Brain最新文献

{"title":"Lesion correlates of impaired acoustic-phonetic perception after unilateral left hemisphere stroke.","authors":"Jeffrey R Binder, Anna Freiberg, Joseph Heffernan, Mónica Giraldo-Chica, Diane S Book, Sara B Pillay","doi":"10.1093/brain/awae417","DOIUrl":"10.1093/brain/awae417","url":null,"abstract":"<p><p>Acoustic-phonetic perception refers to the ability to perceive and discriminate between speech sounds. Acquired impairment of acoustic-phonetic perception is known historically as 'pure word deafness' and typically follows bilateral lesions of the cortical auditory system. The extent to which this deficit occurs after unilateral left hemisphere damage and the critical left hemisphere areas involved are not well defined. We tested acoustic-phonetic perception in 73 individuals with chronic left hemisphere stroke and performed multivariate lesion-symptom mapping incorporating controls for non-specific task confounds, pure tone hearing loss, response bias and lesion size. Separate analyses examined place of articulation, manner of articulation, voicing and vowel discriminations. Overlap of the lesion map with transcallosal pathways linking left and right temporal lobes was examined using a probabilistic diffusion tensor tractography map of these pathways obtained from a healthy control cohort. Compared to an age- and education-matched control sample, 18% of the patients had impaired acoustic-phonetic perception overall, with 44% impaired on voicing, 26% on manner, 15% on place and 14% on vowel discrimination. Lesion-symptom mapping revealed the most critical areas to be the transverse temporal gyrus (TTG) and adjacent medial belt cortex, the acoustic radiation and the posterior superior temporal sulcus (pSTS). There were notable differences between lesion correlates for the different types of discrimination, with place discrimination linked to medial TTG, vowel discrimination to lateral TTG and planum temporale, manner discrimination to posterior planum temporale and voicing discrimination to pSTS. Overlap of the main lesion map with transcallosal temporal lobe pathways was minor but included a deep white matter component at the base of the middle and inferior temporal gyri. The extent of overlap between individual lesions and the transcallosal pathway map was not correlated with acoustic-phonetic perception. The results add further evidence that acoustic-phonetic impairments, particularly impairments of voicing perception, are relatively common after unilateral left temporal lobe damage, and they clarify the lesion correlates of these deficits. Differences between the lesion maps for the discrimination types likely reflect differential reliance on spectral versus temporal analysis for these discriminations.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1421-1434"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944348","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":"Tau, synapse loss and gliosis progress in an Alzheimer's mouse model after amyloid-β immunotherapy.","authors":"Lindsay A Welikovitch, Anastasie Mate de Gerando, Anita Khasnavis, Harshil Bhavsar, Jonah C Meltzer, Luc Buée, Lori B Chibnik, Thierry Bussiere, Bradley T Hyman","doi":"10.1093/brain/awae345","DOIUrl":"10.1093/brain/awae345","url":null,"abstract":"<p><p>Preclinical studies assessing drugs for Alzheimer's disease (AD) are conducted in animal models that usually display only one neuropathological feature of AD, whereas patients present with a complex combination of comorbidities and neuropathologies. Importantly, it is well established that amyloid-β (Aβ) plaque and tau tangle accumulation interact in a phase-dependent manner, making it difficult to predict how targeting one might influence the other, as well as downstream degeneration. We developed a transgenic mouse model, APP/PS1xTau22, with progressive cortical Aβ deposition and hippocampal tau neurofibrillary inclusions, to investigate how both neuropathologies act jointly to bring about neural degeneration, synapse loss and glial phenotypes. We then assessed whether applying murine chimeric aducanumab, an anti-amyloid immunotherapy, could impact the synergistic relationship between amyloid and tau. Drug treatment resulted in a ∼70% reduction in Aβ deposition in hippocampal and cortical areas and produced a robust peri-plaque microglial and astrocytic response. Removing amyloid from the brain did not reverse or slow tau pathology or alter synapse loss. Our findings suggest that, once the interaction between amyloid and tau is set in motion, reducing plaque burden by Aβ immunotherapy may stimulate glial responses, but is insufficient to curb degenerative phenotypes in this model.