Entorhinal Research Articles

MR-Guided PET Reconstruction: A Potential Advancement for Patients With Epilepsy.

We report a case of a 33-year-old man with epilepsy and equivocal EEG, MRI signs of mesiotemporal sclerosis, and nondiagnostic standard FDG-PET imaging. The patient underwent repeat FDG-PET/MRI to clarify the sidedness of the epileptogenic focus and to confirm the suspected MTS. The standard PET reconstruction using block sequential regularized expectation maximization failed to provide evidence of a clear epileptogenic focus. However, using MR-guided PET reconstruction, circumscribed hypometabolism was observed in the right-sided entorhinal cortex, compatible with the epileptogenic focus. The MR-guided PET reconstruction provided significantly improved gray/white matter differentiation, enhancing confidence in imaging interpretation.

Traumatic Brain Injury and Alzheimer's Disease Biomarkers: A Systematic Review of Findings from Amyloid and Tau Positron Emission Tomography.

Traumatic brain injury (TBI) has been discussed as a risk factor for Alzheimer's disease (AD) due to its association with AD risk and earlier cognitive symptom onset. However, the mechanisms behind this relationship are unclear. Some studies have suggested TBI may increase pathological protein deposition in an AD-like pattern; others have failed to find such associations. This review covers literature that uses positron emission tomography (PET) of β-amyloid (Aβ) and/or tau to examine individuals with a history of TBI who are at increased risk for AD due to age. A comprehensive literature search was conducted on January 9, 2023, and 26 resulting citations met inclusion criteria. Common methodological concerns included small samples, limited clinical detail about participants' TBI, recall bias due to reliance on self-reported TBI, and an inability to establish causation. For both Aβ and tau, results were widespread but inconsistent. The regions that showed the most compelling evidence for increased Aβ deposition were the cingulate gyrus and cuneus/precuneus. Evidence for elevated tau was strongest in the medial temporal lobe, entorhinal cortex, precuneus, and frontal, temporal, parietal, and occipital lobes. However, conflicting findings across most regions in both Aβ- and tau-PET studies indicate the critical need for future work in expanded samples and with greater clinical detail to offer a clearer picture of the relationship between TBI and protein deposition in older individuals at risk for AD.

Association of early life cardiovascular risk factors with grey matter structure in young adults in the United Kingdom: the ALSPAC study

Cumulative exposures to obesity, hypertension, and physical inactivity from midlife (40-65 years) onwards are three known cardiovascular risk factors for dementia and associated cerebral structural damage. Exactly how early in the lifespan sensitive periods for exposure to these risk factors begin is yet to be established, specifically with respect to onset of cerebral structural changes. We aimed to investigate whether cardiovascular risk across childhood and adolescence is already associated with cerebral structure in regions previously linked with dementia, during young adulthood. Participants were selected from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK-based prospective cohort of young people, if they had participated in a neuroimaging sub-study (N=862). We entered data from repeated clinical assessments into mixed-effects models to estimate baseline and rate of change in body mass index (BMI) and mean arterial pressure (MAP) between ages 7-17 years, and physical activity (PA) between 11-15 years. Linear models assessed whether cardiovascular risk factors were associated with grey matter macrostructural indices (cortical thickness, surface area, volume) in young adulthood (∼20 years). BMI was found to be associated with grey matter macrostructure in nodes of Default Mode Network previously found to show atrophy in dementia. Baseline BMI was associated with thickness of precuneus cortex and entorhinal surface area, whilst rate of change in BMI across childhood and adolescence was associated with thickness of parahippocampal and middle temporal gyri and inferior parietal cortex in addition to entorhinal and parahippocampal surface area. Further, we identified associations between baseline MAP and PA and entorhinal surface area. Exploratory whole-brain analyses revealed associations between baseline and rate of change in these cardiovascular risk factors and the cortical thickness, surface area, and volume of broader groups of cortical and subcortical regions. Findings provide preliminary evidence that cerebral structural differences in regions linked to dementia in old age may be legacy of developmental differences associated with cardiovascular risk exposure during early life. This has relevance for lifespan models of dementia risk and timing of preventative interventions. Further work is required to generalise findings beyond this predominantly white, male, and middle-class sample to more diverse cohorts. NIHR Oxford Health BRC (NIHR203316), Wellcome Trust (203139/Z/16/Z).

