Gut microbiota plays a critical role in physiological regulation throughout life and is specifically modified to meet the demands of individual life stages and during pregnancy. Maternal gut microbiota is uniquely adapted to the pregnancy demands of the mother and the developing fetus. Both animal studies in pregnant germ-free rodents and human studies have supported a critical association between the composition of maternal microbiota during pregnancy and fetal development. Gut microbiota may also contribute to the development of the fetal gut-brain axis (GBA), which is increasingly recognized for its critical role in health and disease. Most studies consider birth as the time of GBA activation and focus on postnatal GBA development. This review focuses on GBA development during the prenatal period and the impact of maternal gut microbiota on fetal GBA development. It is hypothesized that adaptation of maternal gut microbiota to pregnancy is critical for the GBA prenatal development and maturation of GBA postnatally. Consequently, factors affecting maternal gut microbiota during pregnancy, such as maternal obesity, diet, stress and depression, infection, and medication, also affect fetal GBA development and are critical for GBA activity postnatally. Altered maternal gut microbiota during gestation has been shown to have long-term impact postnatally and multigenerational effects. Thus, understanding the impact of maternal gut microbiota during pregnancy on fetal GBA development is crucial for managing fetal, neonatal, and adult health, and should be included among public health priorities.

Ageing may be characterized by progressive loss of cognitive function as well as decrease in physical activities, in addition to change in appearance. Previously, we reported that intracerebroventricular transplantation of a human neural stem cell (NSC) line (F3) over-expressing choline acetyltransferase (F3.ChAT) gene, an enzyme responsible for acetylcholine synthesis, markedly improved cognitive function and physical activity of aged animals by enhancing acetylcholine and growth factors (GFs) and neurotrophic factors (NFs). In the present study, 10-month-old F344 rats were intravenously transplanted with F3 or F3.ChAT NSCs (1 x 106 cells) once a month to 21st month of age when the cumulative mortality reached 20%, and physical activity and learning/memory function were investigated, in addition to the analyses of brain acetylcholine concentration, and cholinergic and dopaminergic system restoration. Neuroprotective and neuroregenerative activities of stem cells were also confirmed by analyzing oxidative damages, neuronal skeletal protein, angiogenesis, brain and muscle weights, and proliferating host stem cells. Stem cells markedly improved both the cognitive (passive avoidance and water-maze performances) and physical (locomotor and rota-rod activities) functions, in parallel with the elevation of acetylcholine levels in cerebrospinal fluid and in muscles, in which F3.ChAT cells were superior to F3 parental cells. Stem cell transplantation down-regulated CCL11, leading to restoration of microtubule-associated protein 2 as well as functional markers of cholinergic and dopaminergic systems, and preserved brain and muscular capillaries, recovering muscle mass. In addition, stem cells enhanced antioxidative capacity, attenuating oxidative damage of multiple organs including muscles and the brain. The results indicate that NSCs over-expressing ChAT gene improve cognitive function and physical activity of ageing animals by protecting and recovering functions of multiple organs including cholinergic and dopaminergic systems as well as muscles from oxidative injuries through secretion of acetylcholine and GFs/NFs, increased antioxidant elements, and enhanced blood flow.

Steroid-responsive meningitis-arteritis (SRMA) is a predominantly Th-2 immune-mediated dis-ease, but exact pathomechanism remains still unclear. Interleukin-31 (IL-31) is predominantly produced by T cells with a Th-2 phenotype during proinflammatory conditions. We hypothesize, IL-31 might be involved in the pathogenesis of SRMA. IL-31 was measured in archived samples (49 serum and 52 CSF samples) of dogs with SRMA, Meningoencephalitis of unknown origin (MUO), infectious meningoencephalitis, atopic dermatitis and of healthy control dogs using a competitive canine IL-31 ELISA. Mean serum IL-31 level in dogs with SRMA (n=18) was mildly higher compared to dogs with atopic dermatitis (n=3) and MUO (n=15) and markedly higher than in healthy controls (n=10) and dogs with infectious meningoencephalitis (n=3). Dogs with SRMA in the acute stage of the disease and without any pre-treatment had the highest IL-31 levels. The mean CSF IL-31 value of dogs with SRMA (n=23) was quite similar to healthy controls (n=8) and did not differ significantly from dogs with MUO (n=19) and infectious meningoencephalitis (n=2). Based on this study, an involvement of IL-31 in the pathogenesis of the systemic Th-2 im-mune-mediated immune response in SRMA can be assumed as a further component leading to an aberrant immune reaction.

In the 21st century, the effects of HIV-associated neurocognitive disorders (HAND) have been significantly reduced in individuals due to the development of antiretroviral therapies (ARTs). However, the growing epidemic of polysubstance use (PSU) has led to concern for the effects of PSU on HIV-seropositive individuals. To effectively treat individuals affected by HAND, it is critical to understand the biological mechanisms affected by PSU including identification of novel markers. To fill this important knowledge gap, we used an in vivo HIV-Transgenic (HIV-Tg) animal model, to investigate the effects of the combined use of chronic methamphetamine (METH) and oxycodone (oxy). RNA-Seq analysis on the striatum - a brain region that is primarily targeted by both HIV and drugs of abuse - identified key differentially expressed markers post-METH and oxy exposure. Furthermore, ClueGO analysis and Ingenuity Pathway Analysis (IPA) revealed crucial molecular and biological functions associated with ATP-activated adenosine receptor, neuropeptide hormone activity, and the oxytocin signaling pathway to be altered between the different treatment groups. The current study further reveals the harmful effects of chronic PSU and HIV infection that can subsequently impact neurological outcomes in polysubstance users with HAND.

Infective endocarditis is a rare and challenging diagnosis, Q fever endocarditis being a major cause of culture-negative endocarditis (IE). The presence of multiple cerebral microbleeds (CMBs) suggests a particular vascular frailty and could be correlated to potential emergence of a haemorrhagic stroke in IE. We report a case of a 45 years-old patient with Coxiella burnetii endocarditis, with a brainstem hemorrhage and cerebral MRI CMBs resembling those of CAA. However the systemic inflammatory tests, the splenic infarct and kidney pathology could not be explained by a variant of CAA, neither the normal initial cerebral CT scan when the patient had already the brainstem clinical signs without evidencing the hemorrhage. Transthoracic and transesophageal echocardiogram revealed only calcified bicuspid aortic valve with moderate stenosis and regurgitation, without any vegetations and the blood cultures on conventional media were negative. Serology for Coxiella burnetii was positive. Inclusion of CMBs as a new minor imaging criteria for infective endocarditis could upgrade the diagnosis in almost 50% of patients.

In post-COVID-19 syndrome, clinical presentation of the nerve fiber dysfunction plays an important role. The possibility of autoantigen cross-mimicry of coronavirus infection and the peripheral nervous system need to be investigated. The bioinformatic analysis was applied to search for possible common protein sequences located in the immunological epitopes. Among the autoantigens of the human nervous system, fibroblast growth factor receptor protein 3, myelin protein P0, myelin protein P2, sodium channel protein type 9, alpha protein subunit, plexin-D1 protein and ubiquitin-carboxyl-terminal hydrolase protein of the L1 isoenzyme were selected. The “Alignmentaj” program was created. The UniProt database, Protein Data Bank and AlphaFold databases were used. The analysis of protein sequence similarities of spike glycoproteins in human coronaviruses revealed common pentapeptides of the MERS-CoV-2 virus with the fibroblast growth factor receptor 3 and myelin protein P2. Among seasonal coronaviruses, common peptide sequences were identified in HCoV-HKU-1 virus with sodium channel protein type 9 subunit alpha and Plexin-D1, HCoV-OС43 with Plexin-D1, as well as HCoV-NL63 with Plexin-D1 and Ubiquitin carboxyl-terminal hydrolase isozyme L1. The data obtained make it possible to identify new potential targets for the development of autoimmune reactions that occur against the background of the activity of highly pathogenic and seasonal coronaviruses.

Abstract: Autoimmune encephalitis is a complex and multifaceted pathology that involves the immune-mediated inflammation of the brain. It is characterized by the body's immune system mistakenly attacking the brain tissue, leading to a cascade of inflammatory processes. What makes autoimmune encephalitis vast is the wide range of causes, mechanisms, clinical presentations, and diagnostic challenges associated with the condition. The clinical presentations of autoimmune encephalitis are broad and can mimic other neurological disorders, making it a challenging differential diagnosis. This diverse clinical presentation can overlap with other conditions, making it crucial for healthcare professionals to maintain a high level of suspicion for autoimmune encephalitis when evaluating patients. The diagnostic challenges associated with autoimmune encephalitis further contribute to its vastness. Due to the variable nature of the condition, there is no definitive diagnostic test that can confirm autoimmune encephalitis in all cases. In this context, personalized patient management is crucial for achieving favorable outcomes. Each patient's treatment plan should be tailored to their specific clinical presentation, underlying cause, and immune response. Our objective is to raise awareness about the frequent yet under-diagnosed nature of autoimmune encephalitis by sharing five cases we encountered, along with a brief literature review.

Synaptic zinc ions (Zn2+) play an important role in the development of vascular dementia (VD) and Parkinson’s disease (PD). In this article, based on our study and many others, we review the mo-lecular pathways by which Zn2+ causes neurotoxicity. Zn2+ influences calcium homeostasis, energy production pathway, production of reactive oxygen species, endoplasmic reticulum stress pathway, and activated protein kinase/c-Jun amino terminal kinase (SAPK/JNK) pathway and consequently exerts neurotoxicity. Furthermore, we searched various crops for substances that protect neurones from neurotoxicity caused by Zn2+ and clarified that carnosine (β-alanylhistidine) may be a therapeutic drug for VD and PD. Here, we also review the molecular mechanisms underlying the role of carnosine as an endogenous protector and its protective effect against Zn2+-induced cyto-toxicity and discuss prospects for future neurodegenerative diseases therapeutic applications of this dipeptide.

Brainstem auditory evoked potentials (BAEPs) testing is very important when microvascular decompression (MVD) is performed with hemifacial spasm (HFS). The reason for this is that the vestibulocochlear nerve is located right next to the facial nerve, so the vestibulocochlear nerve may be affected by manipulation by surgery. The BAEPs test method for detecting vestibulocochlear nerve damage during surgery has been developed a lot and is helping a lot during surgery. In most HFS patients with normal vestibulocochlear nerve, the degree of vestibulocochlear nerve damage caused by surgery is reflected very well in the BAEPs test waveforms. Therefore, a real time test is the best way to minimize the damage to the vestibulocochlear nerve. The purpose of this study was to review the most recently published BAEPs test used in MVD surgery and to find out in detail the relationship between the vestibulocochlear nerve damage and the BAEPs waveforms.

The effects of hypothermia on neonatal encephalopathy may vary regionally, spatially, and cytopathologically in the gyrencephalic neocortex with manifestations potentially influenced by seizures that alter the severity and distribution of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia with continuous encephalographic (cEEG) monitoring for seizures to study injury in neocortex. Neonatal piglets were randomized to naïve, HI-normothermia (NT), overnight hypothermia (HT) initiated 2 hours after HI, sham-NT, or sham-HT treatments. Some piglets within sham and HI groups received cEEG monitoring during recovery. Survival was 2-7 days (piglets were unmedicated and those with poor recovery and unresolving seizures were euthanized early); there was no differences in survival among groups (p>0.078). Neuropathology was assessed by hematoxylin and eosin staining and immunohistochemistry for RNA Binding FOX-1 Homolog 3 (Rbfox3/NeuN). Normal and ischemic-necrotic neurons were counted (layers II-VI collectively) in somatosensory, motor, and prefrontal cortices, identified by cytoarchitecture and connectomics, and in inferior parietal cortex by layer. Seizure burden was determined. HI-NT piglets had reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to naïve, sham-NT, and sham-HT piglets in anterior and posterior motor and somatosensory cortices. Frontal cortex was vulnerable in the prefrontal lateral bank after HI-NT with ischemic-necrosis. HI-HT piglets had higher normal/total neuron ratios and lower ischemic-necrotic/total neuron ratios than HI-NT piglets in anterior/posterior motor and somatosensory cortices. Total normal neuron density in layer III of inferior parietal cortex was reduced in HI-NT piglets compared to sham piglets and was protected by HT. Laminar analysis of Rbfox3 in somatosensory cortex revealed three types of neurons: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT. Cortical neuron Rbfox3-depletion was partly rescued by HT. Seizure burden was more severe in HI piglets compared to sham piglets, but HI-NT and HI-HT piglets were similar. We conclude that 1) the neonatal piglet neocortex has a suprasylvian spatial vulnerability to HI and seizures; 2) HT protects against neuropathology in functionally different regions of the neonatal gyrencephalic neocortex; 3) neurons in neonatal neocortex have a limited cytopathology repertoire seen by H&E staining; 4) higher seizure burden correlates with more ischemic-necrotic neurons in somatosensory cortex; 5) seizure presence associates with damage spread to inferior parietal cortex; 6) seizure presence is insensitive to HT, and 7) Rbfox3 immunophenotyping identifies a novel neuronal RNA splicing protein nuclear-depletion pathology that appears reversible by HT. This work demonstrates that HT protection of neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores depleted neuronal RNA splicing factor.

Mice are one of the frequently used animal models in science research whose behavioral characteristics can provide much valuable information in biology, neuroscience, and pharmacology. Nowadays, artificial intelligence is widely used in mice behavior analysis. Integrated AI systems such as ChatGPT and VisualGPT are already available, and we discuss the feasibility of MiceGPT to help researchers identify and classify mouse behavior more easily. We review the applications of mice behavior analysis, analyze the tasks of deep learning on these applications based on an AI pyramid, and finally summarize the AI approaches to solve these tasks. Based on these summaries, we propose three MiceGPT architectures to demonstrate the theoretical feasibility of MiceGPT.