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1316-1328"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C>T.","authors":"A Reghan Foley, Véronique Bolduc, Fady Guirguis, Sandra Donkervoort, Ying Hu, Rotem Orbach, Riley M McCarty, Apurva Sarathy, Gina Norato, Beryl B Cummings, Monkol Lek, Anna Sarkozy, Russell J Butterfield, Janbernd Kirschner, Andrés Nascimento, Daniel Natera-de Benito, Susana Quijano-Roy, Tanya Stojkovic, Luciano Merlini, Giacomo Comi, Monique Ryan, Denise McDonald, Pinki Munot, Grace Yoon, Edward Leung, Erika Finanger, Meganne E Leach, James Collins, Cuixia Tian, Payam Mohassel, Sarah B Neuhaus, Dimah Saade, Benjamin T Cocanougher, Mary-Lynn Chu, Mena Scavina, Carla Grosmann, Randal Richardson, Brian D Kossak, Sidney M Gospe, Vikram Bhise, Gita Taurina, Baiba Lace, Monica Troncoso, Mordechai Shohat, Adel Shalata, Sophelia H S Chan, Manu Jokela, Johanna Palmio, Göknur Haliloğlu, Cristina Jou, Corine Gartioux, Herimela Solomon-Degefa, Carolin D Freiburg, Alvise Schiavinato, Haiyan Zhou, Sara Aguti, Yoram Nevo, Ichizo Nishino, Cecilia Jimenez-Mallebrera, Shireen R Lamandé, Valérie Allamand, Francesca Gualandi, Alessandra Ferlini, Daniel G MacArthur, Steve D Wilton, Raimund Wagener, Enrico Bertini, Francesco Muntoni, Carsten G Bönnemann","doi":"10.1093/brain/awaf116","DOIUrl":"10.1093/brain/awaf116","url":null,"abstract":"<p><p>Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen 6 genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771281","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":"Exploiting blood-based biomarkers to align preclinical models with human traumatic brain injury.","authors":"Ilaria Lisi, Federico Moro, Edoardo Mazzone, Niklas Marklund, Francesca Pischiutta, Firas Kobeissy, Xiang Mao, Frances Corrigan, Adel Helmy, Fatima Nasrallah, Valentina Di Pietro, Laura B Ngwenya, Luis V Portela, Bridgette D Semple, Andrea L C Schneider, Ramon Diaz Arrastia, David K Menon, Douglas H Smith, Cheryl Wellington, David J Loane, Kevin K W Wang, Elisa R Zanier","doi":"10.1093/brain/awae350","DOIUrl":"10.1093/brain/awae350","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied on extrapolation from preclinical studies for critical design considerations, including drug dose optimization, post-injury drug treatment initiation and duration. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to identical (or similar) measurements in humans, link to human TBI biomechanics and pathophysiology, and guide therapeutic decisions. To support this translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used GFAP, UCH-L1, NfL, total-Tau (t-Tau) or phosphorylated-Tau (p-Tau) published in PubMed/EMBASE up to 10 April 2024. Although many factors influence clinical TBI outcomes, many of those cannot routinely be assessed in rodent studies (e.g. intracranial pressure monitoring). Thus we focused on blood biomarkers' temporal trajectories and discuss our findings in the context of the latest clinical TBI biomarker data. Of 805 original preclinical studies, 74 met the inclusion criteria, with a median quality score of 5 (25th-75th percentiles: 4-7) on the CAMARADES checklist. GFAP was measured in 43 studies, UCH-L1 in 21, NfL in 20, t-Tau in 19 and p-Tau in seven. Data from rodent models indicate that all biomarkers exhibited injury severity-dependent elevations with distinct temporal profiles. GFAP and UCH-L1 peaked within the first day after TBI (30- and 4-fold increases, respectively, in moderate-to-severe TBI versus sham), with the highest levels observed in the contusion TBI model. NfL peaked within days (18-fold increase) and remained elevated up to 6 months post-injury. GFAP and NfL show a pharmacodynamic response in 64.7% and 60%, respectively, of