Reduced 17β-estradiol following ovariectomy induces mitochondrial dysfunction and degradation of synaptic proteins in the entorhinal cortex

Reductions in circulating estrogens can contribute to cognitive decline, in part by impairing mitochondrial function within the hippocampal region. The entorhinal cortex provides the hippocampus with its main cortical input and, to assess the impact of estrogen deficiency on mitochondrial respiration and synaptic proteins in the entorhinal cortex, wildtype rats received either sham surgery, bilateral ovariectomy, or ovariectomy with implantation of a subdermal capsule to maintain low levels of 17β-estradiol (E2). Mitochondrial respiration in the entorhinal cortex was not significantly affected two weeks following ovariectomy, but there was a reduction in oxygen consumption four weeks after ovariectomy that was prevented by E2 supplementation. The expression of mitochondrial membrane integrity element voltage-dependent anion channel protein (VDAC1) was also reduced four weeks after ovariectomy, suggesting that respiration was reduced due to a decline in mitochondrial density. Ovariectomy also increased mitochondrial and cytoplasmic cytochrome c and upregulated superoxide dismutase 2 (SOD2) both two and four weeks after ovariectomy, reflecting mitochondrial electron leakage and oxidative redox imbalance. Further, the ovariectomy-induced changes in mitochondrial proteins were associated with reductions in postsynaptic density protein 95 (PSD95) and the presynaptic protein synaptophysin. There were no changes in mitochondrial or synaptic proteins in ovariectomized animals that received E2 supplementation. Our findings indicate that reductions in circulating 17β-estradiol induced by ovariectomy disrupt mitochondrial functions in the entorhinal cortex, and suggest that a resulting increase in oxidative stress contributes to the degradation in synaptic proteins that may affect cognitive functions mediated by the hippocampal region.

Impaired spatial coding and neuronal hyperactivity in the medial entorhinal cortex of aged App NL-G-F mice.

The progressive accumulation of amyloid beta (Aβ) pathology in the brain has been associated with aberrant neuronal network activity and poor cognitive performance in preclinical mouse models of Alzheimer's disease (AD). Presently, our understanding of the mechanisms driving pathology-associated neuronal dysfunction and impaired information processing in the brain remains incomplete. Here, we assessed the impact of advanced Aβ pathology on spatial information processing in the medial entorhinal cortex (MEC) of 18-month App NL-G-F/NL- G-F knock-in (APP KI) mice as they explored contextually novel and familiar open field arenas in a two-day, four-session recording paradigm. We tracked single unit firing activity across all sessions and found that spatial information scores were decreased in MEC neurons from APP KI mice versus those in age-matched C57BL/6J controls. MEC single unit spatial representations were also impacted in APP KI mice. Border cell firing preferences were unstable across sessions and spatial periodicity in putative grid cells was disrupted. In contrast, MEC border cells and grid cells in Control mice were intact and stable across sessions. We then quantified the stability of MEC spatial maps across sessions by utilizing a metric based on the Earth Mover's Distance (EMD). We found evidence for increased instability in spatially-tuned APP KI MEC neurons versus Controls when mice were re-exposed to familiar environments and exposed to a novel environment. Additionally, spatial decoding analysis of MEC single units revealed deficits in position and speed coding in APP KI mice in all session comparisons. Finally, MEC single unit analysis revealed a mild hyperactive phenotype in APP KI mice that appeared to be driven by narrow-spiking units (putative interneurons). These findings tie Aβ-associated dysregulation in neuronal firing to disruptions in spatial information processing that may underlie certain cognitive deficits associated with AD.

