Annals of Clinical and Translational Neurology最新文献

Background: Skewed myelopoiesis in the bone marrow has been identified as a key driver of multiple sclerosis (MS) progression. Interestingly, SARS-CoV-2 infection, which has a severe impact on MS patients, can also induce similar skewed myelopoiesis. This shared phenotype raises the question of whether a common mechanism underlies the skewed myelopoiesis in both diseases. Previous studies in mice have demonstrated that the dysregulation of endogenous retroelements (EREs) in HSPCs leads to skewed myelopoiesis. Building on this, we sought to determine whether ERE dysregulation contributes to the skewed myelopoiesis observed in MS and after COVID-19, which remains challenging.

Methods: We undertook a joint investigation of two public single-cell/nuclei cohorts respectively representing MS and following COVID-19. Both cohorts were processed through an identical bioinformatic pipeline to ensure comparable assessment of gene and ERE expression.

Results: We observed enhanced myelopoiesis in the bone marrow of MS patients compared to healthy controls, along with downregulation of the ERE repressor H3.3 and concomitant EREs overexpression. Notably, a similar epigenetic and transcript feature was found in post-COVID-19 individuals.

Conclusion: The H3.3^low/ERE^high signature may not only explain the common skewed myelopoiesis in MS and post-COVID-19 conditions, but also provide a mechanistic link between infection and the innate immune reprogramming that drives MS progression. This offers a novel therapeutic insight for MS.

Objective: Autoimmune encephalitis (AE) is a disease with a potential for recurrence, and patients receive immunotherapy to prevent it. However, there is no consensus on the duration of immunotherapy. This study aimed to determine the recurrence rate and identify the risk factors for AE to provide guidance on the duration of immunotherapy.

Methods: A comprehensive search of the Embase, Web of Science, Cochrane, and PubMed databases was conducted from database inception until January 18, 2025, to identify clinical studies and observational studies reporting the recurrence of AE. Data on recurrence rates across different AE subtypes, age groups, treatments, and follow-up durations were aggregated. A generalized linear model was employed for regression and multivariate regression analyses.

Results: Of the 7892 publications initially identified, 39 observational studies were ultimately included. The overall recurrence rate of AE was 0.162 (95% CI, 0.121-0.207). The recurrence rate for anti-NMDAR encephalitis was 0.148 (95% CI, 0.108-0.193) and significantly decreased after teratoma removal. Second-line treatment decreased the AE recurrence rate. Multivariate regression analysis indicated that having anti-LGI1 encephalitis, age, and shorter delayed treatment duration were risk factors for recurrence. After 1 year of follow-up, the recurrence rate did not increase.

Interpretation: Based on the findings, we recommend proactive second-line immunotherapy for patients with AE to reduce recurrence rates, particularly for those with anti-LGI1 encephalitis and adult individuals. Immunotherapy maintenance over 1 year may not be required.

Objective: Early neurological deterioration (END) adversely affects outcomes in patients with intracerebral hemorrhage (ICH). This study aimed to determine the location-specific hematoma volumes for END in supratentorial ICH patients.

Methods: We retrospectively analyzed supratentorial ICH patients presenting from two prospective cohorts. END was defined as a ≥ 4-point increase in the National Institutes of Health Stroke Scale (NIHSS) score or a ≥ 2-point decrease in the Glasgow Coma Scale score within 24 h of admission. The training cohort was used to determine location-specific hematoma volume cutoffs for END and to develop the location-specific hematoma volume for early neurological deterioration (LIVED) score. Internal validation used 30% of the cohort, with external validation in a separate cohort.

Results: A total of 1199 patients with supratentorial ICH were included, divided into training (n = 633), internal validation (n = 272), and external validation (n = 294) cohorts. Hematoma volume thresholds for END were 21 mL for basal ganglia, 12 mL for thalamus, and 32 mL for lobar hemorrhages. Multivariable logistic regression identified location-specific hematoma volume, right-sided ICH, prior ischemic stroke, and NIHSS score as independent predictors, forming the LIVED score (range 0-5 points). The LIVED score showed superior predictive performance for END compared with established ICH scores, with the highest area under the curve (AUC) across cohorts. Additionally, it exhibited strong discrimination for 3-month outcomes, including functional independence, poor outcomes, and mortality, with AUCs > 0.70 in all cohorts.