In this study, we developed a model that can predict whether patients with cerebral arteriovenous malformation (AVM) will be cured 36 months after intervention by means of stereotactic radiosurgery (SRS), and identified the most important predictors that explain the probability of being cured. A machine learning (ML) approach was applied using decision tree (DT) and logistic regression (LR) techniques on historical data (sociodemographic, clinical, treatment, angioarchitecture, and radiosurgery procedure) of 202 patients with AVM who underwent SRS at the Instituto de Radiocirugía del Perú (IRP) between 2005 and 2018. The LR model obtained the best results for predicting AVM cure with an accuracy of 92.16%, sensitivity of 92.86%, specificity of 88.89%, precision of 97.50%, and AUC of 97.62%, which shows that ML models are suitable for use for predicting the prognosis of medical conditions such as AVM and can be a support tool for medical decision-making. In addition, several factors were identified that could explain whether patients with AMV would be cured at 36 months with the highest likelihood: the location of the AVM, the occupation of the patient, and the presence of hemorrhage.

Neuropathic pain (NP) affects about the 8% of the general population. Current analgesic therapies have limited efficacy, making NP one of the most difficult to treat pain conditions. Evidence indicates that excessive oxidative stress can contribute to the onset of chronic NP and several natural antioxidant compounds have showed promising efficacy in NP models. Thus, the aim of the present study was to investigate the pain-relieving activity of honokiol (HNK)-rich standardized extract of Magnolia officinalis Rehder & E. Wilson bark (MOE), well known for its antioxidant and anti-inflammatory properties, in the spared nerve injury (SNI) model. The molecular mechanisms were investigated in spinal cord samples from SNI mice and in LPS-stimulated BV2. MOE and HNK showed antioxidant activity. MOE (30 mg/kg p.o.), produced an antiallodynic effect in the absence of locomotor impairment. MOE treatment reduced spinal p-p38, p-JNK1, iNOS, p-p65, IL-1ß and Nrf2 overexpression, increased IL-10 and MBP levels and attenuated the Notch signaling pathway by reducing Jagged1 and NEXT. All these effects were prevented by the CB1 antagonist AM251. HNK reduced the proinflammatory state of LPS-stimulated BV2 cells and reduced Jagged1 overexpression. MOE and HNK, by modulating oxidative and proinflammatory responses, might represent interesting candidates for NP management.

In healthy humans, taste sensitivity varies widely, influencing food selection and nutritional status. Chemosensory reductions have been associated with numerous pathological disorders or pharmacological interventions. Reliable psychophysical methods are crucial resources to analyze the taste function during routine clinical assessment. However, in the daily clinical routine, they are often considered to be too time-consuming. We used the Supervised Learning (SL) regression method to analyze with high precision the overall taste status of healthy controls (HC) and patients with chemosensory loss and to characterize the combination of responses that best can predict the overall taste status of two groups. Random Forest regressor allowed us to achieve our objective. The analysis of the order of importance and impact of each parameter on the prediction of overall taste status in the two groups showed that salty (low concentration) and sour (high concentration) stimuli specifically characterized healthy subjects, while bitter (high concentration) and astringent (high concentration) stimuli identified patients with chemosensory loss. The identification of these distinctions appears to be of interest to the health system since they may allow the use of specific stimuli during routine clinical assessments of taste function reducing the commitment in terms of time and costs.

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications and discovered by serendipity to be effective in migraine prevention although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed to identify novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response suggesting that other pathways may play a critical role with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family as adrenomedullin and amylin, molecules of the secretin family as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP), receptors as transient receptor potential (TRP) channels, intracellular downstream determinants as potassium channels but also the opioid system and the purinergic pathway have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways highlighting, based on preclinical and clinical evidences as well as provocative studies, their potential role as future targets for migraine preventive treatment.

The underlying mechanisms of secondary neuronal damage following intracerebellar hemorrhage are not yet clear. We aimed to study the possible mechanisms in the mediation of secondary neuronal damage following intracerebellar hemorrhage. ICbH was induced by collagenase type VII-S into mice in 2 phases (n=24/phase): 12 in control group, 12 in day 1 group, 12 in day 3 group and another 12 in day 7 group. All mice underwent locomotor assessment and subsequently sacrificed on day 1, day 3 and day 7 respectively. Cerebellum from phase one and phase two were taken to study morphological, immunohistochemistry and oxidative stress respectively. Mice behavior disturbed following ICbH at day 3 and y 7 as compared with control. Besides, NO increased-on day 1 post induction and suppressed on day 3 and 7. Expressions of SOD, CAT, nNOS, GPX1 and COX-2 were significantly raised on day 3. Morphological studies of the perihaematoma region and tissue showed neuronal damage occurred from day 1 onwards, peaked on day 3 and continued day 7. NO and expression of genes be correlating with morphological changes. Briefly, NO and oxidative stress has an important role in the cascade of secondary neuronal damage of the perihematomal region of ICbH.

Embryologically, the left brachiocephalic vein (LBV) originates as an anastomotic channel between the right and left anterior cardinal veins 1 . This positions the LBV between the manubrium sterni anteriorly and the innominate artery posteriorly 2 . This pattern of adjacency of the aorta to the LBV is unique to mammals and results from a quirk of evolution 3 . With age, the ascending aorta unfolds, elongates and dilates 4 . Simultaneously, there is a change in the thoracic geometry that reduces the thoracic volume primarily from disc height loss and kyphosis 5 . These transitions progressively compress the LBV. Normally this compression is circumvented via collateral pathways and "Blood finds a way" 6 . However, traversing these circuitous pathways comes at a cost and can result in delayed transit times and venous congestion. While it is possible that compression of the LBV in the setting of adequate collateral channels may fail to provoke any pathologic sequelae, we propose a phenomenon in which such compression in the setting of inadequate collateral circulation may lead to a state of pathologic venous congestion. This anatomic anomaly and its associated clinical features, if identified, can offer a new avenue for treatment options for some of the hitherto unexplained neurologic disorders.

Preoperative angiography in glioblastoma (GBM) often shows arteriovenous shunts and early venous filling (EVF). Here, we investigated the clinical implications of EVF in GBM as a prognostic and vascular mimicry biomarker. In this retrospective multicenter study, we consecutively enrolled patients who underwent angiography with a GBM diagnosis between April 1, 2013, and March 31, 2021. The primary and secondary endpoints were the differences in overall survival (OS) and progression-free survival (PFS), respectively, between cases with and without EVF. Of 133 initially enrolled patients, 91 newly diagnosed with GBM underwent preoperative angi-ography and became the study population. The 6-year OS and PFS were significantly worse in the EVF than in the non-EVF group. Moreover, 20 GBM cases (10 with EVF and 10 without EVF) were randomly selected and evaluated for histological vascular mimicry. Except for two cases that were difficult to evaluate, the EVF group had a significantly higher frequency of vascular mimicry than the non-EVF group (0/8 vs. 5/10, P = 0.04). EVF on preoperative angiography is a robust prognostic biomarker for GBM and may help detect cases with a high frequency of histological vascular mimicry.

Syringomyelia can be associated with multiple etiologies. The treatment of the underlying causes is the first-line therapy, however, a direct approach to the syrinx is accepted as rescue treatment. Any direct intervention on the syrinx requires a myelotomy, posing a significant risk of iatrogenic spinal cord (SC) injury. Intraoperative neurophysiological monitoring (IONM) is crucial to detect and prevent surgically induced damage in neural SC pathways. We retrospectively reviewed the perioperative and intraoperative neurophysiological data and perioperative neurological examinations in ten cases of syringomyelia surgery. All monitored modalities remained stable throughout the surgery in six cases, correlating with no new postoperative neurological deficits. In two patients, significant transitory attenuation, or loss of motor evoked potentials (MEPs), were observed and recovered after a corrective surgical maneuver, with no new postoperative deficit. In two cases, a significant MEP decrement was noted, which lasted until the end of the surgery and was associated with postoperative weakness. A transitory train of neurotonic electromyography (EMG) discharges was reported in one case, the surgical plan was adjusted and the patient showed no postoperative deficit. The dorsal nerve roots were stimulated and identified in the seven cases where the myelotomy was performed via the dorsal root entry zone. Dorsal column mapping guided the myelotomy entry zone in four cases. In conclusion, multimodal IONM is feasible and reliable and may help prevent iatrogenic SC injury during syringomyelia surgery.

Respiratory therapist(RT)internet-supervised At-Home Telespirometry(AHT)was validated in pilot 22/95=23% ALS Clinic population. Erect, supine Vital Capacity(eFVC, sFVC)were measured longitudinally using ZephyRx smartphone interface and database recording in-clinic-conventional(Viaire-Vyasis-)and at-home-portable(MIR-Spirobank-Smart-)spirometers. Bland-Altman(BA)analysis supported content validity-precision and 7-day-test-re-test-validity [mean difference=0.15L(conventional–portable;95%CI -0.40L, 0.70L); = 2.7% predicted (conventional-portable;95%CI -12.1%, 17.5%) ]meeting ATS-ERS performance standards. RT Internet-supervised AHT measured sFVC was more frequently obtained[35/52=67.3 %]in-home-vs-in-clinic sFVC[9/21=42.9 %](Chi-Square;P=0.0533). Monthly mean eFVC slope decline for the eFVC > 60 % predicted baseline cohort was – 1.24% predicted per month[95% CI -2.15 ,-0.33% predicted]statistically significantly(P=0.015)less compared with the – 5.86% predicted per month[95% CI -9.44, -2.29 % predicted]decline for the eFVC < 60 % predicted baseline cohort and in this cohort was associated with statistically significant decreased survival(P=0.0219). RT Internet-supervised AHT facilitated initiation of non-invasive ventilation(NIV)in 5/22[23%]patients including 3/4[75%] homebound subjects. RT Internet-supervised AHT can be deployed for ALS patients stratified according to baseline eFVC for earlier detection of eFVC and sFVC decreases between clinic visits. A prospective research study[NCT05106569]is ongoing to further define the capability of online deployment of Respiratory therapist(RT)internet-supervised AHT in the timely initiation of NIV use to improve ALS respiratory care in larger numbers of ALS subjects.

Hemifacial spasm (HFS) is a rare disorder characterized by involuntary facial muscle contractions. The primary cause is mechanical compression of the facial nerve by nearby structures. Lateral spread response (LSR) is an abnormal muscle response observed during electromyogram (EMG) testing and is associated with HFS. Intraoperative monitoring of LSR is crucial during surgery to confirm successful decompression. Proper anesthesia and electrode positioning are important for accurate LSR monitoring. Stimulation parameters should be carefully adjusted to avoid artifacts. The disappearance of LSR during surgery is associated with short-term outcomes, but its persistence does not necessarily indicate poor long-term outcomes. LSR monitoring has both positive and negative prognostic value, and its predictive ability varies across studies. Early disappearance of LSR can occur before decompression and may indicate better clinical outcomes. Further research is needed to fully understand the implications of LSR monitoring in HFS surgery.

Duchenne muscular dystrophy (DMD), the severest form of muscular dystrophy, is characterized by progressive muscle weakness with fatal outcome most often before the fourth decade of life. Despite recent addition of molecular treatments, DMD remains a disease without a cure, and the need persists for the development of supportive therapies aimed to help improve patients’ quality of life. This review focusses on the therapeutical potential of amino acid and derivative supplements, summarizing results obtained in preclinical studies in the murine disease model. Several promising compounds have come forward, with L-arginine, N-acetylcysteine and taurine featuring among the most intensively investigated. Beneficial effects include improved muscle function and reduced muscle fiber necrosis and reduced inflammatory and oxidative damage to muscle tissues, however mild side effects have also surfaced. In order to identify amino acid formulae that are safe and of true benefit to DMD patients, more explorative, placebo-controlled and long-term clinical trials need to be conducted, documenting therapeutic outcomes.

Spinal Cord Injury in children can be a devastating condition in children with profound implications for their overall health and quality of life. In this review we aim to provide a concise overview of the key aspects associated with SCI in pediatric population. Firstly, we discuss the etiology and epidemiology of SCI in children, highlighting the diverse range of causes. We explore the unique anatomical and physiological characteristics of the developing spinal cord that contribute to the specific challenges faced by pediatric patients. Next, we delve into the clinical presentation and diagnostic methods, emphasizing the importance of prompt and accurate diagnosis to facilitate appropriate interventions. Furthermore, we approach the multidisciplinary management of pediatric SCI, encompassing acute medical care, surgical interventions, and ongoing supportive therapies. Finally, we explore emerging research and innovative therapies in the field and we emphasize the need for continued advancements in understanding and treating SCI in children to improve their functional independence and overall quality of life.

Patients with Parkinson’s Disease (PD) experience REM sleep behavior disorder (RBD) more frequently than healthy controls. RBD is associated with torpid disease evolution. To test the hypothesis that differential genetic signatures might contribute to the torpid disease evolution in PD patients with RBD. We compared the rate of genetic mutations in PD patients with or without probable RBD. Patients with a clinical diagnosis of PD in the Parkinson’s Progression Markers Initiative (PPMI) database entered the study. We excluded those with missing data or a diagnosis change over the first five years from the initial PD diagnosis. Probable RBD (pRBD) was confirmed by a REM Sleep Behavior Disorder Screening Questionnaire score &gt;5 points. Logistic regression and Machine Learning (ML) algorithms were used to relate Single Nucleotide Polymorphism (SNPs) in PD-related genes with pRBD. We included 330 PD patients fulfilling all inclusion and exclusion criteria. The final logistic multivariate model revealed that the following SNPs increased the risk of pRBD: GBA_N370S_rs76763715 (OR, 95% CI: 3.38, 1.45-7.93), SNCA_A53T_rs104893877 (8.21, 2.26-36.34), ANK2. CAMK2D_rs78738012 (2.12, 1.08-4.10), and ZNF184_rs9468199 (1.89, 1.08-3.33). Conversely, SNP COQ7. SYT17_rs11343 reduced pRBD risk (0.36, 0.15-0.78). The ML algorithms led to similar results. The predictive models were highly specific (95-99%) but lacked sensitivity (9-39%). We found a distinctive genetic signature for pRBD in PD. The high specificity and low sensitivity of the predictive models suggest that genetic mutations are necessary but not sufficient to develop RBD in PD. Additional investigations are needed.

