Brain communications最新文献

{"title":"Na_V1.7, 1.8 and 1.9 mutations linked to painful channelopathies have no pain phenotype in UK Biobank.","authors":"Graeme W T Newton, Corin Charman, Aidan P Nickerson, Keith G Phillips, Achim Kless, James P Dunham, Anthony E Pickering","doi":"10.1093/braincomms/fcag374","DOIUrl":"https://doi.org/10.1093/braincomms/fcag374","url":null,"abstract":"<p><p>The voltage-gated sodium channels Na_V1.7, Na_V1.8 and Na_V1.9, encoded by the <i>SCN9A</i>, <i>SCN10A</i> and <i>SCN11A</i> genes, respectively, are integral to nociceptor excitability and pain sensation. Multiple gain-of-function mutations in these ion channels have been reported to cause autosomal dominant painful channelopathies, including primary erythromelalgia, paroxysmal extreme pain disorder and familial episodic pain. Conversely, autosomal recessive loss-of-function mutations in Na_V1.7 have been reported to cause painless channelopathies. The prevalence and impact on carriers of these voltage-gated sodium channel genetic variants in the wider population has yet to be explored. A combined genetic database and literature search was performed to identify pathogenic gain-of-function variants linked to painful channelopathies which had supporting <i>in vitro</i> electrophysiological evidence. Loss-of-function variants were identified by their inferred impact upon protein sequence. We investigated these variants within the UK Biobank cohort 500k whole-exome sequencing dataset. Logistic regression was used to examine whether carrying these variants was associated with chronic pain, neuropathic pain, and analgesic or anti-neuropathic drug prescriptions (adjusting for age, sex and 10 genetic principal components). For Na_V1.7, 20/59 putative pathogenic gain-of-function mutations identified from literature were found in UK Biobank, with 148 901 carriers (>29% of the cohort). For Na_V1.8, 4/5 gain-of-function mutations were found, with 1104 carriers. For Na_V1.9, 13/17 gain-of-function mutations were found, with 1324 carriers. For predicted loss-of-function mutations in Na_V1.7, Na_V1.8 and Na_V1.9, there were 723, 1307 and 1143 heterozygous carriers, respectively, and 2 homozygous Na_V1.9 loss-of-function carriers. A total of 21 Na_V mutation groups had ≥50 heterozygous carriers allowing logistic regression analysis. None of these groups had a significantly altered risk of chronic or neuropathic pain. Similarly, no differences in prescriptions of opioid analgesics or anti-neuropathic pain medications were found. Subsequent pathogenicity prediction indicated that the gain-of-function variants called in UK Biobank had significantly lower predicted pathogenicity scores than those that were absent from the cohort. These findings show that over one-third of the previously reported pathogenic Na_V1.7 gain-of-function mutations are likely to be benign for pain. This study challenges the previously assumed high penetrance of these Na_V gain-of-function mutations for chronic pain, and we make recommendations to optimize the evidence-based criteria for genetic association studies investigating the role of ion channel variants in the pathogenesis of pain.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag374"},"PeriodicalIF":4.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13684400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149248005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of brain-derived versus conventional pTau biomarkers in CSF and plasma for detecting Alzheimer's disease.","authors":"Lydia Trudel, Joseph Therriault, Valentina Ghisays, Arthur C Macedo, Serge Gauthier, Paolo Vitali, Andrea L Benedet, Henrik Zetterberg, Yi Su, Alpana Singh, Tainá Marques, Marisa N Denkinger, Nicholas T Seyfried, Allan I Levey, Michael W Weiner, Kendall Van Keuren-Jensen, Eric M Reiman, Nicholas J Ashton, Pedro Rosa-Neto","doi":"10.1093/braincomms/fcag376","DOIUrl":"10.1093/braincomms/fcag376","url":null,"abstract":"<p><p>Brain-derived phosphorylated tau species are postulated to improve the detection of Alzheimer's disease pathology by mitigating non-specific increases. However, their true diagnostic performance, relative to conventional CSF and plasma phosphorylated tau assays, remains uncharacterized. The objective was to compare the diagnostic performance of brain-derived and conventional phosphorylated tau assays across multiple analytes (phosphorylated tau 181, phosphorylated tau 217, phosphorylated tau 231) in CSF and plasma, and to examine biomarker differences across amyloid-β status and cognitive groups. This study included 1098 participants with amyloid-PET imaging and CSF samples from the Alzheimer's Disease Neuroimaging Initiative, and a subset of 925 individuals with plasma samples. Diagnostic performance of brain-derived and conventional phosphorylated tau assays was assessed by receiver operating characteristic curves, with calculation of area under the curve, sensitivity, specificity and optimal cutpoints. Associations with amyloid-β burden were evaluated using