APOE4 and age affect the brain entorhinal cortex structure and blood arachidonic acid and docosahexaenoic acid levels after mild TBI.

A reduction in the thickness and volume of the brain entorhinal cortex (EC), together with changes in blood arachidonic acid (AA) and docosahexaenoic acid (DHA), are associated with Alzheimer's disease (AD) among apolipoprotein E ε4 carriers. Magnetic Resonance Imaging (n = 631) and plasma lipidomics (n = 181) were performed using the LIMBIC/CENC cohort to examine the influence of ε4 on AA- and DHA-lipids and EC thickness and volume in relation to mild traumatic brain injury (mTBI). Results showed that left EC thickness was higher among ε4 carriers with mTBI. Repeated mTBI (r-mTBI) was associated with reduced right EC thickness after controlling for ε4, age and sex. Age, plus mTBI chronicity were linked to increased EC White Matter Volume (WMV). After controlling for age and sex, the advancing age of ε4 carriers with blast mTBI was associated with reduced right EC Grey Matter Volume (GMV) and thickness. Among ε4 carriers, plasma tau and Aβ40 were associated with mTBI and blast mTBI, respectively. Chronic mTBI, ε4 and AA to DHA ratios in phosphatidylcholine, ethanolamides, and phosphatidylethanolamine were associated with decreased left EC GMV and WMV. Further research is needed to explore these as biomarkers for detecting AD pathology following mTBI.

Test–Retest Reliability of Deep Learning Analysis of Brain Volumes in Adolescent Brain

Magnetic resonance imaging (MRI) is essential for studying brain development and psychiatric disorders in adolescents. However, the imaging consistency remains challenging, highlighting the need for advanced methodologies to improve the diagnostic and research reliability in this unique developmental period. Adolescence is marked by significant neuroanatomical changes, distinguishing adolescent brains from those of adults and making age-specific imaging research crucial for understanding the neuropsychiatric conditions in youth. This study examines the test–retest reliability of anatomical brain MRI scans in adolescents diagnosed with depressive disorders, emphasizing a developmental perspective on neuropsychiatric disorders. Using a sample of 42 adolescents, we assessed the consistency of structural imaging metrics across 95 brain regions with deep learning-based neuroimaging analysis pipelines. The results demonstrated moderate to excellent reliability, with the intraclass correlation coefficients (ICC) ranging from 0.57 to 0.99 across regions. Notably, regions such as the pallidum, amygdala, entorhinal cortex, and white matter hypointensities showed moderate reliability, likely reflecting the challenges in the segmentation or inherent anatomical variability unique to this age group. This study highlights the necessity of integrating advanced imaging technologies to enhance the accuracy and reliability of the neuroimaging data specific to adolescents. Addressing the regional variability and strengthening the methodological rigor are essential for advancing the understanding of brain development and psychiatric disorders in this distinct developmental stage. Future research should focus on larger, more diverse samples, multi-site studies, and emerging imaging techniques to further validate the neuroimaging biomarkers. Such advancements could improve the clinical outcomes and deepen our understanding of the neuropsychiatric conditions unique to adolescence.

The lung-brain axis: genetic evidence for causal effects of asthma, allergic rhinitis, and chronic rhinosinusitis on brain structure.

Previous studies have indicated Asthma, allergic rhinitis (AR) and chronic rhinosinusitis (CRS) may influence brain structure. However, it remains unclear whether these three airway conditions cause brain structural changes and which specific brain regions are affected. We conducted a Mendelian randomization (MR) to explore the causal effect of AR, CRS, and asthma on brain structure. Reverse MR was conducted to investigate potential impact of changes in brain structure on AR, CRS, and asthma. Additionally, to enhance our understanding of the lung-brain axis, we examined bidirectional relationships between Alzheimer's disease, Parkinson's disease, insomnia, major depression, neuroticism, attention deficit hyperactivity disorder and these three respiratory disorders Findings: The genetically predicted CRS could reduce the surface area in the banks of the superior temporal sulcus, paracentral, and superior frontal. Asthma had an association with a decrease in the surface area of the entorhinal, fusiform, and temporal pole, as well as a reduction in the volume of amygdala. Asthma could also increase the thickness of pericalcarine. Reverse MR showed that changes in the surface area of pars opercularis and thickness of entorhinal cortex had a potential effect on CRS. Besides, bidirectional MR between 3 airway disorders and 6 neuropsychiatric disorders indicated neuroticism could raised risk for asthma, and major depression could increased the risk of CRS and asthma Conclusion: Our MR analysis revealed a potential causal relationship among CRS, asthma, and atrophy in specific functional areas of the human brain, supporting the existence of a lung-brain axis.

