Brain最新文献

{"title":"Large-scale genetic characterization of Parkinson’s disease in the African and African admixed populations","authors":"Fulya Akçimen, Kimberly Paquette, Peter Wild Crea, Kathryn Step, Emily Waldo, Mathew J Koretsky, Paula Saffie-Awad, Charles Achoru, Funmilola Taiwo, Simon Ozomma, Gerald Onwuegbuzie, Marzieh Khani, Spencer Grant, Lukman Owolabi, Chiamaka Okereke, Olajumoke Oshinaike, Emmanuel Iwuozo, Suleyman Can Akerman, Paul Suhwan Lee, Shyngle Oyakhire, Nosakhare Osemwegie, Kensuke Daida, Sani Abubakar, Adedunni Olusanya, Mariam Isayan, Christiane Alvarez, Rami Traurig, Adebimpe Ogunmodede, Sarah Samuel, Mary B Makarious, Fadimatu Sa’ad, Rashidat Olanigan, Kristin Levine, Ewere Marie Ogbimi, Dan Vitale, Francis Odiase, Francis Ojini, Olanike Odeniyi, Zih-Hua Fang, Nkechi Obianozie, Deborah A Hall, Ernest Nwazor, Tao Xie, Francesca Nwaokorie, Mahesh Padmanaban, Paul Nwani, Ejaz A Shamim, Alero Nnama, David Standaert, Morenikeji Komolafe, Marissa Dean, Godwin Osaigbovo, Elizabeth Disbrow, Ismaila Ishola, Ashley Rawls, Frank Imarhiagbe, Shivika Chandra, Cyril Erameh, Vanessa Hinson, Naomi Louie, Ahmed Idowu, J Solle, Scott A Norris, Abdullahi Ibrahim, Camilla Kilbane, Gauthaman Sukumar, Lisa M Shulman, Daniel Ezuduemoih, Julia Staisch, Sarah Breaux, Clifton Dalgard, Erin R Foster, Abiodun Bello, Andrew Ameri, Raquel Real, Erica Ikwenu, Huw R Morris, Roosevelt Anyanwu, Erin Furr Stimming, Kimberley Billingsley, Wemimo Alaofin, Pilar Alvarez Jerez, Osigwe Agabi, Dena G Hernandez, Rufus Akinyemi, Sampath Arepalli, Laksh Malik, Raymond Owolabi, Yakub Nyandaiti, Hampton L Leonard, Kolawole Wahab, Oladunni Abiodun, Carlos F Hernandez, Fatima Abdulai, Hirotaka Iwaki, Soraya Bardien, Christine Klein, John Hardy, Henry Houlden, Kamalini Ghosh Galvelis, Mike A Nalls, Nabila Dahodwala, Whitley Aamodt, Emily Hill, Alberto Espay, Stewart Factor, Chantale Branson, Cornelis Blauwendraat, Andrew B Singleton, Oluwadamilola Ojo, Lana M Chahine, Njideka Okubadejo, Sara Bandres-Ciga","doi":"10.1093/brain/awaf379","DOIUrl":"https://doi.org/10.1093/brain/awaf379","url":null,"abstract":"Elucidating the genetic contributions to Parkinson’s disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among PD patients, with a frequency of 4% in our case cohort. Out of the 18 GBA1 variants identified, ten were previously classified as pathogenic or likely pathogenic, four were novel, and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met, and p.Glu365Lys, were not identified among the screened PD cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in PD etiology among West African-ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance overrepresented in cases, two of which—p.Glu268Ala and p.Arg1538Cys—had a higher prevalence in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile PD in these populations. Short tandem repeat analysis also identified ATXN3 repeat expansions within the pathogenic range (CAGn > 45) in three PD patients of African ancestry. Novel genetic variation overrepresented in cases versus controls among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalog of both known and novel coding and splicing variants potentially linked to PD etiology in an underserved population and further conducted global and local ancestry analyses to further explore population-specific effects. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future PD treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"39 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.","authors":"Rebecca E James,Michael Bekier,Pin-Tsun Justin Lee,Frederick A Schroeder,Lauren T Evans,Florence F Wagner,Dean Hickman,Tom Richardson,Theo Hatzipetros,Fernando Vieira,Noëlle Callizot,Souvik Modi,Jacob M Hooker,Janice E Kranz,Robert H Brown,Sami J Barmada,Tonya M Gilbert","doi":"10.1093/brain/awaf380","DOIUrl":"https://doi.org/10.1093/brain/awaf380","url":null,"abstract":"Dysregulated proteostasis and intracellular transport contribute to neurodegeneration. HDAC6, a therapeutic target of interest for neurodegenerative diseases, acts at a nexus modulating both proteostasis and intracellular transport. Inhibition of HDAC6 deacetylase activity promotes autophagic clearance of protein aggregates and increases ⍺-tubulin acetylation, thereby enhancing microtubule resiliency and motor protein-microtubule binding, which facilitates intracellular transport and, subsequently, proteostasis. Despite these benefits, advancement of HDAC6 inhibitor