Brain Communications最新文献

{"title":"Deoxyguanosine kinase deficiency: natural history and liver transplant outcome","authors":"Eleonora Manzoni, S. Carli, Pauline Gaignard, L. D. Schlieben, Michio Hirano, Dario Ronchi, Emmanuel Gonzales, Masaru Shimura, Kei Murayama, Yasushi Okazaki, Ivo Barić, Danijela Petković Ramadža, D. Karall, Johannes Mayr, Diego Martinelli, C. La Morgia, G. Primiano, René Santer, Serenella Servidei, C. Bris, Aline Cano, Francesca Furlan, Serena Gasperini, Nolwenn Laborde, C. Lamperti, Dominic Lenz, Michelangelo Mancuso, V. Montano, F. Menni, O. Musumeci, Victoria Nesbitt, Elena Procopio, C. Rouzier, C. Staufner, J. Taanman, Galit Tal, C. Ticci, D. Cordelli, Valerio Carelli, V. Procaccio, Holger Prokisch, C. Garone","doi":"10.1093/braincomms/fcae160","DOIUrl":"https://doi.org/10.1093/braincomms/fcae160","url":null,"abstract":"Abstract Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype–phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"40 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141010565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enrichment of oligodendrocyte precursor phenotypes in subsets of low-grade glioneuronal tumours","authors":"Z. Duan, Jing Feng, Yuguang Guan, Shouwei Li, Bin Wu, Yang Shao, Zhong Ma, Zejuan Hu, L. Xiang, Mingwang Zhu, Xiaolong Fan, X. Qi","doi":"10.1093/braincomms/fcae156","DOIUrl":"https://doi.org/10.1093/braincomms/fcae156","url":null,"abstract":"Abstract Current histological classification of low-grade glioneuronal tumours does not adequately represent their underlying biology. The neural lineage(s) and differentiation stage(s) involved and the cell state(s) affected by the recurrent genomic alterations are unclear. Here, we describe dysregulated oligodendrocyte lineage developmental programmes in three low-grade glioneuronal tumour subtypes. Ten dysembryoplastic neuroepithelial tumours, four myxoid glioneuronal tumours and five rosette-forming glioneuronal tumours were collected. Besides a comprehensive characterization of clinical features, known diagnostic markers and genomic alterations, we used comprehensive immunohistochemical stainings to characterize activation of rat sarcoma/mitogen-activated protein kinase pathway, involvement of neuronal component, resemblance to glial lineages and differentiation blockage along the stages of oligodendrocyte lineage. The findings were further complemented by gene set enrichment analysis with transcriptome data of dysembryoplastic neuroepithelial tumours from the literature. Dysembryoplastic neuroepithelial tumours, myxoid glioneuronal tumours and rosette-forming glioneuronal tumours occur at different ages, with symptoms closely related to tumour location. Dysembryoplastic neuroepithelial tumours and myxoid glioneuronal tumours contain oligodendrocyte-like cells and neuronal component. Rosette-forming glioneuronal tumours contained regions of rosette-forming neurocytic and astrocytic features. Scattered neurons, identified by neuronal nuclei antigen and microtubule-associated protein-2 staining, were consistently observed in all dysembryoplastic neuroepithelial tumours and myxoid glioneuronal tumours examined, but only in one rosette-forming glioneuronal tumour. Pervasive neurofilament-positive axons were observed only in dysembryoplastic neuroepithelial tumour and myxoid glioneuronal tumour samples. Alterations in B-Raf proto-oncogene, serine/threonine kinase, fibroblast growth factor receptor 1, fibroblast growth factor receptor 3 and platelet-derived growth factor receptor alpha occurred in a mutually exclusive manner, coinciding with strong staining of phospho-p44/42 mitogen-activated protein kinase and low apoptotic signal. All dysembryoplastic neuroepithelial tumours, myxoid glioneuronal tumours and the neurocytic regions of rosette-forming glioneuronal tumours showed strong expression of neuron-glia antigen 2, platelet-derived growth factor receptor alpha (markers of oligodendrocyte precursor cells) and neurite outgrowth inhibitor-A (a marker of developing oligodendrocytes), but lacked the expression of oligodendrocyte markers ectonucleotide pyrophosphatase/phosphodiesterase family member 6 and myelin basic protein. Notably, transcriptomes of dysembryoplastic neuroepithelial tumours were enriched in oligodendrocyte precursor cell signature, but