关键词： Sleep   Neurological disorders   Orexinergic system   Paravascular transport   Brain   Cerebrospinal fluid   Alzheimer's disease   Traumatic brain injury   Epilepsy  

摘要： Until recently, both the purpose of the biological need for sleep and the mechanism by which the central nervous system eliminated metabolic waste products were unknown. The glymphatic system is the recently discovered macroscopic waste clearance system for the CNS, which predominantly functions during sleep states. Important implications for the glymphatic system exist for a significant proportion of neurological disorders, including traumatic brain injury, epilepsy, stroke, migraine, and Alzheimer's disease. Within the limited amount of research pertaining to this novel system there exists controversy regarding several of the key structural and functional aspects of the glymphatic system. In this review we address evidence from both standpoints regarding the prominent debates surrounding the glymphatic system, including the functional differences in wakefulness vs. sleep, the role of glial aquaporin-4 water channels, and whether it reflects a convective flow or a passive diffusion process. The answers that underlie these questions will have crucial and distinct outcomes for the future of the glymphatic system and the disorders it has been implicated in. However, this review also summarizes the potential role of the glymphatic system in the development and progression of the aforementioned neurological disorders. Furthermore, the possible contribution of the orexinergic system to this relationship between the glymphatic system, sleep, and these neurological disorders is also explored. Overall, in order to develop and utilize therapeutic interventions centred around the glymphatic system we must first dedicate further investigation to elucidating these discrepancies and unanswered questions.

关键词： basal ganglia cavitation   ECHS1   HIBCH   Leigh syndrome   methacrylate metabolites   paroxysmal dystonia   valine catabolism  

摘要： The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11;HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

关键词： PARP-1   Neuroinflammation   Neurological disorders   PARP1 inhibitors  

摘要： Poly (ADP-ribose) polymerases (PARPs) constitute a family of enzymes associated with divergent cellular processes that are not limited to DNA repair, chromatin organization, genome integrity, and apoptosis but also found to play a crucial role in inflammation. PARPs mediate poly (ADP-ribosylation) of DNA binding proteins that is often responsible for chromatin remodeling thereby ensure effective repairing of DNA stand breaks although during the conditions of severe genotoxic stress PARPs direct the cell fate towards apoptotic events. Recent discoveries have pushed PARPs into the spotlight as targets for treating cancer, metabolic, inflammatory and neurological disorders. Of note, PARP-1 is the most abundant isoform of PARPs (18 member super family) which executes more than 90% of PARPs functions. Since oxidative/nitrosative stress actuated PARP-1 is linked to vigorous DNA damage and wide spread provocative inflammatory response that underlie the aetiopathogenesis of different neurological disorders, possibility of developing PARP-1 inhibitors as plausible neurotherapeutic agents attracts considerable research interest. This review outlines the recent advances in PARP-1 biology and examines the capability of PARP-1 inhibitors as treatment modalities in intense and interminable diseases of neuronal origin.

摘要： This commentary is on the original article by Verity et al. on pages 287–294 of this issue.

关键词： Interpregnancy interval   Long-term   Offspring   Neurological morbidity   Neurological disease  

摘要： Purpose The purpose of our study was to evaluate the effect of IPI on long-term neurological morbidity of the offspring. Methods In this retrospective cohort study, 144,397 singleton infants born to multiparous mothers, between the years 1991 and 2014 in a tertiary medical center, were evaluated for different perinatal outcomes and were followed until 18 years of age for long-term neurological morbidity according to three IPI groups: Short IPI (< 6 months), long IPI (> 60 months) and intermediate IPI (6-60 months). We used a Kaplan-Meier survival curve to compare cumulative incidence of long-term neurological morbidity, and a Cox regression analysis to control for confounders such as gestational age, birth weight and maternal age. Results Offspring born to mothers with long IPI had higher rates of neurological morbidity (3.62% among offspring born after long IPI vs. 3.18% and 3.19% among offspring born after short and intermediate IPI, respectively,p = 0.041). The cumulative incidence of long-term neurological morbidity was significantly higher in the long IPI group (Kaplan-Meier log-rank testp < 0.001). Being born after a long IPI was found to be an independent risk factor for long-term neurological morbidity of the offspring (adjusted hazard ratio 1.2;95% confidence interval 1.1-1.4;p < 0.001). Conclusion Long IPI is independently associated with an increased risk of long-term neurological morbidity of the offspring.

关键词： Coenzyme Q   Mitochondria   Neurological diseases   Secondary coenzyme Q deficiency   Brain   Muscle  

摘要： Coenzyme Q (CoQ) is a ubiquitous lipid serving essential cellular functions. It is the only component of the mitochondrial respiratory chain that can be exogenously absorbed. Here, we provide an overview of current knowledge, controversies, and open questions about CoQ intracellular and tissue distribution, in particular in brain and skeletal muscle. We discuss human neurological diseases and mouse models associated with secondary CoQ deficiency in these tissues and highlight pharmacokinetic and anatomical challenges in exogenous CoQ biodistribution, recent improvements in CoQ formulations and imaging, as well as alternative therapeutical strategies to CoQ supplementation. The last section proposes possible mechanisms underlying secondary CoQ deficiency in human diseases with emphasis on neurological and neuromuscular disorders.