studies evaluating neuroprotective therapies in preclinical models. However, GFAP's rapid decline post-injury may limit its utility for understanding the response to new therapeutics beyond the hyperacute phase after experimental TBI. Furthermore, as in humans, subacute NfL levels inform on chronic white matter loss after TBI. t-Tau and p-Tau levels increased over weeks after TBI (up to 6- and 16-fold, respectively); however, their relationship with underlying neurodegeneration has yet to be addressed. Further investigation into biomarker levels in the subacute and chronic phases after TBI will be needed to fully understand the pathomechanisms underpinning blood biomarkers' trajectories and select the most suitable experimental model to optimally relate preclinical mechanistic studies to clinical observations in humans. This new a","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1062-1080"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder.","authors":"Gabriel N Aughey, Elisa Cali, Reza Maroofian, Maha S Zaki, Alistair T Pagnamenta, Zafar Ali, Uzma Abdulllah, Fatima Rahman, Lara Menzies, Anum Shafique, Mohnish Suri, Emmanuel Roze, Mohammed Aguennouz, Zouiri Ghizlane, Saadia Maryam Saadi, Ambrin Fatima, Huma Arshad Cheema, Muhammad Nadeem Anjum, Godelieve Morel, Stephanie Robin, Robert McFarland, Umut Altunoglu, Verena Kraus, Moneef Shoukier, David Murphy, Kristina Flemming, Hilde Yttervik, Hajar Rhouda, Gaetan Lesca, Nicolas Chatron, Massimiliano Rossi, Bibi Nazia Murtaza, Mujaddad Ur Rehman, Jenny Lord, Edoardo Giacopuzzi, Azam Hayat, Muhammad Siraj, Reza Shervin Badv, Go Hun Seo, Christian Beetz, Hülya Kayserili, Yamna Krioulie, Wendy K Chung, Sadaf Naz, Shazia Maqbool, Kate E Chandler, Christopher J Kershaw, Thomas Wright, Siddharth Banka, Joseph G Gleeson, Jenny C Taylor, Stephanie Efthymiou, Shahid Mahmood Baig, Mariasavina Severino, James E C Jepson, Henry Houlden","doi":"10.1093/brain/awae363","DOIUrl":"10.1093/brain/awae363","url":null,"abstract":"<p><p>Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have been described in only six individuals carrying five biallelic predicted loss-of-function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 35 patients from 20 families carrying pLOF variants in RBL2, including 15 new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were observed uniformly, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures and non-specific dysmorphic features. Neuroimaging features included cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila, and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, our study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2-linked neurodevelopmental disorder and suggests that restoring RBL2 expression through gene therapy approaches might ameliorate some symptoms caused by RBL2 pLOF.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1194-1211"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates.","authors":"","doi":"10.1093/brain/awaf023","DOIUrl":"10.1093/brain/awaf023","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e30-e32"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051542","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":"Methylphenidate differentially alters corticostriatal connectivity after traumatic brain injury.","authors":"Emma-Jane Mallas, Sara De Simoni, Peter O Jenkins, Michael C B David, Niall J Bourke, David J Sharp","doi":"10.1093/brain/awae334","DOIUrl":"10.1093/brain/awae334","url":null,"abstract":"<p><p>Traumatic brain injury commonly impairs attention and executive function and disrupts the large-scale brain networks that support these cognitive functions. Abnormalities of functional connectivity are seen in corticostriatal networks, which are associated with executive dysfunction and damage to neuromodulatory catecholaminergic systems caused by head injury. Methylphenidate, a stimulant medication that increases extracellular dopamine and noradrenaline, can improve cognitive function following traumatic brain injury. In this experimental medicine add-on study to a randomized, double-blind, placebo-controlled clinical trial, we test whether administration of methylphenidate alters corticostriatal network function and influences drug response. Forty-three moderate-severe traumatic brain injury patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Twenty-eight patients were included in the neuropsychological and functional imaging analysis (four females, mean age 40.9 ± 12.7 years, range 20-65 years) and underwent functional MRI and neuropsychological assessment after each block. 