Hippocampal atrophy over two years in relation to tau, amyloid-β and memory in older adults

In this longitudinal brain imaging study, we aimed to characterize hippocampal tau accumulation and subfield atrophy relative to cortical amyloid-β and memory performance. We measured tau-PET in regions associated with Braak stages I to VI, global amyloid-PET burden, hippocampal subfield volumes and memory assessments from 173 participants aged 55–85. Eighty-six of these participants were tested again two years later. Tau-PET change in the Braak II region, corresponding to the hippocampus and the entorhinal cortex, was significantly associated with the cornu ammonis 1 (CA1) atrophy and memory score. This CA1 atrophy did not significantly mediate the association between tau and memory, nor did global amyloid-PET burden correlate with tau-PET changes in the Braak II region. Longitudinal hippocampal tau accumulation is amyloid-β-independent and co-localized with subfield atrophy. As tau-associated memory decline seems to be independent from hippocampal atrophy, other mechanisms could contribute to the deficit.

Lateral entorhinal cortex afferents reconfigure the activity in piriform cortex circuits

Odors are key signals for guiding spatial behaviors such as foraging and navigation in rodents. Recent findings reveal that odor representations in the piriform cortex (PCx) also encode spatial context information. However, the brain origins of this information and its integration into PCx microcircuitry remain unclear. This study investigates the lateral entorhinal cortex (LEC) as a potential source of spatial contextual information affecting the PCx microcircuit and its olfactory responses. Using mice brain slices, we performed patch-clamp recordings on superficial (SP) and deep (DP) pyramidal neurons, as well as parvalbumin (PV) and somatostatin (SOM) inhibitory interneurons. Concurrently, we optogenetically stimulated excitatory LEC projections to observe their impact on PCx activity. Results show that LEC inputs are heterogeneously distributed in the PCx microcircuit, evoking larger excitatory currents in SP and PV neurons due to higher monosynaptic connectivity. LEC inputs also differentially affect inhibitory circuits, activating PV while suppressing SOM interneurons. Studying the interaction between LEC inputs and sensory signals from the lateral olfactory tract (LOT) revealed that simultaneous LEC and LOT activation increases spiking in SP and DP neurons, with DP neurons showing a sharpened response due to LEC-induced inhibition that suppresses delayed LOT-evoked spikes. This suggests a regulatory mechanism where LEC inputs inhibit recurrent activity by activating PV interneurons. Our findings demonstrate that LEC afferents reconfigure PCx activity, aiding the understanding of how odor objects form within the PCx by integrating olfactory and nonolfactory information.

Multimodal Neuroimaging in the Prediction of Deep TMS Response in OCD.

