NTNG2 Mutasyonu: Erken nöropsikiyatrik manifestasyonlu yeni bir beyin-cilt hastalığı için aday bir gen mi? 3000 hasta üzerinden bir analiz

Aim: In this study, the relationship between genetic analysis and exome sequencing and clinical and neuroimaging findings of four patients from the same family was investigated by analyzing a clinical and genetic (WES) database containing more than 3000 patients. Methods: We analyzed the WES data of approximately 3000 patients performed in our center in terms of NTNG2 biallelic mutations. In addition, MR imaging findings were investigated. Results: We found four patients with the same mutation in the NTNG2 gene, presenting with similar clinical and neuroimaging findings. As a result of filtering, the c242G>A variant was determined in the NTNG2 gene. In addition, mild to severe brain parenchymal volume loss and frontal and temporal lobe atrophy were seen in cases 1, 2, and 4 on axial T2-weighted MRI. c. Conclusion: The current study has similar phenotypic and genotypic features and is a very rare report showing NTNG2 mutation in this context. Existing clinical data are important in choosing NTNG2 gene-related neuropsychiatric disorders as a future treatment target.Amaç: Bu çalışmada 3000'den fazla hastayı içeren klinik ve genetik (WES) veri tabanını analiz ederek aynı aileden dört hastanın genetik analizi ve ekzom dizilimi ile klinik ve nörogörüntüleme bulguları arasındaki ilişki araştırılmıştır. Yöntem: Merkezimizde 3000 hastanın WES verileri NTNG2 bialelik mutasyonları açısından incelendi. Ayrıca MR görüntüleme bulguları araştırıldı. Bulgular: NTNG2 geninde aynı mutasyona sahip, benzer klinik ve nörogörüntüleme bulguları ile başvuran dört hasta bulundu. Filtreleme sonucunda NTNG2 geninde c.242G>A varyantı belirlendi. Ayrıca aksiyel T2 ağırlıklı MRG'de vaka 1, 2 ve 4'te hafif ila şiddetli beyin parankimal hacim kaybı ve frontal ve temporal lob atrofisi görüldü. Sonuç: Mevcut çalışma benzer fenotipik ve genotipik özelliklere sahip olup bu bağlamda NTNG2 mutasyonunu gösteren çok nadir bir rapordur. Mevcut klinik data NTNG2 geniyle ilişkili nöropsikiyatrik bozukluklarda gelecekteki bir tedavi hedefi olarak seçilmesinde öneme sahiptir

Therapeutic role of repetitive transcranial magnetic stimulation in Alzheimer's and Parkinson's disease: Electroencephalography microstate correlates

Introduction: The microstate analysis is a method to convert the electrical potentials on the multi-channel electrode array to topographical electroencephalography (EEG) data. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method that can modulate brain networks. This study explores the pathophysiological changes through microstate analysis in two different neurodegenerative diseases, Alzheimer’s (AD) and Parkinson’s disease (PD), characterized by motor and cognitive symptoms and analysis the effect of rTMS on the impaired cognitive and motor functions. Materials and Methods: We included 18 AD, 8 PD patients, and 13 age-matched controls. For both groups, we applied 5 Hz rTMS on the left pre-SMA in PD patients while 20 Hz rTMS on the left lateral parietal region in AD patients. Each patient was re-evaluated 1 week after the end of the sessions, which included a detailed clinical evaluation and measurement of EEG microstates. Results: At the baseline, the common findings between our AD and PD patients were altered microstate (MS) B, MS D durations and transition frequencies between MS A–MS B, MS C–MS D while global explained variance (GEV) ratio and the extent and frequency of occurrence of MS A, MS B, and MS D were separately altered in AD patients. Although no specific microstate parameter adequately differentiated between AD and PD patients, we observed significant changes in MS B and MS D parameters in PD patients. Further, we observed that Mini-Mental State Examination (MMSE) performances were associated with the transition frequencies between MS A–MS B and MS C–MS D and GEV ratio. After left parietal rTMS application, we have observed significantly increased visual memory recognition and clock drawing scores after left parietal rTMS application associated with improved microstate conditions prominent, especially in the mean duration of MS C in AD patients. Also, pre-SMA rTMS resulted in significant improvement in motor scores and frequency of transitions from MS D to MS C in PD patients. Conclusion: This study shows that PD and AD can cause different and similar microstate changes that can be modulated through rTMS, suggesting the role of MS parameters and rTMS as a possible combination in monitoring the treatment effect in neurodegenerative diseases