not in signatures of neural stem cells, myelinating oligodendrocytes and astrocytes. Dysembry","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"14 20","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141005788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of new and chronic cortical lesions to disability accrual in multiple sclerosis","authors":"E. Beck, W. A. Mullins, Jonadab dos Santos Silva, Stefano Filippini, P. Parvathaneni, J. Maranzano, M. Morrison, D. Suto, Corinne Donnay, Henry Dieckhaus, Nicholas J. Luciano, Kanika Sharma, María I Gaitán, Jiaen Liu, J. D. de Zwart, P. van Gelderen, I. Cortese, S. Narayanan, Jeff H Duyn, G. Nair, P. Sati, Daniel S Reich","doi":"10.1093/braincomms/fcae158","DOIUrl":"https://doi.org/10.1093/braincomms/fcae158","url":null,"abstract":"\u0000 Cortical lesions are common in multiple sclerosis and are associated with with disability and progressive disease. We asked whether cortical lesions continue to form in people with stable white matter lesions and whether the association of cortical lesions with worsening disability relates to pre-existing or new cortical lesions.\u0000 50 adults with multiple sclerosis and no new white matter lesions in the year prior to enrollment (33 relapsing-remitting, 17 progressive) and a comparison group of 9 adults who had formed at least one new white matter lesion in the year prior to enrollment (active relapsing-remitting) were evaluated annually with 7 tesla brain MRI and 3 tesla brain and spine MRI for 2 years, with clinical assessments for 3 years. Cortical lesions and paramagnetic rim lesions were identified on 7 tesla images.\u0000 Seven total cortical lesions formed in 3/30 individuals in the stable relapsing-remitting group (median 0, range 0-5), four total cortical lesions formed in 4/17 individuals in the progressive group (median 0, range 0-1), and 16 cortical lesions formed in 5/9 individuals in the active relapsing-remitting group (median 1, range 0-10, stable relapsing-remitting vs progressive vs active relapsing-remitting P=0.006). New cortical lesions were not associated with greater change in any individual disability measure or in a composite measure of disability worsening (worsening Expanded Disability Status Scale or 9-hole peg test or 25-foot timed walk). Individuals with at least 3 paramagnetic rim lesions had a greater increase in cortical lesion volume over time (median 16µl, range -61-215 vs median 1µl, range -24-184, P=0.007), but change in lesion volume was not associated with disability change. Baseline cortical lesion volume was higher in people with worsening disability (median 1010µl, range 13-9888 vs median 267µl, range 0-3539, P=0.001, adjusted for age and sex) and in individuals with relapsing-remitting multiple sclerosis who subsequently transitioned to secondary progressive multiple sclerosis (median 2183µl, range 270-9888 vs median 321µl, range 0-6392 in those who remained relapsing-remitting, P=0.01, adjusted for age and sex). Baseline white matter lesion volume was not associated with worsening disability or transition from relapsing-remitting to secondary progressive multiple sclerosis.\u0000 Cortical lesion formation is rare in people with stable white matter lesions, even in those with worsening disability. Cortical but not white matter lesion burden predicts disability worsening, suggesting that disability progression is related to long-term effects of cortical lesions that form early in disease, rather than to ongoing cortical lesion formation.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"5 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141021201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mice and minipigs with compromised expression of the Alzheimer´s disease gene SORL1 show cerebral metabolic disturbances on hyperpolarized [1-13C]pyruvate and sodium MRI","authors":"N. Bøgh, Charlotte B Sørensen, A. Alstrup, Esben S S Hansen, Olav M Andersen, C. Laustsen","doi":"10.1093/braincomms/fcae114","DOIUrl":"https://doi.org/10.1093/braincomms/fcae114","url":null,"abstract":"\u0000 The sortilin related receptor 1 (SORL1) gene, encoding the cellular endosomal sorting-related receptor with A-type repeats (SORLA), is now established as a causal gene of Alzheimer’s Disease (AD). As the latest addition to the list of causal