Annals of Neurology最新文献

Objective: Clot composition may offer insights into the mechanism of ischemic stroke. Radiomics, a noninvasive imaging technique, enables tissue characterization through radiomic features (RFs). We aimed to evaluate clot composition using radiomics on non-contrast computed tomography (NCCT).

Methods: In the first phase, we conducted a prospective study comparing RFs with histopathology in thrombi retrieved via mechanical thrombectomy (MT). Thrombi were imaged using micro-computed tomography (micro-CT) and analyzed histologically. Matched micro-CT and histological slices identified red blood cells (RBCs) and fibrin-rich regions. RFs were extracted, and multivariate logistic regression identified features associated with each component. Spearman's correlation was used to assess associations between RFs and percentage composition. The same clots were localized on pre-MT NCCT, and RFs were extracted. Micro-CT and NCCT RFs were correlated to enable histology-informed interpretation. Receiver operating characteristic analysis evaluated the ability of NCCT RFs to discriminate clot composition. In the second phase, radiomics was applied to a retrospective NCCT dataset from patients with ischemic stroke with varying etiologies.

Results: Ten thrombi were analyzed using micro-CT. Total energy (odds ratio [OR] = 1.35, 95% confidence interval [CI] = 1.20-1.54, p < 0.001) and large dependence high gray level emphasis (OR = 1.18, 95% CI = 1.07-1.32, p = 0.01) were associated with RBCs and correlated with >70% RBCs composition on NCCT (Rho = 0.752 and Rho = 0.815). Subsequently, 150 NCCT scans were analyzed, including 50 cardioembolic, 50 large artery atherosclerosis (LAA), and 50 cryptogenic strokes. Radiomic analysis indicated RBCs-predominant composition in 72% of cardioembolic, 30% of LAA, and 50% of cryptogenic clots.

Interpretation: Radiomics is a promising, noninvasive technique for characterizing clot composition. ANN NEUROL 2026.

Objective: Whether cognitive decline in patients with Parkinson's disease (PD) carrying GBA1 variants is accelerated after subthalamic deep brain stimulation (STN-DBS) remains controversial. Clarifying long-term cognitive outcomes is essential for informed decision making.

Methods: We assembled matched cohorts of patients carrying GBA1 variants with STN-DBS (PD_GBA1+DBS+, n = 28) and without (PD_{G BA1+DBS-}, n = 28). Additional cohorts included non-carriers with STN-DBS (PD_GBA1-DBS+, n = 40) and without (PD_GBA1-DBS-, n = 43). Clinical, genetic, and cerebrospinal fluid (CSF) biomarkers (Aβ1-42, h-Tau, p181-Tau, and neurofilament light chain) were analyzed. Cognition was assessed using the Montreal Cognitive Assessment (MoCA). Cognitive slopes were estimated using linear mixed models and the minimally detectable slope difference at 3-year follow-up was 1.33 MoCA points enabling sensitivity to clinically meaningful changes. Secondarily, conversion to dementia was analyzed with Kaplan-Meier-analysis once the MoCA was < 21.

Results: There was no significant difference in cognitive decline between PD_GBA1+DBS+ and PD_GBA1+DBS- (-0.24 MoCA points/year; 95% confidence interval [CI] = -1.11 to 0.70) projecting to -0.72 MoCA points at 3-year-follow-up (p = 0.583). Secondarily, the risk for conversion to dementia did not differ between PD_GBA1+DBS+ and PD_GBA1+DBS- (HR = 0.55, 95% CI = 0.23-1.34, p = 0.119) or between PD_GBA1-DBS+ and PD_GBA1-DBS- (HR = 1.22, 95% CI = 0.53-2.83, p = 0.897). Dementia risk was associated with GBA1 status (HR = 3.04, 95% CI = 1.05-8.79, p = 0.041), baseline MoCA < 26 (HR = 3.05, 95% CI = 1.29-7.21, p = 0.011), and baseline age > 69 years (HR = 4.42, 95% CI = 1.79-10.89, p = 0.001). In GBA1 carriers, a visuospatial/executive domain score < 4/5 predicted dementia (HR = 4.71, 95% CI = 1.25-17.86, p = 0.022).