Spearman correlations, and fold-changes between amyloid-PET-positive and amyloid-PET-negative participants were computed in cognitively unimpaired and cognitively impaired subgroups with 95% confidence intervals from 2000 bootstrap resamples. Brain-derived phosphorylated tau assays showed significantly higher diagnostic performance than conventional phosphorylated tau assays at the same phosphorylation site in both CSF and plasma in the overall sample and in cognitively impaired individuals, except for CSF phosphorylated tau 217. While CSF brain-derived phosphorylated tau correlations with amyloid-PET were similar to conventional CSF assays, pairwise comparisons using DeLong's test revealed significantly higher diagnostic accuracy for brain-derived assays. Receiver operating characteristic performance was generally better in cognitively impaired participants than in cognitively unimpaired participants. Additionally, using a three-range method with cutpoints corresponding to 90% sensitivity and 90% specificity, plasma brain-derived phosphorylated tau 181, phosphorylated tau 217 and brain-derived phosphorylated tau 217 had <20% of participants in the intermediate range overall and in cognitively impaired individuals. In summary, brain-derived phosphorylated tau assays improve detection of amyloid-β positivity relative to conventional assays, especially in plasma, and provide robust differentiation of amyloid-PET-positive and amyloid-PET-negative participants. If these findings are confirmed using fully automated diagnostic platforms that are intended for use in clinical settings, brain-derived phosphorylated tau assays may support future blood-based biomarker triage workflows for identifying Alzheimer's disease.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag376"},"PeriodicalIF":4.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of neurofilament light chain and other fluid biomarkers in cerebellar ataxias.","authors":"Charlotte Mouraux, Magda M Santana, Liana S Rosenthal, Andrea Cortese, Filippo M Santorelli, Puneet Opal, Giulia Coarelli","doi":"10.1093/braincomms/fcag313","DOIUrl":"10.1093/braincomms/fcag313","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The genetic and phenotypic heterogeneity of hereditary ataxias complicates the design of clinical trials since each ataxia progresses at different rates. Consequently, robust biomarkers are urgently needed to monitor therapeutic efficacy and safety of potential therapeutic interventions. Neurofilament light chain has emerged as a leading candidate, serving as a sensitive pharmacodynamic biomarker of neuronal injury and treatment response in neurodegenerative disorders. This review explores the utility of neurofilament light chain across various ataxias, including polyglutamine spinocerebellar ataxias, Friedreich's ataxia, multiple system atrophy, and other genetic ataxias, such as ataxias associated with &lt;i&gt;RCF1&lt;/i&gt; and &lt;i&gt;SPG7&lt;/i&gt; genes. We synthesize evidence from recent studies that have used ultra-sensitive assays. These studies consistently demonstrate elevated neurofilament light chain levels in cerebrospinal fluid and blood, correlating with disease severity, progression and neuroimaging findings. Notably, neurofilament light chain levels rise during the presymptomatic stage in spinocerebellar ataxias, highlighting its potential for stratifying individuals for trial enrolment and tracking therapeutic effects. A treatment-induced reduction in neurofilament light chain could function as a surrogate endpoint for target engagement, analogous to its validated use in amyotrophic lateral sclerosis. Finally, we discuss the results of other studies conducted on other biomarkers, including glial fibrillary acidic protein, total tau and phosphorylated tau, which may reflect complementary aspects of neurodegeneration and glial activation. Glial fibrillary acidic protein may provide insights into astroglial reactivity and neuroinflammation. Similarly, alteration in total tau and phosphorylated tau levels may suggest dysfunction in neuronal cytoskeleton and axonal integrity. The review also focuses on target-engagement biomarkers, including polyglutamine-expanded ataxin proteins in spinocerebellar ataxias and frataxin in Friedreich's ataxia, as critical tools to complement the ataxia biomarker toolkit. The quantification of mutant ataxin proteins provides a mechanistic readout for emerging gene-silencing or protein-lowering therapies. In parallel, the measurement of frataxin levels serves as a pharmacodynamic marker in therapeutic strategies aiming to restore frataxin expression. These target-engagement biomarkers are valuable in early phases of clinical trials, which mainly aim to demonstrate the biological activity of a treatment before later-phase trials assessing clinical efficacy. Finally, we report on somatic instability in polyglutamine spinocerebellar ataxias as an emerging and highly relevant therapeutic target. CAG repeat mosaicism is gene specific and correlates with disease progression. Integrating measures of repeat instability with neurodegenerative biomarkers could provide a comprehensive monitoring approach in clinical studies. Thi","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag313"},"PeriodicalIF":4.