Brain最新文献

{"title":"Stimulation of the human ventral tegmental area increases strategic betting.","authors":"Stephanie T Hirschbichler, Susie Lagrata, Nicholas Shedd, Harith Akram, Petra Schwingenschuh, Christoph Waiß, Stefan Oberndorfer, Manjit S Matharu, Sanjay G Manohar","doi":"10.1093/brain/awaf210","DOIUrl":"https://doi.org/10.1093/brain/awaf210","url":null,"abstract":"<p><p>Learning is a fundamental aspect of human behaviour and is essential for adapting to new environments and situations. The ventral tegmental area is a critical brain area containing neurons that release dopamine to signal reward, drive learning, and bias decision-making. Human data on ventral tegmental area's effects on cognition are scarce, and no studies have causally manipulated the human ventral tegmental area. Here we studied a unique group of patients who had deep brain stimulation surgery in the ventral tegmental area, to improve pain due to trigeminal autonomic cephalalgias refractory to medical therapy. In this study, we asked how deep brain stimulation, which aimed to inhibit the ventral tegmental area, affected reward-related learning and decision-making. Patients performed a reversal learning task while their deep brain stimulation was switched on vs. off, in a powerful within-subject design. In the task, patients learned to choose between two options to win money, based on previous outcomes, but also made post-decision bets based on whether they thought they were likely to win. This allowed us to also investigate the effect of electrical stimulation within the ventral tegmental area on betting behaviour. We found that stimulation did not affect learning in this group of patients but led to a more strategic betting behaviour. First, stimulation reduced the bias where healthy people tend to bet similarly to the previous trial. Second, when on stimulation, bets were more strongly linked to the actual value of the choice. The data indicate that disrupting ventral tegmental area signals by electrical stimulation reduces the perseverative betting bias, permitting more strategic decision-making. We interpret this to mean that mesolimbic dopaminergic signals in humans may be important in producing persistence of reward-driven behaviours over time.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504776","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":"Stimulation of the human ventral tegmental area increases strategic betting.","authors":"Stephanie T Hirschbichler,Susie Lagrata,Nicholas Shedd,Harith Akram,Petra Schwingenschuh,Christoph Waiß,Stefan Oberndorfer,Manjit S Matharu,Sanjay G Manohar","doi":"10.1093/brain/awaf210","DOIUrl":"https://doi.org/10.1093/brain/awaf210","url":null,"abstract":"Learning is a fundamental aspect of human behaviour and is essential for adapting to new environments and situations. The ventral tegmental area is a critical brain area containing neurons that release dopamine to signal reward, drive learning, and bias decision-making. Human data on ventral tegmental area's effects on cognition are scarce, and no studies have causally manipulated the human ventral tegmental area. Here we studied a unique group of patients who had deep brain stimulation surgery in the ventral tegmental area, to improve pain due to trigeminal autonomic cephalalgias refractory to medical therapy. In this study, we asked how deep brain stimulation, which aimed to inhibit the ventral tegmental area, affected reward-related learning and decision-making. Patients performed a reversal learning task while their deep brain stimulation was switched on vs. off, in a powerful within-subject design. In the task, patients learned to choose between two options to win money, based on previous outcomes, but also made post-decision bets based on whether they thought they were likely to win. This allowed us to also investigate the effect of electrical stimulation within the ventral tegmental area on betting behaviour. We found that stimulation did not affect learning in this group of patients but led to a more strategic betting behaviour. First, stimulation reduced the bias where healthy people tend to bet similarly to the previous trial. Second, when on stimulation, bets were more strongly linked to the actual value of the choice. The data indicate that disrupting ventral tegmental area signals by electrical stimulation reduces the perseverative betting bias, permitting more strategic decision-making. We interpret this to mean that mesolimbic dopaminergic signals in humans may be important in producing persistence of reward-driven behaviours over time.