Peripheral Blood Gene Expression Profiling Reveals Molecular Pathways Associated with Cervical Artery Dissection.

Cervical artery dissection (CeAD) is the primary cause of ischemic stroke in young adults. Monogenic heritable connective tissue diseases account for fewer than 5% of cases of CeAD. The remaining sporadic cases have known risk factors. The clinical, radiological, and histological characteristics of systemic vasculopathy and undifferentiated connective tissue dysplasia are present in up to 70% of individuals with sporadic CeAD. Genome-wide association studies identified CeAD-associated genetic variants in the non-coding genomic regions that may impact the gene transcription and RNA processing. However, global gene expression profile analysis has not yet been carried out for CeAD patients. We conducted bulk RNA sequencing and differential gene expression analysis to investigate the expression profile of protein-coding genes in the peripheral blood of 19 CeAD patients and 18 healthy volunteers. This was followed by functional annotation, heatmap clustering, reports on gene-disease associations and protein-protein interactions, as well as gene set enrichment analysis. We found potential correlations between CeAD and the dysregulation of genes linked to nucleolar stress, senescence-associated secretory phenotype, mitochondrial malfunction, and epithelial-mesenchymal plasticity.

L-Arginine-eNOS-NO Functional System in Brain Damage and Cognitive Impairments in Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) is a significant cause of cognitive impairment (CI), disability, and mortality. The insufficient effectiveness of antihypertensive therapy in curbing the disease justifies the search for potential targets for modifying therapy and indicators supporting its use. Using a laser-assisted optical rotational cell analyzer (LORRCA, Mechatronics, The Netherlands), the rheological properties and deformability of erythrocytes before and after incubation with 10 µmol/L of L-arginine, the nitric oxide (NO) donor, blood-brain barrier (BBB) permeability assessed by dynamic contrast-enhanced MRI, clinical, and MRI signs were studied in 73 patients with CSVD (48 women, mean age 60.1 ± 6.5 years). The control group consisted of 19 volunteers (14 women (73.7%), mean age 56.9 ± 6.4 years). The erythrocyte disaggregation rate (y-dis) after incubation with L-arginine showed better performance than other rheological characteristics in differentiating patients with reduced NO bioavailability/NO deficiency by its threshold values. Patients with y-dis > 113 s-1 had more severe CI, arterial hypertension, white matter lesions, and increased BBB permeability in grey matter and normal-appearing white matter (NAWM). A test to assess changes in the erythrocyte disaggregation rate after incubation with L-arginine can be used to identify patients with impaired NO bioavailability. L-arginine may be part of a therapeutic strategy for CSVD with CI.

Neuropoly: An Educational Board Game to Facilitate Neurology Learning.

Introduction: Neurology is arguably one of the most difficult subjects to teach and study in the medical curriculum. Educational games (EG) may be a valid option to enhance motivation in neurology residents. Methods: We developed an educational board game (Neuropoly) to assist in teaching neurology. We present here an overview of the game, as well as the results of a pilot study aimed at determining: (a) the efficacy of the game in teaching certain neurological concepts; and (b) student compliance and satisfaction with the EG. Results: The pre- and post-play questionnaire scores differed significantly (3.2 ± 1.7 vs. 7.8 ± 1.6, p < 0.001). Our group of residents, showing an overwhelmingly positive response, very well received the game. The questions were rated as above average regarding difficulty. Conclusion: The "Neuropoly" educational board game has been shown to be interesting, efficient, and motivational among first- and second-year neurology residents. Novel educational methods for complex medical disciplines should be developed, with board games being a viable and inexpensive approach.

Determination of Brain Death/Death by Neurologic Criteria: The World Brain Death Project.

IMPORTANCE: There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries. OBJECTIVE: To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel. PROCESS: Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery. EVIDENCE SYNTHESIS: Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed. RECOMMENDATIONS: Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability. CONCLUSIONS AND RELEVANCE: This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.

MRI Types of Cerebral Small Vessel Disease and Circulating Markers of Vascular Wall Damage.