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin C-hydrolase L1 as a cerebrospinal fluid and blood biomarker for prion diseases.","authors":"Sezgi Canaslan, Matthias Schmitz, Anna-Lisa Fischer, Susana Da Silva Correia, Angela Da Silva Correia, Tayyaba Saleem, Peter Hermann, Inga Zerr","doi":"10.1093/braincomms/fcag363","DOIUrl":"https://doi.org/10.1093/braincomms/fcag363","url":null,"abstract":"<p><p>Digital enzyme-linked immunosorbent assays are based on single-molecule array technology. In this study, ubiquitin C-terminal hydrolase L1 (UCH-L1) levels were measured in cerebrospinal fluid (CSF) and blood samples (serum or plasma) obtained from patients with sporadic Creutzfeldt-Jakob disease and fatal familial insomnia using a commercially available UCH-L1 assay. We determined the inter- and intra-assay variability as well as the stability of UCH-L1 detection to ensure a reliable assay performance. Cut-off values were calculated to differentiate prion disease patients from neurodegenerative and non-neurodegenerative control groups. Patients with Creutzfeldt-Jakob disease exhibited significantly higher levels of UCH-L1 in both CSF and serum than controls. Receiver operating characteristic (ROC) analysis yielded area under the curve (AUC) values ranging from 0.91 to 0.97 for CSF and from 0.58 to 0.86 for serum. These values allow an excellent discrimination between Creutzfeldt-Jakob disease patients and controls. Similar findings were observed in the fatal familial insomnia cohort. Here, ROC analysis indicated AUC values between 0.79 and 0.91 for CSF and up to 0.95 for plasma when distinguishing fatal familial insomnia patients from neurodegenerative, non-neurodegenerative and healthy controls. Altogether, our study suggests that detection of UCH-L1 levels in CSF and blood is suitable for the diagnosis of prion diseases.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag363"},"PeriodicalIF":4.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COVID-19 pleiotropy with brain imaging-derived phenotypes highlights novel insights into the biology shared between immune function and brain variation.","authors":"Qianyu Chen, Jun He, Brenda Cabrera-Mendoza, Ziang Xu, Dan Qiu, Renato Polimanti","doi":"10.1093/braincomms/fcag372","DOIUrl":"10.1093/braincomms/fcag372","url":null,"abstract":"<p><p>This study investigated the pleiotropy and the underlying biology linking COVID-19 outcomes to brain variation, leveraging genome-wide data from the COVID-19 Host Genetics Initiative and multimodal brain-wide magnetic resonance imaging from the UK Biobank. In our analyses, COVID-19 outcomes showed evidence of polygenic overlap with respect to 11 imaging-derived phenotypes (IDPs) related to brain structure (e.g. parahippocampal and entorhinal cortical thickness) and connectivity (e.g. Broca's area and dorsolateral prefrontal cortex). Among these, the genetic liability to COVID-19 hospitalization and SARS-CoV-2 infection was inversely related to the area of pars opercularis. We also identified local genetic correlations between COVID-19 outcomes and brain IDPs within five loci mapping genes involved in inflammatory response, immune regulation, brain development, and neuropsychiatric disorders (e.g. <i>LAMP3</i>, <i>SOX2</i>, and <i>TSHZ2</i>). Additionally, we uncovered colocalized variants linking COVID-19 outcomes to brain structural variation (rs13107325 with entorhinal mean thickness) and brain transcriptomic regulation of immune-related genes (e.g. <i>IL6R</i> in brain cortex and <i>HLA-C</i> in caudate basal ganglia). Our drug-repurposing analysis based on gene ontologies shared between COVID-19 outcomes and brain IDPs uncovered 41 compounds, including psychiatric medications that appear to also have antiviral and immunomodulatory activity. Overall, the present findings contributed to dissecting the biological mechanisms shared between COVID-19 and brain variation, highlighting the systemic nature of their relationship.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag372"},"PeriodicalIF":4.