Neurobiology of Disease最新文献

{"title":"Gait-cycle-locked cortico-subthalamic signatures underlying freezing of gait and their modulation in Parkinson's disease.","authors":"Yutong Zhuang, Baotian Zhao, Hutao Xie, Quan Zhang, Jiansong Huang, Yue Lu, Shuochen Wang, Fangang Meng, Jun Jia, Jing Wei, Anchao Yang, Tingting Du, Chong Qi, Jianguo Zhang, Yin Jiang","doi":"10.1016/j.nbd.2026.107571","DOIUrl":"10.1016/j.nbd.2026.107571","url":null,"abstract":"<p><strong>Objective: </strong>Research on freezing of gait (FOG) in Parkinson's disease (PD) has identified relevant electrophysiological markers. However, their brief temporal windows limit their utility for individualized deep brain stimulation (DBS). This study explored gait performance and neural features in freezing-susceptible walking to develop novel FOG-predictive biomarkers.</p><p><strong>Methods: </strong>Gait kinematics and local field potentials (LFP) from the cortex and subthalamic nucleus (STN) were simultaneously acquired in FOG patients during walking. Using the gait cycle as the analytic unit, we compared freezing trials (FOGT) and non-freezing trials (nFOGT) under the no-intervention condition (OFF) to identify gait parameters and neural features associated with FOG risk. Subsequently, we assessed the modulatory effects of high-frequency (HFS) and low-frequency (LFS) STN-DBS on abnormal gait and cortical power. Finally, we analyzed changes in abnormal gait and cortico-STN coherence after levodopa administration.</p><p><strong>Results: </strong>FOGT showed aberrant gait parameters compared to nFOGT, along with disrupted lowbeta oscillations in primary somatosensory cortex (S1) and superior parietal lobule (SPL). Both HFS and LFS mitigated gait impairment and freezing severity, with LFS exerting broader effects: HFS reversed pathological lowbeta power reduction in SPL during the double support phase, while LFS restored phase-dependent oscillations between the stance phase and swing phase in S1. Additionally, abnormal theta coherence between S1 and STN could be modulated by levodopa, accompanied by gait recovery.</p><p><strong>Conclusion: </strong>This study identifies gait-cycle-locked cortico-STN signatures for FOG, which have extended temporal windows and are modulable by DBS, suggesting the gait cycle as a promising intervention target.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107571"},"PeriodicalIF":6.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"NOTCH3 R545C mutation drives vascular-neuronal dysfunction and cognitive impairment in CADASIL pathogenesis\" [Neurobiology of Disease 224 (2026) 107404].","authors":"Suning Ping, Bin Hu, Danni Wu, Can Wan, Hongbin Tang, Xiaoyan Xiong, Lijun Long, Mingyang Xu, Huihui Xiong, Qilong Wu, Yuan Chen, Jingsong You, Xuecheng Qiu","doi":"10.1016/j.nbd.2026.107620","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107620","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107620"},"PeriodicalIF":6.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"DNMT3L affects synaptic function and induces neurobehavioral alterations in Drosophila via Sqd\" Neurobiology of Disease, Volume 227 (2026) 107493.","authors":"Ruonan Fan, Zhuo Zhang, Tingting Miao","doi":"10.1016/j.nbd.2026.107621","DOIUrl":"https://doi.org/10.1016/j.nbd.2026.107621","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107621"},"PeriodicalIF":6.0,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of concern: \"Role of caspase-3 in ethanol-induced developmental neurodegeneration\" [Neurobiology of Disease, Volume 20 (2005) Pages 608-614].","authors":"","doi":"10.1016/j.nbd.2026.107417","DOIUrl":"10.1016/j.nbd.2026.107417","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"224 ","pages":"107417"},"PeriodicalIF":5.6,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognitive impairment in SCA3: A multi-center cohort study with demographic, imaging, and biomarker correlates","authors":"Roderick P.P.W.M. Maas ,&nbsp;Hector Garcia-Moreno ,&nbsp;Jennifer Faber ,&nbsp;Carlos Gonzalez ,&nbsp;Ludger Schöls ,&nbsp;Jeroen J. de Vries ,&nbsp;Khalaf Bushara ,&nbsp;Kathrin Reetz ,&nbsp;Chiadi U. Onyike ,&nbsp;Heike Jacobi ,&nbsp;Friedrich Erdlenbruch ,&nbsp;Jon Infante ,&nbsp;Magda M. Santana ,&nbsp;Jeannette Hübener-Schmid ,&nbsp;Luís Pereira de Almeida ,&nbsp;Manuela Lima ,&nbsp;Paola Giunti ,&nbsp;Thomas Klockgether ,&nbsp;ESMI study group ,&nbsp;Bart P.C. van de Warrenburg","doi":"10.1016/j.nbd.2026.107301","DOIUrl":"10.1016/j.nbd.2026.107301","url":null,"abstract":"<div><h3>Background</h3><div>Cognitive deficits are common in spinocerebellar ataxia type 3 (SCA3), but their neurobiological correlates remain largely unknown.