Publications

13 Sep 2021

MicroRNAs in the development of resistance to antiseizure drugs and their potential as biomarkers in pharmacoresistant epilepsy

Although many new antiseizure drugs have been developed in the past decade, approximately 30%-40% of patients remain pharmacoresistant. There are no clinical tools or guidelines for predicting therapeutic response in individual patients, leaving them no choice other than to try all antiseizure drugs available as they suffer debilitating seizures with no relief. The discovery of predictive biomarkers and early identification of pharmacoresistant patients is of the highest priority in this group. MicroRNAs (miRNAs), a class of short noncoding RNAs negatively regulating gene expression, have emerged in recent years in epilepsy, following a broader trend of their exploitation as biomarkers of various complex human diseases. We performed a systematic search of the PubMed database for original research articles focused on miRNA expression level profiling in patients with drug-resistant epilepsy or drug-resistant precilinical models and cell cultures. In this review, we summarize 17 publications concerning miRNAs as potential new biomarkers of resistance to antiseizure drugs and their potential role in the development of drug resistance or epilepsy.

3 Sep 2021

Cortical network organization reflects clinical response to subthalamic nucleus deep brain stimulation in Parkinson's disease

The degree of response to subthalamic nucleus deep brain stimulation (STN-DBS) is individual and hardly predictable. We hypothesized that DBS-related changes in cortical network organization are related to the clinical effect. Network analysis based on graph theory was used to evaluate the high-density electroencephalography (HDEEG) recorded during a visual three-stimuli paradigm in 32 Parkinson's disease (PD) patients treated by STN-DBS in stimulation "off" and "on" states. Preprocessed scalp data were reconstructed into the source space and correlated to the behavioral parameters. In the majority of patients (n = 26), STN-DBS did not lead to changes in global network organization in large-scale brain networks. In a subgroup of suboptimal responders (n = 6), identified according to reaction times (RT) and clinical parameters (lower Unified Parkinson's Disease Rating Scale [UPDRS] score improvement after DBS and worse performance in memory tests), decreased global connectivity in the 1-8 Hz frequency range and regional node strength in frontal areas were detected.

3 Sep 2021

Educational Program Improved Senior Preparedness to Call 911 as a Response to Stroke

27 Aug 2021

Multiple sclerosis and immune system biomarkers: Novel comparison in glatiramer acetate and interferon beta-1a-treated patient groups

Background: Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system (CNS). T cells and B lymphocytes are involved in the development of this disease.

Methods: The following biomarkers were determined in peripheral blood in 28 patients treated with glatiramer acetate (GA) and 21 patients treated with interferon beta 1-a (IFN): IL-10, BAFF, Mx1, IgG, IgG1, IgG2, IgG3 and IgG4 (at baseline and after 6 months of treatment). All participants had confirmed MS diagnosis.

Objectives: The primary objective is to assess a percentual change of biomarkers after 6 months since the first-line treatment initiation with GA or IFN. The secondary objective is to explore correlations between the baseline biomarkers' values (levels).

Results: A positive trend was observed in the increase in IL-10 concentration by 30.33 % (IFN) and by 15.65 % (GA). In the IFN group, we observed a statistically significant increase in the BAFF protein concentration by 29.9% (P < 0.001).

27 Aug 2021

In vivo molecular signatures of cervical spinal cord pathology in degenerative compression

Degenerative cervical myelopathy (DCM) is a severe consequence of degenerative cervical spinal cord (CSC) compression. The non-myelopathic stage of compression (NMDC) is highly prevalent and often progresses to disabling DCM. This study aims to disclose markers of progressive neurochemical alterations in NMDC and DCM by utilizing an approach based on state-of-the-art proton magnetic resonance spectroscopy (1H-MRS). Proton-MRS data were prospectively acquired from 73 participants with CSC compression and 47 healthy controls. Compression-affected participants were clinically categorized as NMDC and DCM, radiologically as mild (MC) or severe (SC) compression. MRS voxel was centered at C2 level. CSC volumes and neurochemicals were quantified and compared between HCNMDCDCM and HCMCSC, with general linear models adjusted for age and height effects (pFWE <0.05) and correlated to stenosis severity, electrophysiology, and myelopathy symptoms (p <0.05). Ratio of total creatine (tCr) to total N-acetylaspartate (tNAA) increased in NMDC (+11%) and in DCM (+26%) and SC (+21%).

27 Aug 2021

Tractography dissection variability: what happens when 42 groups dissect 14 white matter bundles on the same dataset?

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation.

In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway.

