Brain最新文献

{"title":"Phase 2b program with sonlicromanol in patients with mitochondrial disease due to m.3243A>G mutation.","authors":"Jan Smeitink, Just van Es, Brigitte Bosman, Mirian C H Janssen, Thomas Klopstock, Grainne Gorman, John Vissing, Gerrit Ruiterkamp, Chris J Edgar, Evertine J Abbink, Rob van Maanen, Oksana Pogoryelova, Claudia Stendel, Almut Bischoff, Ivan Karin, Mahtab Munshi, Anne Kümmel, Lydia Burgert, Christianne Verhaak, Herma Renkema","doi":"10.1093/brain/awae277","DOIUrl":"10.1093/brain/awae277","url":null,"abstract":"<p><p>Mitochondrial disease incorporates a group of rare conditions with no approved treatment to date, except for Leber hereditary optic neuropathy. Therapeutic options to alleviate the symptoms of mitochondrial disease are urgently needed. Sonlicromanol is a promising candidate, as it positively alters the key metabolic and inflammatory pathways associated with mitochondrial disease. Sonlicromanol is a reductive and oxidative distress modulator, selectively inhibiting microsomal prostaglandin E1 synthase activity. This phase 2b program, aimed at evaluating sonlicromanol in adults with m.3243A>G mutation and primary mitochondrial disease, consisted of a randomized controlled (RCT) study (dose-selection) followed by a 52-week open-label extension study (EXT, long-term tolerability, safety and efficacy of sonlicromanol). Patients were randomized (1:1:1) to receive 100 or 50 mg sonlicromanol or placebo twice daily (bid) for 28 days with a ≥2-week wash-out period between treatments. Patients who completed the RCT study entered the EXT study, wherein they received 100 mg sonlicromanol bid. Overall, 27 patients were randomized (24 RCT patients completed all periods). Fifteen patients entered the EXT, and 12 patients were included in the EXT analysis set. All patients reported good tolerability and favourable safety, with pharmacokinetic results comparable to the earlier phase 2a study. The RCT primary end point [change from placebo in the attentional domain of the cognition score (visual identification; Cogstate IDN)] did not reach statistical significance. Using a categorization of the subject's period baseline a treatment effect over placebo was observed if their baseline was more affected (P = 0.0338). Using this approach, there were signals of improvements over placebo in at least one dose in the Beck Depression Inventory (BDI, P = 0.0143), Cognitive Failure Questionnaire (P = 0.0113) and the depression subscale of the Hospital Anxiety and Depression Scale (P = 0.0256). Statistically and/or clinically meaningful improvements were observed in the patient- and clinician-reported outcome measures at the end of the EXT study [Test of Attentional Performance (TAP) with alarm, P = 0.0102; TAP without alarm, P = 0.0047; BDI somatic, P = 0.0261; BDI total, P = 0.0563; SF12 physical component score, P = 0.0008]. Seven of nine domains of RAND-Short Form-36-like SF-36 pain improved (P = 0.0105). Other promising results were observed in the Neuro-Quality of Life Short Form-Fatigue Scale (P = 0.0036), mini-Balance Evaluation Systems test (P = 0.0009), McGill Pain Questionnaire (P = 0.0105), EuroQol EQ-5D-5L-Visual Analog Scale (P = 0.0213) and EQ-5D-5L-Index (P = 0.0173). Most patients showed improvement in the Five Times Sit-To-Stand Test. Sonlicromanol was well-tolerated and demonstrated a favourable benefit/risk ratio for up to 1 year. Sonlicromanol was efficacious in patients when affected at baseline, as seen across a variety of clinically relevant domain","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"896-907"},"PeriodicalIF":10.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EBV-specific T-cell responses are telling us something important about multiple sclerosis.","authors":"Gavin Giovannoni","doi":"10.1093/brain/awaf027","DOIUrl":"10.1093/brain/awaf027","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"692-694"},"PeriodicalIF":10.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.","authors":"Delphine Sapaly, Flore Cheguillaume, Laure Weill, Zoé Clerc, Olivier Biondi, Sabrina Bendris, Céline Buon, Rasha Slika, Elsie Piller, Venkat Krishnan Sundaram, Andreia da Silva Ramos, Maria Del Mar Amador, Timothée Lenglet, Rabab Debs, Nadine Le Forestier, Pierre-François Pradat, François Salachas, Lucette Lacomblez, Adèle Hesters, Didier Borderie, David Devos, Claude Desnuelle, Anne-Sophie Rolland, Baptiste Periou, Stéphane Vasseur, Maud Chapart, Isabelle Le Ber, Anne-Laure Fauret-Amsellem, Stéphanie Millecamps, Thierry Maisonobe, Sarah Leonard-Louis, Anthony Behin, François-Jérôme Authier, Teresinha Evangelista, Frédéric Charbonnier, Gaëlle Bruneteau","doi":"10.1093/brain/awae270","DOIUrl":"10.1093/brain/awae270","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidaemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analysed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from 13 ALS patients and 10 asymptomatic ALS-mutation gene carriers compared to 16 control subjects. Using human control primary myotubes, we investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"788-802"},"PeriodicalIF":10.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vessel size and clinical features in vasculitic neuropathy: dichotomy or continuum?","authors":"Robert D M Hadden, Michael P Collins","doi":"10.1093/brain/awaf071","DOIUrl":"https://doi.org/10.1093/brain/awaf071","url":null,"abstract":"This scientific commentary refers to ‘Distinctive clinical features in biopsy-proven nerve large-arteriole vasculitis and microvasculitis’ by Soontrapa et al. (https://doi.org/10.1093/brain/awae406).