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| Open AccessNeural precursor cells tune striatal connectivity through the release of IGFBPL1
The physiological role of endogenous neural protenitor cells of the subventricular zone in adult stage is not fully understood. Here the authors show that in mice, these cells tune neuronal activity of the striatum via insulin-like growth factor binding protein-like 1 and cognitive functions.
- Erica Butti
- , Stefano Cattaneo
- & Gianvito Martino
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| Open AccessMetagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms
Here, the authors perform large-scale high-resolution Parkinson’s disease metagenomics analyses, revealing widespread dysbiosis characterized by overabundance of pathogens, immunogens, toxicants, and curli, reduction in neuroprotective and antiinflammatory molecules, and dysregulated neuroactive signaling.
- Zachary D. Wallen
- , Ayse Demirkan
- & Haydeh Payami
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| Open AccessHypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia
Developing brain-protective hypothermia is a medical challenge. Here, the authors show that deep brain stimulation of a particular brain area is a new way to trigger the body into a hibernation-like state with reduced body temperature and brain protection in a mouse model of stroke.
- Shuai Zhang
- , Xinpei Zhang
- & Sheng-Tao Hou
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| Open AccessVascular endothelium deploys caveolin-1 to regulate oligodendrogenesis after chronic cerebral ischemia in mice
OPC-vascular coupling contributes to myelin maintenance. Here the authors show Cav-1 stabilizes interactions and mediates OPC maturation in ischemia.
- Ying Zhao
- , Wusheng Zhu
- & Xinfeng Liu
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| Open AccessAn alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons
Krach et al. dissect the molecular mechanism of the alternative splicing modulator Branaplam in Huntington’s disease. They show that the drug lowers mutant HTT protein levels and ameliorates alternative splicing pathology in an iPSC disease model.
- Florian Krach
- , Judith Stemick
- & Juergen Winkler
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| Open AccessSevere Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study
Both acute and chronic COVID-19 disease (also known as long-COVID) may affect the central nervous system. Here authors characterize the immunological profile of peripheral blood and cerebrospinal fluid of COVID-19 patients in order to identify the main factors that contribute to neurological impairment and the severity of neurological symptoms in Sars-CoV-2 infection.
- Manina M. Etter
- , Tomás A. Martins
- & Gregor Hutter
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Article
| Open AccessGeneralizable spelling using a speech neuroprosthesis in an individual with severe limb and vocal paralysis
Previous work has described a neuroprosthesis to directly decode full words in real time during attempts to speak. Here the authors demonstrate that a patient with anarthria can control this neuroprosthesis to spell out intended messages in real time using attempts to silently speak.
- Sean L. Metzger
- , Jessie R. Liu
- & Edward F. Chang
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| Open AccessT cell responses at diagnosis of amyotrophic lateral sclerosis predict disease progression
Amyotrophic lateral sclerosis (ALS) is a primary neurodegenerative disease, which is characterized by increased immune cell infiltration of the central nervous system. Here authors show that the phenotypic profile of T cells in the blood and cerebrospinal fluid of newly diagnosed ALS patients can predict disease progression, thus providing evidence that T cells contribute to disease pathology.
- Solmaz Yazdani
- , Christina Seitz
- & Fang Fang
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Article
| Open AccessSpecialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing
Whole genome sequencing is emerging as a first-line test for rare genetic diseases. In this study, authors maximise diagnoses by supplementing existing semiautomated analyses with clinically driven reevaluation of genomic data by a specialist multidisciplinary team.
- William L. Macken
- , Micol Falabella
- & Robert D. S. Pitceathly
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| Open AccessAmyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease
The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.
- Alexa Pichet Binette
- , Nicolai Franzmeier
- & Oskar Hansson
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Article
| Open AccessPericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure
Using in vivo two-photon imaging, Berthiaume et al. demonstrate how pericyte loss during aging could contribute to deterioration of cerebral blood flow. They also show how pericyte remodeling reduces the deleterious effects of pericyte loss.
- Andrée-Anne Berthiaume
- , Franca Schmid
- & Andy Y. Shih
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Article
| Open AccessA pilot study combining noninvasive spinal neuromodulation and activity-based neurorehabilitation therapy in children with cerebral palsy
Here the authors report a single arm pilot trial to investigate combined spinal neuromodulation and activity-based neurorehabilitation therapy on voluntary sensory-motor function in children with cerebral palsy.