genes, the pathophysiological effects and biomarker potential of SORL1-variants remain relatively undiscovered. Metabolic dysfunction is, however, well described in patients with AD and is used as an imaging biomarker in clinical diagnosis settings. To understand the metabolic consequences of loss-of-function SORL1-mutations, we applied two metabolic magnetic resonance imaging (MRI) technologies, sodium (23Na) MRI and MRI with hyperpolarized [1-13C]pyruvate, in minipigs and mice with compromised expression of SORL1. At the age analyzed here, both animal models display no conventional imaging evidence of neurodegeneration but show biochemical signs of elevated amyloid production, thus representing the early preclinical disease. With hyperpolarized MRI, the exchange from [1-13C]pyruvate to [1-13C]lactate and 13C-bicarbonate was decreased by 32% and 23%, respectively, in the cerebrum of SORL1 haploinsufficient minipigs. A robust 11% decrease in the sodium content was observed with 23Na-MRI in the same minipigs. Comparably, the brain sodium concentration gradually decreased from control to SORL1 haploinsufficient (-11%) to SORL1 knockout mice (-23%), suggesting a gene dose-dependence in the metabolic dysfunction. The present study highlights that metabolic MRI technologies are sensitive to the functional, metabolic consequences of AD and AD-linked genotypes. Further, the study suggests a potential avenue of research into the mechanisms of metabolic alterations by SORL1-mutations and their potential role in neurodegeneration.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140359515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morphological profiling in human neural progenitor cells classifies hits in a pilot drug screen for Alzheimer’s disease","authors":"Amina H. McDiarmid, Katerina O. Gospodinova, Richard J. R. Elliott, John C. Dawson, Rebecca E. Graham, Marie-Thérèse El-Daher, Susan M Anderson, Sophie C Glen, Simon Glerup, Neil O Carragher, Kathryn L Evans","doi":"10.1093/braincomms/fcae101","DOIUrl":"https://doi.org/10.1093/braincomms/fcae101","url":null,"abstract":"Abstract Alzheimer’s disease accounts for 60–70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently, in cancer, morphological profiling has been used in combination with high-throughput screening of small-molecule libraries in human cells in vitro. To test feasibility of this approach for Alzheimer’s disease, we developed a cell morphology-based drug screen centred on the risk gene, SORL1 (which encodes the protein SORLA). Increased Alzheimer’s disease risk has been repeatedly linked to variants in SORL1, particularly those conferring loss or decreased expression of SORLA, and lower SORL1 levels are observed in post-mortem brain samples from individuals with Alzheimer’s disease. Consistent with its role in the endolysosomal pathway, SORL1 deletion is associated with enlarged endosomes in neural progenitor cells and neurons. We, therefore, hypothesized that multi-parametric, image-based cell phenotyping would identify features characteristic of SORL1 deletion. An automated morphological profiling method (Cell Painting) was adapted to neural progenitor cells and used to determine the phenotypic response of SORL1−/− neural progenitor cells to treatment with compounds from a small internationally approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures for SORL1−/− neural progenitor cells compared to isogenic wild-type controls. Furthermore, we identified 16 compounds (representing 14 drugs) that reversed the mutant morphological signatures in neural progenitor cells derived from three SORL1−/− induced pluripotent stem cell sub-clones. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis identified DNA synthesis/damage/repair, proteases/proteasome and metabolism as key pathways/biological processes. Prediction of novel targets revealed enrichment in pathways associated with neural cell function and Alzheimer’s disease. Overall, this work suggests that (i) a quantitative phenotypic metric can distinguish induced pluripotent stem cell-derived SORL1−/− neural progenitor cells from isogenic wild-type controls and (ii) phenotypic screening combined with multi-parametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimer’s disease.