Complex Neurological Disorder Research Articles

Preterm birth and risk of hospitalisation for complex chronic conditions during childhood and adolescence.

To examine the relationship between preterm birth and hospitalisation for paediatric complex chronic conditions. We conducted a cohort study of 1 269 745 children born between 2006 and 2022 in Quebec, Canada. We classified preterm birth as extreme (<28 weeks), very (28-31 weeks), and moderate (32-36 weeks). The outcome was hospitalisation for complex chronic conditions, including neurologic, neuromuscular, cardiovascular, respiratory, renal, gastrointestinal, haematologic, immunologic, endocrine, and neoplastic disorders up to 16 years of age. We computed adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between preterm birth and complex chronic conditions during 9 948 734 person-years of follow-up. Hospitalisation rates for complex chronic conditions were higher for children born preterm than at term (6.88 vs. 2.24 per 1000 person-years). Preterm birth was associated with all complex chronic conditions, especially respiratory (HR 4.64, 95% CI 4.01-5.37), cardiovascular (HR 3.68, 95% CI 3.47-3.90), and neurologic disorders (HR 3.48, 95% CI 3.21-3.77). Associations were present at all ages and for all degrees of prematurity, but were strongest with extreme prematurity. Preterm birth increases the risk of hospitalisation for complex chronic conditions up to age 16 years. Preterm children may benefit from enhanced care throughout childhood and adolescence.

Multi-omics Mendelian randomization integrating GWAS, eQTL and pQTL data revealed GSTM4 as a potential drug target for migraine

IntroductionMigraine, as a complex neurological disease, brings heavy burden to patients and society. Despite the availability of established therapies, existing medications have limited efficacy. Thus, we aimed to find the drug targets that improve the prognosis of migraine.MethodWe used Mendelian Randomization (MR) and Summary-data-based MR (SMR) analyses to study possible drug targets of migraine by summary statistics from FinnGen cohorts (nCase = 44,616, nControl = 367,565), with further replication in UK Biobank (nCase = 26,052, nControl = 487,214). Genetic instruments were obtained from eQTLGen and UKB-PPP to verify the drug targets at the gene expression and protein levels. The additional analyses including Bayesian co-localization, the heterogeneity in dependent instruments(HEIDI), Linkage Disequilibrium Score(LDSC), bidirectional MR, multivariate MR(MVMR), heterogeneity test, horizontal pleiotropy test, and Steiger filtering were implemented to consolidate the findings further. Lastly, drug prediction analysis and phenome-wide association study(PheWAS) were employed to imply the possibility of drug targets for future clinical applications.ResultThe MR analysis of eQTL data showed that four drug targets (PROCR, GSTM4, SLC4A1, and TNFRSF10A) were significantly associated with migraine risk in both the FinnGen and UK Biobank cohorts. However, only GSTM4 exhibited consistent effect directions across the two outcomes(Discovery cohort: OR(95%CI) = 0.94(0.93–0.96); p = 2.70e − 10; Replication cohort: OR(95%CI) = 0.93(0.91–0.94); p = 4.21e − 17). Furthermore, GSTM4 passed the SMR at p < 0.05 and HEIDI test at p > 0.05 at both the gene expression and protein levels. The protein-level MR analysis revealed a strong correlation between genetically predicted GSTM4 with a lower incidence of migraine and its subtypes(Overall migraine: OR(95%CI) = 0.91(0.87–0.95); p = 6.98e-05; Migraine with aura(MA): OR(95%CI) = 0.90(0.85–0.96); p = 2.54e-03; Migraine without aura(MO): OR(95%CI) = 0.90(0.83–0.96); p = 2.87e-03), indicating a strong co-localization relationship (PPH4 = 0.86). Further analyses provided additional validation for the possibility of GSTM4 as a migraine treatment target.ConclusionThis study identifies GSTM4 as a potential druggable gene and promising therapeutic target for migraine.

