Brain最新文献

{"title":"AAV-based TCAP delivery rescues mitochondria dislocation in limb-girdle muscular dystrophy R7.","authors":"Xiaoqing Lv, Shuangwu Liu, Xi Li, He Lv, Kai Shao, Sushan Luo, Dandan Zhao, Chuanzhu Yan, Pengfei Lin","doi":"10.1093/brain/awae351","DOIUrl":"https://doi.org/10.1093/brain/awae351","url":null,"abstract":"<p><p>Limb-girdle muscular dystrophy R7 is a rare genetic disease caused by homozygous or compound heterozygous variants in the titin-cap (TCAP) gene that results in the absence of the protein telethonin. The primary pathological features of limb-girdle muscular dystrophy R7 are fiber size variation, nuclear centralization, and abnormal mitochondrial distribution. The mechanisms underlying this disease are unclear, and there is currently no specific treatment for limb-girdle muscular dystrophy R7. This study established a Tcap-deficient mouse model to explore the disease mechanism of mitochondria dislocation and potential therapeutic strategies. We use methods such as proteomics, immunofluorescence, histopathological staining, and western blotting to explore the mechanism of mitochondrial dislocation. Moreover, in the quest for a prospective therapeutic intervention for this disorder, the adeno-associated virus serotype 2/9 was employed to deliver the Tcap gene into the muscles of these mice, facilitating preclinical experimentation. After 2 months and 7 months, the muscular phenotype was evaluated and selected mice were humanely euthanized for subsequent molecular and histological analysis. The phenotype of Tcap-/- mice mimicked that observed in individuals diagnosed with limb-girdle muscular dystrophy R7. This study elucidated the mechanism of mitochondrial dislocation in limb-girdle muscular dystrophy R7. Through our in vitro experiments, we discovered that telethonin aids in preserving the integrity of desmin by preventing truncation at the N-terminus. Additionally, telethonin combined with desmin and colocalized at the Z-disc. Research has shown that the Tcap gene plays a crucial role in controlling the desmin cytoskeleton organization. The absence of telethonin leads to a collapsed desmin cytoskeleton. This causes disorganization of the mitochondrial network, leading to mitochondrial dysfunction. In addition, the study investigated the efficacy of adeno-associated virus (AAV)-mediated Tcap replacement in Tcap-/- mice. By intramuscular delivery of AAV, we observed dramatic improvements in muscle phenotype, muscle pathology, CK levels, muscle magnetic resonance imaging, mitochondrial network organization, and mitochondrial function. The results of this study demonstrated that telethonin deficiency led to desmin cytoskeleton collapse that caused mitochondrial dislocation. AAV-mediated replacement therapy could be a promising safe and efficient treatment option for limb-girdle muscular dystrophy R7. The study highlights the potential of AAV-mediated replacement therapy for specific types of limb-girdle muscular dystrophy.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":10.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520989","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":"MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination","authors":"Charles Frison-Roche, Célia Martin Demier, Steve Cottin, Jeanne Lainé, Ludovic Arandel, Marius Halliez, Mégane Lemaitre, Xavière Lornage, Laure Strochlic, Maurice S Swanson, Cécile Martinat, Julien Messéant, Denis Furling, Frédérique Rau","doi":"10.1093/brain/awae336","DOIUrl":"https://doi.org/10.1093/brain/awae336","url":null,"abstract":"Muscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of Myotonic Dystrophy type 1 (DM1). In DM1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease. While attention to MBNL proteins has focused on their functions in skeletal muscle, new evidence suggests that their importance extends to motor neurons (MNs), pivotal cellular components in the control of motor skills and movement. To address this question, we generated conditional double knockout mice in which Mbnl1 and Mbnl2 were specifically deleted in motor neurons (MN-dKO). Adult MN-dKO mice develop gait coordination deficits associated with structural and ultrastructural defects in the neuromuscular junction, indicating that MBNL activity in MNs is crucial for the maintenance of the neuromuscular junction. In addition, transcriptome analysis performed on the spinal cord of MN-dKO mice identified mis-splicing events in genes associated with synaptic transmission and neuromuscular junction homeostasis. In summary, our results highlight the complex roles and regulatory mechanisms of MBNL proteins in MNs for muscle function and locomotion. This work provides valuable insights into fundamental aspects of RNA biology and offers promising avenues for therapeutic intervention in DM1 as well as a range of diseases associated with RNA dysregulation.