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"16 22","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140373258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-dependent effects of metformin on human oligodendrocyte lineage cell ensheathment capacity","authors":"Abdulshakour Mohammadnia, Qiao-Ling Cui, Chao Weng, Moein Yaqubi, M. Fernandes, Jeffery A Hall, Roy Dudley, Myriam Srour, Timothy E Kennedy, Jo Anne Stratton, Jack P. Antel","doi":"10.1093/braincomms/fcae109","DOIUrl":"https://doi.org/10.1093/braincomms/fcae109","url":null,"abstract":"\u0000 Metformin restores myelination potential of aged rat A2B5+ oligodendrocyte progenitor cells and may enhance recovery in children with post-radiation brain injury. Human late progenitor cells (O4 + A2B5+) have superior capacity to ensheath nanofibers compared to mature oligodendrocytes, with cells from pediatric sources exceeding adults. In this study we assessed effects of metformin on ensheathment capacity of human adult and pediatric progenitors and mature oligodendrocytes and relate differences to transcriptional changes. A2B5+ progenitors and mature cells, derived from surgical tissues by immune-magnetic separation, were assessed for ensheathment capacity in nanofiber plates over 2 weeks. Metformin (10 µM every other day) was added to selected cultures. RNA was extracted from treated and control cultures after 2 days. For all ages, ensheathment by progenitors exceeded mature oligodendrocytes. Metformin enhanced ensheathment by adult donor cells but reduced ensheathment by pediatric cells. Metformin marginally increased cell death in pediatric progenitors. Metformin induced changes in gene expression distinct for each cell type. Adult progenitors showed up-regulation of pathways involved in process outgrowth and promoting lipid biosynthesis. Pediatric progenitors showed a relatively greater proportion of down- versus up-regulated pathways, these involved cell morphology, development, and synaptic transmission. Metformin induced AMPK activation in all cell types; AMPK inhibitor BML-275 reduced functional metformin effects only with adult cells. Our results indicate age and differentiation stage related differences of human oligodendroglia lineage cells in response to metformin. Clinical trials for demyelinating conditions will indicate how these differences translate in vivo.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"110 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140370418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insertional effect following electrode implantation: an underreported but important phenomenon","authors":"Clement Hamani, B. Davidson, N. Lipsman, A. Abrahão, Sean M Nestor, Jennifer S Rabin, Peter Giacobbe, Rosana L Pagano, A. C. P. Campos","doi":"10.1093/braincomms/fcae093","DOIUrl":"https://doi.org/10.1093/braincomms/fcae093","url":null,"abstract":"\u0000 Deep brain stimulation has revolutionized the treatment of movement disorders and is gaining momentum in the treatment of several other neuropsychiatric disorders. In almost all applications of this therapy, the insertion of electrodes into the target has been shown to induce some degree of clinical improvement prior to stimulation onset. Disregarding this phenomenon, commonly referred to as “insertional effect”, can lead to biased results in clinical trials, as patients receiving sham stimulation may still experience some degree of symptom amelioration. Similar to the clinical scenario, an improvement in behavioural performance following electrode implantation has also been reported in preclinical models. From a neurohistopathologic perspective, the insertion of electrodes into the brain causes an initial trauma and inflammatory response, the activation of astrocytes, a focal release of gliotransmitters, the hyperexcitability of neurons in the vicinity of the implants, as well as neuroplastic and circuitry changes at a distance from the target. Taken together, it would appear that electrode insertion is not an inert process, but rather, triggers a cascade of biological processes, and, as such, should be considered alongside the active delivery of stimulation, as an active part of the deep brain stimulation therapy.