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"21 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504636","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":"Cholinergic patterns correlate with dopamine medication ON freezing of gait in Parkinson’s disease","authors":"Victor S Hvingelby, Miriam Højholt Terkelsen, Erik L Johnsen, Mette Møller, Erik Hvid Danielsen, Tove Henriksen, Andreas Nørgaard Glud, Yen F Tai, Anne Sofie Møller Andersen, Anne-Lene Knudsen, Kaare Meier, Jacob Horsager, Niels Okkels, Jens Christian Hedemann Sørensen, Per Borghammer, Elena Moro, Nicola Pavese","doi":"10.1093/brain/awaf231","DOIUrl":"https://doi.org/10.1093/brain/awaf231","url":null,"abstract":"Gait problems in people with Parkinson’s (PD) are increasingly common as disease progresses. Symptoms include freezing of gait (FoG), and a predisposition to falls. The causative pathophysiology is still not completely understood. In this study, Positron Emission Tomography (PET) with 18F-fluoro-ethoxy-benzovesamicol (18F-FEOBV), a presynaptic marker of cholinergic terminal density, and 18F-fluoro-deoxy-glucose (18F-FDG) was performed in a cohort of people with PD and gait disorder to derive spatial covariance networks of cholinergic and metabolic activity, and to evaluate the correlation of such networks against frequency of FoG and other gait measures. Fourteen patients with PD and FoG in the ON motor state underwent PET using 18F-FEOBV and 18F-FDG on two separated days. Following spatial normalization, functional networks were derived by Principal Component Analysis (PCA). The individual expression of linear combinations of principal components (PCs) was subsequently correlated with measures of FoG in the ON motor state (ON-FoG) and a lower body and gait (LBG) subsection of the Unified Parkinsons Disease Rating Scale (UPDRS) part III. Gait measures were derived from home-worn measures using a triaxial accelerometer. We found a derived pattern of 18F-FEOBV binding that correlated with ON-FoG (R2= 0.46975, p = 0.045) as well as other lower body and gait signs (R2 = 0.78591, p = 0.0077). Lower levels of cholinergic activity in the thalamus, hippocampus, striatum, anterior cingulate as well as areas of the brainstem consistent with the mesencephalic locomotor region were associated with worse ON-FoG and gait disturbances. The derived pattern was not associated with overall disease duration or progression as assessed by standard motor scores. There was no correlation between 18F-FEOBV and OFF-FoG. For 18F-FDG, no correlation between covariance patterns and gait assessments could be found. However, a statistically significant correlation was found for a subset of lower body and gait symptoms (R2 = 0.78306, p = 0.002). These results exhibit a correlation between lower levels of cholinergic function in locomotor-related areas of the brainstem and objective measures of dopamine medication ON-FoG, potentially indicating a causative link between the two. No association was found with OFF-FoG. Taken together our results provide support for the role of the cholinergic system in the occurrence of dopamine medication ON-FoG.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"225 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288325","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":"Amygdalar and hippocampal volume loss in limbic-predominant age-related TDP-43 encephalopathy","authors":"Alex Wesseling, Ismael L Calandri, Maud M A Bouwman, Niels Reijner, Natasja A C Deshayes, Frederik Barkhof, Rik Ossenkoppele, Wilma D J van de Berg, Annemieke E Rozemuller, Yolande A L Pijnenburg, Jeroen J M Hoozemans, Laura E Jonkman","doi":"10.1093/brain/awaf201","DOIUrl":"https://doi.org/10.1093/brain/awaf201","url":null,"abstract":"Limbic-predominant age-related TAR-DNA binding protein (TDP-43) encephalopathy neuropathological change (LATE-NC) refers to the aberrant accumulation of TDP-43 in the brains of aging individuals either in isolation or in combination with neurodegenerative disease. LATE-NC is most commonly found in the amygdala and hippocampus and is associated with progressive amnestic decline in individuals with a neurodegenerative disease. Since LATE-NC can only be diagnosed post-mortem, there is a need for