Gliomas, which arise from glial cells in the brain, remain a significant challenge due to their location and resistance to traditional treatments. Despite research efforts and advancements in healthcare, the incidence of gliomas has risen dramatically over the past two decades. The dysregulation of microRNAs (miRNAs) has prompted the creation of therapeutic agents that specially target them. However, it has been reported that they are involved in complex signaling pathways that contribute to the loss of expression of tumor suppressor genes and the upregulating of the expression of oncogenes. In addition, numerous miRNAs promote the development, progression, and recurrence of gliomas by targeting crucial proteins and enzymes involved in metabolic pathways such as glycolysis and oxidative phosphorylation. However, the complex interplay among these pathways and other obstacles hinder the ability to apply miRNA targeting in clinical practice. This underscores the importance of pinpointing miRNAs to be targeted for therapy and having a complete understanding of the diverse pathways they are involved in. Therefore, the aim of this review is to provide an overview on the role of miRNAs in the progression and prognosis of gliomas, emphasizing the different pathways involved and identifying potential therapeutic targets.

Background: Seizures in the early postoperative period may impair patient recovery and increase risk of complication. The aim of this study is to determine whether there is any advantage in postoperative seizure prophylaxis following meningioma resection. Methods: This systematic review was conducted in accordance with PRISMA guidelines. PUBMED, Web of Science, Embase, Science Direct, and Cochrane were searched for papers until April 2023. Results: Among 9 studies, a total of 3,249 were evaluated patients, of which 984 patients received antiepileptic drugs (AEDs). A comparison between patients who received AEDs and those who did not showed a non-significant differences between both groups (RR 1.22, 95% CI 0.66 to 2.40; I² = 57%). Postoperative seizures occurred in 5% (95% CI: 1% to 9%) within the early time period (<7 days), and 9% (95% CI: 1% to 17%) in the late time period (>7 days), with significant heterogeneity (I² = 91% and 97% respectively). In seizure-naive patients, the rate of postoperative seizures was 2% (95% CI: 0% to 6%) in the early period and increased to 6% (95% CI: 0% to 15%) in the late period. High heterogeneity led to the use of random-effects models in all analyses. Conclusion: The current evidence does not provide sufficient support for the effectiveness of prophylactic AED medications in preventing postoperative seizures in patients undergoing meningioma resection. This underscores the importance of considering diagnostic criteria and conducting individual patient analysis to guide clinical decision-making in this context.

Judo is a popular Japanese martial art and an Olympic sport. Recently, an increasing interest has been observed in the application of judo as a multicomponent exercise, with a growing body of evidence showing that multicomponent exercise improves physical and cognitive performance in older adults. Therefore, this review highlights the benefits of judo training in preventing physical and cognitive decline in older adults. Specifically, first, this review outlines the basic characteristics of judo (philosophy, match, and training). Next, previous studies investigating the effects of judo training on physical and cognitive aspects of older adults are reviewed. Thereafter, the brain mechanisms underlying the effects of judo training in improving physical and cognitive performance are discussed. Throughout this review, judo training demonstrated some positive effects on physical (gait and balance, among others) and cognitive (memory and executive function) function in older adults. These positive effects are attributed to a variety of changes in the brain (e.g., increased neurotrophic factor expression and increased cerebral blood flow, among others), that affect different brain regions and networks both functionally and structurally. From these findings, this review concludes that judo training can be an effective way to maintain and prevent physical and cognitive decline in older adults.

Intracranial and extracranial large artery atherosclerosis (LAA) are a main cause of ischemic stroke. Biomarkers may aid in the diagnosis of LAA and help to stratify patients´ risk of stroke. We performed a narrative review of the literature mainly published in the last five years with the aim of identifying biomarkers associated either with intracranial or extracranial LAA in humans. Several potential biomarkers of LAA mainly related to lipid pathways and inflammation have been studied. Diagnostic biomarkers of LAA were evaluated by measuring biomarkers levels in patients with LAA stroke and other stroke etiologies. Some biomarkers were associated with prognosis of LAA stroke as evaluated by the modified Rankin score. Increased levels of IL-6 and have been associated with the risk of progression of the atherosclerotic disease. Overall, in most studies, the results were not externally validated. External validation of these results is needed. In the future, biomarkers could be useful for the selection of patients for clinical trials. To adopt these biomarkers in clinical practice we will need robust multicentric studies proving their reproduci-bility and a clear practical applicability for their use.

Bacterial Extracellular Vesicles (BEVs) generated from the bacteria has high feasibility of intracellular interactions with other cells, can be used as a cargo to deliver any therapeutic substances like monoclonal antibodies, proteins, plasmids, siRNA and small molecules for the treatment of neurodegenerative diseases (NDs). BEVs have a high ability for delivering therapeutic molecules across the blood-brain barrier to treat Alzheimer's Disease (AD) via various mechanisms. In this review, we have sum up in-depth research details of the role and advancement of BEVs in NDs, AD and its Therapeutics. Moreover, details about offensive and defensive functions of BEVs in ND pathogenesis and examine the critical BEV networks in the microbiome-gut-brain axis and their role in neurodegenerative disorders. Additionally determining the roles of BEVs in the neuroimmune system and their interaction with neurodegenerative disorders and exploring the risk factors of BEVs in the autophagy-lysosomal pathway and their possible effects on neurodegenerative disorders are summarised in detail. In conclusion, this review seeks to contribute to a better understanding of the potential function of BEVs in NDs and to identify new therapeutic intervention strategies.

Keywords: Pain; Nociception; Disorders of Consciousness; Consciousness

The Lead-DBS imaging toolbox reconstructs the location of β-oscillations in the subthalamic nucleus (STN) in patients with Parkinson’s disease. The objective was to compare this probabilistic location with those of intraoperative monopolar β-oscillations (Vercise Cartesia directional electrodes, Boston Scientific). Also, the efficacy of stimulated structures in reducing motor symptoms were analysed. β-oscillations were computed from local field potentials [0.5-3kHz] by using shielded wires for monopolar recordings with an extracranial shielded reference. For each electrode contact, power spectral densities of the β-band [13-31Hz] were compared with those of all eight electrode contacts. The DISTAL, electrophysiological, and DBS target atlases of the Lead-DBS toolbox were applied to the reconstructed electrodes from preoperative MRI and postoperative CT. Thirty-six electrodes (20 patients: 7 female, 13 male; 16/20 both, 4/20 single STN) were analysed. Stimulation sites dorsal and/or lateral to the sensorimotor STN were most efficient. In 33/36 electrodes at least one contact was measured with stronger β-oscillations, 23 in or touching the ventral subpart of the probabilistic volume with β-oscillations, 10 not located in or touching but adjacent to this volume; in 3/36 electrodes, no contact was found with β-oscillations, they were distant from this volume. Monopolar local field potentials confirmed the ventral subpart of the probabilistic β-oscillations.

A retrospective cohort study was performed to determine the likelihood of malignant stroke after mechanical thrombectomy via ASPECTS-PASS score(A-P score), a novel scoring system using ASPECT score and number of arterial-passes. This prediction score is designed to help clinicians take early measures. Malignant stroke is defined as a large MCA infarct with mass effect that develops during the first 5 days following presentation and is associated with approximately 80% mortality. Previous studies have shown an association of low ASPECTS and high number of passes with poor outcome.We performed a retrospective cohort analysis on 78 patients with anterior circulation stroke who underwent mechanical thrombectomy at our hospital. We analyzed the likelihood of developing malignant stroke post thrombectomy in the first 5 days following successful recanalization (TICI ≽ 2b). Malignant stroke is defined as severe symptoms secondary to edema as evidenced by midline shift, cistern engorgement, and hemorrhagic conversion with edema. Patients with ASPECTS of 0-5 were excluded. We used two variables to predict the outcome: ASPECT score and number-of-passes. We used the equation ASPECT score minus number-of-passes (A-P) to arrive at a single number to predict the risk of malignant stroke. A-P scoring scale ranged from 0-9. Our study showed a statistically significant inverse relationship of A-P score and risk of malignant stroke. Approximately 90% of patients with A-P score < 5 developed malignant stroke in our study. A-P score can help predict malignant stroke post thrombectomy even after successful recanalization. Thus, A-P score of ≤ 5 suggests very high risk. (A-P) Score can assist clinicians to take early measures, and thereby prevent worse outcomes.

Neuronal cell fate is predominantly controlled by the effects of growth factors, such as neurotrophins, and the activation of a variety of signaling pathways acting through neurotrophin receptors, namely Trk and p75 (p75NTR). Despite their beneficial effects on brain function, their therapeutic use is compromised, due to their polypeptidic nature and blood–brain-barrier impermeability. To overcome these limitations, our previous studies have proven that DHEA-derived synthetic analogs can act like neurotrophins, lacking endocrine side effects. The present study focuses on the biological characterization of a newly synthesized analog, ENT-A044, and its role on inducing cell specific functions of p75NTR. We show that ENT-A044 can induce cell death and phosphorylation of JNK protein by activating p75NTR. Additionally, ENT-A044 can induce the phosphorylation of TrkB receptor, indicating that our molecule can activate both neurotrophin receptors, leading towards the protection of neuronal populations that express both receptors. Furthermore, the present study demonstrates for the first time the expression of p75NTR in human induced Pluripotent Stem Cells - derived Neural Progenitor Cells (hiPSCs - derived NPCs) and receptor-dependent cell death induced by ENT-A044 treatment. In conclusion, ENT-A044 could be proven a lead molecule for the development of novel pharmacological agents, aiming on new therapeutic approaches and research tools, by controlling p75NTR actions.

Not in the history of transmissible illnesses has there been an infection as strongly associated with acute cerebrovascular disease as the novel human coronavirus, SARS-CoV-2. While the risk of stroke has known associations with other viral infections, such as influenza and human immunodeficiency virus, the risk of ischemic and hemorrhagic stroke related to SARS-CoV-2 is unprecedented. Furthermore, the coronavirus disease 2019 (COVID-19) pandemic has so profoundly impacted psychosocial behaviors and modern medical care that we have witnessed shifts in epidemiology and have adapted our treatment practices to reduce transmission, address delayed diagnoses, and mitigate gaps in health care. In this narrative review, we summarize the history and impact of the COVID-19 pandemic on cerebrovascular disease, and lessons learned regarding the management of patients as we endure this period of human history.

Aging is a major risk factor for Alzheimer's disease (AD). AD mouse models are frequently used to assess pathology, behavior, and memory in AD research. While the pathological characteristics of AD are well established, our understanding of the changes in the metabolic phenotypes with age and pathology is limited. In this work, we used the Promethion cage systems® to monitor changes in physiological metabolic and behavioral parameters with age and pathology in wild-type and 5xFAD mouse models. Then, we assessed whether these parameters could be altered by treatment with oleocanthal, a phenolic compound with neuroprotective properties. Findings demonstrated metabolic parameters such as body weight, food and water intake, energy expenditure, dehydration, and respiratory exchange rate, and the behavioral parameters of sleep patterns and anxiety-like behavior are altered by age and pathology. However, the effect of pathology on these parameters was significantly greater than normal aging, which could be linked to amyloid-β deposition and blood-brain barrier (BBB) disruption. In addition, and for the first time, our findings suggest an inverse correlation between sleep hours and BBB breakdown. Treatment with oleocanthal improved the assessed parameters and reduced anxiety-like behavior symptoms and sleep disturbances. In conclusion, aging and AD are associated with metabolism and behavior changes, with the changes being greater with the latter, which were rectified by oleocanthal. In addition, our findings suggest that monitoring changes in metabolic and behavioral phenotypes could provide a valuable tool to assess disease severity and treatment efficacy in AD mouse models.

Circular RNAs (circRNAs) are single-stranded RNA molecules often circularized by backsplicing. Growing evidence implicates circRNAs in the underlying mechanisms of various diseases, such as Alzheimer's and Parkinson's disease (PD) - the first and second most prevalent neurodegenerative disorders. Several circRNAs are associated with brain damage, including circSNCA, circHIPK2, circHIPK3, and circSLC8A1. Gain-of-function and loss-of-function studies on circRNAs have shed light on their roles in the pathobiology of various diseases. Gain-of-function approaches typically employ viral or non-viral vectors that hyperexpress RNA sequences capable of circularizing to form the specific circRNA under investigation. In contrast, loss-of-function studies utilize CRISPR/Cas systems, antisense oligonucleotides (ASOs), or RNAi techniques to knockdown the target circRNA. Given that aberrantly expressed circRNAs have been associated with brain pathologies, a critical question arises: could circRNAs serve as viable targets for neuroprotective treatments? Translating any oligonucleotide-based therapy, including those targeting circRNAs, involves developing adequate brain delivery systems, minimizing off-target effects, and addressing the high costs of treatment. Nonetheless, RNAi-based FDA-approved drugs have entered the market, and circRNAs have attracted significant attention and investment from major pharmaceutical companies. Spanning from bench to bedside, circRNAs present a vast opportunity in biotechnology for oligonucleotide-based therapies designed to slow or even halt the progression of neurodegenerative diseases.

Parkinson’s-disease (PD) is an incurable age-related neurodegenerative disease and its global prevalence of disability and death has increased exponentially. Although motor symptoms are the characteristic manifestations of PD, the clinical spectrum also contains a wide variety of non-motor symptoms, which are the main cause of disability and determinants of the decrease in a patient's quality of life. Noteworthy in this regard is the stress on the cardiac system that is often observed in the course of PD, however its effects have not yet been adequately researched. Here, an untargeted metabolomics approach was used to assess changes in cardiac metabolism in the 6-hydroxydopamine model of PD. Beta-sitosterol, campesterol, cholesterol, monoacylglycerol, α-tocopherol, stearic acid, beta-glycerophosphoric acid, o-phosphoethanolamine, myo-inositol-1-phosphate, alanine, valine and allothreonine, are the metabolites that significantly discriminate Parkinsonian rats from sham counterparts. Upon analysis of the metabolic pathways with the aim of uncovering the main biological pathways involved in concentration patterns of cardiac metabolites, biosynthesis of both phosphatidylethanolamine and phosphatidylcholine, glucose-alanine cycle, the glutathione metabolism and plasmalogen synthesis most adequately differentiated sham and Parkinsonian rats. Our results reveal that both lipid and energy metabolism are particularly involved in changes in cardiac metabolism in PD. These results provide insight into cardiac metabolic signatures in PD and indicate potential targets for further investigation.

