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| Open AccessCerebral microcirculation mapped by echo particle tracking velocimetry quantifies the intracranial pressure and detects ischemia
Hydrocephalus involves abnormal accumulation of cerebrospinal fluid, resulting in elevated intracranial pressure. The authors developed contrast-enhanced ultrasound imaging and intravascular microbubbles tracking in hydrocephalic pediatric porcine models to noninvasively assess intracranial pressure and detect cerebral ischemia.
- Zeng Zhang
- , Misun Hwang
- & Joseph Katz
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Article
| Open AccessMapping brain structural differences and neuroreceptor correlates in Parkinson’s disease visual hallucinations
Visual hallucinations are a prevalent symptom of Parkinson’s disease. Here the authors use a structural mega-analysis to show cortical regions and networks involved in visual hallucinations and associations with receptor density maps.
- Miriam Vignando
- , Dominic ffytche
- & Mitul A. Mehta
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| Open AccessFinding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome
There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.
- Catherine S. Storm
- , Demis A. Kia
- & Nicholas W. Wood
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| Open AccessA low-cost and shielding-free ultra-low-field brain MRI scanner
A low cost MRI scanner may have the potential to meet clinical needs at point of care or in low and middle income countries. Here the authors describe a low cost 0.055 Tesla MRI scanner that operates using a standard AC power outlet, and demonstrate its preliminary feasibility in diagnosing brain tumor and stroke.
- Yilong Liu
- , Alex T. L. Leong
- & Ed X. Wu
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| Open AccessA national cohort study (2000–2018) of long-term air pollution exposure and incident dementia in older adults in the United States
Air pollution has been linked to neurodegenerative disease. Here the authors carried out a population-based cohort study to investigate the association between long-term exposure to PM2.5, NO2, and warm-season O3 on dementia and Alzheimer’s disease incidence in the United States.
- Liuhua Shi
- , Kyle Steenland
- & Joel Schwartz
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| Open AccessSpared perilesional V1 activity underlies training-induced recovery of luminance detection sensitivity in cortically-blind patients
In humans, stroke damage to V1 causes large visual field defects. Spared V1 activity prior to training predicts the amount of training-induced recovery in luminance detection sensitivity. Moreover, visual training changes population receptive field properties within residual V1 circuits.
- Antoine Barbot
- , Anasuya Das
- & Krystel R. Huxlin
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Article
| Open AccessMesoNet allows automated scaling and segmentation of mouse mesoscale cortical maps using machine learning
High content imaging of the brain holds the promise of improving our understanding of the brain’s circuitry. Here, the authors present a tool that automates the scaling and segmentation of cortical maps to accelerate neurobiological discovery using mesoscale images.
- Dongsheng Xiao
- , Brandon J. Forys
- & Timothy H. Murphy
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| Open AccessExposure to 16 h of normobaric hypoxia induces ionic edema in the healthy brain
Prolonged hypoxia, which can be due to stroke or ascent to high altitude, can lead to cerebral edema. Here, the authors used a combination of sodium and proton MRI and experimentally induced hypoxic conditions to identify the cause for brain swelling: Ionic edema, an intermediate between cytotoxic and vasogenic edema defined by sodium ion accumulation in extracellular space and an intact endothelium.
- Armin Biller
- , Stephanie Badde
- & Kai Schommer
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Article
| Open AccessAccelerated functional brain aging in pre-clinical familial Alzheimer’s disease
Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.
- Julie Gonneaud
- , Alex T. Baria
- & Etienne Vachon-Presseau
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| Open AccessNeural signatures of hyperdirect pathway activity in Parkinson’s disease
In Parkinson’s disease (PD), beta frequency oscillations are synchronised across the cortico-basal-ganglia circuit. The authors show in human participants that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway, indicating a pathophysiological role for this pathway in PD.
- Ashwini Oswal
- , Chunyan Cao
- & Vladimir Litvak
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| Open AccessPortable, bedside, low-field magnetic resonance imaging for evaluation of intracerebral hemorrhage
Conventional magnetic resonance imaging (MRI) operates at a high magnetic field strength and requires a strict access-controlled environment, making MRI often inaccessible. Here, the authors present a portable low-field MRI device that detects intracerebral hemorrhage with high accuracy.
- Mercy H. Mazurek
- , Bradley A. Cahn
- & Kevin N. Sheth
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Article
| Open AccessMalignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia
Vaccination is an effective strategy in suppressing COVID-19 pandemic, but rare adverse effects have been reported, including cerebral venous thrombosis. Here the authors report two cases of middle cerebral artery infarct within 9-10 days following ChAdOx1 nCov-19 vaccination that also manifest pulmonary and portal vein thrombosis.
