Brain communications最新文献

{"title":"The sixth sense: how much does interictal intracranial EEG add to determining the focality of epileptic networks?","authors":"Ryan S Gallagher, Nishant Sinha, Akash R Pattnaik, William K S Ojemann, Alfredo Lucas, Joshua J LaRocque, John M Bernabei, Adam S Greenblatt, Elizabeth M Sweeney, Iahn Cajigas, H Isaac Chen, Kathryn A Davis, Erin C Conrad, Brian Litt","doi":"10.1093/braincomms/fcae320","DOIUrl":"https://doi.org/10.1093/braincomms/fcae320","url":null,"abstract":"<p><p>Intracranial EEG is used for two main purposes: to determine (i) if epileptic networks are amenable to focal treatment and (ii) where to intervene. Currently, these questions are answered qualitatively and differently across centres. There is a need to quantify the focality of epileptic networks systematically, which may guide surgical decision-making, enable large-scale data analysis and facilitate multi-centre prospective clinical trials. We analysed interictal data from 101 patients with drug-resistant epilepsy who underwent pre-surgical evaluation with intracranial EEG at a single centre. We chose interictal data because of its potential to reduce the morbidity and cost associated with ictal recording. Sixty-five patients had unifocal seizure onset on intracranial EEG, and 36 were non-focal or multi-focal. We quantified the spatial dispersion of implanted electrodes and interictal intracranial EEG abnormalities for each patient. We compared these measures against the '5 Sense Score,' a pre-implant prediction of the likelihood of focal seizure onset, assessed the ability to predict unifocal seizure onset by combining these metrics and evaluated how predicted focality relates to subsequent treatment and outcomes. The spatial dispersion of intracranial EEG electrodes predicted network focality with similar performance to the 5-SENSE score [area under the receiver operating characteristic curve = 0.68 (95% confidence interval 0.57, 0.78)], indicating that electrode placement accurately reflected pre-implant information. A cross-validated model combining the 5-SENSE score and the spatial dispersion of interictal intracranial EEG abnormalities significantly improved this prediction [area under the receiver operating characteristic curve = 0.79 (95% confidence interval 0.70, 0.88); <i>P</i> < 0.05]. Predictions from this combined model differed between surgical- from device-treated patients with an area under the receiver operating characteristic curve of 0.81 (95% confidence interval 0.68, 0.85) and between patients with good and poor post-surgical outcome at 2 years with an area under the receiver operating characteristic curve of 0.70 (95% confidence interval 0.56, 0.85). Spatial measures of interictal intracranial EEG abnormality significantly improved upon pre-implant predictions of network focality by area under the receiver operating characteristic curve and increased sensitivity in a single-centre study. Quantified focality predictions related to ultimate treatment strategy and surgical outcomes. While the 5-SENSE score weighed for specificity in their multi-centre validation to prevent unnecessary implantation, sensitivity improvement found in our single-centre study by including intracranial EEG may aid the decision on whom to perform the focal intervention. We present this study as an important step in building standardized, quantitative tools to guide epilepsy surgery.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae320"},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514658","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":"Patient-derived tau and amyloid-β facilitate long-term depression <i>in vivo</i>: role of tumour necrosis factor-α and the integrated stress response.","authors":"Neng-Wei Hu, Tomas Ondrejcak, Igor Klyubin, Yin Yang, Dominic M Walsh, Frederick J Livesey, Michael J Rowan","doi":"10.1093/braincomms/fcae333","DOIUrl":"10.1093/braincomms/fcae333","url":null,"abstract":"<p><p>Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-β and tau. It is well documented that synaptotoxic soluble amyloid-β aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-β were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-β. <i>In vivo</i> electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-β were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-α or the integrated stress response to prevent the effects of amyloid-β or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-β and synthetic oligomeric amyloid-β, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-β was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-α and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-β. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-β. Pharmacologically targeting shared mechanisms of tau and amyloid-β synaptotoxicity, such as tumour necrosis factor-α or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae333"},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142402330","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":"White matter variations in congenital adrenal hyperplasia: possible implications for glucocorticoid treatment.","authors":"Eileen Luders, Debra Spencer, Christian Gaser, Ajay Thankamony, Ieuan A Hughes, Umasuthan Srirangalingam, Helena Gleeson, Karson T F Kung, Ryan P Cabeen, Melissa Hines, Florian Kurth","doi":"10.1093/braincomms/fcae334","DOIUrl":"10.1093/braincomms/fcae334","url":null,"abstract":"<p><p>Congenital adrenal hyperplasia has been reported to manifest with white matter aberrations. However, many previous studies included only small samples, restricted their analyses to females, lacked a control group and/or did not correct for brain size. Here, we examined the largest sample to date, comprising 53 male and female participants with congenital adrenal hyperplasia, who were matched with 53 male and female controls in terms of sex, age, education, and verbal intelligence. The four groups were compared with respect to their total white matter as well as white matter hyperintensities while applying brain size corrections. For both measures, total white matter and white matter hyperintensities, there were no significant sex differences or group-by-sex interactions. However, individuals with congenital adrenal hyperplasia had significantly smaller total white matter volumes compared to controls. Our findings align with previous reports of white matter variations in congenital adrenal hyperplasia. The absence of a group-by-sex interaction suggests that white matter variations in congenital adrenal hyperplasia may not be attributable to prenatal androgens. Instead, they may be a result of the condition itself and/or its treatment with glucocorticoids. The latter aspect warrants follow-up, particularly given that glucocorticoids are employed not only in congenital adrenal hyperplasia but also in other medical conditions.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae334"},"PeriodicalIF":4.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483050","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":"Motor practice related changes in the sensorimotor cortices of youth with cerebral palsy.","authors":"Max J Kurz, Brittany K Taylor, Elizabeth Heinrichs-Graham, Rachel K Spooner, Sarah E Baker, Tony W Wilson","doi":"10.1093/braincomms/fcae332","DOIUrl":"10.1093/braincomms/fcae332","url":null,"abstract":"<p><p>The altered sensorimotor cortical dynamics seen in youth with cerebral palsy appear to be tightly coupled with their motor performance errors and uncharacteristic mobility. Very few investigations have used these cortical dynamics as potential biomarkers to predict the extent of the motor performance changes that might be seen after physical therapy or in the design of new therapeutic interventions that target a youth's specific neurophysiological deficits. This cohort investigation was directed at evaluating the practice dependent changes in the sensorimotor cortical oscillations exhibited by youth with cerebral palsy as a step towards addressing this gap. We used magnetoencephalography to image the changes in the cortical oscillations before and after youth with cerebral palsy (<i>N</i> = 25; age = 15.2 ± 4.5 years; Gross Motor Function Classification Score Levels I-III) and neurotypical controls (<i>N</i> = 18; age = 14.6 ± 3.1 years) practiced a knee extension isometric target-matching task. Subsequently, structural equation modelling was used to assess the multivariate relationship between changes in beta (16-22 Hz) and gamma (66-82 Hz) oscillations and the motor performance after practice. The structural equation modelling results suggested youth with cerebral palsy who had a faster reaction time after practice tended to also have a stronger peri-movement beta oscillation in the sensorimotor cortices following practicing. The stronger beta oscillations were inferred to reflect greater certainty in the selected motor plan. The models also indicated that youth with cerebral palsy who overshot the targets less and matched the targets sooner tended to have a stronger execution-related gamma response in the sensorimotor cortices after practice. This stronger gamma response may represent improve activation of the sensorimotor neural generators and/or alterations in the GABAergic interneuron inhibitory-excitatory dynamics. These novel neurophysiological results provide a window on the potential neurological changes governing the practice-related outcomes in the context of the physical therapy.