Backgrounds: .Brain morphological biomarkers could contribute to understanding the treatment response in patients with obsessive-compulsive disorder (OCD). Multimodal neuroimaging addresses this issue by providing more comprehensive information regarding neural processes and structures. Objectives. The present study aims to investigate whether patients responsive to deep Transcranial Magnetic Stimulation (TMS) differ from non-responsive individuals in terms of electrophysiology and brain morphology. Secondly, to test whether multimodal neuroimaging is superior to unimodal neuroimaging in predicting response to deep TMS. Methods. Thirty-two OCD patients who underwent thirty sessions of deep TMS treatment were included in the study. Based on a minimum 50% reduction in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores after treatment, patients were grouped as responders (n = 25) and non-responders (n = 7). The baseline resting state qEEG and magnetic resonance imaging (MRI) records of patients were recorded. Independent sample t-test is used to compare the groups. Then, three logistic regression model were calculated for only QEEG markers, only MRI markers, and both QEEG/MRI markers. The predictive values of the three models were compared. Results. OCD patients who responded to deep TMS treatment had increased Alpha-2 power in the left temporal area and increased volume in the left temporal pole, entorhinal area, and parahippocampal gyrus compared to non-responders. The logistic regression model showed better prediction performance when both QEEG and MRI markers were included. Conclusions. This study addresses the gap in the literature regarding new functional and structural neuroimaging markers and highlights the superiority of multimodal neuroimaging to unimodal neuroimaging techniques in predicting treatment response.

Dysregulated neurofluid coupling as a new noninvasive biomarker for primary progressive aphasia

Accumulation of pathological tau is one of the primary causes of Primary Progressive Aphasia (PPA). The glymphatic system is crucial for removing metabolite waste from the brain whereas impairments in glymphatic clearance in PPA are poorly understood. Thus, this study aims to investigate the role of dysregulated macroscopic cerebrospinal fluid (CSF) movement in PPA. Fifty-six PPA individuals and ninety-four healthy controls were included in our analysis after excluding those with excessive head motions during the scan. The coupling strength between blood-oxygen-level-dependent (BOLD) signals in the gray matter and CSF flow was calculated using Pearson correlation and compared between the groups. Its associations with clinical characteristics including scores from Clinical Dementia Rating (CDR), Mini-Mental State Exam, Geriatric Depression Scale and with morphological measures in the hippocampus and entorhinal cortex were examined. PPA subjects exhibited weaker global BOLD-CSF coupling compared to HCs, indicating impairments in glymphatic function in the patients (p = 0.01). In the PPA but not HC group, global BOLD-CSF coupling correlated with the CDR scores (p = 0.04) and hippocampal volume (p = 0.009). The observed decoupling between global brain activity and CSF flow and its association with symptomatology and brain structural changes in PPA converges with previous reports on the same measure in other neurodegenerative diseases. These findings support the potential role of global BOLD-CSF coupling as a noninvasive marker for glymphatic dysregulation in PPA.

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer’s disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses.

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

Association of the Volumes of Limbic Brain Structures with the Development of Psychoneurological Disorders in Patients with Ischemic Stroke

Post-stroke depressive disorders (PSD) and post-stroke cognitive impairments (PCI) are frequent consequences of ischemic stroke (IS). The study was focused on exploring possible associations between relative volumes of cortical and limbic brain structures during the acute period of IS, and changes in biochemical indices of hypothalamic-pituitary-adrenal, sympathoadrenal medullary and inflammatory systems, with the development of PSD or PCI after mild or moderate IS. Patients developing PSD later on had significantly smaller relative volumes of the hippocampus, entorhinal cortex, and temporal pole versus patients without depressive symptoms. PCI development was associated with significantly smaller volumes of temporal pole and supramarginal gyrus versus patients without cognitive changes. Multiple logistic regression analysis showed higher likelihood of developing PSD in patients with smaller temporal pole volume (β0 =10.9; β = –4.27; p = 0.04) and in-creased salivary α-amylase activity (β0 = –3.55; β = 2.68e–05; p = 0.02). PCI likelihood was higher in patients with smaller supramarginal gyrus volume (β0 = 3.41; β = –0.99; p = 0.047), smaller temporal pole volume (β0 = 3.41; β = –3.12; p = 0.06), and increased hair cortisol concentration at admission (index of accumulated stress load within a month before IS; β0 = 3.41; β = –0.05; p = 0.08). The data support the hypothesis suggesting predisposition to PSD and PCI and multi hit scenarios of their pathogenesis with IS providing a final hit.