Comparison of patients with chronic and episodic migraine with healthy individuals by brain volume and cognitive functions

Objectives: Migraine is a complex neurological disease. In addition to headache, individuals with migraine may develop structural changes inside the brain and cognitive impairment. There is increased evidence associated with impairments in brain volume and cognitive functions in patients with migraine. The present study aimed to investigate the impairment in memory function in individuals with migraine using brain magnetic resonance imaging, volume measurement, and neuropsychological tests. Methods: The study included 20 patients with episodic migraine, 20 patients with chronic migraine, and 20 healthy controls. Subcortical volumes of all participants were measured by FreeSurfer, an automatic segmentation method. The Wechsler Memory Scale-Revised Form (WMS-R), Stroop test, Raven’s Standard Progressive Matrices, Verbal Fluency Test, and Lines Orientation Test were applied in all the study participants. Results: Putamen volume decreased as migraine duration increased, and subcortical gray matter, left cerebellar cortex, and bilateral thalamus volumes were lower in the chronic and episodic group compared to the control group, bilateral putamen and right cerebellar cortex volumes were lower in patients with chronic migraine compared to patients in episodic migraine and control groups. Upon neuropsychological examination, delayed memory was affected as the duration of migraine increased, and there was impairment in patients with chronic migraine upon fluency tests and mental control tests. Conclusions: Changes in subcortical volume and cognitive effects in patients with migraine raise questions about whether migraine qualifies as a benign disease. Structural changes and cognitive impairment may contribute to migraine-associated disability, and therefore, these causalities should be investigated by future studies. Silent infarcts, white matter damage, and cortical spreading depression, which occur in migraine cases, may be associated with subcortical volume changes and thus, cognitive effects. In the context, studies with larger samples to achieve a better understanding are needed.

Alzheimer's Disease and Epilepsy: Exploring Shared Pathways and Promising Biomarkers for Future Treatments.

Background: Alzheimer's disease (AD) and epilepsy represent two complex neurological disorders with distinct clinical manifestations, yet recent research has highlighted their intricate interplay. This review examines the association between AD and epilepsy, with particular emphasis on late-onset epilepsy of unknown etiology, increasingly acknowledged as a prodrome of AD. It delves into epidemiology, pathogenic mechanisms, clinical features, diagnostic characteristics, treatment strategies, and emerging biomarkers to provide a comprehensive understanding of this relationship. Methods: A comprehensive literature search was conducted, identifying 128 relevant articles published between 2018 and 2024. Results: Findings underscore a bidirectional relationship between AD and epilepsy, indicating shared pathogenic pathways that extend beyond traditional amyloid-beta and Tau protein pathology. These pathways encompass neuroinflammation, synaptic dysfunction, structural and network alterations, as well as molecular mechanisms. Notably, epileptic activity in AD patients may exacerbate cognitive decline, necessitating prompt detection and treatment. Novel biomarkers, such as subclinical epileptiform activity detected via advanced electroencephalographic techniques, offer promise for early diagnosis and targeted interventions. Furthermore, emerging therapeutic approaches targeting shared pathogenic mechanisms hold potential for disease modification in both AD and epilepsy. Conclusions: This review highlights the importance of understanding the relationship between AD and epilepsy, providing insights into future research directions. Clinical data and diagnostic methods are also reviewed, enabling clinicians to implement more effective treatment strategies.

Advances in pharmacogenomics: optimizing antiepileptic drug therapy for drug-resistant epilepsy

