Annals of Clinical and Translational Neurology最新文献

Background: Myasthenia gravis (MG) is an autoimmune disorder characterized by antibody-mediated complement activation. Efgartigimod, a neonatal Fc receptor (FcRn) antagonist, is approved for treating generalized MG (gMG). However, its modulatory effects on upstream innate and adaptive immune cells remain largely unexplored.

Methods: We first quantified FcRn expression in peripheral immune subsets from acetylcholine receptor antibodies (AChR-Ab) positive gMG. Then we assessed efgartigimod's impact on immune cells via in-depth profiling in vitro and later validated these findings in a prospective real-world cohort treated with efgartigimod.

Results: High FcRn expression was abundantly expressed on monocytes and lymphocytes in an exploratory MG cohort (n = 29), with notable intracellular presence. In vitro studies showed efgartigimod significantly decreased intracellular FcRn in monocytes (p < 0.001) and lymphocytes (p = 0.019). After efgartigimod treatment, non-classical monocytes (CD14^lowCD16⁺, 17.89 ± 9.60 vs. 14.58 ± 9.89 cells/μl, p < 0.001; 3.20 ± 2.06 vs. 2.61% ± 2.12%, p < 0.001) and Th17.1 cells (CXCR3⁺CCR6⁺, 95.83 ± 66.56 vs. 84.06 ± 61.70 cells/μl, p = 0.010; 10.42 ± 4.82 vs. 9.06% ± 4.46%, p = 0.000) were significantly downregulated. In contrast, antibody-producing B cells and effector-memory CD4⁺ and CD8⁺ T cells were expanded. Longitudinal assessments in the gMG cohort displayed similar findings, which likely reflect the direct inhibitory effect of efgartigimod on monocytes, coupled with negative feedback due to decreased IgG levels.

Conclusions: By integrating in vitro and clinical findings, we demonstrate that efgartigimod modulates peripheral immune cell populations, highlighting its significant immunomodulatory effects and clinical potential.

Acute intermittent porphyria (AIP) is a rare metabolic disorder that may present with subacute neuropathy and systemic symptoms, often leading to diagnostic delay. We report a 37-year-old woman with eight weeks of progressive bilateral upper extremity weakness and paresthesias, followed by lower extremity involvement and falls, in the setting of chronic abdominal pain, presyncope, weight loss, and neuropsychiatric symptoms. Examination revealed profound proximal arm weakness, sensory deficits, bulbar involvement, and autonomic features. MRI of the brain and spine and cerebrospinal fluid analysis were normal. Electrodiagnostic studies demonstrated a severe diffuse motor neurogenic process. Markedly elevated urinary porphobilinogen and aminolevulinic acid levels confirmed the diagnosis of acute intermittent porphyric neuropathy, supported by identification of a variant of uncertain significance in the HMBS gene. This case underscores the importance of considering AIP in patients with subacute motor-predominant neuropathy accompanied by abdominal pain and autonomic dysfunction, as early diagnosis enables timely treatment and improved outcomes.

Objective: Dystonia is one of the most common movement disorders, with variants in multiple genes identified as causative. However, an understanding of which developmental stages, brain regions, and cell types are most relevant is crucial for developing relevant disease models and therapeutics. One approach is to examine the timing and anatomical expression of genes in which variants are dystonia-causing, on the assumption that deleterious variants have a greater impact where higher levels of expression are observed.

Methods: We investigated the expression patterns of 44 genes linked with a dystonia phenotype across two bulk and two single-nuclei RNA-sequencing datasets, derived from prenatal and postnatal human brain tissue.

Results: Dystonia genes were most strongly enriched in the striatum, cerebral cortex, hippocampus, amygdala and substantia nigra, and demonstrated higher postnatal expression. Individual genes exhibiting differences in expression across adult brain regions include SQSTM1, SGCE, KMT2B, PRKRA, YY1, DNAJC12, KCNA1, CACNA1A (highest expression in cerebellum), ADCY5, GNAL, ANO3 (highest expression in striatum), RHOBTB2, FOXG1 (highest expression in cerebral cortex). Single-nuclei RNA-sequencing analyses from human frontal cortex, striatum, cerebellum and substantia nigra indicated that dystonia genes are predominantly expressed in neurons (glutamatergic, GABAergic and dopaminergic). Gene Ontology analysis showed prominent enrichment in biological processes such as dopamine biosynthetic and metabolic processes, and in the cellular components axons and neuron projection.