. Background: Recent studies suggest that acquired brain injury with impaired consciousness in infancy is related to more severe and persistent effects and may have a cumulative effect on ongoing development. In this work, we aim to describe vocational outcome in a group of patients at 15 years from a severe brain lesion they suffered in developmental age. Methods: This study included a total of 147 patients aged 1.5 to 14 years with acquired brain lesion. Clinical, functional details (“Glasgow Outcome Scale – Extended”, “Functional Independent Measure”, Intelligence Quotient) were collected at the time of their first hospitalization and vocational outcome was determined after 15 years. Results: 94 patients (63.9%) presented with traumatic brain injury, while 53 patients (36.1%) presented with a brain lesion of other origin. Traumatic patients had a higher probability to be partly or fully productive than non-traumatic ones: 75.5% of traumatic subjects were working –taking into account limitations due to the traumatic event, versus 62.3% of non-traumatic ones. A relationship between some clinical variables and the vocational outcome was found. Conclusions: Rehabilitation should adequately emphasize “vocational rehabilitation” because a significant proportion of people experiencing a disorder of consciousness in childhood may show good social integration in adult age.

Background Some patients with mild cognitive impairment (MCI) experience gait disturbances. However, there are few reports on the relationship between gait disturbance and cognitive function in patients with MCI. Therefore, we investigated the neural correlates of gait characteristics related to cognitive dysfunction. Methods Eighty patients diagnosed with MCI from three dementia centres in Gangwon-do, Korea were recruited for this study. We defined MCI as a Clinical Dementia Rating global score of 0.5 or higher, with a memory domain score of 0.5 or greater. The patients were classified as having either early or late MCI based on their Mini Mental Status Examination z-scores. Multiple logistic regression analysis was performed to examine the association between the gait characteristics and cognitive impairment. Analyses included variables such as age, sex, years of education, number of comorbidities, body mass index and height. Results Gait velocity, step count, step length, heel-to-heel base support, swing and stance phase duration, and support time were associated with cognitive function. A decrease in gray matter volume in the right pericalcarine area was associated with gait characteristics related to cognitive dysfunction. An increase in the curvature of gray matter in the right entorhinal, right lateral orbitofrontal, right cuneus, and right and left pars opercularis areas was also associated with gait characteristics related to cognitive dysfunction. Conclusion Since gait impairment is an important factor in determining activities of daily living in patients with mild cognitive impairment, the evaluation of gait and cognitive functions in patients with mild cognitive impairment is important.

Abstract: Background: Restless Legs Syndrome /Willis-Ekbom disease (RLS/WED) has occasionally -but not consistently- been associated with cognitive, and most notably, language and executive impairment. The present study was conducted to investigate the cognitive trajectories of older individuals with RLS/WED. Methods: Participants were drawn from the randomly selected, older (>64 years), population-based HELIAD cohort. Individuals without dementia, with available neuropsychological evaluations at baseline and follow-up were considered for potential eligibility. A comprehensive assessment examining five principal components of cognition (memory, visuo-spatial ability, attention, executive function, and language) was administered to the partici-pants. Generalized estimating equations analysis was used to examine the unadjusted and adjusted (for critical factors and covariates) effects of RLS/WED on cognition over time. Results: A total of 1003 predominantly female, older (72.9 ±4.9 years) partici-pants, with follow-up evaluations after a mean of 3.09 ±0.85 years and without demen-tia at baseline and follow-up were included in the present study. Among them, 81 were diagnosed with RLS/WED at baseline. Global cognition, memory, attention, executive and visuo-perceptual skills did not differ between those with and without RLS/WED. However, the RLS/WED group performed worse on language at baseline by 0.249 of a standard deviation, while demonstrating a mitigated language decline over time, by 0.063 of a standard deviation. The unadjusted models yielded similar results. Conclu-sions: Our findings were indicative of a baseline language disadvantage among older individuals with RLS/WED, but the initial discrepancy tends to dissolve over time.

Acute vertigo and dizziness are frequent presenting symptoms in patients on the emergency department. With a broad differential diagnosis and symptoms/signs often subtle and transient, the diagnostic approach to the dizzy patient remains challenging. Previous work emphasized the value of combining structured history-taking and a targeted examination focusing on subtle oculomotor signs. Here I review different bedside algorithms proposed for the acutely dizzy patient. Comparing area-under-the-curve ROC-characteristics and sensitivity/specificity, highest diagnostic accuracy was observed for algorithms focusing on subtle oculomotor signs. Both the HINTS+ bedside-exam and the STANDING algorithm have demonstrated higher diagnostic accuracy for identifying strokes than early (<24-48h after symptom-onset) MRI-DWI. Importantly, HINTS and STANDING require moderate training to allow reliable application. Thus, for physicians lacking dedicated training, other approaches are needed. Various scores that rely on vascular risk-factors, clinical symptoms and focal neurologic findings have been proposed (e.g., ABCD2-score, PCI-score, TriAGe+-score). While these scores are more readily applicable for frontline providers, they provide intermediate diagnostic accuracy at best and often lack external validation, thus are an insufficient substitute for algorithms assessing subtle oculomotor findings. Providing dedicated training in HINTS+ or STANDING techniques will be key to improve the diagnostic accuracy and to avoid unnecessary brain imaging.

Charcot–Marie–Tooth disease (CMT) and associated neuropathies constitute the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments remain elusive. The extensive genetic heterogeneity of CMT, which impacts the peripheral nerves and results in a lifelong disability, presents a significant barrier to the development of comprehensive treatments. An estimated 100 loci within the human genome are linked to various forms of CMT and its related inherited neuropathies. This review delves into prospective therapeutic strategies used for the most frequently encountered CMT variants, namely CMT1A, CMT1B, CMTX1, and CMT2A. Compounds such as PXT3003, which are currently under clinical and preclinical investigation, and a broad array of therapeutic agents and their corresponding mechanisms have been discussed in this review. Furthermore, the progress in established gene therapy techniques, including gene replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, and gene knockdown, has been appraised. Each of these gene therapies has the potential for substantial advancements in future research.

Despite the high prevalence of epilepsy in individuals with autism spectrum disorder (ASD) there is little information regarding whether seizure characteristics and treatment effectiveness change across age. Using an on-line survey, seizure characteristics, effectiveness of antiepileptic treatments, comorbidities and ASD diagnosis were collected from individuals with ASD and seizures. We previously reported overall general patterns of treatment effectiveness but did not examine the effect of seizure characteristics or age on antiepileptic treatment effectiveness. Such information would improve the personalized medicine approach to the treatment of seizures in ASD. Survey data from 570 individuals with ASD and clinical seizures were analyzed. Seizure severity (seizure/week) decreased with age of onset of seizures, plateauing in adolescence, with a greater reduction in generalized tonic clonic (GTC) seizures with age. Seizure severity was worse in those with genetic disorders, neurodevelopmental regression (NDR) and poor sleep maintenance. Carbamazepine and oxcarbazepine were reported to be more effective when seizures started in later childhood while surgery and the Atkin’s/Modified Atkin’s Diet (A/MAD) were reported to be more effective when seizures started early in life. A/MAD and the ketogenic diet were reported to be more effective in those with NDR. Interestingly, atypical Landau-Kleffner syndrome was associated with mitochondrial dysfunction and NDR, suggesting a novel syndrome. These interesting findings need to be verified in independent, prospectively collected cohorts, but none-the-less these data provide some insight into novel relationships that may assist in a better understanding of epilepsy in ASD and providing insight into personalizing epilepsy care in ASD.

Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease, char-acterized by the progressive death of motor neurons, leading to paralysis and death. It is a rare disease distinguished by high patient-to-patient heterogeneity, making its study arduous and complex. Extracellular vesicles (EVs) emerged as an important player in ALS development. Thus, ALS phenotype-expressing cells can spread their abnormal bioactive cargos through the secretion of EVs, even at far distant tissues. Importantly, due to their nature and composition, EVs’ formation and cargo can be exploited for the better comprehension of this elusive disease and identification of novel biomarkers, as well as for potential therapeutic applications, such as those based on stem cell-derived exosomes. This review highlights the recent advances in the identification of the role of EVs in ALS etiopathology and how EVs can be promising new approaches for therapeutic strategies.

Mild TBI (mTBI) accounts for most TBI cases, the leading cause of morbidity and mortality worldwide. Despite their high incidence, mTBI pathophysiology remains largely unknown. Recent studies have shown that the inflammatory response is activated early after mTBI and can persist for several weeks or months. However, limited evidence on the utility of inflammatory biomarkers as predictors of clinical outcomes in mTBI was previously provided. Thus, this study aims to provide an overview of the current knowledge on the role of inflammation in the pathogenesis of mTBI and the potential of some inflammatory biomolecules as biomarkers of mTBI. Thus, it was shown that the increase of IL-6, TNF-α, and IL-1β plasma levels could be implicated in the development of the early post-concussion symptoms. On the other hand, the persistence of the increased plasmatic concentrations of IL-10 and IL-8 for as long as six months following the brain injury event could suggest chronic inflammation leading to neuroinflammation and late or persistent symptoms. In this context, our findings showed that the inflammatory biomarkers could be relevant in diagnosing or predicting recovery or long-term outcomes of mTBI.

The introduction of anti-amyloid monoclonal antibodies against Alzheimer’s disease (AD) is of high importance. However, even though treated patients show very little amyloid pathology, there is only a modest effect on the rate of cognitive decline. Although this effect possibly can increase over time, there is still a need for alternative treatments that will improve the cognitive function in patients with AD. Therefore, the purpose of this study was to characterize the triazinetrione ACD856, a novel pan-Trk positive allosteric modulator, in multiple models to address its neuroprotective and potential disease modifying effects. The pharmacological effect of ACD856 was tested in recombinant cell lines, primary cortical neurons or animals. We demonstrate that ACD856 enhanced NGF-induced neurite outgrowth, increased the levels of the pre-synaptic protein SNAP25 in PC12 cells and increased the degree of phosphorylated TrkB in SH-SY5Y cells. In primary cortical neurons, ACD856 led to increased levels of phospho-ERK1/2, showed neuroprotective effect against amyloid-beta or energy-deprivation induced neurotoxicity, and increased the levels of brain derived neurotrophic factor (BDNF). Consequently, administration of ACD856 resulted in a significant increase of BDNF in the brains of 21-months old mice. Furthermore, repeated administration of ACD856 resulted in a sustained anti-depressant effect which lasted up to seven days, suggesting effects that go beyond merely symptomatic effects. In conclusion, the results confirm ACD856 as a cognitive enhancer, but more importantly, they provide substantial in vitro and in vivo evidence of neuroprotective and long-term effects that contribute to neurotrophic support and increased neuroplasticity. Presumably, the described effects of ACD856 may improve cognition, increase resilience, and promote neurorestorative processes, thereby leading to a healthier brain in patients with AD.

The pathogenesis of transient global amnesia (TGA), a dramatic but self-limiting episode of anterograde amnesia with a variable duration of retrograde amnesia, remains unknown. Although most episodes are single, TGA has a finite recurrence rate. Studies of case series and large patient cohorts have typically been used to investigate possible precipitating and predisposing factors for TGA. Study of recurrent TGA episodes in single cases might provide another way to address pathogenetic factors. A patient with recurrent TGA is presented to illustrate such considerations with respect to possible chronobiological factors in TGA pathogenesis.

We aimed to evaluate the effect of hypoxia caused by different levels of chronic carbon monoxide (CO) exposure via total AgNOR area/total nuclear area (TAA/TNA) ratio and mean AgNOR number on rat brain tissue. Eighteen Albino Wistar adult male rats were randomly divided into three groups (control as group A, 1000ppm and 3000ppm concentration of CO gas exposed as group B and C, respectively). CO gas was chronically given as 30 min a day during seven days. Statistically significant differences were found among the groups for both mean AgNOR number (χ2=12.051, p=0.002) and TAA/TNA (χ2=12.316, p=0.002), respectively. When the two groups are compared in terms of TAA/TNA ratio, statistically significant differences were detected between control and 1000ppm (Z=-2.882, p=0.004), between control and 3000 ppm (Z=-2.882, p=0.004) for TAA/TNA ratio. Statistically significant differences were found between control and 1000 ppm (Z=-2.882, p=0.004), between control and 3000 ppm (Z=-2.887, p=0.004) for mean AgNOR number. It is important to determine new markers with high sensitivity and easy to apply in order to determine the effect of toxication in different organs and tissues (especially brain tissues) that are chronically exposed to carbon monoxide intoxication. It seems that AgNOR may be used for this purpose.

Treatment of neurological disease is hampered by the lack of validated specific and sensitive biomarkers, resulting in delayed diagnosis and nonspecific disease modifying therapies. For example, in ALS the lack of a sensitive and specific biomarker impedes the ability to administer a treatment prior to or at the onset of motor neuron dysfunction. Although viral or other infectious etiologies have been proposed as a contributing factor to neurodegeneration, it can be argued that these are casual and not causal associations. In the case of ALS, evidence for direct causality would require in vivo validation of specific nucleotide sequences of microbial origin which are known to be neuroinvasive with tropism for motor neurons, such as polio and non-polio. Several viral enteropathogens recapitulate the pathological events in sporadic ALS, including the ability to cleave TDP-43 resulting in accumulation of misfolded proteins in the cytoplasm. This review provides supporting evidence that motor neuron disease is causally related to specific enteroviruses and argues that prospective validation is imperative for effective prevention and treatment.

Advanced MRI methods and PET using radiolabeled amino acids provide valuable information in addition to conventional MR imaging for brain tumor diagnostics. These methods are particularly helpful in challenging situations such as the differentiation of malignant processes from benign lesions, the identification of non-enhancing glioma subregions, the differentiation of tumor progression from treatment-related changes, and the early assessment of response to anticancer therapy. The debate over which of the methods is preferable in which situation is ongoing and has been addressed in numerous studies. Currently, most radiology and nuclear medicine departments perform these examinations independently of each other leading to multiple examinations for the patient. The advent of hybrid PET/MRI allowed a convergence of the methods but to date simultaneous imaging has reached little relevance in clinical neuro-oncology. This is partly due to the limited availability of hybrid PET/MRI scanners, but is also due to the fact that PET is a second-line examination in brain tumors. PET is only required in equivocal situations, and spatial co-registration of PET examinations of the brain to previous MRI is possible without disadvantage. A key factor for the benefit of PET/MRI in neuro-oncology is a multimodal approach that provides decisive improvements in the diagnostics of brain tumors compared with a single modality. This systematic review focuses on studies that were able to demonstrate the additive value of amino acid PET and ‘advanced’ MRI in the diagnosis of brain tumors. Available studies suggest that the combination of amino acid PET and advanced MRI improves grading and the histomolecular characterization of newly diagnosed tumors. However, data concerning the delineation of tumor extent and biopsy guidance are of limited value. A clear additive diagnostic value of amino acid PET and advanced MRI can be achieved regarding the differentiation of tumor recurrence from treatment-related changes. Here, PET-guided evaluation of advanced MR methods seems to be helpful. In summary, there is growing evidence that a multimodal approach can achieve decisive improvements in the diagnostics of brain tumors, for which hybrid PET/MRI offers optimal conditions.