The evaluation of the clustering of magnetic resonance imaging (MRI) signs into MRI types and their relationship with circulating markers of vascular wall damage were performed in 96 patients with cerebral small vessel disease (cSVD) (31 men and 65 women; mean age, 60.91 ± 6.57 years). The serum concentrations of the tumor necrosis factor-α (TNF-α), transforming growth factor-ß1 (TGF-ß1), vascular endothelial growth factor-A (VEGF-A), and hypoxia-inducible factor 1-α (HIF-1α) were investigated in 70 patients with Fazekas stages 2 and 3 of white matter hyperintensities (WMH) and 21 age- and sex-matched volunteers with normal brain MRI using ELISA. The cluster analysis excluded two patients from the further analysis due to restrictions in their scanning protocol. MRI signs of 94 patients were distributed into two clusters. In the first group there were 18 patients with Fazekas 3 stage WMH. The second group consisted of 76 patients with WMH of different stages. The uneven distribution of patients between clusters limited the subsequent steps of statistical analysis; therefore, a cluster comparison was performed in patients with Fazekas stage 3 WMH, designated as MRI type 1 and type 2 of Fazekas 3 stage. There were no differences in age, sex, degree of hypertension, or other risk factors. MRI type 1 had significantly more widespread WMH, lacunes in many areas, microbleeds, atrophy, severe cognitive and gait impairments, and was associated with downregulation of VEGF-A compared with MRI type 2. MRI type 2 had more severe deep WMH, lacunes in the white matter, no microbleeds or atrophy, and less severe clinical manifestations and was associated with upregulation of TNF-α compared with MRI type 1. The established differences reflect the pathogenetic heterogeneity of cSVD and explain the variations in the clinical manifestations observed in Fazekas stage 3 of this disease.

The Predictive Value of Salt Sensitivity and Osmotic Fragility in the Development of Cerebral Small Vessel Disease.

Increased salt intake in food probably affects the progression of cerebral small vessel disease (CSVD), which justifies the study of disturbances in sodium homeostasis associated with the development of CSVD. We aimed to clarify the role of salt sensitivity and osmotic fragility in the development of CSVD. Erythrocyte salt sensitivity was measured using the modified salt blood test, and osmotic fragility was measured using the classic osmotic fragility test in 73 patients with CSVD (48 women; 60.1 ± 6.5 years) and 19 healthy volunteers (14 women; 56.9 ± 6.4 years). Salt sensitivity and osmotic fragility exhibited a predictive value in relation to CSVD. These parameters were associated with an increase in white matter hyperintensities (P = 0.019 and 0.004, respectively). Their simultaneous use increased their predictive ability for CSVD (P < 0.000001; AUC (95% CI), 0.824 (0.724-0.923)). The possibility of predicting CSVD using erythrocyte salt sensitivity and osmotic fragility indicates the value of the individual glycocalyx buffer capacity in relation to sodium and the activity of sodium channels in the development of CSVD. Increased salt sensitivity and osmotic fragility seem to be risk factors for CSVD.

Combining HF rTMS over the Left DLPFC with Concurrent Cognitive Activity for the Offline Modulation of Working Memory in Healthy Volunteers: A Proof-of-Concept Study.

It has been proposed that the effectiveness of non-invasive brain stimulation (NIBS) as a cognitive enhancement technique may be enhanced by combining the stimulation with concurrent cognitive activity. However, the benefits of such a combination in comparison to protocols without ongoing cognitive activity have not yet been studied. In the present study, we investigate the effects of fMRI-guided high-frequency repetitive transcranial magnetic stimulation (HF rTMS) over the left dorsolateral prefrontal cortex (DLPFC) on working memory (WM) in healthy volunteers, using an n-back task with spatial and verbal stimuli and a spatial span task. In two combined protocols (TMS + WM + (maintenance) and TMS + WM + (rest)) trains of stimuli were applied in the maintenance and rest periods of the modified Sternberg task, respectively. We compared them to HF rTMS without a cognitive load (TMS + WM-) and control stimulation (TMS - WM + (maintenance)). No serious adverse effects appeared in this study. Among all protocols, significant effects on WM were shown only for the TMS + WM- with oppositely directed influences of this protocol on storage and manipulation in spatial WM. Moreover, there was a significant difference between the effects of TMS + WM- and TMS + WM + (maintenance), suggesting that simultaneous cognitive activity does not necessarily lead to an increase in TMS effects.

Tissue Plasminogen Activator and MRI Signs of Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) is one of the leading causes of cognitive impairment and stroke. The importance of endothelial dysfunction and high blood-brain barrier (BBB) permeability in pathogenesis, together with ischemia, is under discussion. The aim of this study was to clarify the relationship between tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), and magnetic resonance imaging (MRI) signs of SVD. We examined 71 patients (23 men and 48 women; mean age: 60.5 ± 6.9 years) with clinical and MRI signs of SVD, and 21 healthy volunteers with normal MRIs. All subjects underwent 3T MRI and measurements of t-PA and PAI-1 levels. An increase in t-PA level is correlated with the volume of white matter hyperintensities (WMH) (R = 0.289, p = 0.034), severity on the Fazekas scale (p = 0.000), and with the size of subcortical (p = 0.002) and semiovale (p = 0.008) perivascular spaces. The PAI-1 level is not correlated with the t-PA level or MRI signs of SVD. The correlation between t-PA and the degree of WMH and perivascular spaces' enlargement, without a correlation with PAI-1 and lacunes, is consistent with the importance of t-PA in BBB disruption and its role in causing brain damage in SVD.