Epilepsy, a complex neurological disorder, is influenced by intricate interactions within cortical, hippocampal, or thalamocortical neuronal networks, presenting a genetically complex condition with non-Mendelian inheritance patterns. This complexity is underscored by the involvement of numerous “susceptibilities” or “modifier” genes, complicating the assessment of risk and therapy outcomes. A critical inquiry in epilepsy treatment involves understanding how genetic diversity impacts treatment strategies and efficacy. Pharmacogenomic advancements have elaborated the connection between genetic variants and antiseizure medication (ASM) safety and response, marking a shift towards precision medicine in epilepsy care. Notably, genetic screening for variants such as HLA-B*1502 and HLA-A*3101 has demonstrated significant efficacy in preventing severe hypersensitivity reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), particularly among specific ethnic populations. However, putting pharmacogenomic discoveries into clinical practice faces numerous challenges, including educational, legal, and economic barriers, emphasizing the need for broader acceptance and integration of pharmacogenomic data. This review synthesizes recent studies on pharmacogenomics in epilepsy, highlighting the current advances and prospects for personalizing epilepsy treatment through genetic insights, aiming to enhance ASM safety, reduce adverse effects, and improve treatment outcomes. Through a comprehensive examination of the genetic basis of epilepsy and its influence on pharmacotherapy, this review endeavors to contribute to the evolving landscape of precision medicine in epilepsy care, advocating for a more individualized and effective treatment approach.

In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model.

Alzheimer's disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer's disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid β aggregation. Three potent compounds, i.e., VN-3, VN-14, and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC50 values of 80 nM, 2.52 μM, and 140 nM against the AChE enzyme, respectively, and IC50 values of 2.07 μM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aβ1-42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 μM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 μM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aβ1-42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3, VN-14, and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.

Multiple Sclerosis Polygenic Risk Is Not Enriched in Three Multicase Families in Comparison to Population-Based Cases

Multiple sclerosis (MS) is a complex neurological and autoimmune disease with an established genetic component. Families with multiple cases of MS are rare but do occur. We hypothesised that multicase families may have a heightened polygenic risk for MS. In this work, we have determined whether polygenic risk for MS is enriched in multicase families in comparison to a case-control cohort. Using the findings from the largest MS genome-wide association study, we calculated a weighted polygenic risk score (wPRS) for MS. We applied this wPRS to study a population-based MS case-control cohort (3,252 people with MS and 5,725 controls) and three multicase MS families (9 individuals with MS, 10 unaffected family members). For both the population-based cohort and the three families, 167 of the 233 known genome-wide significant MS-associated variants were identified and used to calculate the wPRS. Within the population-based cohort, the wPRS was significantly higher in MS cases than controls (P=2.2×10−16). The wPRS of familial MS cases was not significantly different to population-based MS cases (P&gt;0.05). Both affected and unaffected MS family members had higher wPRS than population controls. MS families have a higher polygenic risk for MS, but this did not differ to the polygenic risk of population-based MS cases. Only one family carried the established HLA-DRB1 15:01 MS risk allele, which was present in both affected and unaffected family members. Across families, unaffected family members had an elevated polygenic risk in comparison to population controls indicating that a higher polygenic risk does not fully explain the clustering of MS in families.

Aberrant CHCHD2-associatedmitochondriopathy in Kii ALS/PDC astrocytes.

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as asignificantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

Aberrant individual structure covariance network in patients with mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (mTLE) is a complex neurological disorder that has been recognized as a widespread global network disorder. The group-level structural covariance network (SCN) could reveal the structural connectivity disruption of the mTLE but could not reflect the heterogeneity at the individual level. This study adopted a recently proposed individual structural covariance network (IDSCN) method to clarify the alternated structural covariance connection mode in mTLE and to associate IDSCN features with the clinical manifestations and regional brain atrophy. We found significant IDSCN abnormalities in the ipsilesional hippocampus, ipsilesional precentral gyrus, bilateral caudate, and putamen in mTLE patients than in healthy controls. Moreover, the IDSCNs of these areas were positively correlated with the gray matter atrophy rate. Finally, we identified several connectivities with weak associations with disease duration, frequency, and surgery outcome. Our research highlights the role of hippo-thalamic-basal-cortical circuits in the pathophysiologic process of disrupted whole-brain morphological covariance networks in mTLE, and builds a bridge between brain-wide covariance network changes and regional brain atrophy.