Interpretation: These analyses provide important insights into the anatomical, developmental, and cellular expression patterns of genes associated with dystonia, potentially guiding the development of disease-relevant models and improving the targeting of future therapeutic interventions.

Objective: People with epilepsy (PWE) may experience cognitive deficits but fail to undergo formal evaluation. This study compares cognitive status between PWE and healthy controls in the West African Republic of Guinea.

Methods: A cross-sectional, case-control study was conducted in sequential recruitment phases (July 2024-July 2025) at Ignace Deen Hospital, Conakry. Adult (≥ 18 years) PWE enrolled consecutively, excluding those with a seizure within the past 24 h. Controls were healthy adults accompanying PWE at the hospital. Cognitive status was assessed with the Montreal Cognitive Assessment (MoCA) in French or translated into the patient's preferred language (Pular, Susu, Maninka, Kissi) as needed.

Results: We enrolled 100 PWE (mean age 30.4 years, range 18-71, SD = 12.0) and 100 controls (mean age 39.4 years, range 19-70, SD = 12.3). Although 93% of PWE had previously used anti-seizure medications (ASMs), only 85% were currently receiving treatment and 50% reported interrupted access to ASMs, primarily due to cost barriers. The mean MoCA score of controls (21.8, SD = 4.9) was higher than that of PWE (17.9, SD = 6.1; mean difference -4.2, 95% CI [-5.6, -2.8], SE = 0.69, p < 0.001), adjusted for education level, sex, age, and language. Participants who attended lower secondary, upper secondary, or university education scored 4.9, 5.3, and 8.3 points higher, respectively, than those with no school or primary education (all p < 0.001). Speaking an indigenous language was on average associated with a 2.5-point decline in MoCA scores (95% CI [-3.8, -1.2], SE = 0.65, p < 0.001).

Interpretation: PWE in Guinea demonstrated significantly lower cognitive performance on the MoCA compared to healthy controls, even after adjusting for covariates.

Objective: The Gold Coast criteria permit diagnosis of amyotrophic lateral sclerosis (ALS) even without upper motor neuron (UMN) signs. However, whether ALS patients with UMN signs (ALSwUMN) and those without (ALSwoUMN) share similar characteristics and prognoses remains unclear. This study compared clinical features, disease progression, electrophysiological findings, biomarker profiles, imaging parameters, and survival between these groups.

Methods: ALS patients diagnosed according to the Gold Coast criteria were classified into ALSwUMN (n = 51) and ALSwoUMN (n = 20) groups. We evaluated clinical data, motor evoked potentials (MEP), and serum biomarkers, including cardiac Troponin T, neurofilament light chain, glial fibrillary acidic protein, and brain-derived neurotrophic factor. Imaging parameters, including cortical thickness and white matter volume, were also evaluated. Survival was analyzed using the Kaplan-Meier method.

Results: The groups showed broadly similar clinical features, disease progression, and biomarker profiles. Abnormal MEPs were more frequent in ALSwUMN (94.0%) than in ALSwoUMN (63.2%, p = 0.017). Both groups demonstrated cortical thinning in the precentral and entorhinal regions compared to healthy controls. ALSwUMN exhibited thinning in the lateral orbitofrontal, insular, and temporal pole regions, while ALSwoUMN showed thinning in the pars opercularis. White matter volume was reduced in both groups in the thalamus, cerebellum, and amygdala, with additional brainstem atrophy in ALSwUMN. No significant survival difference was observed.

Interpretation: Despite minor distinctions in electrophysiological and imaging findings, ALSwoUMN had overall comparable clinical profiles and outcomes to ALSwUMN. These findings support recognizing ALSwoUMN within the ALS spectrum under the Gold Coast criteria.