Interpretation: Location-specific hematoma volume thresholds independently predicted END, and the LIVED score demonstrated reliable performance for risk stratification in supratentorial ICH.

Objective: Pathogenic variants in SCN1A, which encodes the voltage-gated sodium channel Na_V1.1, are associated with multiple epilepsy syndromes exhibiting a range of clinical severity. SCN1A variants are reported in different syndromes, including Dravet syndrome, which is associated with loss-of-function, whereas neonatal/infantile-onset developmental and epileptic encephalopathy (DEE) is associated with gain-of-function. Strategies to predict SCN1A variant pathogenicity and dysfunction have been proposed but are limited by available training data. We investigated the functional properties of four epilepsy-associated SCN1A variants affecting the same codon and sought to correlate channel dysfunction with phenotype.

Methods: Whole-cell manual patch-clamp recording was performed on heterologously expressed Na_V1.1 variants. Structural modeling of Na_V1.1 variant proteins was conducted using AlphaFold 3.

Results: We describe an individual with early infantile-onset DEE associated with SCN1A-I1347T, and identified three additional cases from the literature or ClinVar with distinct variations of the same codon (I1347N, I1347V, I1347F). Functional studies demonstrated mixed function properties for I1347T, I1347V, and I1347F, but complete loss-of-function for I1347N. Structural models suggest important interactions between isoleucine-1347 and the sixth transmembrane helices of domains 3 and 4 that are disrupted most significantly with asparagine replacement at this position (I1347N).

Interpretation: Pathogenic variants in SCN1A involving the same codon can produce divergent functional effects. Our findings suggest that predicting specific functional effects of SCN1A variants should not rely heavily on position in the protein.

Histone lysine methyltransferases such as SETD1B regulate chromatin structure and gene transcription. Ketone bodies, including butyrate, act as histone deacetylase inhibitors. We report a 4-year-old boy with SETD1B-related absence epilepsy, refractory to conventional medications, who achieved sustained > 90% seizure reduction on the Modified Atkins ketogenic diet. Single-cell RNA sequencing of 25,159 peripheral mononuclear cells across 3 samples: baseline, 3 months on-diet and age-matched control, revealed widespread dysregulation of the patient's chromatin, ribosomal, immune and mitochondrial pathways at baseline, which were reversed with ketogenic therapy. These findings suggest that the ketogenic diet can improve gene regulation in chromatin-mediated brain disorders.

Background: Emerging evidence suggests that low-frequency neural oscillations are dynamically regulated by consciousness levels, with the recovery of low cortical activity potentially serving as a neurophysiological substrate for conscious emergence. Targeted enhancement of these low-frequency rhythms in patients with disorders of consciousness (DoC) may constitute a promising neuromodulation strategy to facilitate consciousness recovery in severe brain injury.

Objective: This study systematically examined the neurophysiological effects of intermittent theta-burst stimulation (iTBS), specifically its potential to enhance low-frequency cortical activity and promote consciousness recovery in patients with DoC. Through multimodal neural assessments, we aimed to elucidate the mechanistic relationship between iTBS-induced neural oscillation modulation and behavioral manifestations of consciousness improvement.

Results: This prospective cohort study enrolled 30 patients with DoC, of whom 18 completed the full intervention protocol. Two-way repeated-measures analysis of variance revealed significant group × time interaction effects on the Coma Recovery Scale-Revised (CRS-R) scores, F(1, 16) = 6.543, p = 0.021. Post hoc simple effects analysis demonstrated significant temporal improvement in the active transcranial magnetic stimulation (TMS) group, F(1, 16) = 36.463, p < 0.001, with mean CRS-R scores increased from 9.300 ± 1.320 at baseline to 11.700 ± 1.409 post-intervention (p < 0.001). Conversely, sham stimulation revealed statistically nonsignificant changes (9.845 ± 1.476 versus 10.750 ± 1.575, p = 0.067). Neurophysiological assessments revealed emerging neurophysiological changes in the iTBS group, including enhanced resting-state low-frequency oscillations (delta: 21.642% increase, p = 0.449; theta: 6.800% increase, p = 0.789) and augmented auditory-evoked responses (phrase-level 22.917% increase, p = 0.280; syllable-level: 22.963% increase, p = 0.504), suggesting potential neural plasticity mechanisms that require further validation.