Dravet Syndrome from Dental View: A Case Report

Dravet Syndrome is a complex neurological disorder characterized by developmental delays and seizures caused by Gingival hyperplasia (gingival enlargement and frequent bleeding) in a paediatric, four-year-old girl for several years. This condition, often exacerbated secondary to medications used to manage DS, contributed to the development of severe dental caries—the girl with severe dental caries and gingival hyperplasia presented to the clinic. A collaborative approach involving pediatric dentistry, neuro-paediatrics, general medicine, and anaesthesia was employed to extract affected primary teeth—this multidisciplinary effort streamlined management and treatment, leading to successful outcomes. Postoperatively, the patient showed satisfactory recovery and underwent regular follow-ups. Regular follow-up appointments conducted every three months demonstrated significant improvement in the girl’s oral health and overall well-being, including a positive impact on her emotional, cognitive, and motor functions.

Utility of next generation sequencing in paediatric neurological disorders: experience from South Africa.

Next generation sequencing (NGS)-based tests have become routine first-line investigative modalities in paediatric neurology clinics in many high-income countries (HICs). Studies from these countries show that these tests are both cost-effective and reliable in diagnosing many complex childhood neurological diseases. However, NGS-based testing in low-and middle-income countries (LMICs) is limited due to affordability constraints. The primary objective of this study was to evaluate the diagnostic yield and impact of targeted gene panel sequencing in a selected paediatric cohort attending a tertiary paediatric neurology clinic in the Western Cape Province of South Africa. This retrospective study included 124 consecutive paediatric patients with neurological disease, aged 6 weeks to 17 years, referred for NGS-based multi-gene panel testing over a 41-month period. Twenty-four different disease group-specific panels were utilized. A caregiver experience questionnaire was administered when a pathogenic variant was identified. The overall study diagnostic yield (DY) was 45% (56/124 patients). The diagnostic yield in this study is similar to previously reported paediatric cohorts in HICs. The high yields for neuromuscular disorders (52%) and early epileptic encephalopathies (41%) suggest that NGS-based panels may be more cost-effective as first-line testing in well-defined phenotypes. The latter finding argues for early inclusion of all children with developmental epileptic encephalopathies (DEE), as early diagnosis leads to better treatment and avoidance of unnecessary investigations.

What We Know About the Actual Role of Traditional Probiotics in Health and Disease.

The complex relationship between probiotics and human health goes beyond their traditional function in gut health, generating considerable interest for their broad potential in disease treatment. This review explores the various functions of probiotics, highlighting their impact on the immune system, their benefits for gut and oral health, their effects on metabolic and neurological disorders, and their emerging potential in cancer therapy. We give significant importance to studying the effects of probiotics on the gut-brain axis, revealing new and non-invasive therapeutic approaches for complex neurological disorders. In addition, we expand the discussion to encompass the impact of probiotics on the gut-liver and gut-lung axes, recognizing their systemic effects and potential in treating respiratory and hepatic conditions. The use of probiotic "cocktails" to improve cancer immunotherapy outcomes indicates a revolutionary approach to oncological treatments. The review explores the specific benefits associated with various strains and the genetic mechanisms that underlie them. This study sets the stage for precision medicine, where probiotic treatments can be tailored to meet the unique needs of each patient. Recent developments in delivery technologies, including microencapsulation and nanotechnology, hold great potential for enhancing the effectiveness and accuracy of probiotic applications in therapeutic settings. This study provides a strong basis for future scientific research and clinical use, promoting the incorporation of probiotics into treatment plans for a wide range of diseases. This expands our understanding of the potential benefits of probiotics in modern medicine.