therapeutics for neurodegenerative disease has been hindered by inadequate selectivity and CNS-penetrance of first-generation compounds. Here we characterize a next-generation small molecule HDAC6 inhibitor, EKZ-438, in preclinical models of amyotrophic lateral sclerosis and frontotemporal dementia. We present the pharmacological properties of EKZ-438, which demonstrate high selectivity for HDAC6 (>8,500-fold selectivity for HDAC6 versus all other HDAC6 paralogs), low nanomolar potency (12 nM) for HDAC6, and, importantly, CNS-penetrance (Kp,uu,brain) ≥ 0.55 and high oral bioavailability (F% = 70). In complementary preclinical in vitro and in vivo immunolabeling and live imaging studies we tested the hypothesis that selective inhibition of HDAC6 deacetylase activity is sufficient to improve pathophysiological proteostasis and intracellular transport deficits in animal models of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Notably, we extended these findings to human induced pluripotent stem cell-derived neuronal cellular models, supporting the relevance of our findings to human disease. EKZ-438 treatment fully rescued SOD1 (q < 0.0001) and TDP-43 (q < 0.001) proteostasis defects following an excitotoxic glutamate challenge, and increased survival of SOD1G93A and wildtype motor neurons by 59% (q < 0.0001) and 37% (q < 0.01), respectively, demonstrating in vitro neuroprotection. In SOD1G93A mice, EKZ-438 improved axonal transport by 16% (q < 0.05), motor performance by ∼40% (q < 0.05), and decreased plasma neurofilament light chain levels by 35% (q < 0.05), demonstrating in vivo neuroprotection. In a TDP-43 mouse model, EKZ-438 reduced TDP-43 pathology by ∼30% (q < 0.05) and neuroinflammation by ∼26% (q < 0.05) in the brain, supporting HDAC6 inhibition for sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Furthermore, EKZ-438 treatment improved intracellular transport by 39% (q < 0.001), rescued cytoplasmic TDP-43 accumulation by 87% (q < 0.0001), and restored nuclear TDP-43 splicing activity (P < 0.05) in human TARDBP neurons. These mechanistic improvements aligned with nearly complete rescue of human TARDBP and C9orf72 mutant neuron survival (P < 0.0001). We conclude that selective HDAC6 inhibition represents a promising therapeutic approach for potential disease modification in amyotrophic lateral sclerosis and frontotemporal demen","PeriodicalId":9063,"journal":{"name":"Brain","volume":"12 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246425","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":"Engineered neural stem cell vesicles activating Wnt promote blood-brain barrier repair after cerebral haemorrhage.","authors":"Tianwen Li,Peng Wang,Fengshi Li,Kezhu Chen,Jingyu Yu,Chencheng Ma,Xiao Fan,Junjie Zhong,Qisheng Tang,Xiaoming Wang,Guangchao Ji,Tongming Zhu,Jianhong Zhu","doi":"10.1093/brain/awaf381","DOIUrl":"https://doi.org/10.1093/brain/awaf381","url":null,"abstract":"The blood-brain barrier (BBB), a highly specialized neurovascular structure indispensable for preserving cerebral homeostasis, exhibits significant impairment across diverse neurological pathologies; however, its therapeutic targeting persists as a formidable challenge due to the inherent complexity of its multicellular architecture and dynamic regulatory networks. Although the Wnt/β-catenin signaling pathway orchestrates the development and maintenance of the BBB, the clinical translation of Wnt-based interventions remains elusive. We fabricated functionalized extracellular vesicles derived from neural stem cells (EVs-WK) by loading them with an engineered BBB-tropic ligand, Wnt7a-K190A, using electroporation. The therapeutic benefits of EVs-WK for BBB protection and repair were subsequently interrogated through comprehensive in vitro and in vivo analyses. In vitro mechanistic studies demonstrated that EVs-WK had three main effects: they enhanced BBB integrity, promoted synaptogenesis through β-catenin-mediated reinforcement, and significantly attenuated neurotoxic activation of astrocytes. Cross-species validation using humanized EVs (hEVs-WK) confirmed the conserved therapeutic efficacy of this approach, as shown by the mitigation of LPS-induced barrier dysfunction and downregulation of inflammatory pathways. In murine intracerebral hemorrhage (ICH) models, administering EVs-WK significantly reduced hematoma expansion and accelerated motor recovery. This modular EV platform combines BBB restoration with neurovascular unit repair, thus overcoming critical translational barriers in neurological therapeutics through targeted-controlled activation of Wnt signaling.