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490783","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":"CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability","authors":"Marina P Hommersom, Nina Doorn, Sofía Puvogel, Elly I Lewerissa, Annika Mordelt, Ummi Ciptasari, Franziska Kampshoff, Lieke Dillen, Ellen van Beusekom, Astrid Oudakker, Naoki Kogo, Amalia M Dolga, Monica Frega, Dirk Schubert, Bart P C van de Warrenburg, Nael Nadif Kasri, Hans van Bokhoven","doi":"10.1093/brain/awae330","DOIUrl":"https://doi.org/10.1093/brain/awae330","url":null,"abstract":"Haploinsufficiency of the CACNA1A gene, encoding the pore-forming α1 subunit of P/Q-type voltage-gated calcium channels, is associated with a clinically variable phenotype ranging from cerebellar ataxia, to neurodevelopmental syndromes with epilepsy and intellectual disability. To understand the pathological mechanisms of CACNA1A loss-of-function variants, we characterized a human neuronal model for CACNA1A haploinsufficiency, by differentiating isogenic induced pluripotent stem cell lines into glutamatergic neurons, and investigated the effect of CACNA1A haploinsufficiency on mature neuronal networks through a combination of electrophysiology, gene expression analysis, and in silico modeling. We observed an altered network synchronization in CACNA1A+/- networks alongside synaptic deficits, notably marked by an augmented contribution of GluA2-lacking AMPA receptors. Intriguingly, these synaptic perturbations coexisted with increased non-synaptically driven activity, as characterized by inhibition of NMDA and AMPA receptors on micro-electrode arrays. Single-cell electrophysiology and gene expression analysis corroborated this increased intrinsic excitability through reduced potassium channel function and expression. Moreover, we observed partial mitigation of the CACNA1A+/- network phenotype by 4-aminopyridine, a therapeutic intervention for episodic ataxia type 2. Positive modulation of KCa2 channels could reverse the CACNA1A+/- network electrophysiological phenotype. In summary, our study pioneers the characterization of a human induced pluripotent stem cell-derived neuronal model for CACNA1A haploinsufficiency, and has unveiled novel mechanistic insights. Beyond showcasing synaptic deficits, this neuronal model exhibited increased intrinsic excitability mediated by diminished potassium channel function, underscoring its potential as a therapeutic discovery platform with predictive validity.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490794","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":"CCL2 blockade combined with PD-1/P-selectin immunomodulators impedes breast cancer brain metastasis","authors":"Sahar Israeli Dangoor, Rami Khoury, Koren Salomon, Sabina Pozzi, Shir Shahar, Adan Miari, Yael Leichtmann-Bardoogo, Neta Bar-Hai, Neta Frommer, Eilam Yeini, Tom Winkler, Nora Balint Lahat, Iris Kamer, Ori Hadad, Kathrin Laue, Henry Brem, Thomas M Hyde, Jair Bar, Iris Barshack, Uri Ben-David, Dana Ishay-Ronen, Ben M Maoz, Ronit Satchi-Fainaro","doi":"10.1093/brain/awae347","DOIUrl":"https://doi.org/10.1093/brain/awae347","url":null,"abstract":"Over the last two decades, the diagnosis and treatment of breast cancer patients have considerably improved. However, brain metastases remain a major clinical challenge and a leading cause of mortality. Thus, a better understanding of the pathways involved in the metastatic cascade is essential. To this end, we have investigated the reciprocal effects of astrocytes and breast cancer cells, employing traditional 2-dimensional cell culture and our unique 3-dimensional multicellular tumoroid models. Our findings revealed that astrocytes enhance the proliferation, migration, and invasion of breast cancer cells, suggesting a supportive role for astrocytes in breast cancer outgrowth to the brain. Elucidating the key players in astrocyte-breast cancer cells crosstalk, we found that CCL2 is highly expressed in breast cancer brain metastases tissue sections from both patients and mice. Our in vitro and in vivo models further confirmed that CCL2 has a functional role in brain metastasis. Given their aggressive nature, we sought additional immune checkpoints for rationale combination therapy. Among the promising candidates were the adhesion molecule P-selectin, which we have recently shown to play a key role in the crosstalk with microglia cells, and the co-inhibitory receptor PD-1, the main target of currently approved immunotherapies. Finally, combining CCL2 inhibition with immunomodulators targeting either PD-1/PD-L1 or P-selectin/P-Selectin Ligand-1 axes in our human 3-dimensional tumoroid models and in vivo presented more favorable outcomes than each monotherapy. Taken together, we propose that CCL2-CCR2/CCR4 is a key pathway promoting breast cancer brain metastases and a promising target for an immunotherapeutic combination approach.