</div></div><div><h3>Objectives</h3><div>To investigate cognitive performance in a large international cohort of SCA3 mutation carriers covering the entire disease course and to explore associations with posterior cerebellar volumes, basal ganglia and thalamus volumes, and plasma neurofilament light chain (NfL) concentration.</div></div><div><h3>Methods</h3><div>The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive impairment in this prospective, observational cohort study involving 13 ataxia referral centers. Standardized motor assessments, brain MR imaging, and peripheral blood biosampling were also performed.</div></div><div><h3>Results</h3><div>MoCA data were collected from 61 pre-ataxic SCA3 mutation carriers, 231 ataxic SCA3 patients, and 111 healthy controls. After adjustments for educational level and age, there were significant differences in MoCA total score, as well as visuospatial/executive, attention, language, and abstraction subscores, between healthy controls and ataxic, but not pre-ataxic individuals. MoCA scores declined with ataxia severity, especially in patients with a lower educational level. Patients with a MoCA score &lt; 26 had lower pallidal volumes and higher plasma NfL concentrations than those with a score ≥ 26. However, only the interaction term between ataxia severity and educational level was independently associated with cognitive performance in multivariable regression analyses containing demographic, clinical, volumetric, and biochemical parameters.</div></div><div><h3>Conclusion</h3><div>Cognitive deficits in SCA3 generally appear after clinical ataxia onset and progress in parallel with ataxia severity, especially in patients with a lower cognitive reserve. Other measured biochemical and imaging parameters did not have a significant additional contribution.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107301"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glymphatic dysfunction in trigeminal neuralgia: A multimodal MRI study","authors":"Tiantian Chu ,&nbsp;Fei Xiong ,&nbsp;Feng Gao ,&nbsp;Ye Tu","doi":"10.1016/j.nbd.2026.107312","DOIUrl":"10.1016/j.nbd.2026.107312","url":null,"abstract":"<div><h3>Background</h3><div>Trigeminal neuralgia (TN) has traditionally been attributed to peripheral neurovascular compression at the trigeminal nerve root entry zone. Recent evidence, however, suggests central mechanisms may contribute to disease pathogenesis. We investigated whether glymphatic system dysfunction occurs in TN and contributes to its pathophysiology.</div></div><div><h3>Methods</h3><div>This cross-sectional study enrolled 71 patients with classical TN and 52 age-matched healthy controls. All participants underwent comprehensive multimodal MRI assessment, including: (1) diffusion tensor imaging along perivascular spaces (DTI-ALPS) index measurement, (2) free water fraction (FWF) mapping, (3) perivascular space (PVS) burden quantification, and (4) choroid plexus (CP) volumetric analysis using deep learning segmentation to evaluate glymphatic system function.</div></div><div><h3>Results</h3><div>TN patients demonstrated selective glymphatic dysfunction characterized by reduced DTI-ALPS index and increased FWF. Compared to controls, patients showed significantly reduced DTI-ALPS indices (1.34 ± 0.12 vs. 1.41 ± 0.13; <em>p</em> = 0.027) and elevated FWF values (0.34 ± 0.04 vs. 0.32 ± 0.03, <em>p</em> = 0.027), indicating compromised cerebrospinal fluid dynamics. In contrast, structural measures including PVS burden and CP volumes remained comparable between groups (all <em>p</em> &gt; 0.05). Age-related analysis revealed significant correlations with DTI-ALPS decline (ρ = −0.286, <em>p</em> = 0.020) and FWF elevation (ρ = 0.658, <em>p</em> &lt; 0.001), suggesting progressive glymphatic deterioration with aging. However, there is a lack of correlation between glymphatic indicators and pain intensity as well as disease course.