Interpretation: GBA1 variant carriers meeting general STN-DBS indication criteria did not show accelerated cognitive decline in the presence of STN-DBS. In addition, exploratory predictors of dementia could support counseling of DBS candidates. ANN NEUROL 2026.

Objective: Immunothrombosis contributes to ischemic stroke pathophysiology through neutrophil extracellular trap (NET) formation, which promotes thrombus stabilization and microvascular dysfunction. DNase1 is the principal endonuclease responsible for NET degradation. The rs1053874 polymorphism in DNase1 gene influences enzymatic activity and protein stability in vitro, but its clinical relevance in ischemic stroke remains unexplored. We investigated whether this variant modulates systemic NET burden and impacts stroke-related outcomes.

Methods: We conducted a prospective observational cohort study including 492 patients with acute ischemic stroke. Genotyping of rs1053874 was performed via Sanger sequencing and categorized into AA versus GG + GA genotypes (dominant model). Clinical variables, NET biomarkers (elastase, myeloperoxidase [MPO], and dsDNA), DNAse1 activity, infarct volume, thrombectomy metrics, and survival were assessed. Multivariable regression and Cox proportional hazards models were used to explore associations between genotype and outcomes.

Results: AA genotype carriers (7.9%) had a significantly lower burden of prior vascular events compared to GG + GA carriers. At admission, they exhibited higher DNAse1 activity, reduced levels of circulating NET markers (elastase, MPO, and dsDNA), and lower neutrophil and monocyte counts. Despite similar initial stroke severity, AA carriers required fewer thrombectomy passes and had significantly better early neurological recovery and smaller infarcts. In adjusted models, both the AA genotype and dyslipidemia were independently associated with improved long-term survival. However, stratified analyses revealed the most robust survival benefit among AA carriers without dyslipidemia. No significant interaction was observed.

Interpretation: DNase1 rs1053874 polymorphism influences NET-related inflammation and is associated with improved vascular profile, procedural efficiency, and long-term outcomes in ischemic stroke. These findings support the potential of DNase1 as a therapeutic and prognostic target in personalized stroke care. ANN NEUROL 2026.

Objective: Focal hand dystonia (FHD) severely impairs task-specific motor control, yet the optimal surgical target for stereotactic intervention remains uncertain. This study aimed to identify the precise thalamic lesion site associated with symptomatic improvement and to clarify its network connectivity.

Methods: We retrospectively analyzed 164 patients with FHD (mean age = 42.0 years, 26.2% women) who underwent stereotactic thalamotomy of the ventral lateral thalamus. Voxel-wise probabilistic lesion mapping was applied to relate lesion locations to clinical outcomes. Structural connectivity analyses assessed fiber tracts linked to the optimal lesion site. Model performance was evaluated by 10-fold cross-validation, validation in an out-of-sample cohort, and testing in reoperation cases.

Results: We identified that lesioning the border zone between the ventralis oralis posterior (Vop) and ventralis intermedius (Vim) nuclei was associated with improvement of FHD. The predictive model achieved high accuracy in cross-validation (area under the curve [AUC] = 0.836) and performed robustly in independent validation. Connectivity analyses showed that the Vop-Vim border zone was linked to cerebellothalamic and pallidothalamic afferents as well as thalamocortical projections to the supplementary motor area and premotor cortex. In contrast, lesions extending into the ventralis oralis anterior nucleus were associated with an increased risk of motor complications.

Interpretation: Precise targeting of the Vop-Vim border maximizes clinical benefit while minimizing adverse effects in FHD thalamotomy. These findings establish the first evidence-based thalamic target for FHD, offering practical guidance for stereotactic interventions and advancing understanding of dystonia pathophysiology. ANN NEUROL 2026.

Objective: Naturally occurring autoantibodies are commonly considered to be causative of autoimmune diseases or epiphenomena with no known biological impact. Although clinically beneficial autoantibodies have been described, there have been no naturally occurring anti-neuronal antibodies that have been found to be neuroprotective. Here, we identify a recombinant human antibody (TGM-010) derived from a patient with multiple sclerosis (MS) that binds human and mouse neurons, leading to beneficial effects.