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489636","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":"Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts","authors":"Sophie N M Binks, Katherine S Elliott, Sergio Muñiz-Castrillo, Edmund Gilbert, Tânia Kawasaki de Araujo, Andrew R Harper, Andrew C Brown, Amanda Y Chong, Gavin Band, Vicente Peris Sempere, Anne-Laurie Pinto, Felicie Costantino, N William Rayner, Alexander J Mentzer, Norman Delanty, Veronique Rogemond, Géraldine Picard, Adam E Handel, Nico Melzer, Maarten J Titulaer, Soon-Tae Lee, Frank Leypoldt, Gregor Kuhlenbaeumer, Jérôme Honnorat, Emmanuel Mignot, Gianpiero L Cavelleri, Julian C Knight, Sarosh R Irani","doi":"10.1093/brain/awae349","DOIUrl":"https://doi.org/10.1093/brain/awae349","url":null,"abstract":"Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leucocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesised the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms (SNPs) at genome-wide significance (p &amp;lt; 5 x 10−8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490611","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":"Radiosurgery versus observation for brainstem cavernous malformations: a 5-year multicentre cohort study.","authors":"Da Li,Jian-Cong Weng,Shi-Bin Sun,Gui-Jun Zhang,Bo-Han Yao,Guo-Kai Wang,Jing Chen,Shou-Xin Feng,Hai-Tao Liu,Fu-Gui Zhou,Pan-Pan Liu,Lu Kong,Hui Zhou,Hao-Yu Zhang,Xiao-Jun Zeng,Ze-Yu Wu,Jiu-Luan Lin,Cong Ren,Wei Wang,Hong-Jun Zhang,Xiao-Ying Xu,Lai-Rong Song,Xin Du,Liang Wang","doi":"10.1093/brain/awae337","DOIUrl":"https://doi.org/10.1093/brain/awae337","url":null,"abstract":"The role of radiosurgery in preventing haemorrhage in brainstem cavernous malformations remains a subject of debate. This study aims to evaluate whether radiosurgery provides a protective benefit against haemorrhage in these patients. This multicentre, prospective observational study was conducted in 17 centres and enrolled eligible patients with brainstem cavernous malformations consecutively. Data collected included clinical baseline information, radiosurgery planning details, periodic follow-up evaluations, and any adverse radiation effects. The primary outcome of the study was the incidence of first prospective haemorrhage, while the secondary outcome was the development of new or worsening neurological dysfunctions. The impact of radiosurgery was assessed using multivariate Cox regression analysis. From March 2016 to August 2018, the study enrolled 377 patients: 280 in the observation group receiving standard care alone and 97 in the radiosurgery group receiving both radiosurgery and standard care. The overall cohort consisted of 173 females (45.9%) with a mean age of 40.5 years (range, 18-68 years), and there were no significant differences in baseline characteristics between the two groups. After a median follow-up period of 70 months, haemorrhage occurred in 25.0% (n = 70) of patients in the observation group and 10.3% (n = 10) of patients in the radiosurgery group. Multivariate Cox regression analysis identified radiosurgery as an independent protective factor against haemorrhage (hazard ratio 0.379, 95% confidence interval 0.195-0.738, P = 0.004). Following 1:2 propensity score matching, the incidence of prospective haemorrhage were 24.9% (45/181) in the observation group compared to 10.3% (10/97) in the radiosurgery group (hazard ratio 0.379, 95% confidence interval 0.190-0.755, P = 0.006). Adverse radiation effects were observed in 12 patients (12.4%), with none were permanent. Additionally, new or worsening neurological dysfunctions were significantly more common in the observation group (28.9%) compared to the radiosurgery group (16.5%) (P = 0.016). These results suggest that radiosurgery is associated with a low rate of haemorrhage in patients with brainstem cavernous malformations and could provide a benefit in selected patients. However, further research is required to confirm these findings.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489357","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":"Delineating three distinct spatiotemporal patterns of brain atrophy in Parkinson’s disease","authors":"Yusuke Sakato, Atsushi Shima, Yuta Terada, Kiyoaki Takeda, Haruhi Sakamaki-Tsukita, Akira Nishida, Kenji Yoshimura, Ikko Wada, Koji Furukawa, Daisuke Kambe, Hiroki Togo, Yohei Mukai, Masanori Sawamura, Etsuro Nakanishi, Hodaka Yamakado, Yasutaka Fushimi, Tomohisa Okada, Yuji Takahashi, Yuji Nakamoto, Ryosuke Takahashi, Takashi Hanakawa, Nobukatsu Sawamoto","doi":"10.1093/brain/awae303","DOIUrl":"https://doi.org/10.1093/brain/awae303","url":null,"abstract":"The clinical manifestation of Parkinson’s disease exhibits significant heterogeneity in the prevalence of non-motor symptoms