pathology-validated neuroimaging biomarkers for LATE-NC. In the current study we assessed MRI-measured amygdalar and hippocampal volume in brain donors with Alzheimer’s disease or Lewy Body diseases with and without co-occurring LATE-NC pathology. Post-mortem in-situ 3D-T1 3T-MRI data were collected for 51 cases (27 Alzheimer’s disease and 24 Lewy Body Disease) of whom 17 had post-mortem confirmed LATE-NC and 34 were non-LATE-NC (matched on age, sex, and neurodegenerative disease). Amygdalar and hippocampal volumes were calculated using FreeSurfer. Within-subject amygdalar and hippocampal tissue sections were immunostained for TDP-43 (pTDP-43), phosphorylated tau (AT8), amyloid-β (4G8) and α-synuclein (pSer129). Positive cell density (TDP-43 and α-synuclein) and area percentage immunoreactivity (p-tau and amyloid-β) outcome measures were quantified using QuPath. Group differences between LATE-NC and non-LATE-NC donors were assessed with univariate analyses and correlations were assessed with linear regression models, all adjusting for intracranial volume and post-mortem delay and if applicable for primary pathology. Brain donors with LATE-NC showed significantly lower amygdalar (-26%, p=.014) and hippocampal (-19%, p=.003) volumes than non-LATE-NC brain donors, even when correcting for regional phosphorylated tau, amyloid-β and α-synuclein burden. These group differences remained significant in the Alzheimer’s disease group (amygdala -24%, p=.028; hippocampus -21%, p=.002), but in the Lewy body diseases group only the amygdala was smaller in LATE-NC donors compared to non-LATE-NC donors (18%, p=.030). These results suggest that severity of TDP-43 burden plays a role in amygdala and hippocampus atrophy on MRI, even when correcting for effects of primary pathology. This study proposes that exceptionally low amygdalar and hippocampal volumes could indicate LATE-NC and that this may serve as a potential biomarker for in-vivo studies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"649 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288261","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":"Motor recovery through perineuronal net modulation in a Parkinson’s disease mouse model","authors":"David Benacom, Camille Chataing, Alain Prochiantz, Ariel A Di Nardo","doi":"10.1093/brain/awaf226","DOIUrl":"https://doi.org/10.1093/brain/awaf226","url":null,"abstract":"Perineuronal nets are specialized extracellular matrix structures forming preferentially around parvalbumin interneurons to regulate plasticity. While cortical perineuronal nets have been implicated in sensory plasticity and memory modulation, perineuronal nets of the primary motor cortex have been largely overlooked. We found that transient reduction of primary motor cortex perineuronal nets by ChABC treatment in otherwise healthy adult mice resulted in temporary deficits in motor function. In a mouse model of Parkinson's disease based on unilateral 6-hydroxydopamine lesions of the midbrain, perineuronal net levels were decreased in both primary motor cortex hemispheres 2 weeks post-lesion, yet returned to baseline within 5 weeks. We discovered that subsequent transient reduction of primary motor cortex perineuronal nets through ChABC treatment could unlock motor recovery when coupled with motor stimulation. This recovery was associated with a bilateral increase in perineuronal-net-enwrapped parvalbumin interneurons and a rebalancing of parvalbumin cell soma excitatory synaptic markers. These findings reveal distinct roles of perineuronal net plasticity – first in response to the initial midbrain lesion and then during rescue after ChABC treatment – suggesting that primary motor cortex perineuronal nets play a nuanced role in regulating motor function. This duality positions perineuronal nets as potential therapeutic targets for motor rehabilitation strategies in Parkinson's disease.