocytes in human Alzheimer's disease (AD) brain samples are scarce. As far as we know, this is the first study of a 3-D immunohistochemical and microstructural analysis of glial fibrillary acidic protein (GFAP)- and glutamine synthetase (GS)-positive astrocytes performed in the entorhinal cortex (EC) of human SAD and FAD samples. In this study, we report prominent atrophic changes in GFAP and GS astrocytes in the EC of both SAD and FAD characterised by a decrease in area and volume when compared with non-demented control samples (ND). Furthermore, we did not find neither astrocytic loss nor astrocyte proliferation or hypertrophy (gliosis). In contrast with the astrogliosis classically accepted hypothesis, our results show a highly marked astrocyte atrophy that could have a major relevance in AD pathological processes being fundamental and key for AD mnesic and cognitive alterations equivalent in both SAD and FAD.

Progressive Excitability Changes in the Medial Entorhinal Cortex in the 3xTg Mouse Model of Alzheimer's Disease Pathology.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in hippocampus, but less is known about changes in medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at 3 and 10 months of age in the 3xTg mouse model of AD pathology, using male and female mice. At 3 months of age, before the onset of memory impairments, we found early hyperexcitability in intrinsic properties of MECII stellate and pyramidal cells, but this was balanced by a relative reduction in synaptic excitation (E) compared with inhibition (I; E/I ratio), suggesting intact homeostatic mechanisms regulating MECII activity. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable, and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsic and synaptic hyperexcitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this postsymptomatic time point, which may contribute to the emergence of memory deficits in AD.SIGNIFICANCE STATEMENT AD causes cognitive deficits, but the specific neural circuits that are damaged to drive changes in memory remain unknown. Using a mouse model of AD pathology that expresses both amyloid and tau transgenes, we found that neurons in the MEC have altered excitability. Before the onset of memory impairments, neurons in layer 2 of MEC had increased intrinsic excitability, but this was balanced by reduced inputs onto the cell. However, after the onset of memory impairments, stellate cells in MEC became further hyperexcitable, with increased excitability exacerbated by increased synaptic inputs. Thus, it appears that MEC stellate cells are uniquely disrupted during the progression of memory deficits and may contribute to cognitive deficits in AD.

Morphometric analysis of medial temporal lobe subregions in Alzheimer's disease using high-resolution MRI.

The spread pattern of progressive degeneration seen in Alzheimer's disease (AD) to small-scale medial temporal lobe subregions is critical for early diagnosis. In this context, it was aimed to examine the morphometric changes of the hippocampal subfields, amygdala nuclei, entorhinal cortex (ERC), and parahippocampal cortex (PHC) using MRI. MRI data of patients diagnosed with 20 Alzheimer's disease dementia (ADD), 30 amnestic mild cognitive impairment (aMCI), and 30 subjective cognitive impairment (SCI) without demographic differences were used. Segmentation and parcellation were performed using FreeSurfer. The segmentation process obtained volume values of 12 hippocampal subfields and 9 amygdala nuclei. Thickness values of ERC and PHC were calculated with the parcellation process. ANCOVA was performed using age, education and gender as covariates to evaluate the intergroup differences. Linear discriminant analysis was used to investigate whether atrophy predicted groups at an early stage. ERC and PHC thickness decreased significantly throughout the disease continuum, while only ERC was affected in the early stage. When the hippocampal and amygdala subfields were compared volumetrically, significant differences were found in the amygdala between the SCI and aMCI groups. In the early period, only volume reduction in the anterior amygdaloid area of the amygdala nuclei exceeded the significance threshold. Research on AD primarily focuses on original hippocampocentric structures and their main function which is episodic memory. Our results emphasized the significance of so far relatively neglected olfactocentric structures and their functions, such as smell and social cognition in the pre-dementia stages of the AD process.

An Optimized Deep Learning Model for Predicting Mild Cognitive Impairment Using Structural MRI.

Early diagnosis of mild cognitive impairment (MCI) with magnetic resonance imaging (MRI) has been shown to positively affect patients' lives. To save time and costs associated with clinical investigation, deep learning approaches have been used widely to predict MCI. This study proposes optimized deep learning models for differentiating between MCI and normal control samples. In previous studies, the hippocampus region located in the brain is used extensively to diagnose MCI. The entorhinal cortex is a promising area for diagnosing MCI since severe atrophy is observed when diagnosing the disease before the shrinkage of the hippocampus. Due to the small size of the entorhinal cortex area relative to the hippocampus, limited research has been conducted on the entorhinal cortex brain region for predicting MCI. This study involves the construction of a dataset containing only the entorhinal cortex area to implement the classification system. To extract the features of the entorhinal cortex area, three different neural network architectures are optimized independently: VGG16, Inception-V3, and ResNet50. The best outcomes were achieved utilizing the convolution neural network classifier and the Inception-V3 architecture for feature extraction, with accuracy, sensitivity, specificity, and area under the curve scores of 70%, 90%, 54%, and 69%, respectively. Furthermore, the model has an acceptable balance between precision and recall, achieving an F1 score of 73%. The results of this study validate the effectiveness of our approach in predicting MCI and may contribute to diagnosing MCI through MRI.