Oculopalatal Tremor: A Narrative Review of Pathophysiology, Clinical Presentation, and Management Strategy

Abstract Oculopalatal tremor (OPT) is a complex neurological disorder characterized by acquired oscillatory nystagmus synchronized with tremors of the soft palate and other muscles. The article discusses the pathology, clinical manifestations, and diagnostic methods of OPT. A comprehensive literature search was conducted in PubMed and Google Scholar using keywords and relevant articles were studied and analysis was done. Vertical pendular nystagmus is the hallmark, while other muscles such as the neck, head, larynx, and diaphragm may be affected. The pathophysiology is due to lesions of the Guillain–Mollaret triangle (GMT), which causes hypertrophy of the inferior olivary. Neuroimaging reveals hypertrophy of the inferior olivary medulla, which aids in diagnosis. Drug treatments such as gabapentin and memantine can reduce nystagmus, although the visual quality may not permanently improve. The study explores the complexity of the pathophysiology and clinical presentation of OPT. New treatments that target abnormal neuronal connections with drugs such as quinine or mefloquine are being investigated. The potential of deep brain stimulation (DBS) remains uncertain, with promising aspects but limited efficacy. A synergy of technology and treatment is proposed to advance OPT treatment. Future studies will aim to clarify the nuances of responses to OPT and may include a comparative study of medication and DBS. OPT is mainly caused by a disruption in GMT/dentato-rubro-olivary pathway, presenting with tremor, and nystagmus is diagnosed with magnetic resonance imaging. Gabapentin and memantine have proved to be effective in improving the condition except for visual changes.

“Brain Biopsy Revolution: Unveiling the Core Syringe Technique with Clinical Insights”

Obtaining a definitive pathological diagnosis from brain tissue sampling was challenging due to the small, non-representative sample. This study introduced a novel syringe technique for brain biopsy aimed at enhancing diagnostic accuracy by obtaining core tissue samples that better represent the targeted tissue. The ten patients with atypical brain lesions underwent the syringe biopsy. After meticulous preoperative planning with neuronavigation, a minimally invasive approach was used: a 3 cm skin incision and a 14 mm burr hole were created. A modified 3-cc syringe was used to create negative pressure and cannulate the brain tissue. The desired sample size (24 cm³) was obtained by controlling the syringe depth and withdrawal. Medical records were reviewed to assess sample analysis results and any complications RESULTS: The syringe technique successfully yielded adequate tissue samples in 9 out of 10 patients. In one case, the desired tissue could not be retrieved and required a microsurgical approach for removal. In all ten cases, a correct diagnosis was made without significant complications. The preliminary findings suggest that the syringe technique is both safe and effective for obtaining substantial volumes of brain tissue, facilitating accurate pathological evaluation in cases of complex neurological disorders.

Training Datasets for Epilepsy Analysis: Preprocessing and Feature Extraction from Electroencephalography Time Series

We describe 20 datasets derived through signal filtering and feature extraction steps applied to the raw time series EEG data of 20 epileptic patients, as well as the methods we used to derive them. Background: Epilepsy is a complex neurological disorder which has seizures as its hallmark. Electroencephalography plays a crucial role in epilepsy assessment, offering insights into the brain’s electrical activity and advancing our understanding of seizures. The availability of tagged training sets covering all seizure phases—inter-ictal, pre-ictal, ictal, and post-ictal—is crucial for data-driven epilepsy analyses. Methods: Using the sliding window technique with a two-second window length and a one-second time slip, we extract multiple features from the preprocessed EEG time series of 20 patients from the Freiburg Seizure Prediction Database. In addition, we assign a class label to each instance to specify its corresponding seizure phase. All these operations are made through a software application we developed, which is named Training Builder. Results: The 20 tagged training datasets each contain 1080 univariate and bivariate features, and are openly and publicly available. Conclusions: The datasets support the training of data-driven models for seizure detection, prediction, and clustering, based on features engineering.

