Brain最新文献

{"title":"A digital motor score for sensitive detection of progression in Huntington’s disease","authors":"Louis-Solal Giboin, Cedric Simillion, Johannes Rennig, Atieh Bamdadian, Fiona C Kinsella, Anne V Smith, Peter McColgan, Michael Lindemann, Florian Lipsmeier, Edward J Wild, Jonas Dorn","doi":"10.1093/brain/awaf127","DOIUrl":"https://doi.org/10.1093/brain/awaf127","url":null,"abstract":"Remote digital monitoring of Huntington’s disease (HD) has potential to enhance the development of therapeutics, but no data-driven digital motor score exists to quantify the diversity of disease manifestations and track their progression. The Huntington’s Disease Digital Motor progression Score (HDDMS), co-designed by people with HD and neurologists, is a composite score for measuring motor progression of HD in clinical research. It is derived from smartphone sensor-based motor tests included in a remote HD digital monitoring platform. Developing the HDDMS involved selecting features that quantify test performance according to desired measurement properties and combining these features in a weighted composite score using factor analysis. It was developed and subsequently validated using data from four separate studies (HD Natural History Study [NCT03664804], open-label extension [OLE] of the tominersen Phase I/IIa study [NCT03342053], GENERATION HD1 [NCT03761849], and Digital-HD). Based on data from 1,008 individuals, the HDDMS encompasses balance, chorea, speeded tapping, and gait. It has favourable characteristics, including reliability (intraclass correlation coefficient > 0.95), correlation with the composite Unified Huntington’s Disease Rating Scale (cUHDRS) (r = −0.5), and better sensitivity to change (STC) than the cUHDRS. In a post-hoc analysis of GENERATION HD1, the STC of HDDMS at Week 20 was comparable to that of the cUHDRS at Week 68. The HDDMS promises substantial reduction in sample size in clinical trials.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"117 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated cortical excitability and tau phosphorylation in a β3 integrin mouse model of autism","authors":"Carmela Vitale, Fanny Jaudon, Rafael Lujan, Martina Bartolucci, Lucia Celora, Elisa Reisoli, Riccardo Ruggeri, Andrea Petretto, Agnes Thalhammer, Lorenzo A Cingolani","doi":"10.1093/brain/awaf089","DOIUrl":"https://doi.org/10.1093/brain/awaf089","url":null,"abstract":"Autism spectrum disorder is a complex neurodevelopmental disease characterized by altered cortical network excitability. Recent genetic studies have identified deep layer V cortical pyramidal neurons in the frontal cortex as central to autism pathophysiology, yet the cortical circuits, plasticity mechanisms and molecular signalling pathways involved remain poorly understood. Layer V pyramidal neurons consist of two main types with distinct functional roles: intratelencephalic neurons, which respond to low-frequency stimulation and project within the cortex and striatum, and pyramidal tract neurons, which are tuned to theta-frequency inputs and convey information to subcortical structures. Determining which of these two neuron types is more critical to autism pathophysiology and whether disruptions in their synaptic connectivity or intrinsic excitability contribute to autism-related dysfunctions would significantly advance our understanding of the disorder. Integrins, a family of cell adhesion molecules, are vital for neuronal function. The gene encoding β3 integrin (ITGB3) is genetically linked to autism spectrum disorder, with rare mutations identified in affected individuals, while Itgb3 knockout mice exhibit autism-like behaviours, including impaired social memory and increased grooming. However, it remains unclear why loss of β3 integrin is associated with autism spectrum disorder, how it disrupts cortical circuits, and which plasticity mechanisms and molecular pathways are involved. Here, we demonstrate that β3 integrin selectively regulates the excitability of pyramidal tract neurons in the medial prefrontal cortex. Using electrophysiology, proteomics and molecular approaches, we show that β3 integrin regulates the gain, adaptation and precision of action potential discharge by controlling the surface expression of Ca2+-activated SK2 channels. Genetic ablation of Itgb3 impaired intrinsic excitability and SK2 channel function in pyramidal tract neurons, with no effects in intratelencephalic neurons. Furthermore, we identified Tau, a protein traditionally linked to neurodegenerative diseases, as part of the SK2 channel interactome. Proteomic analyses revealed altered protein kinase A-dependent phosphorylation of Tau in Itgb3 knockout mice, while protein kinase A inhibition restored SK2 channel currents, thereby connecting phosphorylation changes to excitability deficits. Our findings expand the current mechanistic framework linking signalling pathway dysfunctions to cortical