</div></div><div><h3>Conclusions</h3><div>These findings indicate that TN is associated with functional impairment of the glymphatic system in the absence of overt perivascular structural abnormalities. This dissociation between functional and structural glymphatic measures challenges conventional neuroimaging paradigms in TN and highlights a previously underrecognized central mechanism.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107312"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impedance-based phenotypic profiling of metabotropic glutamate receptor ligand responses in SCA1 human iPSC-derived neuronal cultures","authors":"Laurie M.C. Kerkhof ,&nbsp;Ronald A.M. Buijsen ,&nbsp;Stefan Hartman ,&nbsp;Barry A. Pepers ,&nbsp;Linda M. van der Graaf ,&nbsp;Jean-Philippe Frimat ,&nbsp;Rongfang Liu ,&nbsp;Laura H. Heitman ,&nbsp;Willeke M.C. van Roon-Mom","doi":"10.1016/j.nbd.2026.107296","DOIUrl":"10.1016/j.nbd.2026.107296","url":null,"abstract":"<div><div>Group 1 metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors (GPCRs) including mGluR1 and mGluR5. These receptors are expressed throughout the central nervous system and play an important role in synaptic plasticity. Dysfunction of mGluR1 in cerebellar Purkinje cells (PC) is observed in spinocerebellar ataxia type 1 (SCA1), an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the <em>ATXN1</em> gene. MGluR1 dysfunction disrupts PC signaling and ultimately contributes to PC death and overall progressive cerebellar dysfunction observed in SCA1. To investigate mGluR1/5 pharmacology in the context of SCA1, mGluR1/5 function was assessed in SCA1 and control human induced pluripotent stem cell (hiPS)cell-derived neuronal cultures using impedance measurements in the xCELLigence real-time cell analyzer (RTCA) system. Culture conditions and protocols for evaluating glutamate receptor activity were first optimized. Subsequently, <em>GRM1</em> and <em>GRM5</em> expression levels were assessed and glutamatergic signaling function was characterized in SCA1 hiPS cell-derived neuronal cultures using both the non-selective endogenous ligand L-glutamate and the selective orthosteric agonist for mGluR1/5, (<em>RS</em>)-3,5-Dihydroxyphenylglycine. To specifically characterize mGluR1 function, mGluR1-specific positive- and negative allosteric modulators (Ro0711401 and JNJ16259685 respectively) were tested. Results showed reduced mGluR1 and decreased mGluR5 RNA expression levels and diminished mGluR1/5 responses in the SCA1 hiPS cell-derived neuronal cultures. These results underline the potential utility of impedance measurements for characterizing GPCR function and pharmacological testing in a high-throughput manner in patient-derived neuronal cultures.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107296"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RhoA deletion in macrophages/microglia aggravates blood-brain barrier disruption after ischemic stroke reperfusion injury by promoting endothelial cell apoptosis and pyroptosis","authors":"Jiale Cai ,&nbsp;Xiongbo Luo ,&nbsp;Wenli Cui ,&nbsp;Xinya Zheng ,&nbsp;Shuyi Xu ,&nbsp;Xinrui Ma ,&nbsp;Ye He ,&nbsp;Xianghai Wang ,&nbsp;Jiasong Guo","doi":"10.1016/j.nbd.2026.107279","DOIUrl":"10.1016/j.nbd.2026.107279","url":null,"abstract":"<div><div>Disruption of the blood-brain barrier (BBB) is an important cause of secondary injury following cerebral ischemia-reperfusion (I/R). Database analyses revealed RhoA upregulation in macrophages/microglia within I/R brain tissue; however, the role of macrophage/microglial RhoA in BBB disruption and I/R injury remains poorly understood. In this study, we verified that macrophage/microglial RhoA was significantly upregulated in I/R mice. Employing conditional knockout (cKO) mice, present study demonstrated that the macrophage/microglial RhoA deficiency exacerbates I/R injury, manifesting as enlarged infarct volumes, aggravated cerebral oedema and BBB leakage. Mechanistically, RhoA deficiency alters the secretory profile of macrophages/microglia, enhancing pro-inflammatory factors production in macrophages/microglia, which subsequently induces pyroptosis and apoptosis while downregulates tight junction proteins in endothelial cells via the NLRP3 pathway. Collectively, our findings revealed a novel macrophage/microglial-endothelial crosstalk mechanism whereby I/R-induced RhoA upregulation in macrophages/microglia serves to attenuate their pro-inflammatory polarization, thereby preserving BBB function through suppression of NLRP3-mediated pyroptosis and apoptosis in the endothelial cells. These findings may reshape the conventional view of RhoA inhibition therapy and pave the way for more precise, cell-targeted interventions in I/R brain injury.