Annals of Clinical and Translational Neurology最新文献

Objective: Rett syndrome (RTT) is a devastating neurodevelopmental disorder with developmental regression affecting motor, sensory, and cognitive functions. Sensory disruptions contribute to the complex behavioral and cognitive difficulties and represent an important target for therapeutic interventions. Although genetic medicine-based therapies targeting MeCP2 have successfully restored motor and respiratory functions in animal models, their ability to reverse sensory deficits across levels of the visual pathway remains largely unexplored.

Methods: Using genetically reversible mouse models of MeCP2 deficiency (Mecp2^stop/y and Mecp2^stop/x), we applied advanced electrophysiological, anatomical, and behavioral techniques to evaluate visual function, a critical sensory domain impaired in both animal models and RTT patients.

Results: In Mecp2^stop/y mice, initiating MeCP2 expression after postnatal day 35 (P35) reversed progressive cortical dysfunction, prevented thalamic circuit disorganization, and restored visual function, despite some remaining cortical anatomical abnormalities. Even in fully regressed adult Mecp2^stop/x heterozygous female mice, MeCP2 reactivation was sufficient to reduce the symptoms.

Interpretation: These findings highlight the remarkable sensitivity of cortical circuits to MeCP2 expression in both developing and mature brain. Importantly, restoring just 60%-70% of MeCP2 protein levels was sufficient to rescue sensory functions, even after the onset of regression. This underscores the transformative potential of genetic medicine-based therapies in RTT, suggesting that even partial restoration of MeCP2 can meaningfully improve sensory processing and quality of life for patients.

Objective: To explore the feasibility of classical (CH50) and alternative (AH50) complement pathway activity as potential biomarkers for treatment guidance and monitoring during therapy with ravulizumab in patients with generalized myasthenia gravis (gMG) and compare these to therapeutic drug monitoring under eculizumab.

Methods: In this prospective, exploratory real-world study CH50 and AH50, eculizumab and ravulizumab blood levels were assessed in patients with acetylcholine-receptor-antibody (AChR-ab) positive gMG. Patients were either pretreated with eculizumab or C5-inhibitor naïve. Samples were collected before the next infusion (end-of-dose). Laboratory data were correlated with patient-reported subjective duration of the ravulizumab effect.

Results: Overall, 61 patients were enrolled. At the end of their respective dosing interval, median AH50 levels were more strongly suppressed with eculizumab than with ravulizumab (1% [0%-2%] versus 5% [3%-9%]; Cohen's d 2.2 [95% CI 1.5-2.8]). Patients who discontinued ravulizumab due to insufficient effects (n = 19; 33%) had higher median AH50 levels than those who continued (7% [4%-13%] versus 5% [3%-8%]; Cohen's d -0.9 [95% CI -1.3 to -0.4]). In 81% (n = 46) of patients, the therapeutic effect of ravulizumab diminished before the subsequent infusion after the standard 8-week interval. Higher AH50 levels were correlated with earlier symptom recurrence.

Interpretation: Our results indicate potential differences in the ability of eculizumab and ravulizumab to suppress complement pathway activity through their respective dosing intervals. Additionally, higher AH50 levels might be a potential biomarker to predict poor therapy response and faster wearing off of ravulizumab's effect. However, these findings need to be validated in large multicenter studies.

Objectives: Variants in the FHL1 gene cause FHL1-related myopathies (FHL1-RMs), a group of neuromuscular disorders with diverse clinical presentations. This study aimed to comprehensively characterize the spatial and temporal patterns of skeletal muscle fat replacement throughout the whole body in FHL1-RMs, to examine disease progression over time, and to evaluate the relationship between imaging findings and clinical symptoms.

Methods: We retrospectively analyzed 21 whole-body imaging studies from 10 patients with genetically confirmed FHL1-RMs. Fatty replacement was scored in 47 muscles using the modified Mercuri score (mMS). Longitudinal data were used to stratify patients into slow, moderate, and rapid progression groups. K-means clustering was applied to classify muscles based on their chronological patterns of fatty infiltration. Hierarchical clustering and violin plots were used to explore inter-muscle and inter-patient variations.

Results: Despite notable variability in the rate of disease progression, a consistent pattern of muscle involvement was observed across patients. Muscles were classified into three progression clusters: early-onset and early attainment of the maximal mMS (e.g., paraspinal and posterior thigh muscles), steadily progressive (e.g., trunk and lower leg muscles), and late-onset with slow changes (e.g., shoulder and anterior thigh muscles). These patterns paralleled the clinical symptom progression. In early-stage patients, STIR imaging revealed muscle signal abnormalities preceding fat replacement detectable on T1-weighted images.