Brain imaging and machine learning reveal uncoupled functional network for contextual threat memory in long sepsis

Positron emission tomography (PET) utilizes radiotracers like [18F]fluorodeoxyglucose (FDG) to measure brain activity in health and disease. Performing behavioral tasks between the FDG injection and the PET scan allows the FDG signal to reflect task-related brain networks. Building on this principle, we introduce an approach called behavioral task–associated PET (beta-PET) consisting of two scans: the first after a mouse is familiarized with a conditioning chamber, and the second upon recall of contextual threat. Associative threat conditioning occurs between scans. Beta-PET focuses on brain regions encoding threat memory (e.g., amygdala, prefrontal cortex) and contextual aspects (e.g., hippocampus, subiculum, entorhinal cortex). Our results show that beta-PET identifies a biologically defined network encoding contextual threat memory and its uncoupling in a mouse model of long sepsis. Moreover, machine learning algorithms (linear logistic regression) and ordinal trends analysis demonstrate that beta-PET robustly predicts the behavioral defense response and its breakdown during long sepsis.

Medial temporal atrophy predicts the limbic comorbidities in lewy body disease.

Although neuropathological comorbidities, including Alzheimer's disease neuropathological change (AD-NC) and limbic-predominant age-related TAR DNA-binding protein 43encephalopathy neuropathological change (LATE-NC), are associated with medial temporal atrophy in patients with Lewy body disease (LBD), the diagnostic performance of magnetic resonance imaging (MRI)-derived indices remains unclear. This study aimed to investigate the diagnostic performance of MRI-derived indices representing medial temporal atrophy in differentiating between LBD with AD-NC and/or LATE-NC (mixed LBD [mLBD]) and without these comorbidities (pure LBD [pLBD]). This study included 24 and 16 patients with pathologically confirmed mLBD and pLBD, respectively. In addition to the well-known medial temporal atrophy and entorhinal cortex atrophy (ERICA) scores, the cross-sectional areas of the bilateral entorhinal cortices/parahippocampal gyri (ABEP) were segmented manually. Even incorporating various covariates such as age at MRI examination, sex, argyrophilic grain, the MRI-derived indices, especially ABEP, significantly correlated with the severity of AD-NC, and showed a trend of correlation with LATE-NC. For the differentiation between all mLBD and pLBD, the ERICA score and ABEP demonstrated higher diagnostic performance (area under the receiver-operating-characteristic curve [AUC] of 0.80 and 0.87, respectively). Additionally, the highest diagnostic performance for ABEP (AUC, 0.94; sensitivity, 100%; specificity, 88.9%; accuracy, 96%) was observed in differentiating between pLBD and mLBD with two comorbidities (AD-NC and LATE-NC). In patients with pathologically confirmed LBD, medial temporal atrophy was significantly correlated with AD-NC, and showed a trend of correlation with LATE-NC. Moreover, MRI-derived indices indicative of medial temporal atrophy were useful in diagnosing these comorbidities.