Methods: TGM-010 was examined for its ability to be internalized by human and mouse neurons and protect neurons from death in vitro following a stress event. TGM-010 was also injected systemically into a relapsing-remitting model of experimental autoimmune encephalomyelitis (EAE) to examine its ability to impact disease score, extent of demyelination, and neuron frequency.

Results: TGM-010 demonstrates many novel characteristics including crossing the blood-brain barrier (BBB) and internalizing into neurons. TGM-010 also protects primary mouse neurons from death in vitro. In a mouse model of MS, TGM-010 ameliorates disease severity and is associated with improved neuronal survival.

Interpretation: This study identified a patient-derived neuron-binding autoantibody that crosses the BBB in mice and reduces neuron loss in a mouse model of MS. These data suggest that the human derived anti-neuronal antibody, TGM-010, may potentially be used to ameliorate neurodegeneration that underlies disability in neurodegenerative conditions. ANN NEUROL 2026.

Objective: Evidence linking modifiable risk factors to age-related brain diseases, such as dementia, stroke, and depression (DSD), is robust, yet limited regarding long-term change in modifiable risk factors in association with these conditions, particularly in real-world settings. This study aimed to assess whether longitudinal changes in modifiable brain health risk factors were associated with reduced risk of DSD.

Methods: We analyzed UK Biobank data (2006-2019) from 155,469 participants with general practitioner-linked data. The Brain Care Score (BCS) assesses 12 modifiable risk factors across lifestyle, physical, and social-emotional domains. Longitudinal BCS measurements were derived from repeated general practitioner (GP)-recorded measurements. Changes in the BCS were modeled using linear mixed-effects models, and associations with DSD were evaluated using multivariable Cox models, adjusting for baseline BCS and genetic risk (polygenic risk scores for stroke and depression, and APOE genotype for dementia).

Results: Among 155,469 participants (median age = 51 years, 54.3% women), the median annual BCS change was 0.14 (Q1-Q3 = 0.008-0.30) points over a median follow-up of 12.3 years (Q1-Q3 = 11.5-13.1 years). Over time, 82.1% improved their BCS, 12.9% remained stable, and 5.0% worsened over time. Each 1-point annual increase in the BCS was associated with 4% lower risk of incident age-related brain diseases (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.95-0.97).

Interpretation: In this large real-world cohort, improvements in modifiable risk factor profiles were associated with lower incidence of DSD, regardless of genetic risk or baseline BCS. Our results provide important information for communicating with patients about the brain health benefits of improving risk factor profiles. ANN NEUROL 2026.

Objective: De novo mutations in the syntaxin-binding protein 1 (STXBP1), encoded by STXBP1, are among the most prevalent causes of variable neurodevelopmental disorders, including epileptic encephalopathy, developmental delay, and movement disorders. Although STXBP1 has been proposed as a critical presynaptic protein controlling synaptic vesicle exocytosis, clinical phenotypes also suggest that its biological function could be more diverse.

Methods: The expression pattern of STXBP1 was studied using immunostaining in vitro and in vivo. Synaptosome isolation was performed to investigate the synaptic and non-synaptic localization of STXBP1 in the brain. STXBP1 immunoprecipitation followed by mass spectrometry (MS) was conducted to identify protein complexes interacting with STXBP1. Cre-in utero electroporation (IUE) was done on Stxbp1^F/F mice to generate an in vivo knockout (KO) cellular model for studying the in vivo function of STXBP1.

Results: Our immunohistochemistry results demonstrated that STXBP1 expression in the cerebral cortex was developmentally regulated and was detected in neuronal soma and processes. STXBP1 was in both the synaptic and cytosolic fractions, interacting with neuronal cytoskeleton and membrane periodic structures. Interestingly, sparse Stxbp1 KO in the mouse forebrain led to cell-autonomous cell death, which was rescued by either wild-type STXBP1 or pathogenic mutants. However, Stxbp1 KO neurons rescued by pathogenic mutants exhibited impaired dendritic growth. Our results also showed that STXBP1 interacted with alpha II Spectrin and ARPC2 and is required for their localization on the neuronal membrane.

