Annals of Clinical and Translational Neurology最新文献

Introduction: Optical coherence tomography (OCT)-derived retina measurements are markers for neuroaxonal visual pathway status. High-quality OCT scans are essential for reliable measurements, but their acquisition is particularly challenging in eyes with severe visual impairment, as often observed in neuromyelitis optica spectrum disorders (NMOSD).

Objective: To investigate OCT quality issues in real-world data from the international Collaborative Retrospective Study on Retinal OCT in Neuromyelitis Optica (CROCTINO).

Methods: We evaluated the quality of peripapillary and macular OCT scans, using Heidelberg Spectralis SD-OCT, Carl Zeiss Cirrus HD-OCT, or Topcon SD-OCT across 22 centers. Experienced graders applied OSCAR-IB criteria for OCT quality. Eyes were classified as severely visually impaired or not based on a 1.0 logMAR cut-off. Quality outcomes were compared using the Chi-square test.

Results: A total of 3075 OCT scans (1630 peripapillary, 1445 macular) from 539 people with NMOSD and related conditions were evaluated. Macular scans were rejected more often than peripapillary scans due to quality issues (20.1% vs. 14.5%, p < 0.001). Rejection rates were higher in eyes with severe visual impairment (peripapillary: 28.9%, macular: 41.6%) compared to eyes without severe visual impairment (peripapillary: 10.7%, p < 0.001; macular: 14.6%, p < 0.001).

Conclusion: Our study revealed that approximately one in six scans was rejected due to low quality, with higher rejection rates in eyes with severe visual impairment. As scan quality can bias quantitative outcomes and artificial intelligence applications, these findings emphasize the unmet need for standardized OCT practices tailored to NMOSD and other conditions involving severe visual impairment.

Objective: To explore how cerebral hypoxia and Normal-Appearing White Matter (NAWM) integrity affect MS lesion burden and clinical course.

Methods: Seventy-nine MS patients, including 13 clinically isolated syndrome (CIS) patients and 66 relapsing-remitting multiple sclerosis (RRMS) patients, and 44 healthy controls (HCs) were recruited from CLUE, NCT04106830. Quantitative susceptibility mapping (QSM) was employed to evaluate the changes of cerebral venous oxygen saturation (SvO₂) in deep cerebral veins. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging analyzes (NODDI) were employed to evaluate microstructural alterations in deep brain white matter (WM), including WM lesion and NAWM between MS and HCs. Partial correlations analyzes were conducted to examine associations between imaging biomarkers and clinical indicators. Mediation analysis was used to evaluate the relationship among SvO₂, microstructural alterations, lesion volumes, and clinical indicators.

Results: Compared with HCs, patients with MS showed significantly decreased SvO₂ in the internal cerebral vein (76.56% ± 1.34% vs. 78.80% ± 0.86%, p < 0.001). Advanced diffusion metrics revealed extensive microstructural disruption in both WM lesions and NAWM (NAWM mean diffusivity [MD]: 1.03 ± 0.12 vs. 0.90 ± 0.04 [×10^-3 mm²/s], p < 0.001). Furthermore, microstructural disruption of NAWM (MD and orientation dispersion index [ODI]) significantly correlated with SvO₂ of the ICV (MD: r = -0.307, p = 0.036; ODI: r = -0.279, p = 0.036). Critically, mediation analysis demonstrated that deep brain WM hypoxia (ICV SvO₂) associated with greater lesion burden and clinical disability via NAWM damage as an intermediate pathway.

Interpretation: In MS patients, lower cerebral SvO₂ (compared with HCs) is statistically associated with microstructural alterations in the NAWM. Our mediation models are consistent with a pathway whereby lower SvO₂ is associated with greater lesion burden and worse functional scores via its association with NAWM damage. These findings support the exploratory value of SvO₂ and NAWM integrity as potential biomarkers for monitoring MS progression, which warrants validation in further longitudinal studies.

Objective: Gait impairment is a distinctive symptom of Parkinson's disease that negatively impact mobility. We assessed the validity of wearable digital insoles against a validated reference gait analysis system for measuring select gait characteristics in patients with Parkinson's disease.

Methods: A comparative analysis between digital insoles (Moticon ReGo Insole) and the GAITRite system was conducted in patients with Parkinson's disease. Patients were assessed in both the OFF and ON medication states. Gait characteristics were measured simultaneously with both systems during two 10 m walk tests. Patients also completed a patient experience survey following the use of the digital insoles.

Results: Overall, 21 patients with Parkinson's disease were included in the study. Analytical validation for gait cadence, speed, and stride length showed excellent agreement (intraclass correlation coefficients between 0.93-0.97) in both the OFF and ON states. Stance, swing, and double support times exhibited lower validity with moderate agreement (intraclass correlation coefficients from 0.48-0.57). Gait speed and stride length were significantly associated with scores on the Movement Disorders Society's Unified Parkinson's Disease Rating Scale (p = 0.0085 and 0.013, respectively). Mean differences in all parameters measured with the insoles, except cadence, were significantly different between OFF and ON states (p < 0.003). The majority of patients liked wearing the digital insoles and found them comfortable and user-friendly.

Interpretation: These findings support the validity of Moticon ReGo digital insoles for the assessment of several important gait characteristics in Parkinson's disease.

In this first application of Quantitative Susceptibility Mapping Source Separation to cerebral adrenoleukodystrophy, we uncovered alterations in iron and myelin within lesions and normal appearing white matter. As validation, we demonstrate abnormal iron accumulation in those same compartments within primary brain tissue. A gradient of microglial activation to absence parallels the transition from normal white matter to demyelinated lesion. In perilesional white matter, increases in myelin peroxidation and Acyl-CoA synthetase long-chain family member 4 are observed. Thus, the unifying mechanistic relationship of apoptosis to lipid peroxidation in the presence of iron implicates ferroptosis in the pathogenesis of cerebral adrenoleukodystrophy.

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.