Conclusion: Collectively, this study established iTBS targeting the left dorsolateral prefrontal cortex as a clinically effective and well-tolerated neuromodulation approach for consciousness rehabilitation in patients with DoC, with therapeutic effects mediated by iTBS-induced enhancement of thalamocortical low-frequency oscillations.

Trial registration: https://www.

Clinicaltrials: gov. Unique identifier: NCT03385278. Registered on October 24, 2017.

Objective: Vestibular symptoms impose a high burden of disability. Understanding real-world diagnostic and treatment pathways can identify care gaps and guide interventions. We aimed to characterize symptom profiles, diagnostic trends, provider involvement, and treatment patterns in vestibular disorders. We also examined whether these real-world pathways align with expected clinical features in vestibular diagnoses.

Methods: Data from the Vestibular Disorders Association (VeDA) patient registry from March 21, 2023, to January 29, 2024 was analyzed, focusing on vestibular diagnoses, symptom patterns, care pathways, treatments, and diagnostic predictors.

Results: Of 172 respondents (75.6% female), 66.3% reported multiple vestibular diagnoses (mean 1.8) and 18.9% reported inability to work. The most prevalent diagnoses were vestibular migraine (VM, 50.6%), benign paroxysmal positional vertigo (BPPV, 36.0%), Meniere's disease (26.9%), persistent postural-perceptual dizziness (PPPD, 20.9%), and vestibular neuritis (VN, 21.6%). VM overlapped with BPPV (44.8%), PPPD (31.0%), and Meniere's disease (27.6%). Patients consulted an average of ~15 providers, underscoring the combined effects of participation bias, diagnostic overlap, and fragmented care pathways characteristic of vestibular conditions. Symptoms, triggers, functional impact, provider involvement, and treatments were broadly similar across diagnoses. Logistic regressions revealed that VM was associated with frequent headaches, spontaneous vertigo, and frequent nausea/vomiting (ORs 24.70, 21.07, 5.58; p = 0.003, 0.02, 0.036), Meniere's with dietary improvement (OR 38.00; p = 0.016), PPPD with VM overlap and visual-induced vertigo (ORs 6.83, 0.02; p = 0.03, 0.02), and VN with the lowest frequency of autonomic symptoms (OR 0.00006; p = 0.005).

Interpretation: The findings reveal a complex clinical landscape of vestibular disorders marked by multiple diagnoses and barriers to effective care. Overlapping symptom profiles across disorders further complicate diagnostic accuracy. Although regression analysis confirmed diagnosis-specific features, neither provider involvement nor treatments aligned consistently with diagnoses, highlighting fragmented care pathways. These findings call for clearer diagnostic pathways, enhanced provider training, and coordinated multidisciplinary care to improve diagnostic accuracy and treatment for vestibular disorders.

Objective: In multiple sclerosis, the optimal time for deploying a therapeutic intervention is before the central nervous system is damaged; given the success of trials treating the earliest stage of MS, the radiologically isolated syndrome, developing primary prevention strategies is an important next challenge. To inform this question, we examined the conversion of asymptomatic family members to a diagnosis of MS among Genes and Environment in Multiple Sclerosis (GEMS) project participants. We also evaluated an updated Genetic and Environmental risk score (GERS) and interest in participation in primary prevention trials.

Methods: GEMS is a nationwide prospective study of first-degree relatives of persons with MS; we analyzed data from seven surveys completed over 11 years. 1903 participants completed all questionnaires at study entry. Biological samples were collected in a subset of participants.

Results: Among these 1903 first degree relatives, 141 participants had MS at the time of enrollment; 18 participants converted to MS; and 1744 participants did not acquire an MS diagnosis during 8526 person-years of observation. The GERS was significantly higher among participants who had MS at the initial survey than those who did not have an MS diagnosis. The incidence rate of MS was estimated as 211 cases with a 95% confidence interval of 113 to 308 cases per 100,000 first-degree family members per year, which is 100 times greater than the reported incidence of sporadic MS. 48% of the asymptomatic participants were willing to participate in a prevention trial, while 75% expressed willingness when presented with a scenario assuming an elevated risk (20%) of developing MS based on genetic tests performed with blood samples.