123I-Ioflupane single-photon emission computed tomography dopamine transporter scans were performed, and specific binding ratios were extracted from caudate subdivisions. Functional connectivity and the relationship to cognition were compared between drug and placebo conditions. Methylphenidate increased caudate to anterior cingulate cortex functional connectivity compared with placebo and decreased connectivity from the caudate to the default mode network. Connectivity within the default mode network was also decreased by methylphenidate administration, and there was a significant relationship between caudate functional connectivity and dopamine transporter binding during methylphenidate administration. Methylphenidate significantly improved executive function in traumatic brain injury patients, and this was associated with alterations in the relationship between executive function and right anterior caudate functional connectivity. Functional connectivity is strengthened to brain regions, including the anterior cingulate, that are activated when attention is focused externally. These results show that methylphenidate alters caudate interactions with cortical brain networks involved in executive control. In contrast, caudate functional connectivity reduces to default mode network regions involved in internally focused attention and that deactivate during tasks that require externally focused attention. These results suggest that the beneficial cognitive effects of methylphenidate might be mediated through its impact on the caudate. Methylphenidate differentially influences how the caudate interacts with large-scale functional brain networks that exhibit co-ordinated but distinct patterns of activity required for attentionally demanding tasks.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1360-1373"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rituximab versus placebo for chronic inflammatory demyelinating polyradiculoneuropathy: a randomized trial.","authors":"Eduardo Nobile-Orazio, Dario Cocito, Fiore Manganelli, Raffaella Fazio, Giuseppe Lauria Pinter, Luana Benedetti, Anna Mazzeo, Erdita Peci, Emanuele Spina, Yuri Falzone, Eleonora Dalla Bella, Francesco Germano, Luca Gentile, Giuseppe Liberatore, Francesca Gallia, Roger Collet-Vidiella, Elisa Bianchi, Pietro Emiliano Doneddu","doi":"10.1093/brain/awae400","DOIUrl":"10.1093/brain/awae400","url":null,"abstract":"<p><p>Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) often requires prolonged ongoing treatment to prevent worsening. The efficacy of rituximab in preventing worsening after the discontinuation of immunoglobulin therapy in patients with CIDP was assessed. In this randomized, double-blind, placebo-controlled study, conducted at seven Italian hospitals, CIDP patients under immunoglobulin therapy were assigned to receive either rituximab (1 g on Days 1, 15 and 180 ± 7) or placebo. Both groups continued their regular immunoglobulin doses for 6 months post-intervention. The primary end point was the proportion of patients who worsened in any of the following three measures at Month 12, within 6 months after immunoglobulin discontinuation: a decrease of at least one point on the adjusted INCAT score, two points on the MRC sum score, or four points on the RODS centile score. Secondary end points included the proportion of patients deteriorating at Month 18 (within 12 months after immunoglobulin discontinuation), treatment cessation due to adverse events or voluntary reasons, and the time until deterioration after immunoglobulin discontinuation. This study was registered with ClinicalTrials.gov (NCT06325943) and EUDRACT (number 2017-005034-36), and is now complete. From April 2019 to March 2022, 39 patients were recruited; two withdrew consent. The remaining 37 patients were assigned to rituximab (n = 19) or placebo (n = 18). Median