- Susan Hastings
- , Hui Zhong
- & V. Reggie Edgerton
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Article
| Open AccessEstimating individual treatment effect on disability progression in multiple sclerosis using deep learning
There are limited predictive biomarkers for drug treatment responses in individuals with multiple sclerosis. Here using existing clinical trials data, the authors propose a deep-learning predictive enrichment strategy to identify which participants are most likely to respond to a treatment.
- Jean-Pierre R. Falet
- , Joshua Durso-Finley
- & Douglas Lorne Arnold
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| Open AccessPreclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration
The authors show in an animal model and in a study in patients with dementia with Lewy bodies (DLB) that the drug neflamapimod has potential to treat diseases, such as DLB, associated with loss of neurons that produce the neurotransmitter acetylcholine.
- Ying Jiang
- , John J. Alam
- & Ralph A. Nixon
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| Open AccessStress induced TDP-43 mobility loss independent of stress granules
Amyotrophic Lateral Sclerosis related TDP-43 protein translocates to stress granules with a concomitant reduction in mobility. Here, the authors use single molecule tracking and find a stress-induced reduction in TDP-43 mobility also in the cytoplasm potentially relevant for TDP-43 aggregation.
- Lisa Streit
- , Timo Kuhn
- & Karin M. Danzer
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| Open AccessSubcortical-cortical dynamical states of the human brain and their breakdown in stroke
Favaretto et al. show that the brain rapidly alternates between transient connectivity patterns, with cortical regions flexibly synchronizing with two groups of subcortical regions, and that this dynamic is abnormal in stroke patients.
- Chiara Favaretto
- , Michele Allegra
- & Maurizio Corbetta
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| Open AccessPneumolysin boosts the neuroinflammatory response to Streptococcus pneumoniae through enhanced endocytosis
Pneumococcal infection of the cerebrospinal fluid results in bacterial lysis, the release of toxic factors and induction of neuroinflammation. Here, the authors show that the virulence factor pneumolysin enhances the neuroinflammatory response to Streptococcus pneumoniae by the enhancement of endocytosis.
- Sabrina Hupp
- , Christina Förtsch
- & Asparouh I. Iliev
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| Open AccessEpigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology
Parkinson’s disease and dementia with Lewy bodies are closely related neurodegenerative disorders, although the epigenetic similarities are not well known. Here, the authors study Lewy pathology and DNA methylation in postmortem human frontal cortex, identifying differentially methylated genomic loci.
- Lasse Pihlstrøm
- , Gemma Shireby
- & Mathias Toft
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| Open AccessEarlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading
Individuals with young onset sporadic Alzheimer’s disease show faster pathological and clinical progression. Here the authors report that earlier symptom onset in Alzheimer’s disease is associated with higher tau pathology in globally connected brain hubs, accelerated connectivity-mediated tau spreading and faster cognitive decline.
- Lukas Frontzkowski
- , Michael Ewers
- & Nicolai Franzmeier
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| Open AccessCross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease
DNA methylation differences in Alzheimer’s disease have been previously reported, although the interpretation of the differences is unclear. Here, the authors performed epigenome-wide meta-analyses of DNA methylation in blood and brain, and developed a methylation-based risk prediction model for AD.
- Tiago C. Silva
- , Juan I. Young
- & Lily Wang
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| Open AccessLocal molecular and global connectomic contributions to cross-disorder cortical abnormalities
Changes to structural and functional connectivity can give rise to neurodegeneration and neurodevelopmental diseases. Here the authors investigate molecular and connectomic patterns in 13 different neurological, psychiatric and neurodevelopmental diseases from the ENIGMA consortium.
- Justine Y. Hansen
- , Golia Shafiei
- & Bratislav Misic
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| Open AccessMulti-cohort and longitudinal Bayesian clustering study of stage and subtype in Alzheimer’s disease
Different types of atrophy in Alzheimer’s disease may reflect different disease stages or biologically distinct subtypes. Here the authors use longitudinal neuroimaging data to demonstrate five distinct patterns of atrophy with different demographical and cognitive characteristics.
- Konstantinos Poulakis
- , Joana B. Pereira
- & Eric Westman
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| Open AccessGenome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities
Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.
- Catherine M. Francis
- , Matthias E. Futschik
- & Paul M. Matthews
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| Open AccessStructural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression
Epilepsy is a brain network disorder with associated genetic risk factors. Here, the authors show that spatial patterns of transcriptomic vulnerability co-vary with structural brain network alterations in focal and generalized epilepsy.