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"39 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fetal malformations of cortical development: review and clinical guidance","authors":"Jeffrey B Russ, Sonika Agarwal, Charu Venkatesan, Barbara Scelsa, Brigitte Vollmer, Tomo Tarui, Andrea C Pardo, Monica E Lemmon, Sarah B Mulkey, Anthony R Hart, Usha D Nagaraj, Jeffrey A Kuller, Matthew T Whitehead, Jennifer L Cohen, Juliana S Gebb, Orit A Glenn, Mary E Norton, Dawn Gano","doi":"10.1093/brain/awaf094","DOIUrl":"https://doi.org/10.1093/brain/awaf094","url":null,"abstract":"Malformations of cortical development (MCDs) are a heterogeneous family of congenital brain malformations that originate from disturbed development of the cerebral cortex. MCDs can arise from primary genetic disorders that lead to dysfunction of the molecular processes controlling neuronal proliferation, neuronal migration, cortical folding, or cortical organization. MCDs can also result from secondary, disruptive causes, such as congenital infection or other in utero brain injuries. Sequelae of MCDs can include epilepsy, intellectual disability, and cerebral palsy, among other symptoms, with a high burden of pediatric morbidity. Advances in antenatal genetic testing and imaging have improved the ability to diagnose MCDs, yet limited literature exists to aid clinicians in prognostication of outcomes and perinatal management. These clinical realities can make it challenging for clinicians caring for fetal neurological conditions to counsel families and make recommendations for interdisciplinary care. We aim to review the literature on fetal MCDs and present practice guidelines for clinicians regarding the pre- and postnatal management of MCDs.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"49 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between neuromelanin depletion and cortical rhythmic activity in Parkinson's disease.","authors":"Alex I Wiesman, Victoria Madge, Edward A Fon, Alain Dagher, D Louis Collins, Sylvain Baillet","doi":"10.1093/brain/awae295","DOIUrl":"10.1093/brain/awae295","url":null,"abstract":"<p><p>Parkinson's disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in the substantia nigra (SN) and the locus coeruleus (LC), respectively, resulting in motor and cognitive impairments. Although SN dopamine dysfunction has clear neurophysiological effects, the association of reduced LC norepinephrine signalling with brain activity in PD remains to be established. We used neuromelanin-sensitive T1-weighted MRI (PD, n = 58; healthy control, n = 27) and task-free magnetoencephalography (PD, n = 58; healthy control, n = 65) to identify neuropathophysiological factors related to the degeneration of the LC and SN in patients with PD. We found pathological increases in rhythmic alpha-band (8-12 Hz) activity in patients with decreased LC neuromelanin, which were more strongly associated in patients with worse attentional impairments. This negative alpha-band-LC neuromelanin relationship is strongest in fronto-motor cortices, where alpha-band activity is inversely related to attention scores. Using neurochemical co-localization analyses with normative atlases of neurotransmitter transporters, we also show that this effect is more pronounced in regions with high densities of norepinephrine transporters. These observations support a noradrenergic association between LC integrity and alpha-band activity. Our data also show that rhythmic beta-band (15-29 Hz) activity in the left somatomotor cortex decreases with lower levels of SN neuromelanin; the same regions where beta activity reflects axial motor symptoms. Together, our findings clarify the association of well-documented alterations of rhythmic neurophysiology in PD with cortical and subcortical neurochemical systems. Specifically, attention-related alpha-band activity is related to dysfunction of the noradrenergic system, and beta activity with relevance to motor impairments reflects dopaminergic dysfunction.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"875-885"},"PeriodicalIF":10.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eighty-six billion and counting: do we know the number of neurons in the human brain?","authors":"Alain Goriely","doi":"10.1093/brain/awae390","DOIUrl":"10.1093/brain/awae390","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"689-691"},"PeriodicalIF":10.