excitability deficits, highlighting the dysregulation of pyramidal tract neuron excitability as a core feature of autism pathophysiology and demonstrating the involvement of β3 integrin, SK2 channels, Tau and PKA in this process. Because pyramidal tract neurons serve as final integrators of cortical computations before relaying information outside the cortex, their impaired excitability may disrupt communication with subcortical targets, contributing to the complex pathop","PeriodicalId":9063,"journal":{"name":"Brain","volume":"17 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic dysregulation in a mouse model of GRIN2D developmental and epileptic encephalopathy.","authors":"JiaJie Teoh, Jane Simko, Chad R Camp, Christine J Liu, Wanqi Wang, Damian Williams, Liang Ma, Divyalakshmi Soundararajan, Caryn Martin, Noah K Taylor, Ekniel François, Sabrina Petri, Ayla Kanber, Aishwarya Ravichandra, Maria Elena Pero, Francesca Bartolini, Theresa C Swayne, Cathleen M Lutz, Aamir Zuberi, Moran Rubinstein, Moran Hausman Kedem, Hongjie Yuan, Jennifer N Gelinas, Tristan T Sands, Scott Q Harper, Stephen F Traynelis, Christopher D Makinson, Wayne N Frankel","doi":"10.1093/brain/awaf125","DOIUrl":"https://doi.org/10.1093/brain/awaf125","url":null,"abstract":"<p><p>Gain-of-function (GoF) variants in the GRIN2D gene, encoding the GluN2D subunit of the N-methyl-D-aspartate receptor (NMDAR), cause a severe developmental and epileptic encephalopathy (DEE), characterized by intractable seizures, hypotonia, and neurodevelopmental delay. We generated mice carrying the GoF V664I variant, orthologous to V667I, which is present in ∼25% of GRIN2D-DEE patients. Heterozygous mutant mice demonstrate behavioral, neuroanatomical, and electrophysiological abnormalities. Lethal convulsive seizures are observed beginning at postnatal day 17. As adults, heterozygotes display abundant and prolonged runs of spike-wave discharges (SWD) that often persist for minutes. The SWD epochs consist of different populations, differentiated by frequency and association with time-locked behavioral arrest. V664I mutant neurons have enlarged presynaptic terminals and increased synaptic distance. Functional analysis reveals increased inhibitory synaptic activity without changes in NMDAR decay kinetics or presynaptic plasticity in CA1 neurons and analysis of hippocampal local field potentials show a 1.5-fold increase in evoked responses and a 1.7-fold increase in action potential generation. Notably, expression of V664I in GABAergic interneurons, but not excitatory forebrain neurons, is sufficient to recapitulate the severe electroclinical phenotype. Altogether our studies show that altered NMDAR function in inhibitory neurons plays a prominent role in DEE associated with GRIN2D gain-of-function variants and suggests that targeted genetic treatment may represent a path forward to successful therapeutic intervention.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial damage is associated with an early immune response in inclusion body myositis","authors":"Felix Kleefeld, Emily Cross, Daniel Lagos, Sara Walli, Benedikt Schoser, Andreas Hentschel, Tobias Ruck, Christopher Nelke, Katrin Hahn, Denisa Hathazi, Andrew L Mammen, Maria Casal-Dominguez, Marta Gut, Ivo Glynne Gut, Simon Heath, Anne Schänzer, Hans-Hilmar Goebel, Iago Pinal-Fernandez, Andreas Roos, Corinna Preuße, Werner Stenzel, Rita Horvath","doi":"10.1093/brain/awaf118","DOIUrl":"https://doi.org/10.1093/brain/awaf118","url":null,"abstract":"Polymyositis with mitochondrial pathology (PM-Mito) was first identified in 1997 as a subtype of idiopathic inflammatory myopathy. Recent findings demonstrated significant molecular similarities between PM-Mito and Inclusion Body Myositis (IBM), suggesting a trajectory from early to late IBM and prompting the inclusion of PM-Mito as an IBM precursor (early IBM) within the IBM spectrum. Both PM-Mito and IBM show mitochondrial abnormalities, suggesting mitochondrial disturbance is a critical element of IBM pathogenesis. The primary objective of this cross-sectional study was to characterize the mitochondrial phenotype in PM-Mito at histological, ultrastructural, and molecular levels and to study the interplay between mitochondrial dysfunction and inflammation. Skeletal muscle biopsies of 27 patients with PM-Mito and 27 with typical IBM were included for morphological and ultrastructural analysis. Mitochondrial DNA (mtDNA) copy number and deletions were assessed by qPCR and long-range PCR, respectively. In addition, full-length single-molecule sequencing of the mtDNA enabled precise mapping of deletions. Protein and RNA levels were studied using unbiased proteomic profiling, immunoblotting, and bulk RNA sequencing. Cell-free mtDNA (cf-mtDNA) was measured in the serum of IBM patients. We found widespread mitochondrial abnormalities in both PM-Mito and IBM, illustrated by elevated numbers of COX-negative and SDH-positive