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"12 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268727","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":"Stimulants for disorders of consciousness in the intensive care unit: a randomized, placebo-controlled trial","authors":"Marwan H Othman, Attila Géry Toury-Puel, Karen Irgens Tanderup Hansen, Moshgan Amiri, Pardis Zarifkar, Costanza Peinkhofer, Sarah Gharabaghi Stückler, Markus Harboe Olsen, Jens Bjerregaard, Margit Smitt, Anna Søgaard Magnussen, Axel Forsse, Jacob Møller, Marie Katrine Klose Nielsen, Cecilie Høgfeldt Jessen, Christian Hassager, Simon Hyttel-Sørensen, Anders Perner, Morten Hylander Møller, Peter Hasse Møller-Sørensen, John Hauerberg, Peter Birkeland, Sigurdur Thor Sigurdsson, Christian Aage Wamberg, Theis Skovsgaard Itenov, Christian S Meyhoff, Kirsten Møller, Tobias S Andersen, Jesper Kjaergaard, Daniel Kondziella","doi":"10.1093/brain/awaf228","DOIUrl":"https://doi.org/10.1093/brain/awaf228","url":null,"abstract":"In the intensive care unit (ICU), management of unresponsive patients with brain injury focuses on preventing secondary brain damage. Therapeutic strategies that directly promote the recovery of consciousness are urgently needed. In an investigator-initiated, randomized, placebo-controlled, double-blind, cross-over trial, we studied the effects of apomorphine and methylphenidate in ICU patients with acute disorders of consciousness (DoC). We hypothesized that these stimulants would improve consciousness biomarkers assessed by automated pupillometry (primary outcome) and clinical signs of consciousness (secondary outcome). We randomized 50 ICU patients with DoC (14 women; mean age 63 ± 10 years; 48 with non-traumatic brain injuries) to strata consisting of three consecutive treatment sessions during which apomorphine, methylphenidate or placebo were administered. In total, we administered 112 study medications, including 36 doses of apomorphine, 39 doses of methylphenidate and 37 doses of placebo. Missing administrations were due to death, ICU discharge, or spontaneous consciousness recovery. Plasma concentrations of stimulants confirmed drug exposure. We found no adverse events related to the trial drugs. Pupillometry recordings of sufficient quality (n = 590) were available from 48 (96%) patients. A pupillary response to a verbal arithmetic command (i.e., ≥3 pupillary dilations on five verbal arithmetic tasks) was identified during 70 (12%) of these recordings. Seven (15%) patients without any other observable response to spoken commands also passed a stricter threshold of ≥4 pupillary dilations, suggesting cognitive motor dissociation. Apomorphine (OR 1.35, 95% CI: 0.93 to 1.96) and methylphenidate (OR 1.29, 95% CI: 0.89 to 1.86) did not significantly increase pupillary responses. However, after study drug administration, 10 (20%) patients showed improved clinical arousal at least once. Signs of arousal were noted after one dose of placebo, four doses of apomorphine (OR 5.04, 95% CI: 0.56 to 120.7), and seven doses of methylphenidate (OR 9.96, 95% CI: 1.36 to 235.8). Changes toward higher consciousness level categories were observed once after placebo, four times after apomorphine (OR 5.67, 95% CI 0.63 to 169.46), and three times after methylphenidate (OR 3.41, 95% CI 0.34 to 88.00). In a post-hoc analysis, patients with greater pupillary responsiveness showed better arousal, suggesting that this condition may predict stimulant drug effects. In conclusion, while pupillometry revealed no direct drug effects on overall pupillary responses, stimulants may have triggered clinical arousal in some patients, particularly in those with greater pupillary responsiveness. These findings require replication but should guide future pharmacological trials aimed at improving consciousness recovery after brain injury.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"26 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268726","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":"Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital myopathy.","authors":"Maureen Jacob, Heike Kölbel, Philip Harrer, Robert Kopajtich, Pinki Munot, Melanie T Achleitner, Susann Badmann, Melanie Brugger, Theresa Brunet, Gisèle Bonne, Marta Codina, Laura Ebner, Peyman Eshraghi, Katharina Eyring, Ahmad Shah Farhat, René G Feichtinger, Elisabeth Graf, Anna Marcé-Grau, Andreas Hahn, Henry Houlden, Ehsan Ghayoor Karimiani, Véronique Manel, Katharina Mayerhanser, Juliette Nectoux, Isabelle Nelson, Rahul Phadke, Holger Prokisch, Saeid Sadeghian, Alice Saparov, Anne Schänzer, Ulrike Schara-Schmidt, Julia Schmidt, Rahel Schuler, Caroline Sewry, Gholamreza Shariati, Silke Slanz, Dmitrii Smirnov, Rivka Sukenik-Halevy, Homa Tajsharghi, Mehran Beiraghi Toosi, Laura Trujillano, Joachim Weis, Louise C Wilson, Rabah Ben Yaou, Mina Zamani, Michael Zech, Jana Zschüntzsch, Uwe Kornak, David Goméz-Andrés, Reza Maroofian, Juliane