Annals of Clinical and Translational Neurology最新文献

Objectives: To evaluate the utility of cerebrospinal fluid (CSF) biomarkers-matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), the MMP-9/TIMP-1 ratio, and osteopontin (OPN)-as indicators of blood-brain barrier (BBB) integrity and disease activity in people with relapsing-remitting multiple sclerosis (pwMS), and to assess their changes following autologous hematopoietic stem cell transplantation (aHSCT).

Methods: CSF samples from pwMS treated with aHSCT (n = 43) and healthy controls (n = 32) were analyzed for MMP-9, TIMP-1, and OPN concentrations using ELISA and electrochemiluminescence assays. Lumbar punctures were performed at baseline and at 1, 2, and 3-5 years post-aHSCT. Biomarker findings were compared with standard CSF parameters, prior treatments, and MRI data.

Results: MMP-9/TIMP-1 ratios and OPN levels were significantly elevated in pwMS compared to controls, particularly in those with gadolinium-enhancing lesions or on first-line therapies. Both biomarkers declined significantly after aHSCT and remained low during follow-up. The MMP-9/TIMP-1 ratio showed superior discriminatory capacity and correlated with inflammatory CSF markers.

Interpretation: CSF MMP-9/TIMP-1 ratio and OPN are elevated in MS and decrease following aHSCT, reflecting reduced inflammation and restored BBB integrity. These biomarkers may support disease monitoring and therapeutic evaluation.

Objective: To project ALS prevalence across multiple countries through 2040, accounting for both population aging and increased survival.

Methods: Data from the Piemonte and Valle d'Aosta ALS register (PARALS) was used to estimate the trends in incidence and prevalence from 2005 to 2019. Survival trends over this period were also assessed. The observed annual increase was then projected into future years up to 2040. Concurrently, the incidence for each future year was calculated using population projections. Finally, the prevalence rate for each year was estimated as the product of the projected incidence and the projected survival. We also estimated survival for fifteen countries by dividing prevalence by incidence, based on available data, and applied the same increase observed in PARALS to project prevalence in these countries up to 2040.

Results: Using data from 3294 patients, we determined that ALS survival increased by 0.06 years annually from 2005 to 2019 in Piemonte and Valle d'Aosta. Considering changes in incidence due to population aging, the prevalence is projected to reach 15.72 per 100,000 population by 2040 in this area, while rising by a median of 24.9% across multiple countries worldwide. If a new drug could provide a 6-month increase in survival starting in 2025, disease prevalence would rise by 37.8% by 2040. We provided a web interface so users can model different data and assumptions.

Interpretation: ALS prevalence is projected to increase significantly over the next decades. This underscores the need for careful planning and allocation of public health resources.

Background: There is growing recognition of the potential of plasma proteomics for Alzheimer's Disease (AD) risk assessment and disease characterization. However, differences between proteomics platforms introduce uncertainties regarding cross-platform applicability.

Objective: We aimed to identify a detailed plasma biosignature for distinguishing AD from cognitively normal (CN) and another signature for classifying mild cognitive impairment (MCI) decliners and non-decliners. We also explored the cross-platform applicability of these models between two proteomic platforms.

Methods: Elastic net was performed on 190 plasma analytes measured using the Luminex xMAP platform in 566 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to model MCI stable/decliner and AD/CN classification. MCI decliner was defined as progression to AD during follow-up (mean 4.2 ± 3.2 years). External cross-platform validation was conducted with 1303 participants from the Spanish Ace study, using the SOMAscan 7k platform.

Results: An 11-analyte signature for distinguishing AD from CN achieved a 93.5% accuracy on ADNI and 95.2% on Ace. The ApoE and BNP proteins were the two most important contributors to the classifier. The MCI classification signature performed less well, with 65.9% accuracy on ADNI and 51.0% accuracy upon validation testing in Ace.

Discussion: Compared with prior proteomic-based studies on the same dataset, our findings attained higher specificity and sensitivity for AD classification while utilizing a smaller panel of analytes. We also confirmed the reliability and consistency of this signature within a different population from a different platform. The plasma proteomic platforms explored were, however, not sufficient to determine MCI decliners versus non-decliners.

Objective: Although 5-Hydroxytryptamine (5-HT) indirectly stimulates muscle contraction and participates in regulating Acetylcholine receptor (AChR) cluster homeostasis in cellular, animal, and clinical studies, evidence regarding its potential to modulate muscle contraction in myasthenia gravis (MG) remains limited. We aim to determine the levels of 5-HT in MG and investigate its potential role as a regulatory neurotransmitter in promoting muscle contraction.

Methods: We collected serum from 109 patients with MG and 110 healthy volunteers, and recorded clinical variables, including myasthenia gravis classification (MGFA), quantitative myasthenia gravis score (QMG), and serological examination. The effects of 5-HT on the neuromuscular junction (NMJ) were further identified using cellular and molecular experiments.