EGb 761 reduces Ca2+ influx and apoptosis after pentylenetetrazole treatment in a neuroblastoma cell line

Background: Transient receptor potential (TRP) channels have been found to have significant implications in neuronal outgrowth, survival, inflammatory neurogenic pain, and various epileptogenic processes. Moreover, there is a growing body of evidence indicating that transient receptor potential (TRP) channels have a significant impact on epilepsy and its drug-resistant subtypes. Objective: We postulated that EGb 761 would modulate TRPA1 channels, thereby exhibiting anti-inflammatory and neuroprotective effects in a neuroblastoma cell line. Our rationale was to investigate the impact of EGb 761 in a controlled model of pentylenetetrazole-induced generalized epilepsy. Methodology: We evaluated the neuroprotective, antioxidant and anti-apoptotic effects of EGb 761 both before and after the pentylenetetrazole application in a neuroblastoma cell line. Specifically, we focused on the effects of EGB 761 on the activity of Transient receptor potential (TRP) channels. Results: EGb 761 applications both before and after the pentylenetetrazole incubation period reduced Ca release and restored apoptosis, ROS changes, mitochondrial depolarization and caspase levels, suggesting a prominent prophylactic and therapeutic effect of EGb 761 in the pentylenetetrazole-induced epileptogenesis process. Conclusion: Our basic mechanistic framework for elucidating the pathophysiological significance of fundamental ion mechanisms in a pentylenetetrazole treated neuroblastoma cell line provided compelling evidence for the favorable efficacy and safety profile of Egb 761 in human-relevant in vitro model of epilepsy. To the best of our knowledge, this is the first study to investigate the combined effects of EGb 761 and pentylenetetrazole on TRP channels and measure their activation level in a relevant model of human epileptic diseases

The effect of resveratrol on sphingosine-1 and oxidative/ nitrosative stress in an experimental heart ischemia reperfusion model

Objectives: Resveratrol (RSV) is a natural polyphenolic compound showing significant antioxidant effects. In this study, we aimed to investigate the effects of resveratrol on the sphingosine-1-phosphate (S1P) and oxidative stress biomarkers in hearth ischemia-reperfusion (I/R). Materials and Methods: The biochemical and histopathological effects of RSV on cardiac ischemia-reperfusion injury were investigated through ELISA- and light microscope. Results: We observed statistically significant differences between the treatment group and the control group in terms of malondialdehyde (MDA) level, catalase (CAT) and superoxide dismutase (SOD) activities (p<0.05). Histopathologically, we also observed decreased Polymorphonuclear Leucocyte (PMNL) infiltration, myocardial edema, miyositolysis in the treatment group compared to the I/R and sham groups. Conclusion: Resveratrol may play an important role in cardiac I/R injury through its anti-inflammatory and antioxidant effects which were biochemically and histopathologically confirmed in the present study

Differentiation of claustrum resting-state functional connectivity in healthy aging, Alzheimer's disease, and Parkinson's disease

The claustrum is a sheet-like of telencephalic gray matter structure whose function is poorly understood. The claustrum is considered a multimodal computing network due to its reciprocal connections with almost all cortical areas as well as subcortical structures. Although the claustrum has been involved in several neurodegenerative diseases, specific changes in connections of the claustrum remain unclear in Alzheimer's disease (AD), and Parkinson's disease (PD). Resting-state fMRI and T1-weighted structural 3D images from healthy elderly (n = 15), AD (n = 16), and PD (n = 12) subjects were analyzed. Seed-based FC analysis was performed using CONN FC toolbox and T1-weighted images were analyzed with the Computational Anatomy Toolbox for voxel-based morphometry analysis. While we observed a decreased FC between the left claustrum and sensorimotor cortex, auditory association cortex, and cortical regions associated with social cognition in PD compared with the healthy control group (HC), no significant difference was found in alterations in the FC of both claustrum comparing the HC and AD groups. In the AD group, high FC of claustrum with regions of sensorimotor cortex and cortical regions related to cognitive control, including cingulate gyrus, supramarginal gyrus, and insular cortex were demonstrated. In addition, the structural results show significantly decreased volume in bilateral claustrum in AD and PD compared with HC. There were no significant differences in the claustrum volumes between PD and AD groups so the FC may offer more precise findings in distinguishing changes for claustrum in AD and PD