fibers and prominent ultrastructural abnormalities with disorganized and concentric cristae within enlarged and dysmorphic mitochondria. MtDNA copy numbers were significantly reduced, and multiple large-scale mtDNA deletions were already evident in PM-Mito, compared to healthy age-matched controls, similar to the IBM group. The canonical cGAS/STING inflammatory pathway was activated in PM-Mito and IBM, and we detected elevated levels of circulating cf-mtDNA indicative of mtDNA leakage. In PM-Mito and IBM, these findings were accompanied by dysregulation of proteins and transcripts linked to the mitochondrial membranes. In summary, we identified that mitochondrial dysfunction with multiple mtDNA deletions and depletion, disturbed mitochondrial ultrastructure, and defects of the inner mitochondrial membrane are features of PM-Mito and IBM, underlining the concept of an IBM-spectrum disease (IBM-SD). Notably, mitochondrial abnormalities precede tissue remodeling and infiltration by specific T-cell subpopulations (e.g., KLRG1+) characteristic of late IBM. The activation of inflammatory, DNA-sensing pathways might be related to mtDNA release, which would indicate a significant role of mitochondria-associated inflammation in the pathogenesis of IBM-SD. This study highlights the critical role of early mitochondrial abnormalities in the pathomechanism of IBM, which may lead to new approaches to therapy.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"25 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In utero therapy for spinal muscular atrophy: closer to clinical translation","authors":"Eduardo F Tizzano, Georg Lindner, Ellie Chilcott, Richard S Finkel, Rafael J Yáñez-Muñoz","doi":"10.1093/brain/awaf123","DOIUrl":"https://doi.org/10.1093/brain/awaf123","url":null,"abstract":"5q-Spinal muscular atrophy (SMA) has been a trailblazer in the development of advanced therapies for inherited diseases. SMA is an autosomal recessive disorder affecting mainly motor neurons in the anterior horn of the spinal cord and brainstem motor nuclei, but currently considered a systemic disease. Advances in understanding of the genetics of SMA led to the development of disease modifying therapies, either transferring a healthy version of SMN1, the causative gene absent or altered in SMA, or modulating SMN2, a highly homologous but less functional version of SMN1, present in all patients. After successful clinical trials, these approaches have resulted in three marketed therapies. Severe SMA, “type I”, is the most common type and is considered both a developmental arrest and neurodegenerative disorder. As pathology starts during fetal life in type I patients, a cure is unlikely even when treatment is started shortly after birth in the pre- or mildly symptomatic state. In utero fetal therapy offers the opportunity to mitigate further or possibly prevent manifestations of the disease. This review discusses clinical and developmental aspects of SMA, the advanced therapies approved (gene therapy, antisense oligonucleotide and small molecule compounds), and the rationale, options and challenges, including ethical and safety issues, to initiate in utero therapy. Looking beyond sporadic case reports of prenatal intervention, clinical trials of in utero SMA therapy can be envisaged and should be carefully designed and evaluated to move closer to clinical translation.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"37 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic Kir4.1 ion channel deficit drives persistent inflammatory facial pain in males","authors":"Sarah Mountadem, Karine Herault, Cedric Peirs, Gisela da Silva Borges, Daniel L Voisin, Myriam Antri, Radhouane Dallel","doi":"10.1093/brain/awaf122","DOIUrl":"https://doi.org/10.1093/brain/awaf122","url":null,"abstract":"Chronic facial pain, a frequent and disabling condition, is maintained by central sensitization, which results in pain hypersensitivity. Although it is well established that reactive astrocytes play a key role in persistent pain mechanisms, the role of disruption of the normal capacity of astrocytes to maintain neuronal homeostasis is much less known. Here we show that persistent facial inflammation disturbs potassium homeostasis in the medullary dorsal horn of male rats, due to a sex-specific, drastic downregulation of astroglial inward rectifier potassium Kir4.1 channels. Using selective genetic tools, we establish that such downregulation, likely due to the release of IL-1β during inflammatory processing, is sufficient and required to drive pain hypersensitivity through altered K+ baseline levels. We further show that this chain of events can be prevented by selective upregulation of astroglial Kir4.1, or through systemic administration of 5-azacytidine, a DNA methylation modulator. Our results thus reveal a critical mechanism by which astrocyte dysfunction drives persistent inflammatory facial pain in males and discover the therapeutic potential of targeting central Kir4.1 for treating this disease.