Results: In this study, we observed that serum 5-HT levels decrease in patients with MG (p < 0.0001) compared with disease-free control. The thymoma-associated complications alleviated this reduction (p < 0.0001). Our functional studies showed that 5-HT promotes the development of motor (cholinergic) neuron-like axons and increases intracellular calcium peaks, which is proportional to the amount of neurotransmitter released (p < 0.0001). AChR-autoantibody treatment increases the expression of 5-HT₂R mRNA in muscle tube cells (p < 0.001), and the downstream signaling pathway of 5-HT₂R is involved in the regulation of AChR cluster homeostasis.

Interpretation: This first report of clinical characteristics and serum 5-HT levels from a cross-sectional cohort study on MG suggests that 5-HT plays a critical role in maintaining NMJ homeostasis. Additional cross-sectional data on more MG phenotypes and longitudinal monitoring data are needed to explore the role of 5-HT in the pathophysiological mechanisms of MG.

Parkinson's disease (PD) is a neurodegenerative disorder that may sometimes be caused by deleterious genetic variants. Among them, RAB39B polymorphisms are known as rare causes of early-onset PD associated with intellectual disability (Waisman's syndrome). Here we describe a 45-year-old white male affected by developmental delay, childhood onset intellectual disability, epilepsy, and PD who was treated with subthalamic deep brain stimulation and subcutaneous L-DOPA infusion. Next Generation Sequencing analysis revealed a currently unknown pathogenic hemizygous sequence variant c.463C>T (NM_171998.4) in the RAB39B gene, confirmed also in the proband's mother, affected by late-onset PD. This report expands the number of described RAB39B mutations in individuals with early- and late-onset, X-linked PD.

This study reported a 25-year-old woman with isolated head tremors as the main manifestation, along with type 1 diabetes, bilateral hearing loss, and leukoencephalopathy, who was diagnosed with mitochondrial disease due to a single large mtDNA deletion (m.8647-16082del).

Background: Leucine-rich glioma-inactivated 1 antibody (LGI1-Ab) encephalitis predominantly affected older individuals, but has also been reported in younger patients. However, the demographic, clinical, and prognostic characteristics of early-onset LGI1-Ab encephalitis have yet to be systematically elucidated. This study aims to systematically describe the clinical features and outcomes of early-onset LGI1-Ab encephalitis and compare them with those of later-onset cases.

Methods: A total of 105 patients with LGI1-Ab encephalitis admitted to the Department of Neurology at Beijing Fengtai You'anmen Hospital were enrolled in this study between January 2019 and December 2024. All patients were divided into early-onset (age at onset younger than 50 years) and late-onset (age at onset 50 years or older) groups. Demographic, clinical, paraclinical, and prognostic data were compared between the two groups.

Results: Among the cohort, 30 (28.5%) patients had early-onset LGI1-Ab encephalitis, with a female predominance (17, 56.7%). Epileptic seizures, psychiatric and behavioral symptoms, and memory impairment were the most common symptoms both at disease onset and throughout the disease course. Compared to later-onset patients, early-onset patients exhibited a lower prevalence of faciobrachial dystonic seizures (FBDS) (p = 0.041) and hyponatremia (p = 0.003). Additionally, they had higher serum albumin (p = 0.012), lower CSF protein (p = 0.006), lower age-normalized QAlb (p = 0.001), and fewer epileptic waves (p = 0.041). As for prognosis, memory deficits (11/30, 36.7%) were the most common residual symptom at follow-up, and early-onset patients were less likely to relapse (p = 0.038).

Conclusions: This study provides the first systematic characterization of early-onset LGI1-Ab encephalitis. Compared to late-onset cases, early-onset patients showed a lower incidence of hyponatremia, milder blood-brain barrier disruption, and fewer clinical relapses.

Objective: To develop a novel deep-learning model of clinical DWI tractography that can accurately predict the general assessment of epilepsy severity (GASE) in pediatric drug-resistant epilepsy (DRE) and test if it can screen diverse neurocognitive impairments identified through neuropsychological assessments.

Methods: DRE children and age-sex-matched healthy controls were enrolled to construct an epilepsy severity network (ESN), whose edges were significantly correlated with GASE scores of DRE children. An ESN-based biomarker called the predicted GASE score was obtained using dilated deep convolutional neural network with a relational network (dilated DCNN+RN) and used to quantify the risk of neurocognitive impairments using global/verbal/non-verbal neuropsychological assessments of 36/37/32 children performed on average 3.2 ± 2.7 months prior to the MRI scan. To warrant the generalizability, the proposed biomarker was trained and evaluated using separate development and independent test sets, with the random score learning experiment included to assess potential overfitting.