- M. De Michele
- , M. Iacobucci
- & D. Toni
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| Open AccessEndo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting
Aβ oligomers (AβO) are thought to represent the main toxic species in Alzheimer’s disease but very high Aβ concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of Aβ termed dimAβ, where two Aβ40 units are linked, which facilitates to study AβO formation kinetics and they observe that Aβ off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimAβ is a disease-relevant model construct for pathogenic AβO formation by showing that dimAβ AβOs target dendritic spines and induce AD-like somatodendritic Tau missorting.
- Marie P. Schützmann
- , Filip Hasecke
- & Wolfgang Hoyer
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| Open AccessBrain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice
Chronic use of mTORC1 inhibitors produces undesirable side effects in humans which limit their value for CNS disorders treatment. The authors present a binary drug strategy to protects mTORC1 activity in the periphery and show its potential utility in preclinical models of alcohol use disorder.
- Yann Ehinger
- , Ziyang Zhang
- & Dorit Ron
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| Open AccessIdentifying individuals with high risk of Alzheimer’s disease using polygenic risk scores
While polygenic risk scores have been shown to be correlated with disease risk, there is little agreement on how the score should be calculated. Here the authors investigate risk scores for Alzheimer’s disease, finding that the most effective approach includes an APOE score and a polygenic score excluding APOE.
- Ganna Leonenko
- , Emily Baker
- & Valentina Escott-Price
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Article
| Open AccessA machine learning approach to brain epigenetic analysis reveals kinases associated with Alzheimer’s disease
Array-based epigenome-wide association studies only test about 2% of the CpG sites in the genome. Here, the authors describe EWASplus, a supervised machine learning strategy that extends EWAS coverage to the entire genome, and use it to identify novel brain CpGs associated with Alzheimer’s disease.
- Yanting Huang
- , Xiaobo Sun
- & Zhaohui S. Qin
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Article
| Open AccessSelf-healing polyurethane-elastomer with mechanical tunability for multiple biomedical applications in vivo
The unique properties of self-healing materials hold great potential in the field of biomedical engineering. Here, the authors designed a series of biodegradable and biocompatible self-healing elastomers with tunable mechanical properties, and apply them to various disease models in vivo, including aortic aneurism, bone fracture and nerve amputation.
- Chenyu Jiang
- , Luzhi Zhang
- & Xiaofeng Ye
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| Open AccessGene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons
Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare neurodevelopmental disorder. Here the authors describe a clinical trial of MR-guided delivery of AAV2-AADC for the treatment of AADC.
- Toni S. Pearson
- , Nalin Gupta
- & Krystof S. Bankiewicz
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| Open AccessA generative network model of neurodevelopmental diversity in structural brain organization
The formation of large-scale brain networks represents crucial developmental processes that can drive individual differences in cognition and which are associated with multiple neurodevelopmental conditions. Here, the authors use generative network modelling to provide a computational framework for understanding neurodevelopmental diversity.
- Danyal Akarca
- , Petra E. Vértes
- & Duncan E. Astle
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| Open AccessProkineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury
Prokineticin-2 (Prok2) is a secreted protein involved in many physiological processes. Here, the authors show that Prok2 prevents neuronal cell ferroptosis after traumatic brain injury and its administration before cortical injury reduces neuronal degeneration, and motor and cognitive impairments.
- Zhongyuan Bao
- , Yinlong Liu
- & Jing Ji
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| Open AccessSETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome
Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome characterized by severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here the authors introduce a human SGS model that displays disease-relevant phenotypes to demonstrate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.
- Federica Banfi
- , Alicia Rubio
- & Alessandro Sessa
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| Open AccessHigher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease
Neuroinflammation is observed in Alzheimer’s disease. Here the authors show that 15 proteins related to inflammation found in CSF can potentially be used as a prognostic biomarker.
- William T. Hu
- , Tugba Ozturk
- & Gloria Chiang
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Article
| Open AccessBarrel cortex plasticity after photothrombotic stroke involves potentiating responses of pre-existing circuits but not functional remapping to new circuits
Definitive evidence for functional remapping after stroke remains lacking. Here, the authors performed in vivo intrinsic signal imaging and two-photon calcium imaging of sensory-evoked responses before and after photothrombotic stroke and found no evidence of remapping of lost functionalities to new circuits in peri-infarct cortex.
- William A. Zeiger
- , Máté Marosi
- & Carlos Portera-Cailliau
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Article
| Open AccessKL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.
- Julia Neitzel
- , Nicolai Franzmeier
- & Michael Ewers
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Article
| Open AccessA molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech
Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome of multiple etiologies which affects spoken communication. Here, the authors characterized the molecular pathology, biochemistry, genetics and longitudinal neuroimaging of 32 autopsy-confirmed patients with PAOS who were followed over 10 years.