Winkelmann, Andreas Roos, Felix Distelmaier, Johannes A Mayr, Matias Wagner","doi":"10.1093/brain/awaf227","DOIUrl":"https://doi.org/10.1093/brain/awaf227","url":null,"abstract":"<p><p>Dystonin (DST) encodes three major isoforms, DST-a, DST-b, and DST-e. Biallelic pathogenic variants in DST have previously been associated with two allelic monogenic disorders: Hereditary Sensory and Autonomic Neuropathy type VI (caused by a loss of DST-a) and Epidermolysis bullosa simplex 3 (caused by a loss of DST-e). We investigated patients diagnosed with congenital myopathy using exome or genome sequencing. In 19 affected individuals from 14 unrelated families, we identified nine different variants in biallelic state located in exons 40-41, specific to DST-b. Affected individuals presented with severe neonatal myopathy characterized by arthrogryposis, hypotonia, and dilated cardiomyopathy. Postnatal CPAP ventilation was required in nine patients, and seven died within the first three years of life. Survivors showed an improvement of symptoms, with the oldest three patients, now over 25 years old, exhibiting normal cognition and being ambulatory. RNA analyses demonstrated that transcripts encoding DST-b are predominantly expressed in skeletal muscle, heart tissue, and cultured fibroblasts, but not in brain matching the phenotypic spectrum. Patient-derived fibroblasts exhibited reduced DST mRNA expression. Proteomic analysis confirmed a reduction of DST protein levels due to an absence of the DST-b isoform. Muscle biopsies from four patients aged 1 month to 3 years revealed mild, non-specific myopathic changes. Ultrastructural analysis in three individuals showed mild and focal myofibrillar disruption and non-specific undulating nuclear membranes, with these changes observed in two cases each. Additionally, we identified two homozygous variants affecting both DST-a and DST-b isoforms in four patients from two unrelated families; all presented with severe arthrogryposis and died intrauterine or shortly after birth. Genotype-Phenotype correlation in these patients and previously published cases with respective variants resulted in the definition of a DST-associated lethal congenital contracture syndrome. Our findings demonstrate that biallelic variants exclusively affecting DST-b cause an autosomal recessive congenital myopathy. Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome. The location of the variant within DST allows for phenotype prediction. We propose redefining DST as a disease-associated gene linked to four distinct allelic disease phenotypes.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265238","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":"POU3F2 regulates canonical Wnt signalling via SOX13 and ADNP to expand the neural progenitor population","authors":"Courtney R Benoit, Lilia B Sattler, Aimee J Aylward, Olivia Pembridge, Bella Kim, Christina R Muratore, Meichen Liao, Amy He, Nancy Ashour, Seeley B Fancher, Alexandra M Lish, Richard V Pearse, Joseph D Buxbaum, Tracy L Young-Pearse","doi":"10.1093/brain/awaf221","DOIUrl":"https://doi.org/10.1093/brain/awaf221","url":null,"abstract":"Loss-of-function mutations in the transcription factor POU3F2 have been identified in individuals with neurodevelopmental disorders. To elucidate the mechanistic role of POU3F2 in human neurodevelopment, we induced POU3F2 disruption in human neural progenitor cells (NPCs). Mutation of POU3F2 in NPCs causes reduced baseline canonical Wnt signalling and decreased proliferation, resulting in premature specification of radial glia. Additionally, POU3F2 levels across genetically diverse NPCs significantly associate positively with baseline canonical Wnt signalling and negatively with markers of radial glia specification. Through a series of unbiased analyses, we show that SOX13 and ADNP are transcriptional targets of POU3F2 which mediate POU3F2’s effects on Wnt signalling in human NPCs. Finally, we describe five individuals with autism spectrum disorder that harbor loss-of-function mutations in POU3F2, enhancing the genetic evidence for its critical role in human neurodevelopment. Together, these studies define POU3F2 as an activator of canonical Wnt signalling and mechanistically link two high-confidence autism genes, ADNP and POU3F2, in the regulation of neurodevelopment.