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149217383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Viral heritability of neurocognitive performances in persons living with HIV and underlying viral residue variants.","authors":"Marius Zeeb, Mélanie Bieler-Aeschlimann, Paul Frischknecht, Kathrin Neumann, Lisa Jörimann, Jasmin Tschumi, Michael Huber, Katharina Kusejko, Enos Bernasconi, Helen Kovari, Karoline Leuzinger, Julia Notter, Matthieu Perreau, Cornelia Staehelin, Alban Ramette, Marcel Stöckle, Sabine Yerly, Alexandra Calmy, Karin J Metzner, Huldrych F Günthard, Matthias Cavassini, Roger D Kouyos","doi":"10.1093/braincomms/fcag371","DOIUrl":"https://doi.org/10.1093/braincomms/fcag371","url":null,"abstract":"<p><p>Neurocognitive impairments (NCI) affect up to 50% of persons living with HIV (PLWH), even under anti-retroviral therapy. Evidence suggests that HIV-1 genotypes at least in part contribute to NCI, but most studies considered composite scores and did not examine specific neurocognitive domains. We considered neurocognitive domains assessed in the Neurocognitive Assessment in the Metabolic and Ageing Cohort, a sub study of the Swiss HIV Cohort Study (SHCS), and determined associations with HIV-1 residues, detected by full-length genome sequencing, previously linked to self-reported neurocognitive complaints (SRNC) in the SHCS, using linear regression. Additionally, we determined the heritability with Brownian motion- and mixed models based on viral <i>pol</i> phylogenies. In 192 out of 981 PLWH with full-length sequences, among the top residue variants identified, Env641E and Rev18I had been previously associated with SRNC. Respectively, of identified residue variants, point estimates correlated highly with previous SRNC-estimates from the SHCS for sensory skills (<i>r</i> = -0.71, <i>P</i> < 0.0001) and speed of processing (<i>r</i> = -0.71, <i>P</i> < 0.0001). Heritability estimates in 981 PLWH were significant for sensory skills [25.9%, 95% confidence interval (CI) 5.5-44.6%], motor skills (24.3%, CI 3.7-43.3%), and speed of processing (23.5%, CI 5.2-40.7%). Our findings support prior observations regarding SRNC-associated viral residues and confirm the relevance of the infecting HIV-1 strains for neurocognitive performances.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag371"},"PeriodicalIF":4.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149247693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reappraising the claims of evolutionary continuity between thanatosis and near-death experiences.","authors":"Jorge A Delgado-Ron","doi":"10.1093/braincomms/fcag368","DOIUrl":"10.1093/braincomms/fcag368","url":null,"abstract":"","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag368"},"PeriodicalIF":4.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13655614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microtesla magnetic therapy for cognitive impairment in long COVID: a randomized pilot study.","authors":"Alexandra Canori, Eric Watson, Devanshi Patel, Arianna Fiorentino, Christopher Santiago, David Maltz, Blake Gurfein, David Putrino, Jacqueline Becker","doi":"10.1093/braincomms/fcag364","DOIUrl":"10.1093/braincomms/fcag364","url":null,"abstract":"<p><p>Cognitive impairment is common in post-acute sequelae of severe acute respiratory syndrome coronavirus 2 infection (long COVID) and substantially affects function and quality of life. Evidence suggests that sustained neuroinflammation, cerebrovascular dysfunction and mitochondrial impairment contribute to cognitive symptoms. Microtesla Magnetic Therapy (MMT) is a transcranial, low-amplitude radiofrequency magnetic field intervention that has shown anti-inflammatory and neuroprotective effects in preclinical models, suggesting potential value in long COVID and other neurological disorders. This is the first randomized controlled trial of MMT for long COVID cognitive impairment. We evaluated the feasibility (primary) and safety (secondary) of at-home MMT in individuals with objective cognitive impairment from long COVID. Thirty participants were randomized 2:1 to active or sham MMT and self-administered 15-min treatments at home twice weekly for 4 weeks, with remote monitoring, using a head-worn device delivering a non-thermal radiofrequency magnetic field to the whole brain. Feasibility was defined as completing at least 80% of prescribed treatments and all study visits. Safety was assessed by adverse events. Cognitive function and self-reported mood and quality of life were exploratory outcomes assessed at baseline, Week 4 (post-treatment) and Week 8 (follow-up). Feasibility was high: all participants who completed the study adhered to 100% of treatments, and usability ratings were strong. No device-related adverse events occurred. Compared with sham, active MMT participants showed significantly greater improvement from baseline to Week 8 in Wechsler Adult Intelligence Scale Digit Span Sequencing (<i>P</i> = 0.026), Hopkins Verbal Learning Test-Revised Total Recall (<i>P</i> = 0.044) and Delis-Kaplan Executive Function System Color Naming (<i>P</i> = 0.049). Other measures of attention, processing speed and executive function did not differ significantly between groups. Emotional well-being on the 36-Item Short Form Survey improved significantly more with active MMT at Week 8 (<i>P</i> = 0.017). Depression and anxiety decreased in both groups; the anxiety reduction was greater with active treatment in the linear mixed-effects model (week × treatment interaction, <i>P</i> = 0.038) but not in the between-group change score comparison (<i>P</i> = 0.057). At-home MMT was feasible, safe and well tolerated in individuals with cognitive impairment from long COVID. These preliminary, exploratory findings showed nominally significant between-group differences favouring active treatment on selected cognitive measures and emotional well-being and require confirmation in larger, adequately powered trials.