Results: The dilated DCNN+RN outperformed other state-of-the art methods to create the predicted GASE scores with significant correlation (r = 0.92 and 0.83 for development and test sets with clinical GASE scores) and minimal overfitting (r = -0.25 and 0.00 for development and test sets with random GASE scores). Both univariate and multivariate models demonstrated that compared with the clinical GASE scores, the predicted GASE scores provide better model fit and discriminatory ability, suggesting more adjusted and accurate estimate of epilepsy severity contributing to the overall risk.

Interpretation: The proposed biomarker shows strong potential for early identification of DRE children at risk of neurocognitive impairments, enabling timely, personalized interventions to prevent long-term effects.

Introduction: Neuronal pentraxin 2 (NPTX2) is a synaptic protein involved in synaptic plasticity and regulation of neuronal excitability. Lower baseline cerebrospinal fluid (CSF) NPTX2 levels have been shown to be associated with an earlier onset of mild cognitive impairment (MCI), a pre-dementia syndrome, even after CSF Alzheimer's Disease (AD) biomarkers (amyloid beta (Aβ_42/40), and phosphorylated tau (p-tau₁₈₁)) were considered. To date, however, it is not known whether CSF NPTX2 levels among cognitively unimpaired individuals are associated with longitudinal brain atrophy.

Objective(s): Evaluate the association between baseline CSF NPTX2 levels and measures of long-term brain atrophy in participants who were cognitively unimpaired at baseline.

Methods: Analyses included 213 participants (M baseline age = 57.2 years, 62% female) from the prospective longitudinal BIOCARD study with 13.9 years (max = 22.6 years) of magnetic resonance imaging (MRI) follow-up, on average. CSF NPTX2 was measured as a composite of three correlated peptides obtained by quantitative parallel reaction monitoring mass spectrometry. MRI brain atrophy was measured longitudinally with three composites. This included two spatial patterns of atrophy: (1) a composite of AD-signature regions (SPARE-AD) and (2) a composite of regions sensitive to brain aging (SPARE-BA), with higher values indicating more atrophy. Additionally, (3) a medial temporal lobe (MTL) composite included volumes of the amygdala, hippocampus, and entorhinal cortex. Linear mixed effect models assessed the association of baseline NPTX2 levels with the rate of change in the brain atrophy measures.

Results: When covarying biomarkers of AD pathology (i.e., the ratio of CSF p-tau₁₈₁/(Aβ_1-42/Aβ_1-40), age, sex, APOE4 genetic status, and years of education), lower baseline NPTX2 levels were associated with greater atrophy over time in both AD-vulnerable regions (SPARE-AD, standardized estimate = -0.008, p = 0.034) as well as regions sensitive to brain aging (SPARE-BA, standardized estimate = -0.011, p = 0.014). These associations were independent of participants having follow-up diagnoses of MCI or dementia.

Conclusion: Our findings suggest that after accounting for biomarkers of AD pathology, CSF NPTX2 is associated with slower longitudinal atrophy in AD-signature and aging-related regions. These findings are consistent with the view that NPTX2 may be a resilience factor in the presence of pathology and modifies rates of neurodegeneration.

Objective: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is a progressive neuromuscular disorder with no approved treatments. Identifying reliable biomarkers is critical to monitor disease severity, activity, and progression. Interleukin-6 (IL-6) has been proposed as a candidate biomarker, but longitudinal validation is limited.

Methods: We analyzed pooled data from two prospective longitudinal cohorts: CTRN-FSHD France (NCT04038138) and Cytokine FSHD (NCT04694456), each comprising 30 genetically confirmed ambulant FSHD1 patients. Serum IL-6 levels and clinical assessments were collected at baseline (M0), 12 months (M12), and 18 months (M18); whole-body muscle MRI (T1-weighted and STIR sequences) was obtained at M0 and M12. Associations between IL-6 levels and clinical severity scores, functional measures, and MRI-derived muscle composition were evaluated.

Results: Serum IL-6 levels correlated significantly with clinical severity metrics, including Clinical Severity Score, 6-Minute Walk Test, Manual Muscle Testing, and Motor Function Measure Domain 1 at all time points. Higher IL-6 levels were associated with increased muscle fat infiltration and free water content compatible with muscle edema on MRI. Longitudinal analyses showed that increases in IL-6 over 12 months were significantly correlated with changes in T1 (fat infiltration) and STIR (muscle edema) composite scores, reflecting structural and inflammatory disease progression.

Interpretation: These findings validate IL-6 as a biomarker of FSHD1 severity and underscore its potential as an activity and progression biomarker. The correlation between IL-6, clinical scores, and MRI-based muscle composition changes highlights its potential utility for monitoring disease evolution and evaluating therapeutic responses in FSHD1 patients.