Myopathies are characterized by a diverse clinical picture affecting the skeletal muscle which includes weakness, fatigue and pain. Acquired myopathies are given importance because treatment is readily available however, some inherited myopathies can be treated as well. These myopathies can be grouped by etiology into infectious myopathies, autoimmune myopathies, granulomatous myopathies, metabolic myopathies, skeletal muscle channelopathies and Duchenne muscular dystrophy. Infectious myopathies are caused by microbiological agents. Autoimmune myopathies result from immunologic disorders causing inflammatory changes in the muscle. Granulomatous myopathy is associated with non-caseating granulomatous inflammation. Metabolic myopathies are caused by abnormal metabolic processes in the myocytes. Drug-induced myopathies are acute or subacute onset of muscle weakness after intake of a certain medications even at therapeutic doses. Critical illness myopathy stem from sepsis syndrome with failure to wean from respirator. Rhabdomyolysis is an acute myopathy, which is an urgent complex condition that involves rapid dissolution of damaged skeletal muscle. Skeletal channel myopathies are due to dysfunctions in the ion channels of the muscle. Duchenne muscular dystrophy is a genetic condition characterized by mutations in the dystrophin gene, resulting in pathologic muscle wasting. Therapies abound in myopathies as these are targeted in Infectious, Granulomatous and Autoimmune Myositides. Included in treatable myopathies are certain metabolic myopathies, rhabdomyolysis, periodic paralysis, critical illness myopathy and drug-induced myopathies. Symptomatic therapies are applied in channelopathies of muscle and dystrophinopathies can be potentially treated nowadays. Complementary rehabilitation practices are part of the management regimen.

Autistic spectrum disease (ASD) is an increasingly common diagnosis nowadays with a prevalence of 1-2% in most countries. Its complex causality – a combination of genetic, immune, metabolic and environmental factors - is translated into pleiomorphic developmental disorders of various severity, which have in common two main aspects: repetitive, restrictive behaviors, and difficulties in social interaction varying from awkward habits and verbalization to complete lack of interest from the ASD child for the outside world. The wide variety of ASD causes also makes it very difficult to find a common denominator – a disease biomarker and medication – and currently there is no commonly used diagnostic and therapeutic strategy besides clinical evaluation and psychotherapy.It is known that inflammation is present in a majority of ASD children, and blood inflammatory markers, together with metabolic, electrophysiological markers and imagistics are useful for ASD diagnostic validation and treatment; however, they tend to leave out a sizeable proportion of ASD kids who do not have such modifications. Genetic testing – whole exome sequencing or targeted profiling on about 500 ASD-linked genes- may also provide good insight into pathophysiology, however many times its results are more restrictive rather than offering additional therapeutic options.Here we describe a new biomarker for ASD - the neuron-specific enolase (NSE) - which was elevated above the normal clinical range (less than 16.3 ng/mL) in the vast majority of ASD kids tested in our study (40 of 41, or 97.5%). This finding opens up a new direction for diagnostic confirmation, dynamic evaluation and therapeutic intervention for ASD kids.

Chronic fatigue syndrome (CFS) and multiple sclerosis (MS) share similarities regarding their epidemiology, symptomatology and craniospinal physiology. Indeed, the cardinal feature of CFS, fatigue, is also a major factor in the symptomatology of the majority of MS patients. Recently, we have found that there is a significant reduction in the craniospinal compliance in MS which affects both the stiffness of the walls of the spinal canal and the walls of the cerebral venous system. This change in compliance brings about an alteration in the effectiveness of the pulse wave dampening in the craniospinal system. The result is an impedance mismatch between the cortical veins and their draining sinuses, leading to dilatation of these upstream veins. We deduce this dilatation can only be brought about by an increase in the pressure gradient between the vein lumen and the subarachnoid space (i.e. the transmural pressure gradient). We hypothesise that given the similarities between MS and CFS, a similar mechanism underlies the physiology of CFS. We present two case studies to highlight the expected findings in CFS patients if this hypothesis were proven to be correct.

Ketamine, a racemic mixture of esketamine (S-ketamine) and arketamine (R-ketamine), has re-ceived particular attention for its rapid antidepressant and antisuicidal effects. NMDA receptor inhibition has been indicated as one of the main mechanisms of action of the racemic mixture, but other pharmacological targets have also been proposed. This study aimed at exploring the possible multiple targets of ketamine enantiomers related to their antidepressant and antisuicidal effects. To this end, targets were predicted in SwissTargetPrediction software for each ketamine enan-tiomer. The targets related to depression and suicide were collected by GeneCards database. The intersections of targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Network pharmacology analysis was performed in GeneMania and Cy-toscape softwares. Molecular docking was used to predict the main targets of the network. The results indicated that esketamine and arketamine share some biological targets, particularly NMDA receptor and phosphodiesterases 3A, 7A and 5A, but have specific molecular targets. While esketamine is predicted to interact with the GABAergic system, arketamine may interact with macrophage migration inhibitory factor (MIF). Both ketamine enantiomers activate neuroplas-ticity-related signaling pathways and show addiction potential. Our results identified novel poorly explored molecular targets that may be related to the beneficial effects of esketamine and arketamine against depression and suicide.

Obstructive sleep apnea (OSA) is multi-faceted world-wide distributed disorder exerting deep effects on the sleeping brain. In the latest years strong efforts have been dedicated to find novel measures assessing the real impact and severity of the pathology, traditionally trivialized by the simplistic apnea/hypopnea index. Due to the unavoidable connection between OSA and sleep we reviewed the key aspects linking the breathing disorder with sleep pathophysiology, focuings on the role of cyclic alternating pattern (CAP). Sleep structure, reflecting the degree of apnea-induced sleep instability, may provide topical informations to stratify OSA severity and foresee some of its dangerous consequences such as excessive daytime sleepiness and cognitive deterioration.

The coronavirus disease 2019 (COVID-19) pandemic has disrupted health care worldwide. As the pandemic has been prolonged, quarantine restrictions have been lightened gradu-ally, which can influence outcomes of pediatric patients with chronic disease such as epi-lepsy by increase of susceptibility of the COVID-19 infection. The aim of this study was to determine impacts of COVID-19 pandemic on seizure control and identify potential risk factors that might worsen seizure attacks during the pandemic in children with epilepsy. We performed a retrospective chart review of 48 pediatric patients with epilepsy during the COVID-19 pandemic from January 2016 to July 2022. During the COVID-19 pandemic period, 25% of pediatric patients experienced sei-zure worsening, showing an increase in seizure frequency or duration or both. Factors associated with worsening seizures during pandemic were: diagnosis of epi-lepsy less than one year, comorbid conditions with cerebral palsy or having a tracheosto-my or a PEG, and infection with other viruses (respiratory syncytial virus, influenza virus A, influenza virus B) rather than COVID-19 infection. Our finding highlights the need to proactively monitor and regularly follow up (es-pecially short period of time) patients after they are diagnosed with epilepsy. It is also important to properly manage those who are susceptible to serious illness and keep sea-sonal viral infections under surveillance to manage exacerbated seizure in children with epilepsy. Furthermore, pediatric physicians should not overlook surveillance of seasonal respiratory viruses since quarantine restrictions are getting eased.

Despite the available literature on traumatic brain injury (TBI) biomarkers elsewhere, data are limited or non-existent in sub-Saharan Africa (SSA). The aim of the study was to analyse associations in acute TBI between admission serum biomarker concentrations and TBI severity, CT-scan findings and outcome as well as explore the influence of concurrent Toxoplasma gondii infection. Concentrations of serum biomarkers (GFAP, NFL Tau, UCH-L1, and S100B) were measured and Toxoplasma gondii detected in samples obtained <24 hours post-injury. The GOSE was used to evaluate 6 months outcome. All biomarkers levels increased with severity of TBI, but this increase was significant only for NFL (P=0.01). GFAP values significantly increased (P=0.026) in those with unfavorable outcome. Tau levels were higher in those who died (P=0.017). GFAP and NFL were sensitive to CT-scan pathology (p values respectively 0.004 and 0.002). S100B levels were higher (P<0.001) in TBI patients seropositive to Toxoplasma gondii. NFL was found to be sensitive to TBI severity while NFL and GFAP were predictive of CT intracranial abnormalities. Increased levels of GFAP and Tau were associated with poorer outcomes 6 months after TBI. S100B levels were significantly higher in T. gondii seropositive TBI patients.

It is yet unknown how the formation of aneurysm inside the human body occurs. Thus, the understanding and analysis of the Coanda effect will result in a better overview of the overall fluid mechanics that develops inside such a structure, leading not only to better treatment plans, but also to diminished postoperative risks. This paper presents how the fluid behaves in this situation, and takes into consideration how this physical phenomenon influences the hemodynamics inside numerous anatomical regions, located in the central nervous system, where aneurysms usually develop. Analyzing the three main areas in which cerebral aneurysms form the Coanda effect can potentially lead to the rupture of the aneurysm, by changing the blood flow trajectory, it should be taken into consideration when choosing a treatment plan, especially in postoperative care. In addition, there are other factors that can influence the evolution of an aneurysm such as shape, size, localization and the patient’s health condition. Understanding and analysis of the Coanda effect will result in a better overview of the overall fluid mechanics that develops inside such a structure, leading not only to better treatment plans, but also to diminished postoperative risks.

People with specific TREM2 gene variants are more prone to develop Alzheimer's disease (AD). The TREM2 receptor regulates the number of myeloid cells, phagocytosis, and the inflammatory response via interacting with apolipoproteins and amyloid. Higher TREM2 expression has been found to protect against AD. When TREM2 activity increases, the activity of genes involved in the activation of microglia cells decreases. This can improve the efficiency of phagocytosis. When TREM2 is highly expressed and the inflammasome is activated, the results are not always congruent. Therefore, this study aimed to discover how sTREM2 levels in CSF and plasma samples relate to other indices of AD pathology. We examined 98 AD plasma samples, 35 plasma samples of subjects with mild cognitive impairment (MCI), 11 healthy controls (HC) plasma samples, as well as 155 AD CSF samples, 90 MCI CSF samples, and 50 HC CSF samples. CSF sTREM2 levels were higher in the AD group than in the MCI and HC groups, in contrast to plasma sTREM2. This shows that CSF sTREM2 levels could be used to distinguish between healthy and AD patients. CSF sTREM2 levels were significantly correlated with neurofibrillary changes, cognitive decline, and inflammasome activity in AD patients. While our findings are consistent with previous research, future studies will need to include more patients and employ standardized methodological approaches to add CSF sTREM2 to the list of biomarkers for AD.

Accumulation of extra fats in the body results in disturbance in homeostasis causing obesity. The pathophysiology of obesity has been associated with various genetic, epigenetic factors and the disturbed lifestyles of an individual. One of the outcomes is disturbance in the sleep cycle which leads to sleep disorders. The evolutionary significance of sleep lies in the fact that it saves energy and is crucial for adjustment of an individual to ecological and environmental factors, and thus maintains homeostasis. Sleep has an anabolic function and replenishes the wakefulness-associated loss of glycogen stores. However, the modern lifestyle is well known to disrupt sleep behavior and patterns affecting human health negatively. Alteration in homeostasis leads to several acute and chronic pathophysiological conditions like obesity and related metabolic morbidities being one amongst them. Shorter sleep duration and poor sleep quality are important risk factors associated with the development of obesity and have more adverse effects on energy homeostasis. Consequently, it is crucial to comprehend the obesity and sleep relationship and its therapeutic strategies, given that strong crosstalk exists between energy balance that favors obesity and sleep apnea. It is therefore highly recommended to the people with a high risk of obesity to maintain sleep discipline and good sleep hygiene in our daily life. Interventions are required to improve both sleep quality and quantity, and associated obesity. More focused research is needed for uncovering the pieces of evidence that determine whether such interventions can improve obesity-related health consequences. The present review discusses the important findings on the therapeutic and neuroendocrine mechanisms regulating sleep and obesity.

Multiple sclerosis (MS) is a heterogeneous disease of the central nervous system that is governed by neural tissue loss and dystrophy during its progressive phase, with complex reactive pathological cellular changes. The immune-mediated mechanisms that promulgate the demyelinating lesions during the relapses of acute episodes are not characteristic of chronic lesions during progressive MS. This has limited our capacity to target the disease effectively as it evolves within the central nervous system white and gray matter, thereby leaving neurologists without effective options to manage individuals as they transition to a secondary progressive phase. The current review highlights the molecular and cellular sequelae that have been identified to cooperate and/or contribute to neurodegeneration that identifies individuals with progressive forms of MS. We emphasize the need for appropriate monitoring via known and novel molecular and imaging biomarkers that can accurately detect and predict progression for the purposes of newly designed clinical trials that may demonstrate efficacy of neuroprotection and potentially neurorepair. To achieve neurorepair, we focus on the modifications required in the reactive cellular and extracellular milieu, in order to enable endogenous cell growth as well as transplanted cells that can integrate and/or renew the degenerative MS plaque.

Gamma-aminobutyric acid (GABA), a non-protein-producing amino acid, is extensively found in microorganisms, plants and vertebrates, and is abundantly expressed in the spinal cord and brain. To date, GABA is considered to be the major inhibitory neurotransmitter in the central nervous system. Its physiological effects are related to the regulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of insomnia and depres-sion. Mediated through its specific receptors, it plays a pivotal role in the control of neuronal ex-citability, which can serve as anovel target for developing analgesics for pain management. This review provides an update on the accumulating evidence of specific GABA receptors and their subtypes in the involvement of pain analgesia.