27 Aug 2021

Autoimmune and limbic encephalitis: case series with some atypical variables in clinical practice

Autoimmune and limbic encephalitides are still rare diseases characterized by rapid diagnostics and treatment development in recent years. The incidence of anti-N-methyl-D- aspartate receptor [NMDAR] encephalitis is about 1.5 per million person per year, and the incidence of paraneoplastic neurological syndromes [PNS] including limbic encephalitis [LE] is about 1.22 per 100 000 person per year (Vogrig et al. J Neurol 267:26-35, 1; Dalmau et al. Ann Neurol 61:25-36, 2). The diagnostic criteria of anti-NMDAR encephalitis are already well established (Zuliani et al. Neurol Sci 40:2017-2030, 10). We provide immunological and clinical characteristics of anti-NMDAR encephalitis case series emphasizing unusual association with colon tumour in one case and complete recovery in two cases. Then we report two cases of onconeural and cell surface antibody negative limbic encephalitis [LE] associated with tumours, seizures, cognitive and behavioural changes resulting in severe cerebellar syndrome and fatal outcome. The clinical characteristics and results of selected paraclinical examinations as electroencephalography [EEG], magnetic resonance imaging [MRI] and cerebrospinal fluid [CSF] analysis are reviewed.

24 Aug 2021

Generic acquisition protocol for quantitative MRI of the spinal cord

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition.

24 Aug 2021

Open-access quantitative MRI data of the spinal cord and reproducibility across participants, sites and manufacturers

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens.

Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics.

Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics.

Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord.

24 Aug 2021

Hemodynamic and white blood cells parameters in patients with first-episode psychosis: a pilot longitudinal study

Objective: Patients with schizophrenia are at higher risk of cardiovascular (CVS) related mortality. Close attention is being paid to the clinical utility of readily available CVS markers.

Methods: A pilot one-year longitudinal study in inpatients with first-episode psychosis (FEP) was carried out to determine markers of inflammation and endothelial dysfunction (monocyte- and neutrophil-to-lymphocyte ratios) and basal blood pressure, pulse, and derived hemodynamic parameters (PP: pulse pressure; RPP: rate pressure product; and MAP: mean arterial pressure).

Results: After one year, PP and RPP increased, as did systolic blood pressure and heart rate. Systolic blood pressure, PP, total white blood cells, and neutrophils correlated with weight gain. After one year, correlations between monocyte-to-lymphocyte ratio and RPP and MAP were observed.

Conclusion: Our study indicates worsening CVS health over the first year of treatment and emphasises the importance of early monitoring of CVS status using easily accessible parameters to prevent CVS-related mortality.

23 Aug 2021

Impact of prenatal stress on amygdala anatomy in young adulthood: Timing and location matter

Background: Exposure to maternal stress in utero has long-term implications for the developing brain and has been linked with a higher risk of depression. The amygdala, which develops during the early embryonic stage and is critical for emotion processing, might be particularly sensitive.

Methods: Using data from a neuroimaging follow-up of the ELSPAC prenatal birth cohort (n=129, 47% men, 23-24 years old), we studied the impact of prenatal stress during the first and second half of pregnancy on the volume of the amygdala and its nuclei in young adult offspring. We further evaluated the relationship between amygdala anatomy and offspring depressive symptomatology. Amygdala nuclei were parcellated using FreeSurfer's automated segmentation pipeline. Depressive symptoms were measured via self-report using the Beck Depression Inventory (BDI).

Results: Exposure to stress during the first half of pregnancy was associated with smaller accessory basal (Cohen's f²=0.27, p(FDR)=0.03) and cortical (Cohen's f²=0.29, p(FDR)=0.03) nuclei volumes.

23 Aug 2021

Targeted mass spectrometry for monitoring of neural differentiation

Human multipotent neural stem cells could effectively be used for the treatment of a variety of neurological disorders. However, a defining signature of neural stem cell lines that would be expandable, non-tumorigenic, and differentiate into desirable neuronal/glial phenotype after in vivo grafting is not yet defined. Employing a mass spectrometry approach, based on selected reaction monitoring, we tested a panel of well-described culture conditions, and measured levels of protein markers routinely used to probe neural differentiation, i.e. POU5F1 (OCT4), SOX2, NES, DCX, TUBB3, MAP2, S100B, GFAP, GALC, and OLIG1. Our multiplexed assay enabled us to simultaneously identify the presence of pluripotent, multipotent, and lineage-committed neural cells, thus representing a powerful tool to optimize novel and highly specific propagation and differentiation protocols. The multiplexing capacity of this method permits the addition of other newly identified cell type-specific markers to further increase the specificity and quantitative accuracy in detecting targeted cell populations. Such an expandable assay may gain the advantage over traditional antibody-based assays, and represents a method of choice for quality control of neural stem cell lines intended for clinical use.