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107279"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-derived neural organoids reveal developmental impairments associated with a novel GJB1 mutation in X-linked Charcot-Marie-Tooth disease","authors":"Jianying Guo ,&nbsp;Qianhui Lee ,&nbsp;Hui Qiu ,&nbsp;Yuan Wei ,&nbsp;Xiaohui Zhu ,&nbsp;Liying Yan ,&nbsp;Jie Na","doi":"10.1016/j.nbd.2026.107299","DOIUrl":"10.1016/j.nbd.2026.107299","url":null,"abstract":"<div><div>Charcot-Marie-Tooth disease (CMT) is one of the most prevalent inherited peripheral neuropathies. CMT type X1 (CMTX1), caused by mutations in the <em>GJB1</em> gene, represents the most common X-linked subtype with central nervous system (CNS) involvement. Here, we report the identification and functional characterization of a novel <em>GJB1</em> variant (c.554C &gt; T, p.Thr185Ile) in a CMTX1-affected family and its pathogenic impact using patient-derived induced pluripotent stem cells (iPSCs) and three-dimensional (3D) neural organoid models. The <em>GJB1</em> gene encodes connexin 32 (Cx32), a gap junction protein. Immunofluorescent analysis revealed aberrant intracellular reduction and aggregation of the mutant Cx32 protein, suggesting impaired gap junction function. iPSC-derived neural organoids carrying the <em>GJB1</em> mutation exhibited significant delay in neural differentiation and disrupted neural rosette organization. These findings underscore the critical role of Cx32 in neural development and provide a physiologically relevant platform for underlying CMTX1 pathological mechanisms on central nervous system. The established <em>GJB1</em>-variant organoid model holds promise for investigating genotype-phenotype correlations and facilitating the development of targeted therapeutic strategies for CMTX1.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107299"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The apolipoprotein gene: a modulating role on brain volume and cognitive function in carriers of the fragile X premutation","authors":"Poonnada Jiraanont ,&nbsp;Jun Yi Wang ,&nbsp;Blythe Durbin-Johnson ,&nbsp;Ye Hyun Hwang ,&nbsp;David Hessl ,&nbsp;Susan M. Rivera ,&nbsp;Randi J. Hagerman ,&nbsp;Flora Tassone","doi":"10.1016/j.nbd.2026.107292","DOIUrl":"10.1016/j.nbd.2026.107292","url":null,"abstract":"<div><div>Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by the <em>FMR1</em> premutation allele, is associated with brain degeneration, yet the mechanisms behind this neurodegeneration still need to be elucidated. <em>Apoε</em> polymorphism has been widely implicated in brain aging in cognitively healthy individuals and brain deterioration in Alzheimer's disease. This study aimed to examine the interaction of <em>Apoε</em> genotypes, FXTAS clinical symptoms, <em>FMR1</em> molecular measures, and age, towards brain pathophysiology and cognitive functions.</div><div>This longitudinal study includes MRI data collected from 205 male premutation carriers with and without FXTAS clinical symptoms and compared to 86 healthy male controls aged 40–85 years. The investigation includes FXTAS-related brain volumes, IQ, self-control behaviors, <em>FMR1</em> molecular measures, and <em>Apoε</em> genotypes.</div><div>In carriers with FXTAS, the presence of the <em>Apoε2</em> allele showed a possible association with more favorable neuroimaging markers, such as reduced white matter hyperintensities, and lower incidence of the middle cerebellar peduncle sign, patterns that were not observed in carriers without FXTAS.</div><div>Specifically, the presence of <em>Apoε2</em> allele exhibited a potential protective effect on brain degeneration, and cognitive functions among FXTAS patients; on the contrary, the <em>Apoε4</em> allele was associated with a worsening of brain volume and brain degeneration in carriers with no FXTAS symptoms. The identification of <em>Apoε</em> genotypes in <em>FMR1</em> premutation carriers before any clinical symptoms of FXTAS are observed may improve symptomatic management leading to better outcomes for these individuals.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107292"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}