Background and Objectives: Ultrasound (US) is a non-invasive tool for the in-vivo detection of peripheral nerve alterations. Materials and Methods: In this study we applied nerve US to assist the discrimination between the spectrum of Amyotrophic Lateral Sclerosis (ALS, n=11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n=5) and genetically confirmed Charcot-Marie-Tooth disease (CMT, n=5). All participants and n=15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. Nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms and nerve conduction studies. Analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (T) magnetic resonance neurography (MRN). Results: Patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. Blood flow was greatest in CIDP, and higher than in CMT, ALS and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP and CMT, even in small sample sized groups. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants along the disease groups.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca2+ dyshomeostasis play a vital role in the pathophysiology of these neurological disorders. Due to an improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. However, there is no effective protective treatment or therapy available but rather only very limited palliative treatment. Therefore, there is an urgent need for the development of preventive strategies and disease-modifying therapies to treat AD/PD. Because dysregulated Ca2+ metabolism drives oxidative damage and neuropathology in these diseases, the identification or development of compounds capable of restoring Ca2+ homeostasis and signaling may provide a neuroprotective avenue for the treatment of neurodegenerative diseases. In addition, a set of strategies to control mitochondrial Ca2+ homeostasis and signaling has been reported, including decreased Ca2+ uptake through voltage-operated Ca2+ channels (VOCCs). In this article, we review the modulatory effects of several heterocyclic compounds on Ca2+ homeostasis and trafficking, and their ability to regulate compromised mitochondrial function and associated free radical production during the onset and progression of AD or PD. This comprehensive review also describes the chemical synthesis of the heterocycles and summarizes the clinical trial outcomes.

The Neurodegenerative Diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to have an exponential growth thanks to numerous advancements in tech, shifts in the understanding of the disease as a phenomenon, and the change of perspective regarding gene editing and the upsides of this action. The aim of this paper is to analyse the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and Amyotrophic Lateral Sclerosis. We intend through this review to focus on the newest treatment, diagnosis and predictions plans regarding this large group of diseases, in order to obtain a better accuracy analysing and spotting the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide future evidence of possible novelty therapies that target the specific genes and could be useful to be taken into consideration when the classical approaches fail to shed light.

Deep-Brain Stimulation (DBS) is a a highly effective and safe medical treatment that improves the lives of patients with a wide range of neurological and psychiatric deceases, and has been consolidated as a first-line tool in the treatment of these conditionsin the last two decades. Closed Loop Deep-Brain Stimulation (CLDBS) pushes this tool further by automatically adjusting the stimulation parameters to the brain response in real time. In this context, this paper presents a Low-Noise Amplifier (LNA) and a Neurostimulator circuits fabricated in the low-power/low-voltage 65 nm CMOS process from the TSMC, which were designed targeting implantable applications. To achieve the best trade-off between input-referred noise and power consuption, metaheuristic algorithms were employed to determine and optimizes the dimentions of the LNA devices during the design phase. The measurement results showed that the LNA had a gain of 40.6 dB, a 3 dB bandwidth spanning over three decades from 10 Hz to 8.6 kHz, and a power consumption of 6.19 uW. Simulations results indicated an input-referred noise of 4.86 uVrms for the LNA. The circuit of the Neurostimulator is a programmable Howland Current-Pump, whose measurements showed its ability to generate currents with arbitrary shapes ranging from between 325 uA to +318 uA. The simulations showed a quiescent power consumption of 0.13 W with a zero neurostimulation current. The LNA and the Neurostimulator circuits are supplied with 1.2 V voltage and occupy a microdevice area of 145 um x 311 um and 88 um x 89 um, respectively, making them suitable for implantation in applications involving Closed Loop Deep-Brain Stimulation.

Accurate evaluation of patients with disorders of consciousness (DoC) is crucial for personalized treatment. However, misdiagnosis remains a serious issue. Neuroimaging methods could observe the conscious activity in patients who have no evidence of consciousness in behavior, and provide objective and quantitative indexes to assist doctors in their diagnosis. In the review, we discussed the current research based on the evaluation of consciousness rehabilitation after DoC using EEG, fMRI, PET, and fNIRS, as well as the advantages and limitations of each method. Nowadays single-modal neuroimaging can no longer meet the researchers` demand. Considering both spatial and temporal resolution, recent studies have attempted to focus on the multi-modal method which can enhance the capability of neuroimaging methods in the evaluation of DoC. As neuroimaging devices become wireless, integrated, and portable, multi-modal neuroimaging methods will drive new advancements in brain science research.

Glutamate NMDA receptor (NMDAR) hypofunction has been proposed to underlie schizophrenia symptoms because administration of NMDAR antagonists reproduces behavioral and molecular schizophrenia-like phenotypes in healthy humans and animal models. However, the role of specific NMDAR subunits in these schizophrenia-relevant characteristics is largely unknown. Mounting evidence implicates the GluN2D subunit of NMDAR in some of these symptoms and pathology. Firstly, genetic and post-mortem studies show changes in the GluN2D subunit in people with schizophrenia. Secondly, the psychosis-inducing effects of NMDAR antagonists are blunted in GluN2D-knockout mice, suggesting that the GluN2D subunit mediates NMDAR antagonist-induced psychotomimetic effects. Thirdly, in the mature brain, the GluN2D subunit is relatively enriched in parvalbumin (PV)-containing interneurons, a cell type hypothesized to underlie the cognitive symptoms of schizophrenia. Lastly, the GluN2D subunit is widely and abundantly expressed early in development which could be of importance considering schizophrenia is a disorder that has its origins in early neurodevelopment. The limitations of currently available therapies warrant further research into novel therapeutic targets such as the GluN2D subunit which may help us better understand underlying disease mechanisms and develop novel and more effective treatment options.

Demyelinating diseases alter myelin or the coating surrounding most nerve fibers in the central and peripheral nervous systems. The grouping of human central nervous system demyelinating disorders today includes Multiple Sclerosis (MS) and Neuromyelitis Optica Spectrum Disorders (NMOSD) as distinct disease categories. Each disease is caused by a complex combination of genetic and environmental variables, many involving an autoimmune response. Even though these conditions are fundamentally similar, research into genetic factors, their unique clinical manifestations, and lesion pathology has helped with differential diagnosis and disease pathogenesis knowledge. This review aims to synthesize the genetic approaches that explain the differential susceptibility between these diseases, explore the overlapping clinical features, and pathological findings, discuss existing and emerging hypotheses on the etiology of demyelination, and assess recent pathogenicity studies and their implications for human demyelination. This review presents critical information from previous studies on the disease, which asks several questions to understand the gaps in research in this field.

Background. In the last decade, it was concluded that glaucomatous optic neuropathy is part of the neurodegenerative diseases in which destructive neuronal lesions are located not only in the structure of the retina, but they are also present at the level of the central visual and nervous pathways. Patients with Primitive Open Angle Glaucoma may have experienced changes such as sensorineural hearing loss as well as balance changes. The purpose of this study is to evaluate the degree of involvement of the auditory system in patients with glaucoma, the structural changes in the optic nerve and, to establish correlation between the hearing loss and structural changes in the optic nerve. The subjects included in the study are grouped as follows: a group of patients with glaucoma that will be compared to a group of patients without glaucoma only as well as identi-fy-ing the evolution of structural changes in optic nerve to patients with glaucoma and to normal patients. Material and methods. It is a prospective, cross-sectional study on 32 eyes of 16 subjects with Primitive Open Angle Glaucoma in a study group and 24 eyes of 12 healthy subjects in con-trol group with a mean age of 62 years in both groups. Both groups underwent ophthalmo-logical, audiological and radio imaging evaluation: Pure-tone audiometry (PTA) were recorded, oph-thalmologic evaluations according to a standardized protocol and MRI cerebral examination was performed. Results: In the Study group patients, compared to the Control group, the average lev-els of the left PTA, the cup/disc (C/D) area in both eyes, the C/D ratio in both eyes are in-creased. The mean level of Retinal nerve fiber layer (RNFL) mean thickness was slightly lower in patients with glaucoma. Multivariate analysis demonstrates that gender can be a good predictor of C/D area, gender and age can be good predictors of PTA both eyes and C/D ratio in the right eye, and gender, age and background can be good predictors of disc area in the left eye. Conclu-sions: Pa-tients with Primitive Open Angle Glaucoma show changes in audiometry test in correla-tion with ophthalmological parameters demonstrating that the auditory system can be affected in Primitive Open Angle Glaucoma. This study emphasizes the problem of interdisciplinarity in medicine with the aim of ensuring the quality of life of patients with glaucoma. A good collabora-tion between ophthalmologist and otolaryngologist will be very useful for these patients.

Background: As pediatric BOLD SV is relatively novel, there is a need to provide a foundational framework that gives researchers an entry point into engaging with the topic. This begins with clarifying the definition of BOLD variability by identifying and categorizing the various metrics utilized to measure BOLD SV; Methods: A systematic review of the literature was conducted. Inclusion criteria were restricted to studies utilizing any metric of BOLD signal variability (BOLD SV) and with individuals younger than 18 in the study population. The definition of BOLD SV was any measure of intra-individual variability in the BOLD signal. Five databases were searched: Psychinfo, Healthstar, Medline, Embase, and Scopus; Results: Seventeen observational studies, including male (n =1796) and female (n =1324) pediatric participants were included. Eight studies quantified variability as the amount of deviation from average BOLD signal, 7 used complexity-based metrics, 3 used correlation measures of variability, and 1 used structure of the hemodynamic response function. Ten methods of quantifying signal variability were identified. Associations and trends in BOLD SV were commonly found with age, factors specific to mental and/or neurological disorders like attention deficit disorder, epilepsy, psychotic symptoms, and performance on psychological and behavioral tasks. Conclusions: BOLD SV is a potential biomarker of neurodevelopmental and neurological conditions and symptom severity in mental disorders for defined pediatric populations. Studies that establish clinical trends and identify the mechanisms underlying BOLD SV with a low risk of bias are needed before clinical applications can be utilized by physicians

Paired associative stimulation (PAS) is a non-invasive brain stimulation technique that modulates synaptic plasticity in the human motor cortex (M1). Since previous studies have primarily used motor evoked potentials (MEPs) as outcome measure, cortical correlates of PAS-induced plasticity remain unknown. Therefore, the aim of this observational study was to investigate cortical correlates of a standard PAS induced plasticity in the primary motor cortex by using a combined TMS-EEG approach in a cohort of eighteen healthy subjects. In addition to the expected long-lasting facilitatory modulation of MEPs amplitude, PAS intervention also induced a significant increase in transcranial magnetic stimulation evoked potentials (TEPs) P30 and P60 amplitude. No significant correlation between the magnitude of PAS-induced changes in TEP components and MEP amplitude were observed. However, the linear regression analysis revealed that the combined changes in P30 and P60 component amplitudes significantly predicted the MEP facilitation after PAS. The findings of our study offer novel insight into the neurophysiological changes associated with PAS-induced plasticity at M1 cortical level and suggest a complex relationship between TEPs and MEPs changes following PAS.

Osmotic demyelination syndrome (ODS) is an acute demyelinating disorder characterized by the loss of myelin in the center of the basis pons which is defined as central pontine myelinolysis (CPM) and demyelination process in locations outside the pons which is defined as extrapontine myelinolysis (EPM). ODS including CPM and EPM is mainly caused by the rapid correction of hyponatremia. However, there are several reports of ODS in medical condition such as malnutrition, alcoholism, liver transplantation, malignancy, sepsis, electrolyte imbalance including hypernatremia, hypokalemia, hypophosphatemia, and chronic illness. Rarely, ODS was reported in patients with hyperammonemia or hyperbilirubinemia without sodium fluctuations. The symptoms usually correspond to the lesion site and EPM precedes CPM. Because ODS may be irreversible, prevention is more important. Here, we report a case of ODS secondary to the hyperammonemia and hyperbilirubinemia, as it can have unfavorable prognosis.

: Background: Parkinson’s disease (PD) is a chronic, progressive illness with a profound impact on health-related quality of life, and it is crucial to know what factors influence quality of life throughout the course of the disease. This study aimed to evaluate PD patients’ motor and non-motor symptoms to compare symptom severity between PD clinical phenotypes and to assess the impact of disease symptoms on quality of life in a cohort of Latvian patients. Methods: We evaluated 43 patients with Parkinson’s disease. Fourteen patients had tremor-dominant (TD) PD, twenty-five patients had postural instability/gait difficulty (PIGD), and four patients had a mixed phenotype. Results: The patients’ mean age was 65.21 years, and the disease’s mean duration was 7 years. The most common non-motor symptoms were fatigue (95.3%), sleep disturbance (83.7%), daytime sleepiness (83.7%), and pain and other sensations (81.4%). PIGD patients had a higher prevalence of depressed mood, daytime sleepiness, constipation, light headedness on standing, cognitive impairment, and severe gastrointestinal and urinary disturbances (as assessed using the SCOPA-AUT domains) compared with TD patients. A high prevalence of fatigue was assessed in both disease subtypes. Health-related quality of life significantly statistically correlated with MDS-UPDRS parts III and IV (r = 0.704), the Hoehn and Yahr scale (r = 0.723), as well as the SCOPA-AUT scale’s gastrointestinal (r = 0.639), cardiovascular (r = 0.586), thermoregulatory (r = 0.566) and pupillomotor domains (r = 0.597). Conclusion: The severity of motor symptoms, as well as non-motor symptoms, such as fatigue, apathy, sleep problems and daytime sleepiness, pain, and disturbances in gastrointestinal and cardiovascular function, negatively affect PD patients’ health-related quality of life. Thermoregulatory and pupillomotor symptoms also significantly affect PD patients’ well-being.