Objective: Plasma fibrinogen is essential in thrombosis and fibrinolysis, yet its dynamic changes pre- and post-intravenous thrombolysis (IVT) for predicting brain injury severity and prognosis in acute ischemic stroke (AIS) patients remain unclear.

Aims: This study examined how fibrinogen trends before and after IVT correlate with brain injury severity and clinical outcomes in IVT-treated patients.

Methods: This multicenter study prospectively enrolled AIS patients treated with IVT at 16 hospitals and recorded their fibrinogen trends before and after thrombolysis. Levels of brain injury markers were measured to represent the extent of brain injury, including glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), S100β, and neuron-specific enolase (NSE). Prognostic indicators included early neurological deterioration (END), hemorrhagic transformation, infarct volume, National Institutes of Health Stroke Scale (NIHSS) score at 7 days, 3-month poor outcome (modified Rankin Scale [mRS] score > 1), and mortality.

Results: A total of 827 patients were enrolled, with 207 exhibiting elevated fibrinogen levels 24 h after IVT. Patients with elevated fibrinogen levels exhibited significantly higher levels of brain injury markers (GFAP, UCH-L1, S100β), larger infarct volumes, higher NIHSS scores at 7 days, and a higher incidence of END and poor outcomes compared to those with non-elevated fibrinogen levels. Both univariate and multivariate analyses identified elevated fibrinogen levels after IVT as an independent predictor of severe brain injury, larger infarct volume, higher NIHSS score, occurrence of END, and poor outcomes.

Interpretation: Elevated fibrinogen levels 24 h after IVT are independently associated with more severe brain injury and worse clinical outcomes in AIS patients.

The FMR1 gene premutation (55-200 CGG repeats) is usually associated with a wide range of symptoms and phenotypes within the Fragile X-tremor/ataxia syndrome (FXTAS), but may also manifest as predominant or isolated cognitive decline. We describe three male patients referred for progressive cognitive impairment and behavioral changes. Standard work-up, including MRI, FDG-PET, CSF biomarkers, and neuropsychological testing, excluded common dementias. Brain MRI imaging revealed callosal and peduncular white matter changes, while 18FDG-PET showed consistent anterior cingulate hypometabolism. Genetic analysis confirmed FMR1 premutation in all cases. Clinicians in memory clinics should consider this diagnosis in cases of unexplained cognitive decline.

Objective: Accurate localization of epileptogenic tubers (ETs) in patients with tuberous sclerosis complex (TSC) is essential but challenging, as these tubers lack distinct pathological or genetic markers to differentiate them from other cortical tubers. Approximately 60% of patients fail to have their ETs identified through noninvasive preoperative evaluations, creating an urgent clinical need for effective, noninvasive localization strategies.

Methods: A novel fusion model was developed, integrating lesion network mapping-based risk assessment with a machine learning prediction model that utilizes brain functional connectivity and random forest algorithms. The model was built based on magnetic resonance imaging data. Retrospective analysis was conducted on patients with TSC-related epilepsy who had undergone resective surgery and achieved seizure freedom at the 1-year follow-up; tubers were classified as true epileptogenic tubers (true ETs) or true non-epileptogenic tubers (true non-ETs) according to the resected regions. The model calculated and ranked the probability of each tuber being an ET for every patient.

Results: A total of 47 patients were enrolled in the study. The fusion model successfully ranked the true ETs within the top three in 91% of the cases. Significant differences in the probability rankings of ETs were observed among true ETs, true non-ETs, and random tubers (p < 0.01). Receiver operating characteristic curves were plotted to evaluate the accuracy of true ET localization across different methods, and the fusion model exhibited an area under the curve of 0.86. This performance significantly outperformed that of scalp electroencephalography, semiology, and positron emission tomography based on structural magnetic resonance imaging in the same cohort. Cross-validation in three independent epilepsy centers confirmed the model's high generalizability.