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"34 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive spinal neuromodulation enables stepping in children with complete spinal cord injury.","authors":"Kathryn Lucas, Goutam Singh, Luis R Alvarado, Molly King, Nicole Stepp, Parth Parikh, Beatrice Ugiliweneza, Yury Gerasimenko, Andrea L Behrman","doi":"10.1093/brain/awaf115","DOIUrl":"https://doi.org/10.1093/brain/awaf115","url":null,"abstract":"<p><p>Paralysis is assumed permanent in persons with motor-complete spinal cord injury (SCI). However, spinal epidural stimulation combined with activity-based locomotor training (ABLT) and cognitive intent enabled two adults with motor-complete SCI to walk with a walker. Transcutaneous spinal stimulation (scTS), also capable of promoting a cyclic step-like pattern, might be a viable alternative in children with SCI. These findings prompted our investigation into multimodal neuromodulation training using ABLT (enhancing afferent input), spinal stimulation (scTS), and descending (intent) drive to restore voluntary stepping in children with chronic motor-complete SCI. Five non-ambulatory children (9.6 ± 2.5 years old, 3F, 4 thoracic/1 cervical injury) with chronic (>1 year, 5.2 ± 2.5 years), complete SCI underwent 60 sessions of combined ABLT and scTS training with cognitive intent to step and returned for a 3 to 6-month follow-up. During the first training session in a gravity-neutral position, all five children (5/5) made small reciprocal cycles of the hips/knees in a flexion/extension step-like pattern with stimulation, with increased excursion at session 20 for 5/5 children (right hip excursion increased from 10.1 ± 15.1 to 25.9 ± 21.3 degrees and right knee excursion increased from 9.3 ± 13.9 to 39.6 ± 29.2 degrees, p = 0.02). The children stepped overground at session 50 (P15), 60 (P34), and 20 (P32, P14, P240), voluntarily initiating and alternating left/right leg swings on the treadmill and overground with and without scTS. Three to six months post-training, all children maintained the capacity to step. The parents and children reported unanticipated improvements in sensation, bladder function, proprioception, assist to stand, transfers, and dressing. In children with chronic, motor-complete SCI, multimodal neuromodulation training can potentiate the intrinsic stepping capacity of the spinal locomotor centers to enable voluntary stepping. Remarkably, these enhancements are durable and observed even in the absence of spinal stimulation.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asymmetry in amyotrophic lateral sclerosis: clinical, neuroimaging and histological observations","authors":"Katie Yoganathan, Thanuja Dharmadasa, Alicia Northall, Kevin Talbot, Alexander G Thompson, Martin R Turner","doi":"10.1093/brain/awaf121","DOIUrl":"https://doi.org/10.1093/brain/awaf121","url":null,"abstract":"Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor system marked by significant phenotypic heterogeneity. Motor symptoms in the limbs consistently emerge focally and asymmetrically and, whilst variable, the pattern of regional progression related to the balance of clinical upper and lower motor neuron signs, upper versus lower limb onset and hand dominance to some extent. The neurobiological mechanisms and pathological correlates for this lateralised onset and non-random progression are uncertain. Cerebral neuroimaging studies have commonly reported structural and functional asymmetries in ALS, but the limited analysis of the pre-symptomatic phase has limited their implications. Post-mortem study of spinal cord provided strong evidence for focal pathology at symptom onset in ALS. Histopathological staging of molecular pathology in post mortem tissue lacks clinical correlation and an ordered, sequential temporal progression in life cannot be assumed. The development of integrated brain and cord MRI holds the hope of deepening understanding of the relationship between focal symptomatology and histopathological progression. This review considers the nature and implications of asymmetry in ALS across clinical, neuroimaging and post mortem histopathology, highlighting the current gaps in knowledge and the need for a broader investigative framework.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"18 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From shadows to spotlight: the evolution of migraine stigma since the 17th century.","authors":"Alexis Demas","doi":"10.1093/brain/awae393","DOIUrl":"10.1093/brain/awae393","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e22-e23"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy.","authors":"","doi":"10.1093/brain/awaf041","DOIUrl":"10.1093/brain/awaf041","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e33"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}