关键词： Alzheimer's disease   caspase-6   neurodegeneration   knock-out mice  

摘要： Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-alpha, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-beta plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD.

摘要： The paradigm of central nervous system (CNS) drug discovery has mostly relied on traditional approaches of rodent models or cell-based in vitro models. Owing to the issues of species differences between humans and rodents, it is difficult to correlate the robustness of data for neurodevelopmental studies. With advances in the stem-cell field, 3D CNS organoids have been developed and explored owing to their resemblance to the human brain architecture and functions. Further, CNS organoids provide a unique opportunity to mimic the human brain physiology and serve as a modeling tool to study the normal versus pathological brain or the elucidation of mechanisms of neurological disorders. Here, we discuss the recent application of a CNS organoid explored for neurodevelopment disease or a screening tool for CNS drug development.

关键词： Parkinson's disease   Repetitive transcranial magnetic stimulation   Mesenchymal stem cell   Neurotrophic factor   Anti-   pro-inflammatory cytokine  

摘要： Background: Repetitive transcranial magnetic stimulation (rTMS) has been in use for the treatment of various neurological diseases, including depression, anxiety, stroke and Parkinson's disease (PD), while its underlying mechanism is stills unclear. This study was undertaken to evaluate the potential synergism of rTMS treatment to the beneficial effect of human mesenchymal stem cells (hMSCs) administration for PD and to clarify the mechanism of action of this therapeutic approach. Methods: The neuroprotective effect in nigral dopamine neurons, neurotrophic/growth factors and anti-/pro-inflammatory cytokine regulation, and functional recovery were assessed in the rat 6-hydroxydopamine (6-OHDA) model of PD upon administration of hMSCs and rTMS. Results: Transplanted hMSCs were identified in the substantia nigra, and striatum. Enhancement of the survival of SN dopamine neurons and the expression of the tyrosine hydroxylase protein were observed in the hMSCs + rTMS compared to that of controls. Combination therapy significantly elevated the expression of several key neurotrophic factors, of which the highest expression was recorded in the rTMS + hMSC group. In addition, the combination therapy significantly upregulated IL-10 expression while decreased IFN-gamma and TNF-alpha production in a synergistic manner. The treadmill locomotion test (TLT) revealed that motor function was improved in the rTMS + hMSC treatment with synergy. Conclusion: Our findings demonstrate that rTMS treatment and hMSC transplantation could synergistically create a favorable microenvironment for cell survival within the PD rat brain, through alteration of soluble factors such as neurotrophic/growth factors and anti-/pro-inflammatory cytokines related to neuronal protection or repair, with preservation of DA neurons and improvement of motor functions.

关键词： calcaneovalgus   cavovarus   deformity   equinovalgus   equinovarus   neuromuscular   planovalgus  

摘要： Deformities of the foot and ankle in neuromuscular conditions are often complex and occur at multiple levels. Careful examination of the patient is key to identifying the deformity, and whether it is flexible or fixed. This will help to guide management options. This paper outlines treatment options for the common deformity patterns seen in clinical practice. © 2019

关键词： Post traumatic stress disorder   Functional neurological symptom disorder   Psychogenic non-epileptic seizures   Anxiety   Depression   Trauma  

摘要： Objective: To describe prevalence and relevance of Post-Traumatic Stress Disorder (PTSD) symptoms in Functional Neurological Symptom Disorder (FNSD) and explore differences in PTSD symptom scores between subgroups with Psychogenic Non-Epileptic Seizures (PNES) or other FNSD. Methods: This cross-sectional study evaluated data from 430 consecutive patients referred to a specialist psychotherapy service (69.3% female, 56% with PNES/44% with other FNSD). We analysed self-reported symptoms of Post-Traumatic Stress Disorder (PTSD Civilian Checklist, PCL-C), depression (PHQ-9), anxiety (GAD-7), physical symptoms (PHQ-15), social functioning (WSAS), and health related quality of life (SF-36). Relationships between PTSD scores, diagnosis and other measures were examined. Independent associations of PTSD scores were identified using multilinear regression. Results: Symptom scores likely to indicate clinical PTSD were reported by 60.7% of patients with no difference between PNES and FNSD subgroups. Those potentially symptomatic of PTSD were less likely to be living with a partner OR 2.95 (95% CI 1.83-4.04), or to be in employment OR 2.23 (95% CI 1.46-3.41) than less symptomatic patients. There were higher levels of anxiety (r = 0.62), depression (r = 0.63) and somatic symptoms (r = 0.45) and lower quality of life scores (r = 0.48) in patients with high PTSD symptom scores (p < .0001 for all comparisons). Anxiety, depression and somatic symptoms made independent contributions to the variance of PTSD symptoms. Conclusion There is a high prevalence of PTSD symptoms in patient with FNSD regardless of whether they have PNES. Trauma and PTSD symptoms are negatively correlated with quality of life. Self-report instruments for anxiety, depression and somatic symptoms may predict the presence of PTSD.