Chemogenetic inhibition of MCH neurons does not alter memory performance in mice

Memory storage in the brain is one of the most extensively studied subjects in neuroscience. However, due to the highly complex structure of the memory-related systems in the brain, the mystery remains unsolved. Consolidation is one of the most important parts of the memory process, and one that can be affected by numerous neurodegenerative diseases. Hypothalamic melanin-concentrating hormone (MCH) neuronal activity has been of particular interest to researchers in terms of the association between sleep, neurodegenerative diseases, and memory consolidation. We used Pmch-Cre animals to investigate the role of MCH neuronal activity in memory consolidation. In order to observe the differences in memory consolidation, we chemogenetically inhibited MCH neurons using the DREADD method and measured hippocampus-dependent memory performance with a novel object recognition test applicable to early memory impairment in Alzheimer's disease. Our results revealed no significant improvement or worsening with MCH inhibition, suggesting that the role of MCH should now be evaluated in a wider setting

Propuesta de guía de implementación de un sistema de gestión de seguridad y salud en el trabajo basado en la norma INTE/ISO 45001:2018 para la empresa Corporación de Profesionales en Ingeniería S.A.

Proyecto de Graduación (Licenciatura en Ingeniería en Seguridad Laboral e Higiene Ambiental) Instituto Tecnológico de Costa Rica, Escuela de Ingeniería en Seguridad Laboral e Higiene Ambiental, 2019.The project was carried out in the company Corporación de Profesionales en Ingeniería S.A., dedicated to the construction sector. The objective was to develop a guide for the implementation of a Work Health and Safety Management System based on the INTE/ISO 45001: 2018 standard. For the development of the proposal, the current management of the company was initially analyzed through a review of documents, the application of the checklist based on NTP 308, a survey for managers and another for collaborators. Subsequently, the analysis of the organization's context, internal and external, is carried out through an analysis of PESTEL and finally the information is synthesized in a SWOT. Then an assessment of risks and opportunities is carried out by means of a non-participatory observation and the guidelines for the verification of conditions in the construction sector are applied in the projects to be subsequently evaluated through the risk evaluation matrix according to the standard INTE 31-06-07: 2011. After analyzing the tools, results were obtained such as the absence of a formal written commitment from management, the lack of documentation and the presence of important risks for workers in the activities they carry out. This is summarized in the current management of the company in health and safety has great opportunities for improvement and shows the need for immediate intervention measures to improve the situation, which leads to the implementation guide of a health and safety system in work to improve the working conditions of the organization.El proyecto se realizó en la empresa Corporación de Profesionales en Ingeniería S.A., dedicada al sector construcción. El objetivo fue desarrollar una guía de implementación de un Sistema de Gestión de Salud y Seguridad en el trabajo basada en la norma INTE/ISO 45001:2018. Para el desarrollo de la propuesta se analizó inicialmente la gestión actual de la empresa por medio de una revisión de documentos, la aplicación de la lista de verificación basada en la NTP 308, una encuesta para los gerentes y otra a los colaboradores. Posteriormente se realiza el análisis del contexto de la organización, interno y externo por medio de un análisis de PESTEL y por último se sintetiza la información en un FODA. Luego se realiza una evaluación de riesgos y oportunidades por medio de una observación no participativa y se aplica en los proyectos la guía de verificación de condiciones en el sector construcción para posteriormente ser valorados mediante la matriz de evaluación de riesgos según la norma INTE 31-06-07:2011. Tras el análisis de las herramientas se obtuvieron resultados como la ausencia de un compromiso formal por escrito de parte de la dirección, la inexistencia de documentación y la presencia de riesgos importantes para los trabajadores en las actividades que desarrollan. Esto se sintetiza en que la gestión actual de la empresa en salud y seguridad tiene grandes oportunidades de mejora y muestra la necesidad de medidas de intervención inmediatas para mejorar la situación, lo que conlleva a la guía de implementación de un sistema de salud y seguridad en el trabajo para mejorar las condiciones laborales de la organización

Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: A randomised, double-blinded, placebo-controlled phase-II trial

Background: Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods: Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. Results: We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Conclusion: Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases

Background: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. Methods: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. Findings: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. Interpretation: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.PoLiMeR Innovative Training Network ; SNIC ; ScandiBio Therapeutics ; ScandiBio Therapeutics and Knut ; Knut och Alice Wallenbergs Stiftels