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"35 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140372482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of abnormal explicit sense of agency with cerebellar impairment in myoclonus-dystonia","authors":"C. Tarrano, Cécile Galléa, C. Delorme, Eavan McGovern, Cyril Atkinson-Clement, Isaac Jarratt Barnham, V. Brochard, Stéphane Thobois, Christine Tranchant, D. Grabli, Bertrand Degos, J. Corvol, Jean-Michel Pedespan, Pierre Krystkowiak, J. Houeto, A. Degardin, Luc Defebvre, Romain Valabrègue, Benoit Beranger, E. Apartis, Marie Vidailhet, Emmanuel Roze, Yulia Worbe","doi":"10.1093/braincomms/fcae105","DOIUrl":"https://doi.org/10.1093/braincomms/fcae105","url":null,"abstract":"\u0000 Non-motor aspects in dystonia are now well recognized. The sense of agency, which refers to the experience of controlling one's own actions, has been scarcely studied in dystonia, even though its disturbances can contribute to movement disorders.\u0000 Among various brain structures, the cerebral cortex, the cerebellum, and the basal ganglia are involved in shaping the sense of agency. In myoclonus-dystonia, resulting from a dysfunction of the motor network, an altered sense of agency may contribute to the clinical phenotype of the condition.\u0000 In this study, we compared the explicit and implicit sense of agency in patients with myoclonus-dystonia caused by a pathogenic variant of SGCE (DYT-SGCE) and control participants. We utilized behavioral tasks to assess the sense of agency and performed neuroimaging analyses, including structural, resting-state functional connectivity, and dynamic causal modeling, to explore the relevant brain regions involved in the sense of agency. Additionally, we examined the relationship between behavioral performance, symptom severity, and neuroimaging findings.\u0000 We compared 19 patients with DYT-SGCE and 24 healthy volunteers. Our findings revealed that patients with myoclonus-dystonia exhibited a specific impairment in explicit sense of agency, particularly when implicit motor learning was involved. However, their implicit sense of agency remained intact. These patients also displayed grey matter abnormalities in the motor cerebellum, as well as increased functional connectivity between the cerebellum and pre-supplementary motor area (pre-SMA). Dynamic causal modeling analysis further identified reduced inhibitory effects of the cerebellum on the pre-SMA, decreased excitatory effects of the pre-SMA on the cerebellum, and increased self-inhibition within the pre-SMA. Importantly, both cerebellar grey matter alterations and functional connectivity abnormalities between the cerebellum and pre-SMA were found to correlate with explicit sense of agency impairment. Increased self-inhibition within the pre-SMA was associated with less severe myoclonus symptoms.\u0000 These findings highlight the disruption of higher-level cognitive processes in patients with myoclonus-dystonia, further expanding the spectrum of neurological and psychiatric dysfunction already identified in this disorder.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"16 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140374689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular diversity in IDH-wildtype glioblastoma","authors":"Jawad Fares, Yizhou Wan, Richard Mair, Stephen J Price","doi":"10.1093/braincomms/fcae108","DOIUrl":"https://doi.org/10.1093/braincomms/fcae108","url":null,"abstract":"\u0000 In the dynamic landscape of glioblastoma, the 2021 World Health Organization Classification of Central Nervous System tumors endeavored to establish biological homogeneity, yet IDH-wildtype glioblastoma persists as a tapestry of clinical and molecular diversity. Intertumoral heterogeneity in IDH-wildtype glioblastoma presents a formidable challenge in treatment strategies. Recent strides in genetics and molecular biology have enhanced diagnostic precision, revealing distinct subtypes and invasive patterns that influence survival in patients with IDH-wildtype glioblastoma. Genetic and molecular biomarkers, such as the overexpression of neurofibromin 1 (NF1), phosphatase and tensin homolog (PTEN), and/or cyclin-dependent kinase inhibitor 2A (CDKN2A), along with specific immune cell abundance, correlate with favorable outcomes. Conversely, increased expression of epidermal growth factor receptor tyrosine kinase (EGFR), platelet derived growth factor receptor alpha (PDGFRA), and/or vascular