- Keith A. Josephs
- , Joseph R. Duffy
- & Jennifer L. Whitwell
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| Open AccessOutcome after acute ischemic stroke is linked to sex-specific lesion patterns
Acute ischemic stroke impacts men and women differently. Here, the authors show how different lesion patterns in men and women are linked to the extent of stroke severity.
- Anna K. Bonkhoff
- , Markus D. Schirmer
- & Natalia S. Rost
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| Open AccessUBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation
Hyperphosphorylated Tau accumulation promotes neurodegeneration in Alzheimer’s disease. Here, the authors screen a miRNA library in Drosophila and identify a conserved ubiquitin ligase that directs Tau for autophagic degradation, uncovering a potential target to treat Tau-mediated neurodegeneration.
- Manivannan Subramanian
- , Seung Jae Hyeon
- & Kweon Yu
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| Open AccessNon-productive angiogenesis disassembles Aß plaque-associated blood vessels
Aß are extracellular deposits relevant in Alzheimer’s disease (AD). This study shows that Aß plaques are hubs of endothelial disassembly that induce non-productive angiogenesis. This process is aided by the microglia and unchained by reduced presenilin function, a trait of AD, in endothelial cells.
- Maria I. Alvarez-Vergara
- , Alicia E. Rosales-Nieves
- & Alberto Pascual
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| Open AccessPredicting optimal deep brain stimulation parameters for Parkinson’s disease using functional MRI and machine learning
Deep brain stimulation programming for Parkinson’s disease entails the assessment of a large number of possible simulation settings, requiring numerous clinic visits after surgery. Here, the authors show that patterns of functional MRI can predict the optimal stimulation settings.
- Alexandre Boutet
- , Radhika Madhavan
- & Andres M. Lozano
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| Open AccessThe genetic architecture of the human thalamus and its overlap with ten common brain disorders
Differences in thalamic structure have been observed in several psychiatric disorders, but the genetic overlap has not been explored. Here, the authors perform a genome-wide association study on thalamic nuclei volume and find genetic loci in common between thalamic volumes and brain disorders.
- Torbjørn Elvsåshagen
- , Alexey Shadrin
- & Tobias Kaufmann
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| Open AccessRHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex
Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections. Here, the authors generate iPSC-derived neurons from patients with TSC. TSC2 +/− neurons show impaired mTOR-independent RhoA signaling-mediated axon guidance.
- Timothy S. Catlett
- , Massimo M. Onesto
- & Timothy M. Gómez
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| Open AccessIncreased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
Synaptic loss may disturb the excitatory to inhibitory balance (E/I ratio) in circuits vulnerable in Alzheimer’s disease (AD). The authors find reduced synaptic levels of PSD-95 and gephyrin and show that individuals with AD exhibit a pro-excitatory shift of postsynaptic densities and the electrophysiological synaptic E/I ratio in the parietal cortex.
- Julie C. Lauterborn
- , Pietro Scaduto
- & Agenor Limon
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| Open AccessAssociation of sleep duration in middle and old age with incidence of dementia
Sleep dysregulation has been linked to dementia, but it is unknown whether sleep duration earlier in life is associated with dementia risk. Here, the authors show higher dementia risk associated with short sleep duration (six hours or less) in a longitudinal study of middle and older age adults.
- Séverine Sabia
- , Aurore Fayosse
- & Archana Singh-Manoux
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| Open AccessEnhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1
Narcolepsy type 1 (NT1) is a severe sleep disorder with strong association to the HLA type DQB1*0602 and increased incidence among children vaccinated with the Influenza A vaccine Pandemrix. Here the authors show that these children develop T and B cell autoimmunity against protein-O-mannosyltransferase 1 via cross-reactivity.
- A. Vuorela
- , T. L. Freitag
- & O. Vaarala
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| Open AccessDefective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome
Leigh syndrome (LS) is a severe neurometabolic disorder which lacks effective models. Here, the authors developed human neuronal models of LS carrying mutations in SURF1 which show impaired neuronal morphogenesis due to metabolic deficiencies.
- Gizem Inak
- , Agnieszka Rybak-Wolf
- & Alessandro Prigione
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Article
| Open AccessNeurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy
X-linked adrenoleukodystophy (X-ALD) is a highly variable, progressive neurodegenerative disorder. In this study, neurofilament light chain protein (NfL) was identified as a potential early distinguishing biomarker.
