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| Open AccessMicroglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy
Wang et al show that microglial NF-κB activation is essential for tau spreading and tau-mediated spatial learning and memory deficits in tauopathy mice. Inactivation of NF-κB reversed tau associated microglial states and rescued autophagy deficits.
- Chao Wang
- , Li Fan
- & Li Gan
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| Open AccessA robust and interpretable machine learning approach using multimodal biological data to predict future pathological tau accumulation
The authors present a machine learning approach that combines baseline multimodal data to accurately predict individualised trajectories of future pathological tau accumulation at asymptomatic and mildly impaired stages of Alzheimer’s disease.
- Joseph Giorgio
- , William J. Jagust
- & Zoe Kourtzi
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| Open AccessGain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies
Genetic variants of γ-aminobutyric acid (GABAA) receptors are associated with early onset epilepsies. Here, the authors show that functional loss or gain-of-function defines clinical outcomes, with gain-of-function variants unexpectedly more severe.
- Nathan L. Absalom
- , Vivian W. Y. Liao
- & Philip K. Ahring
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| Open AccessA computational model of neurodegeneration in Alzheimer’s disease
Low-dimensional representations of functional brain anatomy relevant for dementia syndromes may exist. Here the authors propose a computational model of mental functions to catalogue this anatomy in Alzheimer’s and related dementias.
- D. Jones
- , V. Lowe
- & C. Jack
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| Open AccessLower novelty-related locus coeruleus function is associated with Aβ-related cognitive decline in clinically healthy individuals
Older individuals exhibiting diminished function of the locus coeruleus while learning new information show faster cognitive decline that is typical for Alzheimer’s disease.
- Prokopis C. Prokopiou
- , Nina Engels-Domínguez
- & Heidi I. L. Jacobs
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| Open AccessSpelling interface using intracortical signals in a completely locked-in patient enabled via auditory neurofeedback training
The authors record neural firing rates in a patient with ALS in completely locked-in state and show that the patient can modulate neural firing rates based on auditory feedback to select letters to form words and phrases to communicate his needs and experiences.
- Ujwal Chaudhary
- , Ioannis Vlachos
- & Niels Birbaumer
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| Open AccessDissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease
In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.
- Michael Tran Duong
- , Sandhitsu R. Das
- & Ilya M. Nasrallah
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| Open AccessSirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43
TDP-43 is a nucleic acid binding protein, whose insoluble aggregates are neuropathological hallmarks of specific subsets of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Post-translational modifications and acetylation of TDP-43 impact its interaction with RNA, its localization in the cells, and are linked to disease. Using antibodies generated against TDP-43 lysine acetylation sites, sirtuin-1 was found to potently deacetylate amber suppressed [acK136]TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding as well as phase separation and aggregation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
- Jorge Garcia Morato
- , Friederike Hans
- & Philipp J. Kahle
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Article
| Open AccessAssociations between alcohol consumption and gray and white matter volumes in the UK Biobank
Heavy alcohol consumption has been associated with brain structural changes. Here, using data from the UK biobank, the authors report associations between alcohol intake and brain macrostructure and microstructure.
- Remi Daviet
- , Gökhan Aydogan
- & Reagan R. Wetherill
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Article
| Open AccessAstrocytic phagocytosis contributes to demyelination after focal cortical ischemia in mice
Ischemic stroke can cause secondary demyelination. Whether phagocytic astrocytes can contribute to such demyelination is unclear. Here, the authors show that lipocalin-2 (LCN-2) expression increased in astrocytes upon injury. LCN-2 expressing astrocytes acquire a phagocytic phenotype and contribute to secondary demyelination in a mouse model of ischemic stroke.
- Ting Wan
- , Wusheng Zhu
- & Xinfeng Liu
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| Open AccessQuantifying arousal and awareness in altered states of consciousness using interpretable deep learning
The authors propose an explainable consciousness indicator using deep learning to quantify arousal and awareness under sleep, anesthesia, and in patients with disorders of consciousness.
- Minji Lee
- , Leandro R. D. Sanz
- & Seong-Whan Lee
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Article
| Open AccessVirtual intracranial EEG signals reconstructed from MEG with potential for epilepsy surgery
Dynamic network models offer insight into brain networks affected by epileptic seizures. Here the authors derive ViEEG (virtual intracranial EEG) from non-invasive MEG recordings that show brain areas involved in seizure generation in patients with epilepsy.
- Miao Cao
- , Daniel Galvis
- & Mark J. Cook
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Article
| Open AccessStroke induces disease-specific myeloid cells in the brain parenchyma and pia
How ischaemic stroke affects the brain borders is not fully understood. Here the authors show that a stroke-associated myeloid cell population occurs exclusively in brain parenchyma that shares features with neurodegenerative microglia and blockade of proteins on these cells can ameliorate stroke symptoms.
- Carolin Beuker
- , David Schafflick
- & Jens Minnerup
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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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| 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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Article
| 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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| 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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| 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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| 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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| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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