and the rate of progression of motor symptoms, suggesting that Parkinson’s disease can be classified into distinct subtypes. In this study, we aimed to explore this heterogeneity by identifying a set of subtypes with distinct patterns of spatiotemporal trajectories of neurodegeneration. We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that combined disease progression modelling with clustering methods, to cortical and subcortical neurodegeneration visible on 3 T structural MRI of a large cross-sectional sample of 504 patients and 279 healthy controls. Serial longitudinal data were available for a subset of 178 patients at the 2-year follow-up and for 140 patients at the 4-year follow-up. In a subset of 210 patients, concomitant Alzheimer’s disease pathology was assessed by evaluating amyloid-β concentrations in the CSF or via the amyloid-specific radiotracer 18F-flutemetamol with PET. The SuStaIn analysis revealed three distinct subtypes, each characterized by unique patterns of spatiotemporal evolution of brain atrophy: neocortical, limbic and brainstem. In the neocortical subtype, a reduction in brain volume occurred in the frontal and parietal cortices in the earliest disease stage and progressed across the entire neocortex during the early stage, although with relative sparing of the striatum, pallidum, accumbens area and brainstem. The limbic subtype represented comparative regional vulnerability, which was characterized by early volume loss in the amygdala, accumbens area, striatum and temporal cortex, subsequently spreading to the parietal and frontal cortices across disease stage. The brainstem subtype showed gradual rostral progression from the brainstem extending to the amygdala and hippocampus, followed by the temporal and other cortices. Longitudinal MRI data confirmed that 77.8% of participants at the 2-year follow-up and 84.0% at the 4-year follow-up were assigned to subtypes consistent with estimates from the cross-sectional data. This three-subtype model aligned with empirically proposed subtypes based on age at onset, because the neocortical subtype demonstrated characteristics similar to those found in the old-onset phenotype, including older onset and cognitive decline symptoms (P &amp;lt; 0.05). Moreover, the subtypes correspond to the three categories of the neuropathological consensus criteria for symptomatic patients with Lewy pathology, proposing neocortex-, limbic- and brainstem-predominant patterns as different subgroups of α-synuclein distributions. Among the subtypes, the prevalence of biomarker evidence of amyloid-β pathology was comparable. Upon validation, the subtype model might be applied to individual cases, potentially serving as a biomarker to track disease progression and predict temporal evolution.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489062","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":"Central nervous system manifestations in acute and chronic graft-versus-host disease.","authors":"Nicolas Lambert,Florence Forte,Majdouline El Moussaoui,Justine Monseur,Nicole Raus,Alexey Polushin,David Michonneau,Carl Shultz,William J Hogan,Aitana Balaguer-Roselló,Sara Gil-Perotìn,Jan Brijs,Paul Chauvet,Maria Gavriilaki,Martin Carre,Adriana Octaviana Dulamea,Yves Chalandon,Urpu Salmenniemi,Andrea Duminuco,Ron Ram,Irene García-Cadenas,Gaetana Porto,Stéphanie Nguyen,Portia Smallbone,Marta González-Vicent,Jonathan D Santoro,Evelyne Willems,Frédéric Baron,Sophie Servais,Yves Beguin,Pierre Maquet,","doi":"10.1093/brain/awae340","DOIUrl":"https://doi.org/10.1093/brain/awae340","url":null,"abstract":"Despite the growing evidence supporting the existence of CNS involvement in acute and chronic graft-versus-host disease (CNS-GvHD), the characteristics and course of the disease are still largely unknown. In this multicenter retrospective study, we analyzed the clinical, biological, radiological, and histopathological characteristics, as well as the clinical course of 66 patients diagnosed with possible CNS-GvHD (pCNS-GvHD), selected by predetermined diagnostic criteria. Results were then contrasted depending on whether pCNS-GvHD occurred before or after day 100 following allogeneic hematopoietic stem cell transplantation. Median time between hematopoietic stem cell transplantation and pCNS-GvHD onset was 149 days (IQ25-75 48-321), and pCNS-GvHD onset occurred before day 100 following transplantation in 44% of patients. The most frequent findings at presentation were cognitive impairment (41%), paresis (21%), altered consciousness (20%), sensory impairment (18%), and headache (15%). Clinical presentation did not significantly differ between patients with pCNS-GvHD occurring before or after day 100 following transplantation. Brain MRI found abnormalities compatible with the clinical picture in 57% of patients, while CT detected abnormalities in only 