Microglia sense astrocyte dysfunction and prevent disease progression in an Alexander disease model
AbstractAlexander disease (AxD) is an intractable neurodegenerative disorder caused byGFAP mutations. It is a primary astrocyte disease with a pathological hallmark of Rosenthal fibres within astrocytes. AxD astrocytes show several abnormal phenotypes. Our previous study showed that AxD astrocytes in model mice exhibit aberrant Ca2+ signals that induce AxD aetiology. Here, we show that microglia have unique phenotypes with morphological and functional alterations, which are related to the pathogenesis of AxD. Immunohistochemical studies of 60TM mice (AxD model) showed that AxD microglia exhibited highly ramified morphology...
Source: Brain - November 13, 2023 Category: Neurology Source Type: research
Correction to: Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses
Edward J. Needham, Alexander L. Ren, Richard J. Digby, Emma J. Norton, Soraya Ebrahimi, Joanne G. Outtrim, Doris A. Chatfield, Anne E. Manktelow, Maya M. Leibowitz, Virginia F. J. Newcombe, Rainer Doffinger, Gabriela Barcenas-Morales, Claudia Fonseca, Michael J. Taussig, Rowan M. Burnstein, Romit J. Samanta, Cordelia Dunai, Nyarie Sithole, Nicholas J. Ashton, Henrik Zetterberg, Magnus Gissl én, Arvid Edén, Emelie Marklund, Peter J. M. Openshaw, Jake Dunning, Michael J. Griffiths, Jonathan Cavanagh, Gerome Breen, Sarosh R. Irani, Anne Elmer, Nathalie Kingston, Charlotte Summers, John R. Bradley, Leonie S. Taams, Benedict ...
Source: Brain - November 6, 2023 Category: Neurology Source Type: research
Vortioxetine for the treatment of post-COVID-19 condition: a randomized controlled trial
AbstractHitherto no therapeutic has received regulatory approval for the treatment of post-COVID-19 condition (PCC). Cognitive deficits, mood symptoms and significant reduction in health-related quality of life (HRQoL) are highly replicated and debilitating aspects of PCC. We sought to determine the impact of vortioxetine on the foregoing symptoms and HRQoL in persons living with PCC.An 8-week randomized, double-blind, placebo-controlled study of adults ≥ 18 years of age residing in Canada and who are experiencing symptoms of World Health Organization (WHO)-defined PCC, with a history of confirmed SARS-CoV-2 infection, w...
Source: Brain - November 4, 2023 Category: Neurology Source Type: research
Caspase cleavage of gasdermin E causes neuronal pyroptosis in HIV-associated neurocognitive disorder
AbstractDespite effective antiretroviral therapies, 20 –30% of persons with treated HIV infection develop a neurodegenerative syndrome termed HIV-associated neurocognitive disorder (HAND).HAND is driven by HIV expression coupled with inflammation in the brain but the mechanisms underlying neuronal damage and death are uncertain. The inflammasome-pyrop tosis axis coordinates an inflammatory type of regulated lytic cell death that is underpinned by the caspase-activated pore-forming gasdermin proteins. The mechanisms driving neuronal pyroptosis were investigated herein in models of HAND, using multi-platform molecular and ...
Source: Brain - November 1, 2023 Category: Neurology Source Type: research
Elevated 4R tau contributes to endolysosomal dysfunction and neurodegeneration in VCP-related frontotemporal dementia
AbstractFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two incurable neurodegenerative diseases that exist on a clinical, genetic and pathological spectrum. TheVCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects ofVCP mutations on the cellular homoeostasis of human induced pluripotent stem cell-derived cortical neurons, focusing on endolysosomal biology and tau pathology. We found thatVCP mutations cause abnormal accumulation of enlarged endolysosomes accompanied by impaired interaction between two nuclear RNA binding proteins: fused in sar...
Source: Brain - October 26, 2023 Category: Neurology Source Type: research
Glioma-associated mesenchymal stem cells
AbstractRecent studies have revealed that glioma-associated mesenchymal stem cells play instrumental roles in tumorigenesis and tumour progression and cannot be ignored as a cellular component of the glioma microenvironment. Nevertheless, the origin of these cells and their roles are poorly understood. The only relevant studies have shown that glioma-associated mesenchymal stem cells play a large role in promoting tumour proliferation, invasion and angiogenesis.This review provides a comprehensive summary of their discovery and definition, origin, differences from other tissue-derived mesenchymal stem cells, spatial distri...