- Isabelle Weinhofer
- , Paulus Rommer
- & Johannes Berger
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| Open AccessCerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1
How the activity of the neuronal Kv3.3 voltage-dependent channel is regulated is unclear. Here, the authors show that the known Kv3.3 channel complex with Hax1, which affects spinal cerebellar ataxia, regulates the enzyme Tank Binding Kinase 1, modulating survival of cerebellar neurons.
- Yalan Zhang
- , Luis Varela
- & Leonard K. Kaczmarek
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Article
| Open AccessPOLRMT mutations impair mitochondrial transcription causing neurological disease
POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.
- Monika Oláhová
- , Bradley Peter
- & Robert W. Taylor
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Article
| Open AccessMachine learning identifies candidates for drug repurposing in Alzheimer’s disease
Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have provided largely negative results, so far. Here, the authors present a machine learning framework that quantifies potential associations between the pathology of AD severity and gene-based molecular mechanisms to enable drug repurposing.
- Steve Rodriguez
- , Clemens Hug
- & Artem Sokolov
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Article
| Open AccessBlood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia
Blood brain barrier (BBB) opening is being investigated as a therapeutic approach for neurodegenerative diseases. Here, the authors report the results of a phase I trial to evaluate the feasibility and safety of BBB opening of the right parieto-occipito-temporal cortex in Parkinson´s disease with dementia.
- Carmen Gasca-Salas
- , Beatriz Fernández-Rodríguez
- & José A. Obeso
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Article
| Open AccessA CD8+ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis
A better understanding of how multiple sclerosis (MS) can relapse and remit is needed for the identification of biomarkers and better therapeutics. Here the authors identify a CD8 + NK cell population in patients with relapsing remitting MS and validate its association with clinical outcome.
- Eoin F. McKinney
- , Iona Cuthbertson
- & Kenneth G. C. Smith
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Article
| Open AccessRecruitment of upper-limb motoneurons with epidural electrical stimulation of the cervical spinal cord
The efficacy of epidural electrical stimulation (EES) to engage arm muscles and improve movement after spinal cord injury is still unclear. Here, the authors investigated how EES can recruit upper-limb motor neurons by combining computational modelling with experiments in non-human primates.
- Nathan Greiner
- , Beatrice Barra
- & Marco Capogrosso
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Article
| Open AccessNon-invasive suppression of essential tremor via phase-locked disruption of its temporal coherence
Aberrant synchronous oscillations have been associated with numerous brain disorders, including essential tremor. The authors show that synchronous cerebellar activity can casually affect essential tremor and that its underlying mechanism may be related to the temporal coherence of the tremulous movement.
- Sebastian R. Schreglmann
- , David Wang
- & Nir Grossman
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Article
| Open AccessCerebral small vessel disease genomics and its implications across the lifespan
White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.
- Muralidharan Sargurupremraj
- , Hideaki Suzuki
- & Stéphanie Debette
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Perspective
| Open AccessIncreasing the reproducibility of fluid biomarker studies in neurodegenerative studies
Many fluid biomarker findings have had low reproducibility despite initially promising results. Here, the authors review possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases and suggest guidelines for the biomarker community to agree on and implement.
- Niklas Mattsson-Carlgren
- , Sebastian Palmqvist
- & Oskar Hansson
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Article
| Open AccessAstrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway
Mutations of α2-Na/K ATPase can cause familial hemiplegic migraine via unclear mechanisms. Here, the authors show that deletion of α2-Na/K ATPase in astrocytes results in gene expression and metabolic changes leading to cortical spreading depression and episodic transient motor paralysis in mice.
- Sarah E. Smith
- , Xiaoying Chen
- & Azad Bonni
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Article
| Open AccessEssential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain
Altered fatty acid intake during pregnancy is associated with neurodevelopmental disorders. Here, the authors show that maternal omega-3 fatty acids deficiency results in altered microglia-mediated phagocytosis of synaptic elements leading to impaired cognitive functions in the offspring in mice.
- C. Madore
- , Q. Leyrolle
- & S. Layé
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Article
| Open AccessA clinically applicable deep-learning model for detecting intracranial aneurysm in computed tomography angiography images
Interpretation of Computed Tomography Angiography for intracranial aneurysm diagnosis can be time-consuming and challenging. Here, the authors present a deep-learning-based framework achieving improved performance compared to that of radiologists and expert neurosurgeons.
- Zhao Shi
- , Chongchang Miao
- & Long Jiang Zhang
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Article
| Open AccessPlasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals
Previously it was shown that an N-terminal tau fragment (NT1) measured in plasma can differentiate individuals with Alzheimer’s disease from healthy controls. Here the authors show that plasma levels of NT1 can associate with future cognitive decline in cognitively normal elderly individuals.
- Jasmeer P. Chhatwal
- , Aaron P. Schultz
- & Dennis J. Selkoe