23 Aug 2021

Derivation and Molecular Characterization of a Morphological Subpopulation of Human iPSC Astrocytes Reveal a Potential Role in Schizophrenia and Clozapine Response

Astrocytes are the most abundant cell type in the human brain and are important regulators of several critical cellular functions, including synaptic transmission. Although astrocytes are known to play a central role in the etiology and pathophysiology of schizophrenia, little is known about their potential involvement in clinical response to the antipsychotic clozapine. Moreover, astrocytes display a remarkable degree of morphological diversity, but the potential contribution of astrocytic subtypes to disease biology and drug response has received little attention. Here, we used state-of-the-art human induced pluripotent stem cell (hiPSC) technology to derive a morphological subtype of astrocytes from healthy individuals and individuals with schizophrenia, including responders and nonresponders to clozapine. Using functional assays and transcriptional profiling, we identified a distinct gene expression signature highly specific to schizophrenia as shown by disease association analysis of more than 10 000 diseases.

23 Aug 2021

Posttraumatic Stress and Posttraumatic Growth in Three Generations of Czech and Slovak Holocaust Survivors

The psychological consequences of trauma related to the Holocaust have been primarily studied in samples derived from Israel, North America, and Western Europe. Few studies have examined postcommunist countries in Central and Eastern Europe. The present study focused on three generations living in the Czech Republic and Slovakia after World War II (WWII): Holocaust survivors (71-95 years of age), their children (30-73 years of age), and their grandchildren (15-48 years of age). We compared scores on measures of posttraumatic stress symptoms (PTSS; the Posttraumatic Stress Disorder Checklist-Civilian Version) and posttraumatic growth (PTG; the Posttraumatic Growth Inventory) derived from three focal samples with scores from age-matched comparison participants. Higher PTSS scores emerged for Holocaust survivors in all generations, η² _P=.087 but only participants in the first generation reported higher PTG scores relative to the comparison group, with small effect sizes for the overall group differences, η² _P=.029 . These results are discussed in the historical and political context of postwar Czechoslovakia.

23 Aug 2021

Altered Spatiotemporal Dynamics of the Resting Brain in Mild Cognitive Impairment with Lewy Bodies

Background: Electrophysiological markers of prodromal dementia with Lewy bodies were described in the spectral domain. The sub-second temporal resolution may provide additional information.

Objective: To evaluate electroencephalography (EEG) microstates in patients with mild cognitive impairment with Lewy bodies and to assess the association between their temporal dynamics and the spectral marker.

Methods: Temporal parameters of microstates were compared between 21 patients with mild cognitive impairment with Lewy bodies and 21 healthy controls. The dominant alpha frequency was correlated with microstate parameters.

Results: Microstates A-D showed higher occurrence in the patient group. Microstate B additionally revealed shorter mean duration and increased time coverage; its occurrence correlated with the dominant alpha frequency in the patient group.

23 Aug 2021

Modulation of Working Memory and Resting-State fMRI by tDCS of the Right Frontoparietal Network

Many cognitive functions, including working memory, are processed within large-scale brain networks. We targeted the right frontoparietal network (FPN) with one session of transcranial direct current stimulation (tDCS) in an attempt to modulate the cognitive speed of a visual working memory task (WMT) in 27 young healthy subjects using a double-blind crossover design. We further explored the neural underpinnings of induced changes by performing resting-state fMRI prior to and immediately after each stimulation session with the main focus on the interaction between a task-positive FPN and a task-negative default mode network (DMN). Twenty minutes of 2 mA anodal tDCS was superior to sham stimulation in terms of cognitive speed manipulation of a subtask with processing of objects and tools in unconventional views (i.e., the higher cognitive load subtask of the offline WMT). This result was linked to the magnitude of resting-state functional connectivity decreases between the stimulated FPN seed and DMN seeds. We provide the first evidence for the action reappraisal mechanism of object and tool processing.

23 Aug 2021

Divergent estimates of the ratio between Na+-Ca2+ current densities in t-tubular and surface membranes of rat ventricular cardiomyocytes

The ratio between Na+-Ca2+ exchange current densities in t-tubular and surface membranes of rat ventricular cardiomyocytes (JNaCa-ratio) estimated from electrophysiological data published to date yields strikingly different values between 1.7 and nearly 40. Possible reasons for such divergence were analysed by Monte Carlo simulations assuming both normal and log-normal distribution of the measured data. The confidence intervals CI95 of the mean JNaCa-ratios computed from the reported data showed an overlap of values between 1 and 3, and between 0.3 and 4.3 in the case of normal and log-normal distribution, respectively. Further analyses revealed that the published high values likely result from a large scatter of data due to transmural differences in JNaCa, dispersion of cell membrane capacitances and variability in incomplete detubulation. Taking into account the asymmetric distribution of the measured data, the reduction of mean current densities after detubulation and the substantially smaller CI95 of lower values of the mean JNaCa-ratio, the values between 1.6 and 3.2 may be considered as the most accurate estimates.

23 Aug 2021

Progressive Tumefactive Demyelination as the Only Result of Extensive Diagnostic Work-Up: A Case Report

Keywords: case report; demyelinating diseases; multiple sclerosis; neuropathology; neuroradiology.