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment of neurological pathology and inflammation in Machado-Joseph disease through in vivo self-assembled siRNA.","authors":"Zhizong Li, Xinghu Du, Yixuan Yang, Li Zhang, Penglu Chen, Yansheng Kan, Jinmeng Pan, Lishan Lin, Ding Liu, Xiaohong Jiang, Chen-Yu Zhang, Zhong Pei, Xi Chen","doi":"10.1093/brain/awae304","DOIUrl":"10.1093/brain/awae304","url":null,"abstract":"<p><p>Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3), is a fatal autosomal dominant hereditary ataxia characterized by cerebellar ataxia resulting from the abnormal expansion of CAG repeats in exon 10 of the ATXN3 gene. At present, there is no effective treatment for SCA3. Small interfering RNAs (siRNAs) are emerging as potential therapeutic strategies to target the disease-causing mutant ATXN3 (mATXN3) protein specifically. However, the efficiency of delivery of siRNAs remains a major obstacle for clinical application, particularly in brain disorders. The aim of this study was to develop a synthetic biology strategy to reprogram the host liver as a tissue chassis to induce and deliver in vivo self-assembled siRNAs to target the ATXN3 gene. A synthetic construct directed by a cytomegalovirus promoter was designed to encode a neuron-targeting rabies virus glycoprotein tag and mATXN3-siRNA. After intravenous injection, the synthetic construct was taken up by mouse livers, which were then reprogrammed to enable the self-assembly, production and secretion of small extracellular vesicles encapsulating mATXN3-siRNA. The small extracellular vesicle-encapsulated mATXN3-siRNA was transported through the endogenous circulating system of small extracellular vesicles, crossing the blood-brain barrier and reaching the cerebellar cortex and spinal cerebellar tract, where they silenced the ATXN3 gene. Treatment with the synthetic construct for 8 or 12 weeks led to significant improvements in motor balance ability and reduction of cerebellar atrophy in YACMJD84.2 transgenic mice. The number of Purkinje cells in the cerebellar cortex was significantly increased, and the loss of myelin basic protein was reduced. Moreover, the quantity of neurotoxic nuclear inclusion bodies and the expression of glial fibrillary acidic protein, which promotes neuroinflammation in activated astrocytes, were decreased significantly. The synthetic construct facilitated the generation and delivery of in vivo self-assembled siRNA to the cerebellar cortex and spinal cerebellar tract, thereby inhibiting the expression of mATXN3 protein. This treatment successfully addressed motor impairments, alleviated neuropathological phenotypes and mitigated neuroinflammation in YACMJD84.2 transgenic mice. Our strategy effectively overcomes the primary challenges associated with siRNA therapy for cerebellar ataxia, offering a promising avenue for future clinical treatments.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"817-832"},"PeriodicalIF":10.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma.","authors":"","doi":"10.1093/brain/awae353","DOIUrl":"10.1093/brain/awae353","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e16-e20"},"PeriodicalIF":10.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stereo-EEG propagating source reconstruction identifies new surgical targets for epilepsy patients","authors":"Brandon J Thio, Nishant Sinha, Kathryn A Davis, Saurabh R Sinha, Warren M Grill","doi":"10.1093/brain/awae297","DOIUrl":"https://doi.org/10.1093/brain/awae297","url":null,"abstract":"Epilepsy surgery can eliminate seizures in patients with drug-resistant focal epilepsy. Surgical intervention requires proper identification of the epileptic network and often involves implanting stereo-EEG electrodes in patients where non-invasive methods are insufficient. However, only ∼60% of patients achieve seizure-freedom following surgery. Quantitative methods have been developed to help improve surgical outcomes. However, previous quantitative methods that localized interictal spike and seizure activity using stereo-EEG recordings did not account for the propagation path encoded by the temporal dynamics of stereo-EEG recordings. Reconstructing the seizure propagation path can aid in determining whether a signal originated from the seizure onset or propagation zone, which directly informs treatment decisions. We developed a novel source reconstruction algorithm, Temporally Dependent Iterative Expansion (TEDIE), that accurately reconstructs propagating and expanding neural sources over time. TEDIE iteratively optimizes the number, location and size of neural sources to minimize the differences between the reconstructed and recorded stereo-EEG signals using temporal information to refine the reconstructions. The TEDIE output comprises a movie of seizure activity projected onto patient-specific brain anatomy. We analysed data from 46 epilepsy patients implanted with stereo-EEG electrodes at Duke Hospital (12 patients) and the Hospital of the University of Pennsylvania (34 patients). We reconstructed seizure recordings and found that TEDIE’s seizure onset zone reconstructions were closer to the resected brain region for Engel 1 compared to Engel 2–4 patients, retrospectively validating the clinical utility of TEDIE. We also demonstrated that TEDIE has prospective clinical value, whereby metrics that can be determined presurgically accurately predict whether a patient would achieve seizure-freedom following surgery. Furthermore, we used TEDIE to delineate new potential surgical targets in 12/23 patients who are currently Engel 2–4. We validated TEDIE by accurately reconstructing various dynamic synthetic neural sources with known locations and sizes. TEDIE generated more accurate, focal and interpretable dynamic reconstructions of seizures compared to other algorithms (sLORETA and IRES). Our findings demonstrate that TEDIE is a promising clinical tool that can greatly improve epileptogenic zone localization and epilepsy surgery outcomes.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"87 1 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}