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"29 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246426","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":"Imposter in the brain: aetiological, clinical and neuroimaging characteristics of Capgras syndrome","authors":"Hiroyuki Watanabe, Jennifer L Whitwell, Jerusha G Bhaskaran, Val J Lowe, Keith A Josephs","doi":"10.1093/brain/awaf378","DOIUrl":"https://doi.org/10.1093/brain/awaf378","url":null,"abstract":"Capgras syndrome is a delusional misidentification syndrome characterized by the recurrent belief that someone, usually a family member, has been replaced by an impostor. Although described over a century ago, its etiology, clinical features, and neuroimaging characteristics remain poorly understood due to its rarity. This study aimed to clarify these aspects through the analysis of a large cohort and to explore its clinical implications and underlying mechanisms. We conducted a retrospective cohort study by reviewing medical records of patients diagnosed with Capgras syndrome at the Mayo Clinic (Rochester, Minnesota) over a 28-year period (January 1995–December 2022). Clinical, neuropathological, and neuroimaging data were analyzed. A total of 204 patients were included (median age at onset: 73 years; 44% female). Twelve patients underwent neuropathological examination, all of whom exhibited α-synuclein pathology, including one patient with a clinical diagnosis of Alzheimer’s disease (AD). Regarding clinical diagnoses, neurodegenerative diseases were the most common (69%, n=140), with dementia with Lewy bodies (DLB) being predominant (58%, n=118), followed by mixed etiologies (“two-hits”) (18%, n=36) and AD (10%, n=21). Psychotic disorders accounted for 9% (n=18) of cases. No case was attributed to a single stroke, although 9% (n=19) involved coexisting cerebrovascular disease in the context of AD or DLB. In DLB, the timing of Capgras syndrome onset varied: it occurred later than cognitive decline and core clinical features (e.g., visual hallucinations, fluctuating cognition, parkinsonism) in both DLB and mild cognitive impairment (MCI)-onset prodromal DLB, but earlier in psychiatric-onset prodromal DLB. In both DLB and AD, Capgras syndrome typically targeted a single spouse, whereas in psychotic disorders, it often involved multiple, non-spousal targets. Depression or anxiety was present in 55% (n=112). Capgras syndrome worsened in the evening or at night (87%, n=45/52), suggesting a link to negative affective states. Among 82 patients with DLB and AD treated with cholinesterase inhibitors, 15% (n=12) showed symptomatic improvement. Neuroimaging with MRI and 18F-fluorodeoxyglucose-PET revealed widespread bilateral cortical involvement and prominent right frontal dysfunction in DLB and AD. Capgras syndrome is associated with DLB and could serve as a potential early diagnostic clue. Recognizing its phenomenological features—the number and type of targeted individuals—can help differentiate between neurodegenerative and psychiatric etiologies. In neurodegenerative diseases, Capgras syndrome may reflect a multifactorial, dynamic process, driven by widespread bilateral cortical dysfunction (particularly involving the right frontal lobe), and psychological factors. Thus, a combined approach involving pharmacological and non-pharmacological interventions may offer effective management strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"86 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241893","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":"Neuronal activity and amyloid-β promote tau seeding in the entorhinal cortex in Alzheimer’s disease","authors":"Christoffer G Alexandersen, Dani S Bassett, Alain Goriely, Pavanjit Chaggar","doi":"10.1093/brain/awaf374","DOIUrl":"https://doi.org/10.1093/brain/awaf374","url":null,"abstract":"The entorhinal cortex is the first region to develop tau pathology in Alzheimer’s disease and primary age-related tauopathy, yet the reasons for this selective vulnerability remain unclear. We developed a computational model in which neuronal activity and amyloid-β (Aβ) modulate tau transport, hypothesizing that this mechanism explains entorhinal vulnerability to early tau pathology. The model combines structural connectivity with either neuronal activity (measured by heading