Publications

4 Feb

Mitochondrial DNA variants and their impact on epigenetic and biological aging in young adulthood

The pace of biological aging varies between people independently of chronological age and mitochondria dysfunction is a key hallmark of biological aging. We hypothesized that higher functional impact (FI) score of mitochondrial DNA (mtDNA) variants might contribute to premature aging and tested the relationships between a novel FI score of mtDNA variants and epigenetic and biological aging in young adulthood.

A total of 81 participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort had good quality genetic data as well as blood-based markers to estimate biological aging in the late 20. A subset of these participants (n = 69) also had epigenetic data to estimate epigenetic aging in the early 20s using Horvath's epigenetic clock.

The novel FI score was calculated based on 7 potentially pathogenic mtDNA variants. Greater FI score of mtDNA variants was associated with older epigenetic age in the early 20s and older biological age in the late 20s. These medium to large effects were independent of sex, current BMI, cigarette smoking, cannabis, and alcohol use. These findings suggest that elevated FI score of mtDNA variants might contribute to premature aging in young adulthood.

4 Feb

Robust acute myeloid leukemia engraftment in humanized scaffolds using injectable biomaterials and intravenous xenotransplantation

Keywords: AML; T‐cell; collagen; mouse model; ossicles; patient‐derived xenografts.

4 Feb

The role of the somatosensory cortex in self-paced movement impairment in Parkinson's disease

Objective: The aim of this work was to study the differences at the whole-brain level between self-paced and cued movement processing in Parkinson's disease (PD).

Methods: High density electroencephalogram (HD-EEG) was recorded during the performance of self-paced movements (Bereitschaftspotential - BP) and visually cued movements (VMT) in PD patients (n = 38) and in a group of healthy controls (HC, n = 23). Oscillatory changes in the alpha, beta, and gamma frequencies were evaluated and correlated to the clinical scales- MDS-UPDRS and Freezing of Gait Questionnaire (FOGQ).

Results: The main difference in the alpha range was an activation in the basal ganglia area during VMT performance as compared to BP performance; this activation was present only in HC. The most important finding was observed in the high beta range: a higher activation of the right postcentral area during BP performance in PD subjects as compared to HC, correlating to the severity of FOG. Moreover, PD patients had lower gamma activation of the right frontal areas.

Conclusion: A simplification of motor circuits and a hyperactivation of the right somatosensory cortex were observed in PD subjects.

Significance: Future studies should be focused on this area to confirm or disprove its role in FOG.

4 Feb

Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study

Background: Given burdensome side-effects and long latency for efficacy with conventional agents, there is a continued need for generalised myasthenia gravis treatments that are safe and provide consistently sustained, long-term disease control. Nipocalimab, a neonatal Fc receptor blocker, was associated with dose-dependent reductions in total IgG and anti-acetylcholine receptor (AChR) antibodies and clinically meaningful improvements in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale in patients with generalised myasthenia gravis in a phase 2 study. We aimed to assess the safety and efficacy of nipocalimab in a phase 3 study.

Methods: Vivacity-MG3 was a phase 3, randomised, double-blind, placebo-controlled, phase 3 study conducted at 81 outpatient centres with expertise in myasthenia gravis in 17 countries in Asia-Pacific, Europe, and North America. Adults (aged ≥18 years) with generalised myasthenia gravis inadequately controlled with standard-of-care therapy (MG-ADL score ≥6) were randomly assigned (1:1) to either nipocalimab (30 mg/kg loading dose then 15 mg/kg every 2 weeks for maintenance dosing) or placebo infusions every 2 weeks, added to standard-of-care therapy in both groups, for 24 weeks. Randomisation was stratified by antibody status, day 1 MG-ADL total score, and region. The sponsor, investigators, clinical raters, and participants were masked to treatment assignment. 

4 Feb

Breaking boundaries: role of the brain barriers in metastatic process

Keywords: Blood-cerebrospinal fluid barrier; Blood-spinal cord barrier; Blood–brain barrier; Brain Metastasis; Cancer.

4 Feb

The Intrinsic Neuronal Activation of the CXCR4 Signaling Axis Is Associated with a Pro-Regenerative State in Cervical Primary Sensory Neurons Conditioned by a Sciatic Nerve Lesion

CXCL12 and CXCR4 proteins and mRNAs were monitored in the dorsal root ganglia (DRGs) of lumbar (L4-L5) and cervical (C7-C8) spinal segments of naïve rats, rats subjected to sham operation, and those undergoing unilateral complete sciatic nerve transection (CSNT) on post-operation day 7 (POD7). Immunohistochemical, Western blot, and RT-PCR analyses revealed bilaterally increased levels of CXCR4 protein and mRNA in both lumbar and cervical DRG neurons after CSNT. Similarly, CXCL12 protein levels increased, and CXCL12 mRNA was upregulated primarily in lumbar DRGs ipsilateral to the nerve lesion. Intrathecal application of the CXCR4 inhibitor AMD3100 following CSNT reduced CXCL12 and CXCR4 protein levels in cervical DRG neurons, as well as the length of afferent axons regenerated distal to the ulnar nerve crush. Furthermore, treatment with the CXCR4 inhibitor decreased levels of activated Signal Transducer and Activator of Transcription 3 (STAT3), a critical transforming factor in the neuronal regeneration program. Administration of IL-6 increased CXCR4 levels, whereas the JAK2-dependent STAT3 phosphorylation inhibitor (AG490) conversely decreased CXCR4 levels. This indicates a link between the CXCL12/CXCR4 signaling axis and IL-6-induced activation of STAT3 in the sciatic nerve injury-induced pro-regenerative state of cervical DRG neurons.

29 Jan

Pre-implantation Scalp EEG Can Predict VNS Efficacy in Children

Introduction. Vagal nerve stimulation (VNS) is a therapeutical option for the treatment of drug-resistant epileptic patients. The response to VNS varies from patient to patient and is difficult to predict. The proposed study is based on our previous work, identifying relative mean power in pre-implantation EEG as a reliable marker for VNS efficacy prediction in adult patients. Our study has two main tasks. Firstly, to confirm the utility of relative mean power as a feature correlating with VNS efficacy in children. The second is to validate the applicability of our prediction classifier, Pre-X-Stim, in the pediatric population. Material and Methods. We identified a group of children with drug-resistant epilepsy. We included only children in whom EEG contained photic stimulation (Task 1) or was recorded based on the defined acquisition protocol used for development Pre-X-Stim (Task 2). Relative mean powers were calculated. VNS responders and non-responders were compared based on relative mean powers' values. In the next step, we evaluate the utility of our classifier, Pre-X-Stim, in the children population. Results: We identified 57 children treated with VNS - 17 patients were recruited for the Task 1 and 7 patients for the Task 2. When focusing on relative mean powers in EEG spectra, we observed statistically significant differences in theta range. The Pre-X-Stim algorithm was able to predict VNS efficacy correctly in 6 out of 7 patients (the accuracy 83.3%, the sensitivity 75%, the specificity 100%). Conclusions. Based on our results, it seems that children and adults share a similar pattern of EEG relative mean power changes. These changes can be used for pre-implantation prediction of VNS efficacy.

29 Jan

Revealing connectivity patterns of deep brain stimulation efficacy in Parkinson's disease

Keywords: Connectivity patterns; Deep brain stimulation; EEG; Functional connectivity; Parkinson’s disease; Subthalamic nucleus.

29 Jan

A roadmap toward promoting and improving brain health in Europe and closing the awareness and funding gap

Background and purpose: The global burden of neurological diseases exceeds 43.1%, imposing a significant burden on patients, caregivers and society. This paper presents a roadmap to reduce this burden and improve brain health (BH) in Europe.

Methods: The roadmap is based on the European Academy of Neurology's (EAN) five-pillar BH strategy: advancing a global BH approach (P1), supporting policymaking (P2), fostering research (P3), promoting education (P4), and raising awareness of prevention and treatment (P5). It reviews current efforts, collaborations and future directions aligned with the WHO Intersectoral Global Action Plan (iGAP) for Neurological Disorders and suggests future initiatives and call for action.

Results: P1: Support WHO-iGAP through defined action points, international collaborations, in particular, the WHO BH Unit, and the EAN Brain Health Mission. P2: Collaborate with 48 national neurological societies to promote National Brain Plans (NBPs), addressing local needs, and improving access to care. P3: Advocate for more research funding; identify determinants of BH; develop preventive measures. P4: Provide educational opportunities for neurologists, public education programs, and advocacy training, including tools to educate the public. P5: Spearhead global awareness campaigns, organize public educational activities, and train BH advocates to contribute toward sustainable and long-term public health campaigns and policy engagement.

29 Jan

Exploring medical error taxonomies and human factors in simulation-based healthcare education

This study aims to provide an updated overview of medical error taxonomies by building on a robust review conducted in 2011. It seeks to identify the key characteristics of the most suitable taxonomy for use in high-fidelity simulation-based postgraduate courses in Critical Care. While many taxonomies are available, none seem to be explicitly designed for the unique context of healthcare simulation-based education, in which errors are regarded as essential learning opportunities. Rather than creating a new classification system, this study proposes integrating existing taxonomies to enhance their applicability in simulation training. Through data from surveys of participants and tutors in postgraduate simulation-based courses, this study provides an exploratory analysis of whether a generic or domain-specific taxonomy is more suitable for healthcare education. While a generic classification may cover a broad spectrum of errors, a domain-specific approach could be more relatable and practical for healthcare professionals in a given domain, potentially improving error-reporting rates. Seven strong links were identified in the reviewed classification systems. These correlations allowed the authors to propose various simulation training strategies to address the errors identified in both the classification systems. This approach focuses on error management and fostering a safety culture, aiming to reduce communication-related errors by introducing the principles of Crisis Resource Management, effective communication methods, and overall teamwork improvement. 

29 Jan

The Blood-Cerebrospinal Fluid Barrier as a Potential Entry Site for the SARS-CoV-2 Virus

Keywords: COVID‐19; SARS‐CoV‐2; blood‐cerebrospinal fluid barrier; choroid plexus; neuroinvasion.

29 Jan

Inflammatory changes in the choroid plexus following subarachnoid hemorrhage: the role of innate immune receptors and inflammatory molecules

Introduction: The choroid plexus is located in the cerebral ventricles. It consists of a stromal core and a single layer of cuboidal epithelial cells that forms the blood-cerebrospinal barrier. The main function of the choroid plexus is to produce cerebrospinal fluid. Subarachnoid hemorrhage due to aneurysm rupture is a devastating type of hemorrhagic stroke. Following subarachnoid hemorrhage, blood and the blood degradation products that disperse into the cerebrospinal fluid come in direct contact with choroid plexus epithelial cells. The aim of the current study was to elucidate the pathophysiological cascades responsible for the inflammatory reaction that is seen in the choroid plexus following subarachnoid hemorrhage.

Methods: Subarachnoid hemorrhage was induced in rats by injecting non-heparinized autologous blood to the cisterna magna. Increased intracranial pressure following subarachnoid hemorrhage was modeled by using artificial cerebrospinal fluid instead of blood. Subarachnoid hemorrhage and artificial cerebrospinal fluid animals were left to survive for 1, 3, 7 and 14 days. Immunohistochemical staining of TLR4, TLR9, FPR2, CCL2, TNFα, IL-1β, CCR2 and CX3CR1 was performed on the cryostat sections of choroid plexus tissue. The level of TLR4, TLR9, FPR2, CCL2, TNFα, IL-1β was detected by measuring immunofluorescence intensity in randomly selected epithelial cells. 

29 Jan

The role of the somatosensory cortex in self-paced movement impairment in Parkinson's disease

Objective: The aim of this work was to study the differences at the whole-brain level between self-paced and cued movement processing in Parkinson's disease (PD).

Methods: High density electroencephalogram (HD-EEG) was recorded during the performance of self-paced movements (Bereitschaftspotential - BP) and visually cued movements (VMT) in PD patients (n = 38) and in a group of healthy controls (HC, n = 23). Oscillatory changes in the alpha, beta, and gamma frequencies were evaluated and correlated to the clinical scales- MDS-UPDRS and Freezing of Gait Questionnaire (FOGQ).

Results: The main difference in the alpha range was an activation in the basal ganglia area during VMT performance as compared to BP performance; this activation was present only in HC. The most important finding was observed in the high beta range: a higher activation of the right postcentral area during BP performance in PD subjects as compared to HC, correlating to the severity of FOG. Moreover, PD patients had lower gamma activation of the right frontal areas.

Conclusion: A simplification of motor circuits and a hyperactivation of the right somatosensory cortex were observed in PD subjects.

10 Dec 2024

Diagnostic efficacy and clinical utility of whole-exome sequencing in Czech pediatric patients with rare and undiagnosed diseases

In the last decade, undiagnosed disease programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases. In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023. A total of 58 Czech patients with undiagnosed diseases were enrolled in the study. All children underwent singleton WES with targeted phenotype-driven analysis. We identified 28 variants, including 11 pathogenic, 13 likely pathogenic, and 4 VUS according to ACMG guidelines, as diagnostic of genetic diseases in 25 patients, resulting in an overall diagnostic yield of 43%. Eleven variants were novel and had not been previously reported in any public database. The overall clinical utility (actionability) enabling at least one type of change in the medical care of the patient was 76%, whereas the average number of clinical implications to individual patient care was two.

10 Dec 2024

Early Changes in the Locus Coeruleus in Mild Cognitive Impairment with Lewy Bodies

Background: Although neuromelanin-sensitive magnetic resonance imaging (NM-MRI) has been used to evaluate early neurodegeneration in Parkinson's disease, studies concentrating on the locus coeruleus (LC) in pre-dementia stages of dementia with Lewy bodies (DLB) are lacking.

Objectives: The aims were to evaluate NM-MRI signal changes in the LC in patients with mild cognitive impairment with Lewy bodies (MCI-LB) compared to healthy controls (HC) and to identify the cognitive correlates of the changes. We also aimed to test the hypothesis of a caudal-rostral α-synuclein pathology spread using NM-MRI of the different LC subparts.

Methods: A total of 38 MCI-LB patients and 59 HCs underwent clinical and cognitive testing and NM-MRI of the LC. We calculated the contrast ratio of NM-MRI signal (LC-CR) in the whole LC as well as in its caudal, middle, and rostral MRI slices, and we compared the LC-CR values between the MCI-LB and HC groups. Linear regression analyses were performed to assess the relationship between the LC-CR and cognitive outcomes.

Results: The MCI-LB group exhibited a significant reduction in the right LC-CR compared to HCs (P = 0.021). 

10 Dec 2024

Metrics for evaluation of automatic epileptogenic zone localization in intracranial electrophysiology

Introduction: Precise localization of the epileptogenic zone is critical for successful epilepsy surgery. However, imbalanced datasets in terms of epileptic vs. normal electrode contacts and a lack of standardized evaluation guidelines hinder the consistent evaluation of automatic machine learning localization models.

Methods: This study addresses these challenges by analyzing class imbalance in clinical datasets and evaluating common assessment metrics. Data from 139 drug-resistant epilepsy patients across two Institutions were analyzed. Metric behaviors were examined using clinical and simulated data.

Results: Complementary use of Area Under the Receiver Operating Characteristic (AUROC) and Area Under the Precision-Recall Curve (AUPRC) provides an optimal evaluation approach. This must be paired with an analysis of class imbalance and its impact due to significant variations found in clinical datasets.

Conclusions: The proposed framework offers a comprehensive and reliable method for evaluating machine learning models in epileptogenic zone localization, improving their precision and clinical relevance.

5 Nov 2024

Pharmacotherapy for behavioural manifestations in frontotemporal dementia: An expert consensus from the European Reference Network for Rare Neurological Diseases (ERN-RND)

Background and purpose: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by pervasive personality and behavioural disturbances with severe impact on patients and caregivers. In current clinical practice, treatment is based on nonpharmacological and pharmacological approaches. Unfortunately, trial-based evidence supporting symptomatic pharmacological treatment for the behavioural disturbances in FTD is scarce despite the significant burden this poses on the patients and caregivers.

Method: The study examined drug management decisions for several behavioural disturbances in patients with FTD by 21 experts across European expert centres affiliated with the European Reference Network for Rare Neurological Diseases (ERN-RND).

Results: The study revealed the highest consensus on drug treatments for physical and verbal aggression, impulsivity and obsessive delusions. Antipsychotics (primarily quetiapine) were recommended for behaviours posing safety risks to both patients and caregivers (aggression, self-injury and self-harm) and nightly unrest.

5 Nov 2024

Changes in Cx43 and AQP4 Proteins, and the Capture of 3 kDa Dextran in Subpial Astrocytes of the Rat Medial Prefrontal Cortex after Both Sham Surgery and Sciatic Nerve Injury

A subpopulation of astrocytes on the brain's surface, known as subpial astrocytes, constitutes the "glia limitans superficialis" (GLS), which is an interface between the brain parenchyma and the cerebrospinal fluid (CSF) in the subpial space. Changes in connexin-43 (Cx43) and aquaporin-4 (AQP4) proteins in subpial astrocytes were examined in the medial prefrontal cortex at postoperative day 1, 3, 7, 14, and 21 after sham operation and sciatic nerve compression (SNC). In addition, we tested the altered uptake of TRITC-conjugated 3 kDa dextran by reactive subpial astrocytes. Cellular immunofluorescence (IF) detection and image analysis were used to examine changes in Cx43 and AQP4 protein levels, as well as TRITC-conjugated 3 kDa dextran, in subpial astrocytes. The intensity of Cx43-IF was significantly increased, but AQP4-IF decreased in subpial astrocytes of sham- and SNC-operated rats during all survival periods compared to naïve controls. Similarly, the uptake of 3 kDa dextran in the GLS was reduced following both sham and SNC operations. The results suggest that both sciatic nerve injury and peripheral tissue injury alone can induce changes in subpial astrocytes related to the spread of their reactivity across the cortical surface mediated by increased amounts of gap junctions.