关键词： Neurological softs signs   Akathisia   Parkinsonism   EPMS   Antipsychotics   Schizophrenia spectrum disorders  

摘要： Neurological soft signs (NSS) have garnered increasing attention in psychiatric research on motor abnormalities in schizophrenia spectrum disorders (SSD). However, it remains unclear whether the assessment of NSS severity could have been confounded by current antipsychotic dosage. In this study, we recruited 105 patients with SSD that underwent a comprehensive motor assessment evaluating NSS and extrapyramidal motor symptoms (EPMS) by means of standardized instruments. Current antipsychotic dosage equivalence estimates were determined by the classical mean dose method (doses equivalent to 1 mg/d olanzapine). We used multiple regression analyses to describe the relationship between NSS, EPMS and antipsychotic medication. In line with our expectations, current antipsychotic dosage had no significant effects on NSS total score (p = 0.27), abnormal involuntary movements (p = 0.17), akathisia (p = 0.32) and parkinsonism (p = 0.26). Further, NSS total score had a significant effect on akathisia (p = 0.003) and parkinsonism (p = 0.0001, Bonferroni corr.), but only marginal effect on abnormal involuntary movements (p = 0.08). Our results support the notion that NSS are not significantly modulated by current antipsychotic dosage in SSD. The associations between NSS, akathisia and parkinsonism, as revealed by this study, support the genuine rather than medication-dependent origin of particular motor abnormalities in SSD. (C) 2019 Elsevier B.V. and ECNP. All rights reserved.

关键词： ischemic stroke   alteplase   randomised trial   computed tomography perfusion imaging   penumbral mismatch   thrombolysis   thrombolytic therapy   time window   wake-up stroke  

摘要： Background EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) is a randomized, multicenter, double-blinded, placebo-controlled phase 3 trial to test the hypothesis of extending the thrombolysis time window to 9 h from stroke onset and in wake-up stroke (WUS) patients. Objective To formulate the detailed statistical analysis plan for the EXTEND trial prior to database lock. This statistical analysis plan is based on the published and registered EXTEND trial protocol and is developed by the blinded steering committee and management team. Results The developed EXTEND statistical analysis plan is transparent, verifiable, and predetermined before the database lock. It is consistent with reporting standards for clinical trials and provides for clear and open reporting. Conclusions Publication of a statistical analysis plan serves to reduce potential trial analysis and reporting bias and outlines pre-specified analyses to quantify the benefits and harms of extending the thrombolysis time window to 9 h from stroke onset and in wake-up stroke patients. Trial registration: *** number NCT00887328 registered 23/Apr/2009 and NCT01580839 (EXTEND International) registered 19/Apr/2012

关键词： ataxia   cerebellar ataxia   cerebellum   diagnostic testing   exome   gait disorders   genetics   genomics   neurogenetics   spastic paraparesis   spastic paraplegia   spinocerebellar ataxia  

摘要： Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.

关键词： Neuron-specific enolase   Cardiac arrest   Neurological prognosis   Targeted temperature management  

摘要： Introduction and objectives: To analyze neuron-specific enolase (NSE) kinetics as a prognostic biomarker of neurological outcome in cardiac arrest survivors treated with targeted temperature management. Methods: We performed a retrospective analysis of patients resuscitated from in- or out-of-hospital cardiac arrest admitted from September 2006 to May 2018 in a single tertiary care center and cooled to 32 degrees C to 34 degrees C for 24 hours. Blood samples for measurement of NSE values were drawn at hospital admission and at 24, 48, and 72 hours after return of spontaneous circulation (ROSC). Neurological outcome was evaluated by means of the Cerebral Performance Category (CPC) score at 3 months and was characterized as good (CPC 1-2) or poor (CPC 3-5). Results: Of 451 patients, 320 fulfilled the inclusion criteria and were analyzed (80.3% male, mean age 61 +/- 14.1 years). Among these, 174 patients (54.4%) survived with good neurological status. Poor outcome patients had higher median NSE values at hospital admission and at 24, 48 and 72 hours after ROSC. At 48 and 72 hours after ROSC, NSE predicted poor neurological outcome with areas under the receiver-operating characteristic curves of 0.85 (95%CI, 0.81-0.90) and 0.88 (95%CI, 0.83-0.93), respectively. In addition, delta NSE values between 72 hours after ROSC and hospital admission predicted poor neurological outcome with an area under the receiver-operating characteristic curve of 0.90 (95%CI, 0.85-0.95) and was an independent predictor of unfavorable outcome on multivariate analysis (P < .001). Conclusions: In cardiac arrest survivors treated with targeted temperature management, delta NSE values between 72 hours after ROSC and hospital admission strongly predicted poor neurological outcome. (C) 2019 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved.