10 Dec

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

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

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

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

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.

5 Nov

Using Polycaprolactone Nanofibers for the Proof-of-Concept Construction of the Alveolar-Capillary Interface

The alveolar-capillary interface is the key functional element of gas exchange in the human lung, and disruptions to this interface can lead to significant medical complications. However, it is currently challenging to adequately model this interface in vitro, as it requires not only the co-culture of human alveolar epithelial and endothelial cells but mainly the preparation of a biocompatible scaffold that mimics the basement membrane. This scaffold should support cell seeding from both sides, and maintain optimal cell adhesion, growth, and differentiation conditions. Our study investigates the use of polycaprolactone (PCL) nanofibers as a versatile substrate for such cell cultures, aiming to model the alveolar-capillary interface more accurately. We optimized nanofiber production parameters, utilized polyamide mesh UHELON as a mechanical support for scaffold handling, and created 3D-printed inserts for specialized co-cultures. Our findings confirm that PCL nanofibrous scaffolds are manageable and support the co-culture of diverse cell types, effectively enabling cell attachment, proliferation, and differentiation. Our research establishes a proof-of-concept model for the alveolar-capillary interface, offering significant potential for enhancing cell-based testing and advancing tissue-engineering applications that require specific nanofibrous matrices.

31 Oct

Dataset of DNA methylation profiles of 189 pediatric central nervous system, soft tissue, and bone tumors

Keywords: Epigenetics; Pediatric oncology; Precision medicine; Targeted methylation sequencing.

31 Oct

Development of a stereo-EEG based seizure matching system for clinical decision making in epilepsy surgery

Objective.The proportion of patients becoming seizure-free after epilepsy surgery has stagnated. Large multi-center stereo-electroencephalography (SEEG) datasets can allow comparing new patients to past similar cases and making clinical decisions with the knowledge of how cases were treated in the past. However, the complexity of these evaluations makes the manual search for similar patients impractical. We aim to develop an automated system that electrographically and anatomically matches seizures to those in a database. Additionally, since features that define seizure similarity are unknown, we evaluate the agreement and features among experts in classifying similarity.Approach.We utilized 320 SEEG seizures from 95 consecutive patients who underwent epilepsy surgery. Eight international experts evaluated seizure-pair similarity using a four-level similarity score. As our primary outcome, we developed and validated an automated seizure matching system by employing patient data marked by independent experts. Secondary outcomes included the inter-rater agreement (IRA) and features for classifying seizure similarity.Main results.The seizure matching system achieved a median area-under-the-curve of 0.76 (interquartile range, 0.1), indicating its feasibility. Six distinct seizure similarity features were identified and proved effective: onset region, onset pattern, propagation region, duration, extent of spread, and propagation speed. Among these features, the onset region showed the strongest correlation with expert scores (Spearman's rho = 0.75,p< 0.001).