GNG5 is a novel regulator of Aβ42 production in Alzheimer’s disease

The therapeutic options for Alzheimer’s disease (AD) are limited, underscoring the critical need for finding an effective regulator of Aβ42 production. In this study, with 489 human postmortem brains, we revealed that homotrimer G protein subunit gamma 5 (GNG5) expression is upregulated in the hippocampal–entorhinal region of pathological AD compared with normal controls, and is positively correlated with Aβ pathology. In vivo and in vitro experiments confirm that increased GNG5 significantly promotes Aβ pathology and Aβ42 production. Mechanically, GNG5 regulates the cleavage preference of γ-secretase towards Aβ42 by directly interacting with the γ-secretase catalytic subunit presenilin 1 (PS1). Moreover, excessive GNG5 increases the protein levels and the activation of Rab5, leading to the increased number of early endosomes, the major cellular organelle for production of Aβ42. Furthermore, immunoprecipitation and immunofluorescence revealed co-interaction of Aβ42 with GPCR family CXCR2, which is known as the receptor for IL-8, thus facilitating the dissociation of G-proteins βγ from α subunits. Treatment of Aβ42 in neurons combined with structure prediction indicated Aβ42 oligomers as a new ligand of CXCR2, upregulating γ subunit GNG5 protein levels. The co-localizations of GNG5 and PS1, CXCR2 and Aβ42 were verified in eight human brain regions. Besides, GNG5 is significantly reduced in extracellular vesicles (EVs) derived from cerebral cortex or serum of AD patients compared with healthy cognition controls. In brief, GNG5 is a novel regulator of Aβ42 production, suggesting its clinical potential as a diagnosis biomarker and the therapeutic target for AD.The GNG5 content in EVs derived from serum and brain tissue of patients with AD significantly reduced. The GNG5 expression in the hippocampal-entorhinal neurons of donors with pathological AD significantly increased, and can exist in homotrimer subtypes. GNG5 expression positively correlates with Aβ pathology and Aβ42 production. Homotrimer-GNG5 binds to the γ-secretase catalytic subunit PS1 and preferentially generates Aβ42 in early endosome. GNG5 leads to enhanced Rab5 protein and activation levels, increased number of early endosome, promoting Aβ42 production. Further, Aβ42 binds to CXCR2 to upregulate GNG5 levels in a feedback loop.

Early movement restriction impairs the development of sensorimotor integration, motor skills and memory in rats: Towards a preclinical model of developmental coordination disorder?

Children with neurodevelopmental disorders, such as developmental coordination disorder (DCD), exhibit gross to fine sensorimotor impairments, reduced physical activity and interactions with the environment and people. This disorder co-exists with cognitive deficits, executive dysfunctions and learning impairments. Previously, we demonstrated in rats that limited amounts and atypical patterns of movements and somatosensory feedback during early movement restriction manifested in adulthood as degraded postural and locomotor abilities, and musculoskeletal histopathology, including muscle atrophy, hyperexcitability within sensorimotor circuitry and maladaptive cortical plasticity, leading to functional disorganization of the primary somatosensory and motor cortices in the absence of cortical histopathology. In this study, we asked how this developmental sensorimotor restriction (SMR) started to impact the integration of multisensory information and the emergence of sensorimotor reflexes in rats. We also questioned the enduring impact of SMR on motor activities, pain and memory. SMR led to deficits in the emergence of swimming and sensorimotor reflexes, the development of pain and altered locomotor patterns and posture with toe-walking, adult motor performance and night spontaneous activity. In addition, SMR induced exploratory hyperactivity, short-term impairments in object-recognition tasks and long-term deficits in object-location tasks. SMR rats displayed minor alterations in histological features of the hippocampus, entorhinal, perirhinal and postrhinal cortices yet no obvious changes in the prefrontal cortex. Taken all together, these results show similarities with the symptoms observed in children with DCD, although further exploration seems required to postulate whether developmental SMR corresponds to a rat model of DCD.

Evidence for convergence of distributed cortical processing in band-like functional zones in human entorhinal cortex

The wide array of cognitive functions associated with the hippocampus is supported through interactions with the cerebral cortex. However, most of the direct cortical input to the hippocampus originates in the entorhinal cortex, forming the hippocampal-entorhinal system. In humans, the role of the entorhinal cortex in mediating hippocampal-cortical interactions remains unknown. In this study, we used precision neuroimaging to examine the distributed cortical anatomy associated with the human hippocampal-entorhinal system. Consistent with animal anatomy, our results associate different subregions of the entorhinal cortex with different parts of the hippocampus long axis. Furthermore, we find that the entorhinal cortex comprises three band-like zones that are associated with functionally distinct cortical networks. Importantly, the entorhinal cortex bands traverse the proposed human homologs of rodent lateral and medial entorhinal cortices. Finally, we show that the entorhinal cortex is a major convergence area of distributed cortical processing and that the topography of cortical networks associated with the anterior medial temporal lobe mirrors the macroscale structure of high-order cortical processing.