Recent studies show that repetitive transcranial magnetic stimulation (rTMS) improves cognitive and motor functions in patients with Parkinson’s Disease (PD). Gamma rhythm low-field magnetic stimulation (LFMS) is a new non-invasive rTMS technique that generates diffused and low-intensity magnetic stimulation to deep cortical and subcortical areas. To investigate potential therapeutic effects of LFMS in PD, we subjected an experimental mouse model to LFMS (as early treatment). We examined the LFMS effect on motor functions as well as neuronal and glial activities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced male C57BL/6J mice. Mice received MPTP injection (30 mg/kg, i.p., once daily for 5 days) followed by LFMS treatment, 20 minutes each day for 7 days. LFMS treatment improved motor functions compared to the sham-treated MPTP mice. Further, LFMS significantly improved tyrosine hydroxylase (TH) and decreased glial fibrillary acidic protein (GFAP) levels, in substantia nigra pars compacta (SNpc) and non- significantly in striatal (ST) regions. LFMS treatment improved neuronal nuclei (NeuN) level in SNpc. Our findings suggest that early LFMS treatment improved the neuron survival and in turn, motor functions in MPTP intoxicated mice brain. Further investigation is required to clearly define the molecular mechanisms by which LFMS improves motor and cognitive function in PD patients.

Acute encephalopathy with biphasic seizures and reduced diffusion (AESD) is characterized by biphasic seizures following febrile viral infections and delayed reduced diffusion of the cerebral white matter on magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) (bright tree appearance, BTA). However, hypoxic encephalopathy with biphasic seizures and AESD-mimicking imaging findings has not been reported. Herein, we report an case of hypoxic encephalopathy due to suffocation with concomitant biphasic seizures and BTA, mimicking AESD. On day 1, a 5-month-old female was found face down with breathing cessation and deteriorating consciousness level. The electroencephalography (EEG) revealed periodic epileptic discharges, suggesting possible nonconvulsive status epilepticus. Despite the improvements in consciousness level and EEG abnormalities on day 2, her consciousness level deteriorated again with generalized tonic-clonic seizures on day 3, and head MRI-DWI revealed restricted diffusion predominantly in the subcortical areas, suggesting BTA. Treatment for acute encephalopathy resolved clinical sei-zures and EEG abnormalities. The persistence of abnormal EEG, reflecting abnormal excitation and accumulation of neurotoxic substances caused by hypoxia, may have contributed to the devel-opment of AESD-like findings. As hypoxic encephalopathy causes AESD-like biphasic seizures, monitoring the consciousness level, seizure occurrence, and EEG abnormalities even after acute symptoms have temporarily improved following hypoxia is essential.

Migraine is a debilitating neurovascular disorder characterized by recurrent headache attacks of moderate to severe intensity. Calcitonin gene-related peptide (GGRP), which is abundantly expressed in trigeminal ganglion (TG) neurons, plays a crucial role in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate of migraine aura, activates the trigeminovascular system. In the present study, we investigated CGRP mRNA expression in TG neurons in a CSD-based mouse migraine model. Our in situ hybridization analysis showed that CGRP mRNA expression was observed in smaller neuronal populations. CSD did not significantly change the density of CGRP mRNA-synthesizing neurons in the ipsilateral TG. However, the cell sizes of CGRP mRNA-synthesizing TG neurons were significantly larger in the 48 h and 72 h post-CSD groups than in the control group. The proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters less than 14 μm became significantly less at several time points after CSD. In contrast, we found significantly greater proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters of 14–18 μm at 24 h, 48, and 72 h post-CSD. We deduce that the CSD-induced upward cell size shift in CGRP mRNA-synthesizing TG neurons might be causative of greater disease activity and/or less responsiveness to CGRP-based therapy.

Seizure development relies on two factors. One is the existence of an overexcitable neuronal network and the other is a trigger that switches normal activity of that network into a paroxysmal state. While mechanisms of local overexcitation have been the focus of many studies, the process of triggering remains poorly understood. We suggest that, apart from the known exteroceptive sources of reflex epilepsy – visual, auditory or olfactory, there is a range of interoceptive triggers, relevant for seizure development in Temporal Lobe Epilepsy (TLE). The hypothesis proposed here aims to explain the prevalence of epileptic activity in sleep and in drowsiness states and provide a detailed mechanism of seizure triggering by interoceptive signals.

The enteric nervous system (ENS) is a neural network referred to as "the brain in the gut" because of its similarities to the central nervous system (CNS). The ENS consists of numerous types of neurons and glial cells distributed in two intramuscular plexuses that span the length of the intestine and control coordinated smooth muscle contractile activity and other intestinal functions. It is well-established that reciprocal communication exists between the brain and the gastrointestinal tract. Although the ENS can function independently, it is connected to the CNS through the afferent and efferent pathways of the parasympathetic and sympathetic nervous systems. In addition to regulating ENS function by the CNS, these connections are likely to be critically involved in the pathophysiology of Parkinson's disease (PD). PD is a common neurodegenerative disorder that presents with non-motor and motor symptoms. Surprisingly, ENS lesions have been shown to occur very early in the disease, even before CNS involvement. This has led to the postulation that the ENS may be central to the pathophysiology of PD. Autopsy studies have shown that α-synuclein (αS) aggregates in PD patients are found both in the substantia nigra (SN) and the ENS. Therefore, it has been hypothesized that the pathological process leading to PD may initially occur in the ENS years before the appearance of motor features. This process induces misfolding and aggregation of αS in specific subtypes of neurons in the CNS. Finally, it spreads retrogradely in the CNS through preganglionic vagal fibers to the dorsal motor nucleus of this nerve and to other central nervous structures. In addition to the presumed role in the spread of the disease process, it has also been suggested that pathological changes in the ENS might be involved in the gastrointestinal dysfunction frequently seen in Pd patients. Starting from the evidence in animal models and using a translational point of view, in this review, we aim to summarize the role of the ENS in the pathogenesis of PD and how this system could be modulated for a novel therapeutic approach. While acknowledging the presumed role of the microbiome in the gut-brain axis, we will shift the focus from this point of view to focus more on the neurons of the ENS.

Neuroinflammation is one disease hallmark on the road to neurodegeneration in primary tauopathies. Thus, immunomodulation might be a suitable treatment strategy to delay or even prevent the occurrence of symptoms and thus relieve the burden for patients and caregivers. In the last years, the peroxisome proliferator-activated receptor γ (PPARγ) received increasing attention as it is immediately involved in the regulation of the immune system and can be targeted by the anti-diabetic drug pioglitazone. Previous studies have shown significant immunomodulation in amyloid-β (Aβ) mouse models by pioglitazone. In this study, we performed long-term treatment over six months in P301S mice as a tauopathy model with either pioglitazone or placebo. We performed serial 18 kDa translocator protein positron-emission-tomography (TSPO-PET) imaging and terminal immunohistochemistry to assess microglial activation during treatment. Tau pathology was quantified via immunohistochemistry at the end of the study. Long-term pioglitazone treatment had no significant effect on TSPO-PET, immunohistochemistry read-outs of microglial activation, or tau pathology levels in P301S mice. Thus, we conclude that pioglitazone modifies the time course of Aβ-dependent microglial activation, but does not significantly modulate microglial activation in response to tau pathology.

It has been proposed that upregulation of the noradrenergic (NA) system through exposure to novelty might be one of the key components for building cognitive reserve and resilience to neurodegeneration. A personality trait that promotes greater interest in novel experiences is Openness to Experience (OE). Individuals who are high in OE exhibit strong curiosity towards novelty and are more likely to be exposed to novel stimuli throughout the lifespan.Performing voxel-based morphometry analyses, we examined whether OE in 135 healthy young adults was associated with Locus Coeruleus (LC) - the main core of the noradrenergic system. We also investigated whether LC mediates the relationship between OE and a key measure of reserve, I.Q. In comparison with other neuromodulators’ seeds (Dorsal and Median Raphe [DR-MR] -5-HT, Ventral Tegmental Area [VTA] -DA- and Nucleus Basalis of Meynert [NBM] -Ach-), results show that greater LC integrity was related to greater OE and IQ. Additionally, mediation analyses revealed that only LC mediated the relationship between OE and IQ. Furthermore, a Bayesian multiple regression was conducted to model the contribution of both isolated and combined neuromodulator seeds to OE trait express. This approach found that the LC + VTA could account for more variance in OE expression compared to the LC alone. Other weaker but significant associations were observed between DR and OE, between LC + NBM and Conscientiousness and between DR + NBM and Extraversion. These results are together suggestive that OE is primarily underpinned by monoaminergic functioning, and that the LC-NA system plays a central role mediating the interdependence between OE expression and cognition (IQ level). While offering further understanding of the neurobiology of human personality, these findings indicate a pivotal role of LC-NA system integrity in novelty seeking in daily life. This provides a psychobiological account for how OE expression may be beneficial for maintaining the noradrenergic system to facilitate cognitive reserve and resilience to neurodegenerative conditions.

Subarachnoid hemorrhage (SAH) is most commonly seen in patients over 55 years of age and often results in a loss of many productive years. SAH has a high mortality rate, and sur-vivors often suffer from early and secondary brain injuries. Understanding the pathophysiology of the SAH is crucial to identifying potential therapeutic agents. One promising target for diagno-sis and prognosis of SAH is circulating microRNAs, which regulate gene expression and are in-volved in various physiological and pathological processes. In this review, we discuss the poten-tial of microRNAs as a target for diagnosis, treatment, and prognosis in SAH.

Background: Air-pouch balloon-assisted probes have proven to be both simple and reliable tools for intracranial pressure (ICP) monitoring. However, we experienced reproducible falsely high ICP measurement when the ICP probe was inserted in the intracerebral hematoma cavity. Thus, the aim of the experimental and translational study was to analyze the influence of ICP probe placement with regard to measured ICP values. Methods: Two Spiegelberg 3PN-sensors were simultaneously inserted into a closed drain system and were connected to two separate ICP monitors thereby allowing for simultaneous ICP measurements. This closed system was also engineered to allow for pressure to be gradually increased in a controlled fashion. Once the pressure was verified using two identical ICP probes, one of the probes was coated with blood in an effort to replicate placement within an intraparenchymal hematoma. Pressures recorded using the coated probe and control probe were then recorded and compared across a range of 0-60 mmHg. In an effort to further the translational relevance of our results two ICP probes were inserted in a patient that presented with a large basal ganglia hemorrhage that met criteria for ICP monitoring. One probe was inserted into the hematoma and the other into brain parenchyma; ICP values were recorded from both probes and the results compared. Results: The experimental set-up demonstrated a reliable correlation between both control ICP probes. Interestingly, the ICP probe covered with clot displayed a significantly higher average ICP value when compared to the control probe between 0mmHg and 50mmHg (p<0.001); at 60mmHg there was no significant difference noted. Critically, this trend in discordance was even more pronounced in the clinical setting with the ICP probe placed within the hematoma cavity having reported significantly higher ICP values as compared to the probe within brain parenchyma. Conclusion: Our experimental study and clinical pilot highlight a potential pitfall in ICP measurement that may result secondary to probe placement within hematoma. Such aberrant results may lead to inappropriate interventions in an effort to falsely addresses falsely elevated ICPs.

Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin’s amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid beta peptide (Aβ) in driving Alzheimer’s disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of APP is likely the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5’ iron responsive element (IRE). Similar arguments support that the pathological effects of familial Alzheimer’s disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in APP cleavage to produce different ratios of Aβ length. Rather, these mutations likely affect the stability of presenilin holoprotein and/or γ-secretase multimers with consequences for γ-secretase activity and other important cellular functions. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of “pseudo-hypoxia” being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern (DAMP) enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease. We also discuss fascinating, but largely ignored, data on presenilin biology that may be important in understanding presenilins’ central role in familial Alzheimer’s disease.

The present study examined mechanisms underlying memory deficits in patients with Parkinson disease (PD)and their associations with structural metrics. Nineteen PD and 22 matched controls underwent two memory experiments. In experiment 1 (delayed memory task), subjects were asked to remember an array of colored rectangles with varying memory set sizes [Low-Load (2 items), Low-Load with Distractor, &amp; High-Load (5 items)]. After a 7s delay period, they reported whether the orientation of any relevant figures had changed (test period). In experiment 2 (working memory task), memory arrays were presented in varying set sizes (2 to 6 items) with no distractors that were followed by a 2s delay period and subsequent test period. Brain MRI data were acquired to assess structural differences (volumes and cortical thickness) in brain areas related to attention, working memory storage, and episodic memory. Compared to controls, PD patients had lower memory capacity scores in all memory load conditions for experiment 1 (p &lt;0.021) whereas there were no group differences in any memory load conditions for experiment 2 (p&gt;0.06). In addition, PD patients had lower thickness in the left superior temporal gyrus (p=0.02). Lower thickness values in the left superior temporal gyrus were significant predictors of lower delayed memory performance in Low-Load and Low-Load with Distractor conditions (ps’&lt;0.044) and working memory performance of memory load conditions of 4 and 5 items (p’s&lt;0.012). The present findings suggest that PD patients may have intact working memory storage capacity but impaired attentional filtering and memory consolidation that may lead to lower delayed memory scores. Lower delayed memory in PD may partly be associated with lower cortical thickness in the left superior temporal gyrus.

Migraine is a neurovascular disorder that affects approximately 12% of the global population. While its exact causes are still being studied, researchers believe that nociceptors in the trigeminal ganglia play a key role in the pain signals of migraine. These nociceptors innervate the intracranial meninges and convey pain signals from the meninges to the thalamus. Targeting these nociceptors is considered promising due to their accessibility and distinct molecular profile, which includes the expression of several transient receptor potential (TRP) channels. These channels have been linked to various pain conditions, including migraine. This review discusses the role and mechanisms of nociceptors in migraine, the challenges of current antimigraine drugs, and the evidence for well-studied and emerging TRP channels, particularly TRPC4, as novel targets for migraine prevention and treatment.

Background: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder that has no curative treatment. Diagnosis is based on a set of criteria established by Gilman (1998 and 2008) and recently updated by Wenning (2022). We aim to determine the effectiveness of [123I]Ioflupane SPECT in MSA, especially at the initial clinical suspicion. Methods: Cross-sectional study of patients at initial clinical suspicion of MSA, referred for [123I]Ioflupane SPECT. Results: 139 patients (68 men, 71 women) were included, 104 being MSA-probable and 35 MSA-possible. MRI was normal in 89.2% while SPECT was positive in 78.45%. SPECT showed high sensitivity (82.46%) and positive predictive value (86.24), reaching maximum sensitivity in MSA-P (97.26%). Significant differences were found when relating both SPECT assessments in the healthy-sick and inconclusive-sick groups. We also found an association when relating SPECT to the subtype (MSA-C or MSA-P), as well as to the presence of parkinsonian symptoms. Lateralization of striatal involvement was detected (left side). Conclusions: [123I]Ioflupane SPECT is a useful and reliable tool for diagnosing MSA, with good effectiveness and accuracy. Qualitative assessment shows a clear superiority when distinguishing between the healthy-sick categories, as well as between the parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes at initial clinical suspicion.