Interpretation: Overall, this fusion model demonstrates high accuracy and robust clinical utility as a noninvasive tool for the localization of ETs. It effectively addresses the current challenges in identifying ETs, providing valuable support for surgical planning in patients with TSC-related epilepsy.

Background: Familial dysautonomia (FD) is a hereditary neurodevelopmental disorder caused by aberrant splicing of the ELP1 gene, leading to a tissue-specific reduction in ELP1 protein expression. Preclinical models indicate that increasing ELP1 levels can mitigate disease manifestations. A blood-based ELP-1 protein assay may provide a reliable way to monitor gene target engagement.

Design and methods: Using a newly developed radioimmunoassay, we quantified ELP1 protein levels in peripheral blood samples collected from 59 homozygous FD patients carrying the IVS20 + 6T>C mutation and 66 heterozygous carriers. To assess the reproducibility of the measurement, replicate samples were collected in 43 participants. Longitudinal variability was evaluated in 22 participants who underwent repeat sampling 1 year later.

Results: ELP1 protein levels were significantly lower in FD patients compared to heterozygous carriers (244 ± 75 vs. 2210 ± 1031 pg/mL, p < 0.001). Replicate analysis of 43 paired samples showed strong consistency in ELP1 levels (p < 0.000). Repeat measurements 1 year after baseline showed longitudinal stability (R² = 0.827, p < 0.001). An ELP1 threshold of 492 pg/mL yielded a sensitivity of 80.2% (CI of 70.6 to 87.2%) and a specificity of 98.2% (95% CI of 90%-99%) with a positive likelihood ratio of 46.5, indicating that individuals with FD were over 46 times more likely to have ELP1 levels below this threshold compared to non-affected carriers.

Conclusion: Blood ELP1 levels are robust and reproducible, with concentrations below 492 pg/mL strongly indicative of disease. Moreover, given their longitudinal stability, ELP1 can serve as a marker of target engagement to evaluate the efficacy of gene-targeted therapies aimed at correcting ELP1 gene splicing and protein production.

Background: Ambulatory ability after intracerebral hemorrhage (ICH) is important to patients. We tested whether asymmetry between ipsi- and contra-lesional corticospinal tracts (CSTs) assessed by diffusion tensor imaging (DTI) is associated with post-ICH ambulation.

Methods: Patients with spontaneous supratentorial ICH were recruited from 8 US sites between 2017 and 2024. For each patient, fractional anisotropy (FA) asymmetry index (AI) was computed for the whole CST and on a subset of fibers restricted to the cerebral peduncle (CP). Clinical and radiographic features were collected. The primary outcome was Barthel Index Mobility Score (BIMS) at 3 months (dichotomized outcome [DO]: BIMS 15 = good [independent ambulation]; BIMS < 15 = poor [non-independent ambulation]; ordinal outcome [OO]: BIMS 0, 5, 10, 15). Two imputation-based multiple logistic regression analyses accounted for whether ICH prevented tracking of CSTs. Odds ratios (ORs) were reported for a change of 0.1 and 95% confidence intervals (CIs).

Results: At 3 months, 124 patients were eligible for inclusion. In addition to known clinical variables, CST and CP FA AI were associated with poor BIMS (OR 2.97, CI 1.12-7.90, p = 0.029; OR 3.80, CI 1.63-8.84, p = 0.002). In Model 1, unresolved FA (FA zero) was not correlated with lower BIMS (DO: OR 3.25, CI 0.62-17.07, p = 0.163; ordinal outcomes: OR 2.02, CI 0.48-8.55, p = 0.341). In Model 2, the combination of CST FA AI and FA zero correlated with lower BIMS (DO: joint p-value =0.041; OO: p = 0.030). CP FA asymmetry was associated with lower BIMS (DO: OR 3.96, CI 1.25-12.55, p = 0.019; OO: OR 3.39, CI 1.24-9.27, p = 0.017).

Conclusion: DTI-assessed CST integrity may be an additional tool physicians can utilize to guide post-ICH ambulatory expectations.