endothelial growth factor receptor (VEGFR), coupled with the prevalence of glioma stem cells, tumor-associated myeloid cells, regulatory T cells, and exhausted effector cells, signifies an unfavorable prognosis. The methylation status of O6-methylguanine-DNA methyltransferase (MGMT) and the influence of microenvironmental factors and neurotransmitters further shape treatment responses. Understanding intertumoral heterogeneity is complemented by insights into intratumoral dynamics and cellular interactions within the tumor microenvironment. Glioma stem cells and immune cell composition significantly impact progression and outcomes, emphasizing the need for personalized therapies targeting pro-tumoral signaling pathways and resistance mechanisms. Successful glioblastoma management demands biomarker identification, combination therapies, and a nuanced approach considering intratumoral variability. These advancements herald a transformative era in glioblastoma comprehension and treatment.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"72 16","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140376188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic density patterns in early Alzheimer’s disease assessed by independent component analysis","authors":"Xiaotian T Fang, N. Raval, Ryan S. O'Dell, M. Naganawa, A. Mecca, Ming-Kai Chen, C. V. van Dyck, Richard E. Carson","doi":"10.1093/braincomms/fcae107","DOIUrl":"https://doi.org/10.1093/braincomms/fcae107","url":null,"abstract":"\u0000 Synaptic loss is a primary pathology in Alzheimer's disease (AD) and correlates best with cognitive impairment as found in postmortem studies. Previously, we observed in vivo reductions of synaptic density with [11C]UCB-J PET (radiotracer for synaptic vesicle protein 2A, SV2A) throughout the neocortex and medial temporal brain regions in early AD. Here, we applied independent component analysis (ICA) to SV2A-PET data to identify brain networks associated with cognitive deficits in AD in a blinded data-driven manner.\u0000 [11C]UCB-J binding to SV2A was measured in 38 AD (24 mild AD dementia, 14 mild cognitive impairment (MCI) and 19 cognitively normal (CN) participants. [11C]UCB-J distribution volume ratio values were calculated with a whole cerebellum reference region. Principal components analysis was first used to extract 18 independent components (IC) to which ICA was then applied. Subject loading weights per pattern were compared between groups using Kruskal-Wallis tests. Spearman’s rank correlations were used to assess relationships between loading weights and measures of cognitive and functional performance: logical memory II (LMII), Rey auditory verbal learning test (RAVLT-delay), clinical dementia rating sum of boxes (CDR-sb), and mini-mental state examination (MMSE).\u0000 We observed significant differences in loading weights between CN, MCI, and mild AD dementia groups in 5 of the 18 ICs, as determined by Kruskal-Wallis tests. Only Patterns 1 and 2 demonstrating significant differences in group loading weights after correction for multiple comparisons. Excluding the CN group, we observed significant correlations between the loading weights for Pattern 1 (left temporal cortex and the cingulate gyrus) and CDR-sb (r=-0.54, p=0.0019), MMSE (r=0.48, p=0.0055), and LMII score (r=0.44, p=0.013). For Pattern 2 (temporal cortices), significant associations were demonstrated between its loading weights and LMII score (r=0.34, p=0.0384). Following false discovery rate correction, only the relationship between the Pattern 1 loading weights with CDR-sb (r=-0.54, p=0.0019) and MMSE (r=0.48, p=0.0055) remained statistically significant.\u0000 We demonstrated that ICA could define coherent spatial patterns of synaptic density. Furthermore, commonly used measures of cognitive performance correlated significantly with loading weights for two patterns within only the MCI/mild AD dementia group. This study leverages data-centric approaches to augment the conventional region-of-interest based methods, revealing distinct patterns that differentiate between MCI and mild AD dementia, marking a significant advancement in the field.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"102 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140381123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}