Source: Brain - October 18, 2023 Category: Neurology Source Type: research
Impact of multiple sclerosis risk alleles on the plasma proteome
MRC Clinical Research Training FellowshipUK Multiple Sclerosis SocietyCentre for Preventive NeurologyBarts Charity10.13039/100015652 (Source: Brain)
Source: Brain - October 18, 2023 Category: Neurology Source Type: research
Subcortical contributions to the sense of body ownership
AbstractThe sense of body ownership (i.e. the feeling that our body or its parts belong to us) plays a key role in bodily self-consciousness and is believed to stem from multisensory integration. Experimental paradigms such as the rubber hand illusion have been developed to allow the controlled manipulation of body ownership in laboratory settings, providing effective tools for investigating malleability in the sense of body ownership and the boundaries that distinguish self from other.Neuroimaging studies of body ownership converge on the involvement of several cortical regions, including the premotor cortex and posterior...
Source: Brain - October 17, 2023 Category: Neurology Source Type: research
Principal component analysis-based latent-space dimensionality under-estimation, with uncorrelated latent variables
Wellcome Trust10.13039/100010269205103/Z/16/Z203147/Z/16/ZMedical Research Council10.13039/501100000265MR/V031481/1 (Source: Brain)
Source: Brain - October 13, 2023 Category: Neurology Source Type: research
Increased presynaptic excitability in a migraine with aura mutation
AbstractMigraine is a common and disabling neurological disorder. The headache and sensory amplifications of migraine are attributed to hyperexcitable sensory circuits, but a detailed understanding remains elusive. A mutation in casein kinase 1 delta (CK1 δ) was identified in non-hemiplegic familial migraine with aura and advanced sleep phase syndrome. Mice carrying the CK1δT44A mutation were more susceptible to spreading depolarization (the phenomenon that underlies migraine aura), but mechanisms underlying this migraine-relevant phenotype were not known. We used a combination of whole-cell electrophysiology and multiph...
Source: Brain - October 13, 2023 Category: Neurology Source Type: research
Testing the disconnectome symptom discoverer model on out-of-sample post-stroke language outcomes
Wellcome10.13039/100004440203147/Z/16/Z205103/Z/16/Z224562/Z/21/ZMedical Research Council10.13039/501100000265MR/M023672/1Stroke Association10.13039/501100000364TSA 2014/02Donders Mohrmann2401515European Research Council10.13039/501100000781818521 (Source: Brain)
Source: Brain - October 11, 2023 Category: Neurology Source Type: research
Multimodal layer modelling reveals in vivo pathology in amyotrophic lateral sclerosis
AbstractAmyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the loss of motor control. Current understanding of ALS pathology is largely based on post-mortem investigations at advanced disease stages. A systematicin vivo description of the microstructural changes that characterize early stage ALS, and their subsequent development, is so far lacking.Recent advances in ultra-high field (7 T) MRI data modelling allow us to investigate cortical layersin vivo. Given the layer-specific and topographic signature of ALS pathology, we combined submillimetre structural 7 T MRI d...
Source: Brain - October 10, 2023 Category: Neurology Source Type: research
Extracellular vesicle biomarkers for complement dysfunction in schizophrenia
In this study, we used cutting-edge extracellular vesicles ’ (EVs) proteome profiling and XGBoost-based machine learning to develop new markers and personalized discrimination scores for schizophrenia diagnosis and prediction of treatment response. We analysed plasma and plasma-derived EVs from 343 participants, including 100 individuals with chronic schi zophrenia, 34 first-episode and drug-naïve patients, 35 individuals with bipolar disorder, 25 individuals with major depressive disorder and 149 age- and sex-matched healthy controls.Our innovative approach uncovered EVs-based complement changes in patients, specific t...
Source: Brain - October 10, 2023 Category: Neurology Source Type: research
Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5
AbstractAFG3L2 is a mitochondrial protease exerting protein quality control in the inner mitochondrial membrane. HeterozygousAFG3L2 mutations cause spinocerebellar ataxia type 28 (SCA28) or dominant optic atrophy type 12 (DOA12), while biallelicAFG3L2 mutations result in the rare and severe spastic ataxia type 5 (SPAX5). The clinical spectrum of SPAX5 includes childhood-onset cerebellar ataxia, spasticity, dystonia and myoclonic epilepsy.We previously reported that the absence or mutation of AFG3L2 leads to the accumulation of mitochondria-encoded proteins, causing the overactivation of the stress-sensitive protease OMA1, ...
Source: Brain - October 7, 2023 Category: Neurology Source Type: research
Synthesizing images of tau pathology from cross-modal neuroimaging using deep learning
In this study, we present a convolutional neural network (CNN) model that imputes tau-PET images from more widely available cross-modality ima ging inputs. Participants (n = 1192) with brain T1-weighted MRI (T1w), fluorodeoxyglucose (FDG)-PET, amyloid-PET and tau-PET were included. We found that a CNN model can impute tau-PET images with high accuracy, the highest being for the FDG-based model followed by amyloid-PET and T1w. In testing implications of artificial intelligence-imputed tau-PET, only the FDG-based model showed a significant improvement of performance in classifying tau positivity and diagnostic groups compare...
Source: Brain - October 7, 2023 Category: Neurology Source Type: research