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag364"},"PeriodicalIF":4.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149139772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition/excitation balance is associated with functional connectivity during cognitive flexibility performance.","authors":"Geraldine Rodríguez-Nieto, Mark Mikkelsen, Stephan P Swinnen","doi":"10.1093/braincomms/fcag319","DOIUrl":"10.1093/braincomms/fcag319","url":null,"abstract":"<p><p>The primary excitatory and inhibitory neurotransmitters, glutamate and GABA, regulate neural communication. In this cross-sectional study, we investigated whether the large-scale functional connectivity of two important brain hubs, the inferior frontal cortex and the inferior parietal lobe, is associated with changes in the GABA/Glx (glutamate + glutamine) balance in the in vivo human brain during a cognitive flexibility task. Furthermore, we explored age differences in this relationship, given the alterations in neurotransmitter levels and in cognitive flexibility performance in older adults. Forty young (18-35 years; 26 females) and forty older (60-85 years; 21 females) adults participated. The MRI protocol included functional MRI and baseline and task-related magnetic resonance spectroscopy. Results showed that task-induced modulation of GABA+/Glx is associated with functional connectivity from the inferior frontal cortex and inferior parietal lobe during cognitive flexibility performance. In particular, young adults showed stronger functional connectivity associated with increased inhibitory tone in the inferior frontal cortex than older adults, whereas the pattern was reversed in the inferior parietal lobe. In addition, whereas the connectivity between the left inferior parietal lobe and the bilateral putamen in young adults predicted better cognitive flexibility (left putamen: r = 0.41, <i>P</i> = 0.05; right putamen: r = 0.51 <i>P</i> = 0.01; controlling for GABA modulation), this relationship had an opposite direction in older adults (left putamen: r = -0.33, <i>P</i> = 0.05; right putamen: r = -0.31 <i>P</i> = 0.01; controlling for GABA modulation). In sum, these results show that neurometabolic dynamics and functional connectivity underlying cognitive flexibility undergo substantial changes during ageing.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag319"},"PeriodicalIF":4.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149070654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum circulating cell-free messenger RNA profile response to risdiplam treatment in adult patients with late-onset spinal muscular atrophy.","authors":"Markus Leo, Linda-Isabell Schmitt, Kai Christine Liebig, Stefanie Hezel, Svenja Neuhoff, Andreas Roos, Tobias Ruck, Christoph Kleinschnitz, Tim Hagenacker","doi":"10.1093/braincomms/fcag352","DOIUrl":"10.1093/braincomms/fcag352","url":null,"abstract":"<p><p>SMN-enhancing therapies have improved outcomes in adult late-onset spinal muscular atrophy (loSMA), but minimally invasive biomarkers that reflect systemic disease and treatment effects are lacking. In this retrospective cohort study, we profiled circulating cell-free messenger RNA (ccfmRNA) in serum samples from 17 adults with loSMA type 2 (<i>n</i> = 14) and type 3 (<i>n</i> = 3) and healthy controls (<i>n</i> = 12) using the NanoString neuroimmunology panel before (T0) and after 8-10 (T1) and 12-14 (T2) months of risdiplam treatment. A separate exploratory subgroup of patients switching from nusinersen to risdiplam (<i>n</i> = 7) was analysed at comparable time points. Differential ccfmRNA expression, gene ontology and network analyses were performed. At baseline, adult loSMA showed a distinct inflammatory and stress-related ccfmRNA signature and reduced expression of selected glial- and vascular-associated transcripts compared to controls. Risdiplam partially normalized immune and proteostasis transcripts, whereas glial and vascular modules remained persistently dysregulated. Exploratory subgroup analyses suggested larger transcriptional deviations in type 2 than in type 3, although these findings are limited by small sample size. In switcher patients, additional transcriptional changes involving epigenetic- and lipid-associated pathways were observed and should be regarded as hypothesis-generating. Serum ccfmRNA profiles distinguish adult loSMA from controls and capture risdiplam-associated molecular responses. These findings support the concept that serum ccfmRNA profiling may provide a useful exploratory framework for studying disease-associated and treatment-associated molecular changes in adult loSMA.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"8 5","pages":"fcag352"},"PeriodicalIF":4.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149066057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}