关键词： Escin   Intracerebral hemorrhage   Blood brain barrier   Systemic inflammation  

摘要： This study aims to investigate whether escin ameliorates the impairments of neurological function by ameliorating systemic inflammation instead of targeting the brain directly in intracerebral hemorrhage (ICH) mice. It showed that escin did not cross the blood brain barrier (BBB). Compared with the ICH group, the Garcia test scores in the escin groups were significantly increased. Brain water contents and Evans blue extravasation of the right basal ganglia in the ICH group were augmented, and significantly reduced by escin. Escin abated the increases of monocyte counts and serum IL-1 beta levels induced by ICH. IL-1 beta administration reversed the effect of escin on Garcia test scores, the brain water contents, and the Evans blue extravasation. Escin ameliorated the increasing levels of RhoA, ROCK1, nuclear NF-kappa B and the decreasing expression of I kappa B alpha, cytosolic NF-kappa B, occludin, claudin-5 in the ICH group. IL-1 beta administration blocked not only escin-mediated increases of I kappa B alpha, cytosolic NF-kappa B, occludin, and claudin-5, but also escin-caused decreases of RhoA, ROCK1, and nuclear NF-kappa B. The results indicate that escin improves neurological outcomes and the BBB function in ICH mice, which is associated with attenuating ICH-induced peripheral system inflammation, and therefore, inhibiting IL-1 beta/RhoA/NF-kappa B signaling pathway in BBB, at least in part. These findings suggest that it may be useful to ameliorate brain injury by inhibiting systemic inflammation instead of aiming to target the brain directly after ICH.

关键词： Asphyxial cardiac arrest   Cardiopulmonary resuscitation   Electroencephalogram   Neuroplasticity   Transcranial direct current stimulation  

摘要： Background: Non-shockable rhythms present an increasing proportion of out-of-hospital cardiac arrest (CA) patients, but are associated with poor prognosis and received limited therapeutic effect of targeted temperature management (TTM). Previous study showed repetitive anodal transcranial direct current stimulation (tDCS) improved neurological outcomes in animals with ventricular fibrillation. Here, we examine the effectiveness of tDCS on neurological recovery and the potential mechanisms in a rat model of asphyxial CA. Method: Cardiopulmonary resuscitation was initiated after 5 min of untreated asphyxial CA. Animals were randomized to three experimental groups immediately after successful resuscitation (n = 12/group, 6 males): no-treatment control (NTC) group, TTM group, and tDCS group. Post resuscitation hemodynamics, quantitative electroencephalogram (EEG), neurological deficit score, and 96-h survival were evaluated. Brain tissues of additional animals undergoing same experimental procedure was harvested for enzyme-linked immunoassay-based quantification assays of neuroplasticity-related biomarkers and compared with the sham-operated rats (n = 6/group). Results: We observed that after resuscitation tDCS-treated animals exhibited significantly higher mean arterial pressure and left ventricular ejection fraction than NTC group and showed greatly improved EEG characteristics including weighted-permutation entropy and gamma band power, and neurologic deficit scores and 96-h survival rates compared to NTC and TTM groups. Furthermore, neuroplastic biomarkers including microtubule-associated protein 2, growth-associated protein 43, postsynaptic density protein 95 and synaptophysin, were significantly higher in tDCS group when compared with NTC and TTM groups. Conclusion: In this rat model of asphyxial CA, repetitive anodal tDCS commenced after resuscitation improved neurological recovery, and it may exert a neuroprotective effect by preserving the neuroplasticity. ? 20

关键词： Cardiac arrest   Coma   Prognosis  

摘要： Background: Bilaterally absent pupillary light reflexes (PLR) or N20 waves of short-latency evoked potentials (SSEPs) are recommended by the 2015 ERC-ESICM guidelines as robust, first-line predictors of poor neurological outcome after cardiac arrest. However, recent evidence shows that the false positive rates (FPRs) of these tests may be higher than previously reported. We investigated if testing accuracy is improved when combining PLR/SSEPs with malignant electroencephalogram (EEG), oedema on brain computed tomography (CT), or early status myoclonus (SM). Methods: Post-hoc analysis of ProNeCA multicentre prognostication study. We compared the prognostic accuracy of the ERC-ESICM prognostication strategy vs. that of a new strategy combining ≥2 abnormal results from any of PLR, SSEPs, EEG, CT and SM. We also investigated if using alternative classifications for abnormal SSEPs (absent-pathological vs. bilaterally-absent N20) or malignant EEG (ACNS-defined suppression or burst-suppression vs. unreactive burst-suppression or status epilepticus) improved test sensitivity. Results: We assessed 210 adult comatose resuscitated patients of whom 164 (78%) had poor neurological outcome (CPC 3–5) at six months. FPRs and sensitivities of the ≥2 abnormal test strategy vs. the ERC-ESICM algorithm were 0[0−8]% vs. 7 [1–18]% and 49[41−57]% vs. 63[56−71]%, respectively (p < .0001). Using alternative SSEP/EEG definitions increased the number of patients with ≥2 concordant test results and the sensitivity of both strategies (67[59−74]% and 54[46−61]% respectively), with no loss of specificity. Conclusions: In comatose resuscitated patients, a prognostication strategy combining ≥2 among PLR, SSEPs, EEG, CT and SM was more specific than the 2015 ERC-ESICM prognostication algorithm for predicting 6-month poor neurological outcome. © 2020 The Author(s)