Interpretation: Primary prevention trials in MS are urgently needed. Our findings support the feasibility for such studies and inform the design of future primary prevention trials in individuals at risk for MS.

Trial registration: ClinicalTrials.gov identifier: NCT01353547.

Background: Patients with N-methyl-D-aspartate (NMDA) receptor-immunoglobulin G (IgG) autoimmune encephalitis (NMDAR-IgG AE) demonstrate occipital lobe hypometabolism on baseline brain fluorodeoxyglucose-positron emission tomography (bFDG-PET). The goal of this study was to determine whether there is an association between bFDG-PET findings, disease severity, and clinical outcomes in these patients.

Methods: This retrospective analysis included adult patients with NMDAR-IgG AE who underwent bFDG-PET within 3 months of symptom onset. Qualitative and quantitative assessments of bFDG-PET findings were performed. Spearman's correlation analysis was used to evaluate potential associations between bFDG-PET findings and clinical severity at diagnosis and at 1 year using modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores.

Results: Sixteen patients (13 women, 3 men; median age, 29.0 years) were included in the analysis. The median time between symptom onset and bFDG-PET was 5 weeks (interquartile range: 3-8). All patients received immunosuppressive therapy. Qualitative and quantitative assessments demonstrated the highest correlation between occipital lobe hypometabolism and clinical severity at diagnosis (Quantitative: mRS: -0.65 [95% confidence interval (CI): -0.87, -0.22]; CASE: -0.68 [95% CI: -0.88, -0.28]). At 1 year (n = 12), quantitative baseline occipital lobe hypometabolism was correlated with higher mRS scores (-0.71 [95% CI: -0.91, -0.23]).

Conclusions: In patients with NMDAR-IgG AE, occipital lobe hypometabolism on baseline bFDG-PET is correlated with mRS and CASE scores at the time of diagnosis and mRS scores 1 year later, suggesting that bFDG-PET findings correlate with disease severity and longitudinal outcomes. However, studies with larger patient populations are needed to confirm these findings.

Objective: Cognitive decline is a disabling and variable feature of Parkinson disease (PD). While cholinergic system degeneration is linked to cognitive impairments in PD, most prior research reported cross-sectional associations. We aimed to fill this gap by investigating whether baseline regional cerebral vesicular acetylcholine transporter ligand [¹⁸F]-fluoroethoxybenzovesamicol ([¹⁸F]-FEOBV) binding predicts longitudinal cognitive changes in mild-moderate, non-demented PD subjects.

Methods: Seventy-five non-demented, mild-moderate PD subjects underwent baseline [¹⁸F]-FEOBV PET and standardized cognitive evaluations, with repeat cognitive testing after 2 years. Participants were classified into four cognitive classes: persistent normal (no MCI at either time point; N = 41), persistent MCI (MCI at both; N = 21), MCI conversion (normal to MCI; N = 6), and MCI reversion (MCI to normal; N = 7). We performed whole-brain voxel comparisons (controls and between classes) and used linear and multinomial regression to predict follow-up cognitive status.

Results: Whole-brain voxel analyses revealed class-specific [¹⁸F]-FEOBV binding deficits. Persistent MCI showed the most widespread reductions, extending into frontal regions. Compared with MCI reverter and persistently normal groups, persistent MCI had lower binding in occipito-temporal and temporo-parieto-frontal regions, respectively, while MCI reverters showed higher occipital binding than converters. Binding in occipital, temporo-parietal, and medial frontal regions predicted follow-up cognitive decline, with medial frontal binding showing the strongest association (esp. global cognition, memory, and visuospatial domains).

Interpretation: Baseline cholinergic system changes associate with varying cognitive trajectories in mild-moderate PD. Assessment of regional cholinergic deficits may be useful for prediction of cognitive trajectories in this population, enhancing subject selection and stratification for intervention trials aimed at improving cognition in PD.