- Sara Larivière
- , Jessica Royer
- & Boris C. Bernhardt
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| Open AccessShared mechanisms across the major psychiatric and neurodegenerative diseases
Studying the shared genetic etiology of disease can help improve diagnosis and treatment. Here, the authors find evidence for shared genetic and molecular pathophysiology between several common psychiatric and neurodegenerative diseases using results of 25 GWAS and large-scale human brain transcriptomic and proteomic sequencing.
- Thomas S. Wingo
- , Yue Liu
- & Aliza P. Wingo
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| Open AccessCryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain
Here, Chi et al. report cryo-EM structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic T1 domain, which allows the interactions with the C-terminal axonal targeting motif and key components of the gating machinery. These findings provide insights into the functional relevance of previously unknown interdomain interactions in Kv3 channels and may guide the design of new pharmaceutical drugs.
- Gamma Chi
- , Qiansheng Liang
- & Katharina L. Dürr
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| Open AccessSLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice
The protein SLITRK2 plays an important role in synaptic communication. This study identifies X-linked SLITRK2 variants that underlie neurodevelopmental disorders by impairing excitatory synapses.
- Salima El Chehadeh
- , Kyung Ah Han
- & Ji Won Um
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| Open AccessMultimodal deep learning for Alzheimer’s disease dementia assessment
Here the authors present a deep learning framework for dementia diagnosis, which can identify persons with normal cognition, mild cognitive impairment, Alzheimer’s disease, and dementia due to other etiologies.
- Shangran Qiu
- , Matthew I. Miller
- & Vijaya B. Kolachalama
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| Open AccessDistributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders
The hippocampus has been associated with memory traits and a variety of neurodegenerative and psychiatric disorders. Here, the authors have done a multivariate GWAS revealing 177 genetic loci, and overlap with various brain disorders may suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.
- Shahram Bahrami
- , Kaja Nordengen
- & Tobias Kaufmann
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| Open AccessNUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
ALS and FTLD are both characterized by insoluble cytoplasmic depositions of TDP43. Here the authors show that the nucleopore protein NUP62 is mislocalized in C9orf72 and sporadic ALS/FTLD and propose that it interacts with TDP-43 to promote its insolubility.
- Amanda M. Gleixner
- , Brandie Morris Verdone
- & Christopher J. Donnelly
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Article
| Open AccessSubthalamic nucleus stabilizes movements by reducing neural spike variability in monkey basal ganglia
Chemogenetic inactivation of the subthalamic nucleus in monkeys increases spike train variability in the pallidum and prolongs movement time, suggesting its role in stabilizing pallidal spike trains to achieve stable motor control.
- Taku Hasegawa
- , Satomi Chiken
- & Atsushi Nambu
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| Open AccessStearoyl-CoA Desaturase inhibition reverses immune, synaptic and cognitive impairments in an Alzheimer’s disease mouse model
Alzheimer’s disease (AD) is characterized by lipid abnormalities which are not well understood. Here, the authors investigate the role of Stearoyl-CoA desaturase (SCD) in a mouse model of AD. They show that inhibiting SCD activity induces major brain and immune cell transcriptional changes and restores dendritic structure and learning and memory.
- Laura K. Hamilton
- , Gaël Moquin-Beaudry
- & Karl J. L. Fernandes
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| Open AccessAn analysis of neuroscience and psychiatry papers published from 2009 and 2019 outlines opportunities for increasing discovery of sex differences
Sex differences occur in many neurological and psychiatric diseases, and yet research is not always designed optimally to identify these. Here the authors perform a study of how sex was incorporated into the design and analyses of papers published six journals in neuroscience and psychiatry in 2009 compared with 2019.
- Rebecca K. Rechlin
- , Tallinn F. L. Splinter
- & Liisa A. M. Galea
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| Open AccessMicrovascular stabilization via blood-brain barrier regulation prevents seizure activity
The mechanisms underlying epilepsy development are not well understood. Here the authors show that loss of a key component of the so called blood-brain barrier drives seizures in mice and is also lost in humans with treatment resistant epilepsy
- Chris Greene
- , Nicole Hanley
- & Matthew Campbell
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| Open AccessPresenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα
Hyperimmunity is associated with Alzheimer disease. Here the authors show that the Presenilin 2 N141I mutation causes overproduction of clock-controlled cytokines and memory deficits through suppression of REV-ERBα gene by hypermethylation.
- Hyeri Nam
- , Younghwan Lee
- & Seong-Woon Yu
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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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Article
| 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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Article
| 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