age was 53 (interquartile range 45-64), with 11 (30%) females. A similar proportion of patients in both the rituximab (12/19, 63.2%) and placebo (12/18, 66.6%) groups worsened at Month 12 [odds ratio (OR) 0.86; 95% confidence interval (CI) 0.22-3.32]. No significant differences were noted at Month 18 (OR 0.62; 95% CI 0.14-2.70), or in the mean scores of each scale at Months 6, 12 and 18. The median time to worsening was 5 months for rituximab and 2 months for placebo (Log-rank P = 0.4372). Treatment was suspended due to adverse events in one rituximab patient. In this study, rituximab was not more effective than placebo in preventing clinical deterioration following the discontinuation of immunoglobulin therapy in CIDP. Further studies might evaluate the efficacy of more frequent or earlier administration of rituximab.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1112-1121"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated cholesterol is a common phenotype for dominant and recessive ATAD3-associated disorders.","authors":"Ann-Sophie Kiesel, Lucia Laugwitz, Rebecca Buchert, Mona Grimmel, Sarah Baumann, Marc Sturm, Selina Reich, Martje G Pauly, Norbert Brüggemann, Alexander Münchau, Olga Oleksiuk, Matthis Synofzik, Tobias B Haack, Susana Peralta","doi":"10.1093/brain/awae402","DOIUrl":"10.1093/brain/awae402","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e24-e28"},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent Na+ current couples spreading depolarization to seizures in Scn8a gain of function mice.","authors":"Isamu Aiba, Yao Ning, Jeffrey L Noebels","doi":"10.1093/brain/awaf120","DOIUrl":"10.1093/brain/awaf120","url":null,"abstract":"<p><p>Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization that transiently impairs the function of affected brain regions. While SD typically arises as an isolated hemispheric event, we previously reported that reducing M-type potassium current (IKM) by ablation of Kcnq2 in forebrain excitatory neurons results in tightly coupled spontaneous bilateral seizure-SD complexes in the awake mouse cortex. Here we find that enhanced persistent Na+ current due to gain-of-function (GOF) mutations in Scn8a (N1768D/+, hereafter D/+) produces a similar compound cortical excitability phenotype. Chronic DC-band EEG recording detected spontaneous bilateral seizure-SD complexes accompanied by seizures with a profound tonic motor component, which occur predominantly during the light phase and were detected at ages between P33-100. Laser speckle contrast imaging of cerebral blood flow dynamics resolved SD as a bilateral wave of hypoperfusion and subsequent hour-lasting hypoperfusion in Scn8aD/+ cortex in awake head-restrained mice evoked by a PTZ injection. Subcortical recordings in freely moving mice revealed that approximately half of the spontaneous cortical seizure-SD complexes arose with a concurrent SD-like depolarization in the thalamus and delayed depolarization in the striatum. In contrast, SD-like DC potential shifts were rarely detected in the hippocampus or upper pons. Consistent with the high spontaneous incidence in vivo, cortical slices from Scn8aD/+ mice showed a raised SD susceptibility, and pharmacological inhibition of persistent Na+ current (INaP), which is enhanced in Scn8aD/+ neurons, inhibited SD generation in cortical slices ex vivo as well as in head-fixed mice in vivo, indicating that INaP contributes to SD susceptibility. Ex vivo Ca2+ imaging studies using acute brain slices expressing genetic Ca2+ sensor (Thy1-GCAMP6s) demonstrated that pharmacological activation of IKM suppressed Ca2+ spikes and SD, whereas an IKM inhibitor strongly increased the frequency of hippocampal Ca2+ spikes in Scn8aD/+, but not WT slices, suggesting that IKM restrains the Scn8a GOF hyperexcitability. Together, our study identifies a cortical SD phenotype in Scn8a GOF mice shared with the Kcnq2-cKO model of developmental epileptic encephalopathy, and reveals that an imbalance of non-inactivating inward and outward tonic membrane currents bidirectionally modulates spatiotemporal SD susceptibility.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771283","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}