7%. Seven patients had documented spinal cord MRI abnormalities, all of them with pCNS-GvHD occurring after day 100 following transplantation. In the cerebrospinal fluid, white blood cell count was increased in 56% of the population (median 18 cells/μL). Histopathological analyses were performed on 12 specimens and were suggestive of pCNS-GvHD in 10. All compatible specimens showed parenchymal and perivascular infiltration by CD3+ and CD163+ cells. Immunosuppressive therapy was prescribed in 97% of patients, achieving complete clinical response in 27%, partial improvement in 47% and stable disease in 6%. Response to immunosuppressive therapy did not significantly differ between patients with pCNS-GvHD occurring before or after day 100 following transplantation. Clinical relapse was observed in 31% of patients who initially responded to treatment. One-year overall survival following pCNS-GvHD onset was 41%. Onset before day 100 following hematopoietic stem cell transplantation (HR [95%CI]: 2.1 [1.0-4.5]; P=0.041) and altered consciousness at initial presentation (HR [95%CI]: 3.0 [1.3-6.7]; P=0.0077) were associated with a reduced one-year overall survival probability. Among surviving patients, 61% had neurological sequelae. This study supports that immune-mediated CNS manifestations may occur following allo-HSCT. These can be associated with both acute and chronic GvHD and carry a grim prognosis. The clinical presentation as well as the radiological and biological findings appear variable.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489653","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":"A long look at Copley's A Boy with a Flying Squirrel: implications for the default mode network.","authors":"Geoffrey D Schott","doi":"10.1093/brain/awae342","DOIUrl":"https://doi.org/10.1093/brain/awae342","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488276","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":"α2δ-2 regulates synaptic GluK1 kainate receptors in Purkinje cells and motor coordination.","authors":"Meng-Hua Zhou,Jing-Jing Zhou,Shao-Rui Chen,Hong Chen,Daozhong Jin,Yuying Huang,Jian-Ying Shao,Hui-Lin Pan","doi":"10.1093/brain/awae333","DOIUrl":"https://doi.org/10.1093/brain/awae333","url":null,"abstract":"Gabapentin and pregabalin are inhibitory ligands of both α2δ-1 and α2δ-2 proteins (also known as subunits of voltage-activated Ca2+ channels) and are commonly prescribed for the treatment of neuropathic pain and epilepsy. However, these drugs can cause gait disorders and ataxia through unknown mechanisms. α2δ-2 and GluK1, a glutamate-gated kainate receptor subtype, are coexpressed in cerebellar Purkinje cells. In this study, we used a heterologous expression system and Purkinje cells to investigate the potential role of α2δ-2 in regulating GluK1-containing kainate receptor activity. Whole-cell patch clamp recordings showed that α2δ-2 coexpression augmented GluK1, but not GluK2, currents in HEK293 cells, and pregabalin abolished this augmentation. Pregabalin lost its inhibitory effect on GluK1 currents in HEK293 cells expressing both GluK1 and the α2δ-2(R282A) mutant. Blocking GluK1-containing receptors with UBP310 substantially reduced the amplitude of excitatory postsynaptic currents at parallel fiber-Purkinje cell synapses in mice. Also, pregabalin markedly attenuated the amplitude of excitatory postsynaptic currents and currents elicited by ATPA, a selective GluK1 receptor agonist, in Purkinje cells in Cacna2d1 knockout mice. Coimmunoprecipitation assays indicated that α2δ-2, but not α2δ-1, formed a protein complex with GluK1 in cerebellar tissues and HEK293 cells through its C terminus. Furthermore, α2δ-2 coexpression potentiated surface expression of GluK1 proteins in HEK293 cells, whereas pregabalin reduced GluK1 proteins in cerebellar synaptosomes. Disrupting α2δ-2-GluK1 interactions using α2δ-2 C-terminus peptide abrogated the potentiating effect of α2δ-2 on GluK1 currents and attenuated the amplitude of GluK1-mediated excitatory postsynaptic currents in Purkinje cells. However, neither pregabalin nor α2δ-2 C-terminus peptide had significant effect on P/Q-type currents in HEK293 cells. Additionally, CRISPR/Cas9-induced conditional knockdown of Cacna2d2 or Grik1 in Purkinje cells, as well as microinjection of α2δ-2 C-terminus peptide or UBP310 into the cerebellum, substantially impaired beam walking and rotarod performance in mice. Our study reveals that α2δ-2 directly interacts with GluK1 independently of its conventional role as a voltage-activated Ca2+ channel subunit. α2δ-2 regulates motor coordination by promoting synaptic expression and activity in GluK1-containing kainate receptors in Purkinje cells.","PeriodicalId":9063,"journal":{"name":"Brain","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488277","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}