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae332"},"PeriodicalIF":4.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142402329","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":"<i>FILIP1</i>-associated neuromuscular disorder and phenotypic blending due to paternal UPD6.","authors":"Laura M Watts, David J Bunyan, Edoardo Giacopuzzi, Susan Walker, Gabriella Gazdagh, N Simon Thomas, Volker Straub, Anne-Marie Childs, Joan Forsyth, Julie Vogt, Shagufta Khan, Tracey A Willis, Jenny C Taylor, Alistair T Pagnamenta","doi":"10.1093/braincomms/fcae330","DOIUrl":"10.1093/braincomms/fcae330","url":null,"abstract":"","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae330"},"PeriodicalIF":4.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395939","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":"Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.","authors":"Natalie C Edwards, Patrick J Lao, Mohamad J Alshikho, Olivia M Ericsson, Batool Rizvi, Melissa E Petersen, Sid O'Bryant, Lisi Flores Aguilar, Sabrina Simoes, Mark Mapstone, Dana L Tudorascu, Shorena Janelidze, Oskar Hansson, Benjamin L Handen, Bradley T Christian, Joseph H Lee, Florence Lai, H Diana Rosas, Shahid Zaman, Ira T Lott, Michael A Yassa, José Gutierrez, Donna M Wilcock, Elizabeth Head, Adam M Brickman","doi":"10.1093/braincomms/fcae331","DOIUrl":"10.1093/braincomms/fcae331","url":null,"abstract":"<p><p>By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae331"},"PeriodicalIF":4.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483038","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":"Lessons on neurodegeneration and aging from the Lagoon of Venice: the marine invertebrate <i>Botryllus schlosseri</i>.","authors":"Tommaso Bocci, Chiara Anselmi, Federico La Torre, Emanuela De Lisa, Giacomo Sabbadin, Matteo Guidetti, Natale Maiorana, Alberto Priori, Lucia Manni","doi":"10.1093/braincomms/fcae257","DOIUrl":"https://doi.org/10.1093/braincomms/fcae257","url":null,"abstract":"<p><p>In this work, the authors proposed a novel and interesting animal model for studying human neurodegenerative diseases, <i>Botryllus schlosseri</i>, a small invertebrate inhabiting temperate seas worldwide, which shares remarkable similarities with mammals in the expression of genes involved in pathological aging.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae257"},"PeriodicalIF":4.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11422668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334341","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":"Structural lesions and transcriptomic specializations shape gradient perturbations in Wilson disease.","authors":"Sheng Hu, Chuanfu Li, Yanming Wang, Taohua Wei, Xiaoxiao Wang, Ting Dong, Yulong Yang, Yufeng Ding, Bensheng Qiu, Wenming Yang","doi":"10.1093/braincomms/fcae329","DOIUrl":"10.1093/braincomms/fcae329","url":null,"abstract":"<p><p>Functional dysregulations in multiple regions are caused by excessive copper deposition in the brain in Wilson disease (WD) patients. The genetic mechanism of WD is thought to involve the abnormal expression of <i>ATP7B</i> in the liver, whereas the biological and molecular processes involved in functional dysregulation within the brain remain unexplored. The objective of this study was to unravel the underpinnings of functional gradient perturbations underlying structural lesions and transcriptomic specializations in WD. In this study, we included 105 WD patients and 93 healthy controls who underwent structural and functional MRI assessments. We used the diffusion mapping embedding model to derive the functional connectome gradient and further employed gray matter volume to uncover structure-function decoupling for WD. Then, we used Neurosynth, clinical data, and whole-brain gene expression data to examine the meta-analytic cognitive function, clinical phenotypes, and transcriptomic specializations related to WD gradient alterations. Compared with controls, WD patients exhibited global topographic changes in the principal pramary-to-transmodal gradient. Meta-analytic terms and clinical characteristics were correlated with these gradient alterations in motor-related processing, higher-order cognition, neurological symptoms, and age. Spatial correlations revealed structure-function decoupling in multiple networks, especially in subcortical and visual networks. Within the cortex, the spatial association between gradient alterations and gene expression profiles has revealed transcriptomic specilizations