Annals of Clinical and Translational Neurology最新文献

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.

Gliomas are among the most malignant and aggressive tumors of the central nervous system, characterized by the absence of early diagnostic markers, poor prognosis, and a lack of effective treatments. Advances in high-throughput technologies have facilitated a refined molecular classification of gliomas, incorporating genetic features. However, diagnosis and clinical management based on isolated genetic data often fail to capture the full histological and molecular complexity of these tumors, posing significant challenges. In the era of computational methodologies and artificial intelligence, the integration of multiple omics layers—genomics, transcriptomics (including sex-dependent differential expression patterns), epigenomics, proteomics, metabolomics, radiomics, single-cell analysis, and spatial omics—into a comprehensive framework holds the potential to deepen our understanding of glioma biology and enhance diagnostic precision, prognostic accuracy, and treatment efficacy. Herein, we provide a comprehensive overview of multi-omics strategies used to decipher the adult-type diffuse glioma molecular taxonomy and describe how the integration of multilayer data combined with machine-learning-based algorithms is paving the way for advancements in patient prognosis and the development of personalized, targeted therapeutic interventions.

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: 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.

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.

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.

Objective: The aging population of people with HIV (PWH) raises heightened concerns regarding accelerated aging and dementia. Portable, low-field MRI (LF-MRI) is an innovative technology that could enhance access and facilitate routine monitoring of PWH. We sought to evaluate the feasibility of LF-MRI and apply a machine learning (ML) segmentation algorithm to examine atrophy and white matter hyperintensities (WMH) in PWH compared to people without HIV (PWoH) of similar age.

Methods: Individuals with a confirmed diagnosis of HIV on antiretroviral therapy underwent LF-MRI (64 mT) acquisition in the outpatient neurology clinic. PWoH with > 1 vascular comorbidity (VC cohort, n = 25) or with mild cognitive impairment (MCI cohort, n = 24) due to Alzheimer's disease served as comparators. LF-MRI brain region segmentations were derived using the ML algorithm WMH-SynthSeg in FreeSurfer. Brain regions corrected for intracranial volume were compared between cohorts after adjusting for age and sex.

Results: Thirty virally suppressed PWH were included. LF-MRI derived brain volumes from PWH demonstrated a reduction in volume of the caudate relative to PWoH with VC (p < 0.05). Volume of the putamen and white matter was reduced in PWH compared to VC (p < 0.05). Hippocampal volume was comparable between PWH and PWoH (p ≥ 0.05), while volume of the amygdala was reduced in those with MCI alone (p < 0.05). No differences in WMH were seen between these cohorts (p > 0.05).

Interpretation: LF-MRI is feasible in an outpatient setting, and ML algorithms enable detection of regional atrophy and WMH in PWH. LF-MRI may enable more frequent monitoring and earlier detection of atrophy in at-risk populations.