Interpretation: The rate of fat replacement in FHL1-RMs varies individually, but spatial patterns are conserved and reflect clinical evolution. Serial imaging is a valuable tool to monitor disease progression and may serve as a sensitive biomarker in clinical trials.

Background: Fatigue is among the most common symptoms and one of the main factors determining the quality of life in multiple sclerosis (MS). However, the neurobiological mechanisms underlying fatigue are not fully understood. Here we studied lesion locations and their connections in individuals with MS, aiming to identify brain networks associated with fatigue.

Methods: 38 MS patients with and 21 without fatigue were included in the study. Association between fatigue and lesion locations was investigated using voxel-lesion symptom mapping and lesion connectivity using lesion network mapping. The findings were tested in two independent datasets, including (1) MS patients scanned using resting-state functional connectivity MRI (rs-fcMRI) (n = 199) and (2) individuals with stroke lesions (n = 85).

Results: There were no specific anatomical MS lesion locations significantly associated with fatigue, but lesions associated with fatigue were connected to a common network with peak positive connectivity to the right premotor cortex and negative connectivity to the left temporal pole (p_FWE < 0.05). Of the two identified network nodes, connectivity from the premotor cortex to multiple other brain regions was significantly associated with MS fatigue severity in the independent dataset of MS patients (p < 0.05). The MS fatigue network was also reproducible in poststroke fatigue (spatial correlation r = 0.57, permutation test p = 0.02), again showing that lesion connectivity to the premotor cortex, but not the temporal pole, was associated with fatigue (p = 0.04).

Conclusions: Our results show that fatigue in MS localizes to a brain network, lending insight into the neural substrates of fatigue.

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.

Pathogenic variants in KIF1C cause Spastic Paraplegia 58 (SPG58), typically presenting with cerebellar ataxia and spastic paraparesis. We report two unrelated patients with spastic paraparesis, cerebellar ataxia, and tremor. Whole-exome sequence analysis identified novel homozygous variants in the motor domain of KIF1C (NM_006612.6): c.921G>A (p.Trp307Ter) and c.607C>T (p.Arg203Trp). In addition to the canonical brain MRI showing leukoencephalopathy with posterior dominance and hyperintensity along the corticospinal tracts, both patients showed symmetric T2 hyperintensity confined to the lateral and dorsal columns of the cervical cord. Given the long disease durations (22 and 51 years), these findings may represent late-emerging or previously overlooked spinal cord involvement and broaden the neuroradiological spectrum of SPG58.

Objective: Satralizumab, a monoclonal antibody targeting the interleukin-6 receptor, has demonstrated efficacy in clinical trials for neuromyelitis optica spectrum disorder (NMOSD). However, its real-world effectiveness and safety compared to conventional immunosuppressive therapies remain uncertain.

Methods: We identified patients diagnosed with NMOSD in the TriNetX federated health research platform between January 2018 and April 2024. This international platform was accessed via Taipei Medical University. Patients were followed for 1 month to 3 years. A 1:1 propensity-score matching (PSM) analysis balanced baseline characteristics between the satralizumab and conventional immunosuppressant groups. Risk ratios (RRs) were calculated for relapse risk and safety outcomes, including sepsis, respiratory infection, urinary tract infection, anemia, neutropenia, and mortality.

Results: A total of 220 patients received satralizumab, while 1744 received conventional immunosuppressants. After PSM, 218 patients remained in each group. Satralizumab was associated with a significantly lower relapse risk at 1 month (RR: 0.38, 95% CI 0.21-0.66), 3 months (RR: 0.43, 95% CI 0.28-0.66), 6 months (RR: 0.50, 95% CI 0.33-0.70), 9 months (RR: 0.62, 95% CI 0.46-0.83), 12 months (RR: 0.63, 95% CI 0.47-0.83), 24 months (RR: 0.60, 95% CI 0.42-0.86) and 36 months (RR: 0.52, 95% CI 0.32-0.83). Across all follow-up intervals, numbers needed to treat were consistently between 4 and 9. No significant differences were observed in infection rates, anemia, neutropenia, or mortality between the groups.

Interpretation: Satralizumab demonstrated superior efficacy in reducing NMOSD relapse rates compared to conventional immunosuppressants while maintaining a comparable safety profile.

Background: To evaluate frailty in severe progressive multiple sclerosis (PMS) and to investigate the underlying mechanisms.

Methods: This prospective, cross-sectional, multicenter study enrolled a late severe PMS group requiring skilled nursing (n = 53) and an age, sex, and disease duration-matched control PMS group (n = 53). Participants received neurological and MRI assessments and provided blood samples. Frailty was measured on the Edmonton Frail Scale. Disability was measured on the Expanded Disability Status Scale (EDSS), and fatigue was assessed on the Fatigue Severity Scale. The inflammatory vulnerability index (IVX) and metabolic vulnerability index (MVX) were computed from nuclear magnetic resonance spectroscopy-derived metabolomic profiling. Serum neurofilament (sNfL), glial fibrillary acidic protein (GFAP), and growth differentiation factor 15 (GDF15) levels were obtained.