hierarchy okayfluorodeoxyglucose, FDG PET) or amyloid-β burden (measured by Aβ PET). We analyzed Alzheimer’s Disease Neuroimaging Initiative (ADNI) data comprising 527 FDG PET scans (mean age 71.8 years; 174 cognitively normal, 293 mild cognitive impairment, 60 Alzheimer’s disease) and 1,244 Aβ PET scans (mean age 72.4 years; 501 cognitively normal, 588 mild cognitive impairment, 155 Alzheimer’s disease). From these, 253 FDG–tau and 453 Aβ–tau PET pairs were used in regression analyses. Key results were replicated in the Harvard Aging Brain Study (HABS; 300 FDG, 348 Aβ, 116 FDG–tau, and 255 Aβ–tau pairs). Both FDG- and Aβ-based models consistently identified the entorhinal cortex as a primary tau seeding region in ADNI (FDG: z ≈ 4.6–4.9, p < 0.0066; Aβ: z ≈ 4.0–8.7, p ≤ 0.011) and in HABS (FDG: z = 5.7, p = 0.030; Aβ: z = 6.0, p = 0.0018). Simple linear regression showed modest associations between model-derived seeding and empirical entorhinal tau in ADNI (FDG: β = 6.7, p = 0.0039; Aβ: β = 11.3, p < 0.001), which remained significant after adjustment for age, sex, and APOE4 status (FDG: β = 7.1, p < 0.001; Aβ: β = 9.7, p < 0.001). Aβ-based associations replicated in HABS (β = 3.3, p < 0.001), while FDG-based correlations were not detectable in this predominantly cognitively normal cohort (β = −0.43, p = 0.80; power = 49%). These findings support a mechanistic role for neuronal activity and amyloid-β in initiating tau pathology, with the entorhinal cortex consistently emerging as highly vulnerable. Our computational model reliably identifies this region as the epicenter of pathology, supporting the idea that brain-wide patterns of neuronal activity and amyloid burden determine where tau pathology begins.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"18 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235373","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":"Fibre bundle capacity addresses structural connectivity biases in surgical resection cohorts.","authors":"Robert E Smith,Philip Pruckner,David F Abbott","doi":"10.1093/brain/awaf363","DOIUrl":"https://doi.org/10.1093/brain/awaf363","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"108 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235973","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":"Reply: Classifying neurogenic dysphagia: neuroanatomical hierarchy versus clinical syndromology.","authors":"Corinne A Jones, Maggie-Lee Huckabee, Georgia A Malandraki, David Paydarfar","doi":"10.1093/brain/awaf368","DOIUrl":"https://doi.org/10.1093/brain/awaf368","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238154","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":"EIPR1 variants cause a neurodevelopmental disorder with endolysosomal and dense core vesicle defects.","authors":"Saikat Ghosh,Jaskaran Singh,Nadirah S Damseh,Mariasavina Severino,Raffaella De Pace,Adriana E Golding,Michal Jarnik,Poonam Thakran,Laurence Faivre,Jade Heitz,Anne-Sophie Denommé-Pichon,Antonio Vitobello,Lama AlAbdi,Firdous Abdulwahab,Safia Sumayli,Mashael Alqahtani,Huma Arshad Cheema,Iram Javed,JiHye Kim,Hanns Lochmuller,Hagar Mor-Shaked,Jennifer E Neil,Ganeshwaran H Mochida,Giovanni Zifarelli,Peter Bauer,Ehsan Barkhordari,Ehsan Ghayoor Karimiani,Henry Houlden,Bassam Abu-Libdeh,Shimon Edvardson,Orly Elpeleg,Reza Maroofian,Shunmoogum A Patten,Juan S Bonifacino","doi":"10.1093/brain/awaf371","DOIUrl":"https://doi.org/10.1093/brain/awaf371","url":null,"abstract":"EIPR1 (EARP-interacting protein 1, formerly known as TSSC1) is a WD40-domain protein that interacts with the EARP (endosome-associated recycling protein) and GARP (Golgi-associated retrograde protein) complexes in the process of delivering endosome-derived transmembrane cargos to the plasma membrane and the trans-Golgi network (TGN), respectively. Additionally, EIPR1 cooperates with EARP in the biogenesis of dense core vesicles. While these properties of EIPR1 were established in cultured cells and model organisms, the physiological and pathological importance of EIPR1 in humans remains to be determined. Here we report the identification of five EIPR1 homozygous missense variants [NM_003310.5:c.835C>G p.(Arg279Gly), NM_003310.5:c.813C>G p.(His271Gln), NM_003310.5:c.694C>T p.(Arg232Trp), NM_003310.5:c.47G>A p.(Arg16His) and NM_003310.5:c.419T>A p.