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"9 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268728","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":"Disentangling epilepsy and dementia: more to do, together","authors":"Arjune Sen","doi":"10.1093/brain/awaf225","DOIUrl":"https://doi.org/10.1093/brain/awaf225","url":null,"abstract":"This scientific commentary refers to ‘The association of seizure control with neuropathology in dementia’ by Zawar et al. (https://doi.org/10.1093/brain/awaf017).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"10 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260008","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":"Disease spectrum and long-term prognosis of patients with BAG3-associated neuromuscular diseases in Europe","authors":"Gorka Fernández-Eulate, Cyril Gitiaux, Simone Thiele, Heinz Jungbluth, Anna Potulska-Chromik, Chiara Marini-Bettolo, Jean Baptiste Davion, Germán Morís, Eduard Gallardo, Montsé Olivé, Carlos Pablo de Fuenmayor-Fernández de la Hoz, Frederique Audic, Arnaud Isapof, Maggie C Walter, Corrado Angelini, Enrico Bertini, Ulrike Schara-Schmidt, Kristl G Claeys, Maike F Dohrn, Mohamed Dembele, Frederic Fer, Guy Brochier, Teresinha Evangelista, Anna Kostera-Pruszczyk, Shahram Attarian, Volker Straub, Cristina Dominguez-Gonzalez, John Vissing, Pascale Richard, Corinne Metay, Diala Khraiche, Karim Wahbi, Tanya Stojkovic","doi":"10.1093/brain/awaf223","DOIUrl":"https://doi.org/10.1093/brain/awaf223","url":null,"abstract":"De novo or autosomal dominant BAG3 gene variants cause a wide range of skeletal and cardiac muscle diseases encompassing Charcot–Marie–Tooth disease, myofibrillar myopathy, cardiomyopathy or a combination of them. Given the severity and rarity of BAG3-neuromuscular diseases (NMD), series of patients are lacking. Our aim was to characterize the clinical and genetic spectrum as well as the natural history of BAG3-NMD in Europe. In this multicentre retrospective study, we collected clinical, ancillary, and genetic data of patients with NMD and BAG3 variants, identified from European paediatric and adult neuromuscular reference centres from May to December 2023 following a call circulated through the European Reference Network EURO-NMD and other partners. Responses were received from 35 centres in 17 countries. Twenty-six patients (65.4% males, 34.6% females) with BAG3-NMD from 18 different families were included in the study. The c.626C&amp;gt;T p.(Pro209Leu) variant, carried by 16 patients, was the only recurrent variant and was associated with a homogeneous and severe phenotype, with predominantly lower-limb motor weakness (n=13, 81.25%) or heart failure (n=3, 18.75%) as the presenting feature, and a mean age at symptom onset of 7.8±3.4 years. Where available (n=13), electroneuromyography showed a polyneuropathy with demyelinating features and a frequently associated myopathy. Eleven (68.8%) patients had restrictive cardiomyopathy on initial assessment. Orthopaedic manifestations were common, with contractures (n=15, 93.8%), foot deformities (n=11, 84.6%), and scoliosis and/or rigid spine (n=12, 80%). At last follow-up (age 21.5±8.6 years), of the patients carrying the p.(Pro209Leu) variant, 10 (62.5%) had lost ambulation, 14 (93.3%) had respiratory insufficiency (11 requiring ventilation), and 12 (75%) had a restrictive cardiomyopathy, leading to heart failure and heart transplantation in five and four patients, respectively. Eight (50%) patients died prematurely at a mean age of 22.5±9.6 years, most frequently from sudden death (n=5). The other 10 patients carried three other BAG3 variants, and showed a milder disease course, with all patients remaining ambulatory, without cardiorespiratory manifestations at last follow-up. The p.(Arg309*) nonsense variant, known to cause isolated dilated cardiomyopathy, as well as the p.(Val505Glyfs*6) frameshift variant resulting in a premature stop codon, caused distal hereditary motor neuropathy. This is the largest study of patients with BAG3-NMD, delineating the frequency, specific presentation, and the natural history in patients with the recurrent BAG3 p.(Pro209Leu) missense variant, crucial for informing patient management in the context of a rapidly progressive disease. All other BAG3 variants were rare and caused milder clinical presentations.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"25 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260137","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}