in WD that display properties indicative of ion homeostasis, neural development, and motor control. Furthermore, for the first time, we characterized the role of the <i>ATP7B</i> gene in impacting subcortical function. The transcriptomic specializations of WD were also associated with other neurological and psychiatric disorders. Finally, we revealed that structural lesions and gradient perturbations may share similar transcriptomic specializations in WD. In conclusion, these findings bridged functional gradient perturbations to structural lesions and gene expression profiles in WD patients, possibly promoting our understanding of the neurobiological mechanisms underlying the emergence of complex neurological and psychiatric phenotypes.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae329"},"PeriodicalIF":4.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382757","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":"Childhood anaesthesia and autism risk: population and murine study.","authors":"Mingyang Sun, Ningning Fu, Ting Li, Mengrong Miao, Wan-Ming Chen, Szu-Yuan Wu, Jiaqiang Zhang","doi":"10.1093/braincomms/fcae325","DOIUrl":"10.1093/braincomms/fcae325","url":null,"abstract":"<p><p>Early childhood exposure to general anaesthesia has been linked to potential changes in infant brain morphology and behaviour in preclinical studies, contributing to long-term behaviours associated with autism spectrum disorder. This study investigates the association between early childhood exposure to general anaesthesia and the risk of autism, using a population-based cohort study with matching for baseline characteristics and evaluates the effect of sevoflurane exposure on autism-like behaviour in mice, using the Taiwan Maternal and Child Health Database. Children aged 0-3 who received at least one exposure to general anaesthesia between 2004 and 2014 were matched 1:1 with children who were not exposed. Risk ratios and confidence intervals were used to assess the relationship between general anaesthesia and the occurrence of autism. Additionally, mice were exposed to sevoflurane for 2 h on postnatal days 5-7, and changes in behaviour related to autism were evaluated. Propensity score matching resulted in 7530 children in each group. The incidence rates (IRs) of autism were 11.26 and 6.05 per 100 000 person-years in the exposed and unexposed groups, respectively. The incidence ratio for autism following exposure to general anaesthesia was 1.86 (95% confidence interval, 1.34-2.59). In mice, sevoflurane exposure induced autism-like behaviours and led to the downregulation of high-risk autism genes, including <i>ARID1B</i>, <i>GABRA5</i>, <i>GABRB3</i>, <i>GRIN2B</i>, <i>SHANK3</i> and <i>SUV420H1</i>. Early childhood exposure to general anaesthesia is associated with an increased risk of autism. Repeated exposure to sevoflurane in mice induces autism-like behaviours, suggesting a potential link between anaesthesia and the development of autism.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae325"},"PeriodicalIF":4.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382756","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":"Investigating the prevalence of <i>MFN2</i> mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.","authors":"Elena Abati, Delia Gagliardi, Arianna Manini, Roberto Del Bo, Dario Ronchi, Megi Meneri, Francesca Beretta, Annalisa Sarno, Federica Rizzo, Edoardo Monfrini, Alessio Di Fonzo, Maria Teresa Pellecchia, Alberto Brusati, Vincenzo Silani, Giacomo Pietro Comi, Antonia Ratti, Federico Verde, Nicola Ticozzi, Stefania Corti","doi":"10.1093/braincomms/fcae312","DOIUrl":"10.1093/braincomms/fcae312","url":null,"abstract":"<p><p>The <i>MFN2</i> gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. <i>MFN2</i> mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant <i>MFN2</i> mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous <i>MFN2</i> mutations. A group of patients (<i>n</i> = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including <i>MFN2</i>. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. <i>C9orf72</i>, <i>SOD1</i>, <i>FUS</i> and <i>TARDBP</i>), <i>MFN2</i> variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of <i>MFN2</i>-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous <i>MFN2</i> variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous <i>MFN2</i> variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether <i>MFN2</i> mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":"6 5","pages":"fcae312"},"PeriodicalIF":4.1,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142309362","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}