Ageing is the strongest known risk factor for many of the neurodegenerative diseases causing cognitive decline and dementia. Identification of cognitive impairment may be a prelude to appropriate treatment, hopefully disease-modifying. Use of cognitive screening instruments may be an equitable way to identify cognitive impairment. This study examined the use of two such instruments, Free-Cog and Mini-Addenbrooke’s Cognitive Examination (MACE), in patient cohorts referred to a dedicated cognitive disorders clinic based at a tertiary neurosciences centre. Results showed that: (1) specificity and positive predictive value increased with patient age for both tests with some loss of sensitivity and negative predictive value. (2) In the oldest age groups (≥75 and ≥70 years respectively) where specificity was at maximum, a positive test result (i.e. below the specified test cut-off) rules in the diagnosis of cognitive impairment. (3) Values of an “Efficiency Index” for each test indicated qualitatively a moderate change in the probability of correct diagnosis and quantitatively an approximately 15-25% increase in the probability of correct diagnosis. These findings show that both Free-Cog and MACE may be used with confidence for the identification of cognitive impairment and dementia in older patient cohorts. These findings may have implications for public health policies directed to case-finding in clinical practice as opposed to population-based screening.

Introduction: Unlike cigarette smoking, secondhand smoke (SHS) has not been as well described as an environmental risk for Multiple sclerosis (MS) nor as a risk factor for disease progression. We systematically reviewed the association between SHS and the risk of onset and/or progression of MS.Methods: We systematically screened MEDLINE/PUBMED, Science Direct, LILACs, and SCIELO searching for publications between January 1st , 2010, and July 5, 2021 with the following keywords: “multiple sclerosis and smoking”; “multiple sclerosis and passive smoking”; “multiple sclerosis and secondhand smoking”. An 11-year filter was applied from 2010 to 2021. Results: Fifteen articles were included in this review, which consisted of systematic reviews with meta-analysis (N = 2), systematic reviews (N = 2), and observational studies (N = 11). Both meta-analyses reported an impact of SHS on MS onset among secondhand smokers. One of the systematic reviews selected two observational studies showing the association between SHS and MS development, and one study that did not find a significant association between SHS and the risk of MS development. The other systematic review identified selected eight articles showing a relationship between SHS and MS. Seven observational studies reported higher odds of MS onset when associated with SHS. Four observational studies did not show a relationship between SHS and MS onset or progression.Discussion: Most articles showed a positive association between SHS exposure and the risk of developing MS. On the other hand, an association between SHS and a higher risk for MS progression could not be established.

With the growing hope that disease-modifying treatments could target the molecular basis of neurodegenerative diseases even before the onset of symptoms, there is mounting pressure to define disease entities based on pathophysiology rather than on clinical syndromes. The Alzheimer’s disease research community has recently transitioned from diagnostic criteria based on an amnestic syndrome to a purely biomarker-based disease definition, relying on the demonstration of amyloid-beta pathology, tau pathology, and neurodegeneration. In contrast, current diagnostic criteria for Parkinson’s disease still rely on the presence of the well-described clinical syndrome of parkinsonism, with the addition of characteristic motor- and non-motor signs and symptoms. However, there is now unequivocal evidence that Parkinson’s disease starts years before the onset of parkinsonism. Furthermore, neuropathologically defined Lewy body disease is clinically heterogeneous, combining a range of motor, non-motor, dopaminergic and non-dopaminergic features. Finally, clinically defined Parkinson’s disease has diverse underlying etiologies most, but not all, associated with α-synuclein positive Lewy pathology. In light of recent scientific advances, we propose a biologically based definition for the diagnosis of Parkinson's disease, initially to be used for research purposes. The criteria use a three-component ‘G-S-N’ system. The first is documentation of defined gene variants (‘G’), which cause or strongly predispose to PD as the most upstream component. The second is α-synuclein pathology (‘S’), currently defined as pathological α-synuclein deposition in tissue or positive α-synuclein seeding assays. The third is evidence of underlying neurodegeneration (‘N’), currently defined by specific neuroimaging procedures. The associated clinical syndrome (‘C’) is defined by a single high-specificity feature or multiple lower-specificity features. Initiating this transition will enable the field to fuel both basic and clinical research and move closer to the precision medicine required to develop clinically meaningful disease-modifying therapies. We acknowledge current limitations, ethical implications, and the need for prospective validation of this approach.

Small, Ubiquitin-like Modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes including the mammalian stress response. Of particular interest is its neuroprotective effects, first recognized in the 13-lined ground squirrel (Ictidomys tridecemlineatus), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and preconditioning of neural stem cells, make it a promising therapeutic target for acute cerebral ischemia. Recent advances in high-throughput screening have enabled the identification of small molecules that can upregulate SUMOylation, some of which have been validated in pertinent preclinical models of cerebral ischemia. Accordingly, the present review aims to summarize current knowledge and highlight the translational potential of the SUMOylation pathway in brain ischemia.

Many metrics exist for the evaluation of binary classifiers, all with their particular advantages and shortcomings. Recently an “Efficiency Index” for the evaluation of classifiers has been proposed, based on the consistency, or matching, and contradiction, or mismatching, of outcomes. This metric and its confidence intervals are easy to calculate from base data in a 2x2 contingency table, and values can be qualitatively and semi-quantitatively categorised. For medical tests, in which context the Efficiency Index was originally proposed, it facilitates communication of risk (of correct diagnosis versus misdiagnosis) to both clinicians and patients. Variants of the efficiency index (balanced, unbiased) which take into account disease prevalence and test cut-offs have also been described. The objectives of the current paper were firstly to extend the EI construct to other formulations (balanced level, quality) and secondly to explore the utility of EI and all four of its variants when applied to the dataset of a large prospective test accuracy study of a cognitive screening instrument. This showed that the balanced level, quality, and unbiased formulations of EI are more stringent measures.

Despite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of Mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders, even though the neurological symptoms are currently incurable, even in the cases where a dis-ease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every pa-tient-derived cell holds potential to recapitulate relevant disease features. For the neurodegenerative forms of these diseases in particular, it is challenging to grow neuronal cultures that accurately represent them because of the obvious inability to access live neurons. This scenario changed sig-nificantly since Yamanaka et al. published their protocol for induction of pluripotent stem cells (SC) from adult human fibroblasts. From then on, a series of differentiation protocols to generate neurons from induced pluripotent stem cells (iPSC) was developed and extensively used for disease mod-eling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPS and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analysis. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also comment on a tempting alternative to establish MPS pa-tient-derived neuronal cells in a much more expedite way by taking advantage of the existence of a population of multipotent SC in human dental pulp, to establish mixed neuronal and glial cultures.

Regional heterogeneity of microglia was first described a century ago by Pio del Rio Hortega. Currently, new hints on microglia heterogeneity across central nervous system (CNS) regions are still being unraveled by high-throughput techniques. It remains unclear whether these spatial specificities translate into different microglial behaviors in vitro. We cultured microglia isolated from the cortex and spinal cord and analyzed the effect of the CNS spatial source on in vitro behavior by applying the same experimental protocol and culture conditions. We analyzed microglial cell numbers, function, and morphology and found a distinctive in vitro phenotype. We found that microglia were present in higher numbers in spinal cord-derived glial cultures, presenting different expression of inflammatory genes and a lower phagocytosis rate under basal conditions or after activation with LPS and IFN-. Morphologically, cortical microglial cells are more complex and present longer ramifications, which were also observed in vivo in CX3CR1+/GFP transgenic reporter mice. Collectively, our data demonstrated that microglial behavior in vitro is defined according to specific spatial characteristics acquired in the tissue. Thus, our study highlights the importance of microglia as a source of CNS for in vitro studies.

The Neurovascular Unit (NVU), comprised of glia (astrocytes, oligodendrocytes, microglia), neurons, pericytes and endothelial cells, is a dynamic interface ensuring physiological functioning of the central nervous system (CNS), that gets affected and contributes to the pathology of several neurodegenerative diseases. Neuroinflammation is a common feature of neurodegenerative diseases and is primarily related to the activation state of perivascular microglia and astrocytes, which constitute two of its major cellular components. Our studies focus on monitoring in real time the morphological changes of perivascular astrocytes and microglia, as well as their dynamic interactions with the brain vasculature, under physiological conditions and following systemic neuroinflammation triggering both microgliosis and astrogliosis. To this end, we performed 2-photon laser scanning microscopy (2P-LSM) for intravital imaging of the cortex of transgenic mice visualizing the dynamics of microglia and astroglia following neuroinflammation induced by systemic administration of the endotoxin lipopolysaccharide (LPS). Our results indicate that following neuroinflammation the end-feet of activated perivascular astrocytes lose their close proximity and physiological crosstalk with vasculature, an event that most possibly contributes to a loss of blood-brain-barrier (BBB) integrity. At the same time, microglial cells get activated with more frequent contacts of the blood vessels. These dynamic responses of perivascular astrocytes and microglial are peaking at 4 days following LPS administration, however they still persist at a lower level 8 days after LPS, revealing incomplete reversal of inflammation affecting the glial properties and interactions with the NVU.

Much evidence suggests a correlation between degeneration and mitochondrial impairment. Typical cases of degeneration can also be observed in physiological phenomena (aging) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have as a common denominator the dyshomeostasis of mitochondrial bioenergy. Even neurodegenerative diseases show a bioenergetics imbalance in their pathogenesis or progression. Huntington's chorea and Parkinson's disease are both neurodegenerative diseases, but while Huntington's disease is a genetic, and progressive disease with early manifestation and severe penetrance, Parkinson's disease is a pathology with a multifactorial aspect. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early onset diseases linked to gene mutation, others can appear in young adults and senescent only post-injury, and a final group is idiopathic. Huntington's was defined as a hyperkinetic disorder, while Parkinson's is a hypokinetic disorder; but in the middle, there are a lot of similarities as well as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In the review, we would embrace the theories that both diseases start and develop in light of mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas.

This case report examined the characteristics of body composition, sleep quality, and autonomic nerve activity in active older adults with a younger body age—calculated from age trends in body composition and basal metabolic rate. We selected two cases who had a metabolic age younger than their actual age. They had good sleep quality, low sleep quality scores, no sarco-penia, strong muscle and grip strength, and balanced autonomic nervous system activity. Fur-thermore, they were determined to be much younger than their actual age. They were compared with two other age- and sex-matched cases, who had poor sleep quality, unbalanced autonomic nervous system activity, and had a physical age closer to their actual age. Older adults with more muscle mass and higher basal metabolism were younger than their actual age, had a better sleep status, and a good balance of autonomic nervous activity in the exercise stimulation. They also had lower percentages of body- and visceral fat and higher body water. Meanwhile, the older adults with standard muscle mass and basal metabolic rate had a poor sleep status and no sympathetic hyperactivity in the exercise simulation.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Despite extensive research efforts, the majority of trialed monotherapies to date have failed to demonstrate significant benefit. It has been suggested that this is due to the complex pathophysiology of TBI, which may possibly be addressed by a combination of therapeutic interventions. In this article, we have reviewed combinations of different pharmacologic treatments, combinations of non-pharmacologic interventions, and combined pharmacologic and non-pharmacologic interventions for TBI. Both preclinical and clinical studies have been included. While promising results have been found in animal models, clinical trials of combination therapies have not yet shown clear benefit. This may possibly be due to their application without consideration of the evolving pathophysiology of TBI. Improvements of this paradigm may come from novel interventions guided by multimodal neuromonitoring and multimodal imaging techniques, as well as the application of multi-targeted non-pharmacologic and endogenous therapies. There also needs to be a greater representation of female subjects in preclinical and clinical studies.

Background: Demonstrate a theoretical and empirical justification for including potentially protective factors in Sporadic Creutzfeldt-Jakob case-controlled studies alongside the almost exclusively studied risk-enhancing factors. Methods: Synthesize existing sCJD and Alzheimer's disease (AD) research to suggest the plausibility of shared neuroprotective factors. A fixed effects longitudinal analysis of 26 countries across 10 time periods examines whether factors identified to protect against AD are associated with population-level sCJD incidence rates. Results: Increased consumption of beans and nuts, both of which are thought to protect against AD risk, is associated with lower population level sCJD incidence. Conclusion: This study suggests that factors that protect against other neurodegenerative diseases might offer protection from sCJD. The low marginal burden of including protective factors in sCJD questionnaires offers a chance to better understand sCJD at little additional cost.

Objective: To investigate the feasibility and preliminary effects of a 12-week home-based moderate intensity cycling programme in stroke survivors. Design: Single-blinded, parallel group, Randomised Controlled Trial Setting: Home-based Participants: Participants will be survivors of first-ever stroke and randomly assigned to an Active Cycling Group (ACG) or control group. Intervention: The ACG performed a 12-week home-based cycling programme, three sessions per week. Work intervals were executed at 75% of the maximal heart rate (HR_max), recovery intervals at 50% of HR_max. Work interval duration increased from three ten-minute intervals to 30 minutes continuous cycling. The control group completed a 12-week neurocognitive exercise programme. Main outcome measurements: Primary outcome measures are compliance with training, adherence to protocol and safety as measured by adverse events. Secondary outcome measurements included a: simplified modified Rankin Scale questionnaire (stroke severity), Six-Minute Walking Test (walking ability), Ten-meter Walk Test (walking ability), Rivermead Mobility Index (walking ability), graded submaximal cycling test (exercise capacity), Physical Activity for Individuals with Physical Disability questionnaire (physical activity), EQ-5D-5L (quality of life), Stroke Specific Quality of Life questionnaire (quality of life), Montreal Cognitive Assessment (cognition), General Self-Efficacy Scale (self-efficacy), and Exercise Self-Regulation Questionnaire (self-regulation).