Results: The late severe PMS group had a higher median EDSS (8.0 vs. 6.0, p < 0.001) than the matched control PMS group. The late severe PMS group had a higher prevalence of frailty (73.1% vs. 23.1%, p < 0.001) and higher frailty scores (8.87 vs. 5.52, p < 0.001) than the control PMS group. EFS was associated with EDSS in both PMS groups. Positive frailty status was associated with a 1.19-point greater EDSS (p = 0.012) in the control PMS group and a 0.436-point greater EDSS in the late severe PMS group (p = 0.002). In PMS controls, the EFS and frailty status were associated with IVX (p = 0.044 for EFS) and MVX (p = 0.036 for EFS).

Conclusions: Frailty is positively associated with MS disability. Inflammatory and metabolic vulnerability are associated with frailty in PMS.

Objective: To compare the effectiveness and safety of tenecteplase (TNK) versus alteplase (TPA) in patients with basilar artery occlusion prior to endovascular treatment (EVT).

Methods: In this retrospective multicenter study (BAO-TNK), we analyzed consecutive BAO patients from 14 U.S. stroke systems who received TNK or TPA within 4.5 h of last known well and were referred for EVT (01/2020-08/2024). Multivariable logistic regression models were adjusted for age, sex, NIH Stroke Scale (NIHSS), posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS), last-known-well-to-door time, and stroke etiology. Outcomes included 90-day modified Rankin Scale (mRS), reperfusion rates, and intracranial hemorrhage (ICH) per Heidelberg classification.

Results: Of 163 BAO patients, 75 (46.0%) received TNK and 88 (54.0%) received TPA. Rates of 90-day good functional outcome (mRS 0-3) were comparable between groups (TNK: 61.8% vs. TPA: 48.8%, adjusted odds ratio [aOR] 1.372, 95% CI 0.616-3.054, p = 0.439). No significant differences were observed in rates of pre-thrombectomy early reperfusion (18.7% vs. 14.8%, aOR 0.933, 95% CI 0.369-2.359, p = 0.884), post-thrombectomy final reperfusion (97.3% vs. 92.0%, aOR 2.133, 95% CI 0.376-12.116, p = 0.393), 90-day mortality (32.4% vs. 39.5%, aOR 0.989, 95% CI 0.436-2.244, p = 0.979), or symptomatic ICH (4.0% vs. 4.5%, aOR 1.319, 95% CI 0.245-7.114, p = 0.747). Predictors of favorable outcome included younger age, lower NIHSS, higher pc-ASPECTS, shorter LKW-to-puncture time, and non-atherothrombotic stroke etiology.

Interpretation: In BAO stroke, TNK and TPA administered within 4.5 h pre-EVT were associated with similar functional outcomes, reperfusion success and hemorrhage rates.

Objective: A 2-min digital clock-drawing test (DCTclock) captures more granular features of the clock-drawing process than the pencil-and-paper clock-drawing test, revealing more subtle deficits at the preclinical stage of Alzheimer's disease (AD). A previous cross-sectional study demonstrated that worse DCTclock performance was associated with higher Aβ and tau burden in older cognitively normal (CN) participants. This study investigates whether longitudinal changes in DCTclock performance are associated with amyloid-β (Aβ) and tau burden in preclinical AD.

Methods: A total of 219 CN participants completed baseline and follow-up DCTclock assessments, baseline Aβ ([¹¹C]PiB) and tau ([¹⁸F]Flortaucipir) PET imaging. Global Aβ and regional tau burden were estimated. Linear mixed models examined associations between longitudinal DCTclock and (1) Aβ, (2) tau, and (3) Aβ and tau burden, adjusted for age, sex, and education. Cognitive domain-specific performance and fine-grained features of DCTclock were analyzed.

Results: Elevated baseline Aβ or tau was most strongly associated with accelerated decline in DCTclock performance, particularly in the Information Processing cognitive domain, with stronger associations noted for tau burden. The associations were driven by pen-stroke latency-related features. Participants without elevated Aβ or tau burden demonstrated improved performance in these latency features, suggesting practice effects.

Interpretation: Longitudinal declines in DCTclock performance, especially in Information Processing involving speed and executive function, were linked to early Aβ and tau burden in preclinical AD. These findings highlight the potential of digital cognitive assessment tools for tracking disease progression and assessing therapeutic efficacy in clinical trials.