(Val140Asp)] in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Cellular studies using a heterologous transfection system demonstrate that these variants reduce EIPR1 protein levels and its physical interaction with EARP and GARP complexes. Furthermore, we show that the Arg279Gly and His271Gln variants reduce the ability of EIPR1 to promote EARP association with endosomes in non-neuronal cells and dense core vesicle biogenesis in iPSC-derived neurons. Additionally, skin fibroblasts from one of the Arg279Gly affected individuals shows reduced recycling of internalized transferrin to the plasma membrane (an EARP-deficiency phenotype) and impaired retrograde transport of internalized Shiga toxin B-subunit to the TGN (a GARP-deficiency phenotype) compared to fibroblasts from an unaffected parent. Moreover, these patient fibroblasts exhibit enlarged lysosomes, increased levels of the lysosomal membrane protein LAMP1, and increased levels of the autophagic markers LC3B-II and SQSTM1, all phenotypes previously associated with GARP deficiency. Knockout of the orthologous eipr1 in zebrafish results in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients. Injection of WT human EIPR1 mRNA into eipr1 KO zebrafish rescues these defects, whereas mRNAs encoding the human EIPR1 variants Arg279Gly or His271Gln fail to do so, confirming the impaired activity of these variants. These findings identify EIPR1 as a novel genetic locus associated with a neurodevelopmental disorder and underscore its critical role in endosomal recycling and dense core vesicle biogenesis, processes essential for the development and function of the nervous system.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"26 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240860","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":"Cortical cerebral microinfarcts spark cognitive decline","authors":"Gemma Solé-Guardia, Anil M Tuladhar, Frank-Erik de Leeuw","doi":"10.1093/brain/awaf377","DOIUrl":"https://doi.org/10.1093/brain/awaf377","url":null,"abstract":"This scientific commentary refers to ‘Synergistic effect between cortical cerebral microinfarcts and brain atrophy on cognitive decline’ by Huang et al. (https://doi.org/10.1093/brain/awaf301).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"17 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235375","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":"Ageing and remyelination failure in people with multiple sclerosis","authors":"Trisha Mukherjee, Christopher E McMurran, Jonathon Holland, Cyrus Daruwalla, Gioia Riboni-Verri, J William L Brown, Robin J M Franklin, Alasdair Coles, Nick G Cunniffe","doi":"10.1093/brain/awaf373","DOIUrl":"https://doi.org/10.1093/brain/awaf373","url":null,"abstract":"One of the most promising strategies to delay, prevent, or reverse disability progression in multiple sclerosis (MS) is enhancing endogenous remyelination. While preclinical research has established a strong connection between ageing and remyelination failure, evidence for this same link in people with MS remains less secure. As clinical trials for remyelinating therapies progress, clarifying this relationship is essential. A deeper understanding could guide the selection of therapeutic candidates, refine patient selection, and optimise the timing of treatment delivery. In this review, we describe the available evidence that has investigated the impact of age on remyelination in people with MS. We categorise these into pathological, imaging and clinical studies. We explore the challenges in measuring remyelination in humans and determine the implications for the connection between remyelination and age. Current evidence suggests that there is reduced capacity for remyelination with advancing age in people with MS. However, these findings are at times inconsistent and the precise contribution of ageing to remyelination failure is unclear. There does not appear to be an age cut-off beyond which remyelination is not possible, as there are pathological data supporting remyelination occurring, to some extent, across all ages. Interestingly, the impact of age may vary by lesion location. Further targeted research, specifically exploring the relationship between ageing and remyelination, is needed. With emerging evidence that ageing processes might be malleable, we conclude that targeting the biology of ageing might also be an important strategy to therapeutically enhance remyelination.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"77 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228869","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}