Interpretation: Our data suggest that STXBP1 has diverse functions in the nervous system and regulates the trafficking of membrane cytoskeleton proteins in the brain. ANN NEUROL 2025 ANN NEUROL 2026.

Objective: The objective of this study was to compare clinical features and prognosis of late-onset neuromyelitis optica spectrum disorder (LO-NMOSD, onset age ≥60 years) with adult-onset NMOSD (AO-NMOSD, onset age 18-59 years), and to provide insights for individualized management in elderly patients.

Methods: Data from 748 patients with NMOSD (diagnosed according to the 2015 International Panel for NMO Diagnosis criteria) in the China National Registry of Neuro-Inflammatory Diseases (CNRID) were analyzed. Patients were stratified into AO-NMOSD (18-59 years, n = 617) and LO-NMOSD (≥ 60 years, n = 131). Demographics, clinical manifestations, imaging, treatments, and outcomes were compared using appropriate statistical methods including Kaplan-Meier survival curves and Cox proportional hazards regression.

Results: LO-NMOSD showed distinct traits: a lower female predominance (76.34% vs 86.55%), higher transverse myelitis (TM) incidence at onset (57.36% vs 40.17%), elevated annualized relapse rate (ARR; 0.52 ± 0.03 vs 0.38 ± 0.01), and accelerated disability (median Expanded Disability Status Scale [EDSS] 4.75 vs 3.0). TM-predominant relapses (39 of 45, 86.67% in LO vs 96 of 148, 64.86% in AO) contributed significantly to disability. Kaplan-Meier analysis showed LO-NMOSD had a higher risk of relapse (hazard ratio [HR] = 1.932, 95% confidence interval [CI] = 1.427-2.615), disability (HR = 3.192, 95% CI = 1.932-5.274) and reaching visual acuity (VA) ≤20 of 30 (HR = 3.523, 95% CI = 1.585-7.828). Cox regression confirmed that onset age ≥60 years was an independent risk factor for relapse (HR = 2.05, 95% CI = 1.60-2.59), disability (HR = 3.16, 95% CI = 2.14-4.62), and reaching VA ≤20 of 30 (HR 3.26, 95% CI = 1.83-5.48).

Interpretation: LO-NMOSD is characterized by myelitis-predominance with recurrent spinal cord involvement, high risk of relapses, and severe disability. It thus underscores the need for heightened clinical attention, with rigorous monitoring that balance safety and efficacy for elderly patients with NMOSD. ANN NEUROL 2026.

Objective: Carpal tunnel syndrome (CTS) can drastically impair one's ability to work and interferes with activities of daily living. We recently demonstrated that, in rodents, conditioning electrical stimulation (CES) delivered to the nerve 7 days prior to surgery imparts a conditioning lesion-like effect by accelerating the rate of regeneration along the entire length of the nerve. The goal of this study is to test the hypothesis that CES could accelerate nerve regeneration and improve function in patients with moderate or severe CTS.

Methods: Using a double-blind randomized controlled study design, patients received surgery + CES or surgery + sham stimulation. They were evaluated at regular intervals for 12 months following intervention. Primary outcome was motor unit number estimation (MUNE), supplemented with secondary outcomes including motor and sensory nerve conduction studies, Semmes Weinstein Monofilaments, and Moberg Pick-Up Test.

Results: Sixty-four participants were randomized to either the treatment or control groups. There was no significant demographic or physiological difference at baseline between the groups. No major adverse event was found with treatment. Following intervention, there was significantly greater increase in MUNE of 62 ± 71 in the treatment group compared to 25 ± 66 in the controls after 12 months. In the treatment group, there was correspondingly better physiological and functional recovery and hand dexterity compared with the controls.

Interpretation: CES is a safe, feasible, and efficacious treatment to improve nerve reinnervation and functional outcomes in patients with moderate or severe CTS. This may open future possibilities for more effective treatment for other peripheral nerve injuries. ANN NEUROL 2026.