Using artificial intelligence methods to study the effectiveness of exercise in patients with ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder that significantly affects children and adults worldwide, characterized by persistent inattention, hyperactivity, and impulsivity. Current research in this field faces challenges, particularly in accurate diagnosis and effective treatment strategies. The analysis of motor information, enriched by artificial intelligence methodologies, plays a vital role in deepening our understanding and improving the management of ADHD. The integration of AI techniques, such as machine learning and data analysis, into the study of ADHD-related motor behaviors, allows for a more nuanced understanding of the disorder. This approach facilitates the identification of patterns and anomalies in motor activity that are often characteristic of ADHD, thereby contributing to more precise diagnostics and tailored treatment strategies. Our approach focuses on utilizing AI techniques to deeply analyze patients' motor information and cognitive processes, aiming to improve ADHD diagnosis and treatment strategies. On the ADHD dataset, the model significantly improved accuracy to 98.21% and recall to 93.86%, especially excelling in EEG data processing with accuracy and recall rates of 96.62 and 95.21%, respectively, demonstrating precise capturing of ADHD characteristic behaviors and physiological responses. These results not only reveal the great potential of our model in improving ADHD diagnostic accuracy and developing personalized treatment plans, but also open up new research perspectives for understanding the complex neurological logic of ADHD. In addition, our study not only suggests innovative perspectives and approaches for ADHD treatment, but also provides a solid foundation for future research exploring similar complex neurological disorders, providing valuable data and insights. This is scientifically important for improving treatment outcomes and patients' quality of life, and points the way for future-oriented medical research and clinical practice.

Dynamic fluctuations of salivary CGRP levels during migraine attacks: association with clinical variables and phenotypic characterization

BackgroundMigraine is a complex neurological disorder with significant heterogeneity in its clinical presentation and molecular mechanisms. Calcitonin gene-related peptide (CGRP) has emerged as a key player in migraine pathophysiology, but challenges remain in its utilization as a biomarker. This study aimed to investigate salivary CGRP levels during migraine attacks across the frequency spectrum and explore associations with clinical variables.MethodsA prospective longitudinal pilot study was conducted, recruiting migraine patients from an outpatient headache clinic. Salivary CGRP levels were measured at interictal, onset, post-2 h of onset and end-of-attack. Using generalized linear mixed models, we explored the effect of CGRP changes over the attack in presence of depressive symptoms (DS), acute attack treatment, and after three-months of erenumab treatment. Finally, patients were classified and compared according to their CGRP phenotype.ResultsA total of 44 migraine patients were included (90.9% women), with 80 migraine attacks analyzed. Salivary CGRP levels increased at the onset of migraine attacks. We observed statistically significant interactions between DS and both the linear (Est. [SE]: 19.4 [5.8], p = 0.001) and quadratic terms of time (-19.1 [6.0], p = 0.002). Additionally, a significant three-way interaction within the use of acute treated attack (linear-term: -18.5 [6.2], p = 0.005; quadratic-term: 19.2 [6.8], p = 0.005) was also found. Molecular phenotyping revealed that 72.7% (32/44) of patients presented only CGRP-dependent attacks, while 27.3% (12/44) presented non-CGRP-dependent migraine attacks. Patients with only CGRP-dependent attacks were associated with younger age, shorter disease evolution time, a higher proportion of aura, and fewer monthly headache days (p < 0.05). Exploratory analysis of erenumab treatment effects did not result in changes in CGRP levels during migraine attacks.ConclusionsOur study underscores the dynamic nature of migraine at a molecular level and emphasizes the importance of integrating clinical variables, such as depressive symptoms, in understanding its pathophysiology. The identification of distinct migraine subtypes based on CGRP dependence suggests potential opportunities for personalized treatment approaches.

A survey-based approach on restless legs syndrome: practices and perspectives among Italian neurologists.

Restless Legs Syndrome (RLS) is a widely prevalent and complex neurological disorder. Despite notable advancements in managing RLS, the disorder continues to face challenges related to its recognition and management. This study seeks to gain comprehensive insights into the knowledge and clinical practices among Italian neurologists regarding RLS diagnosis, management, and treatment, comparing approaches among general neurologists, movement disorder specialists, and sleep experts. Members of the Italian Society of Neurology, the Italian Society of Parkinson and Movement Disorders, and the Italian Association of Sleep Medicine were invited to participate in a 19-question online survey. Among the 343 surveyed neurologists, 60% categorized RLS as a "sleep-related movement disorder." Forty% indicated managing 5-15 RLS patients annually, with sleep specialists handling the highest patient volume. Of note, only 34% adhered strictly to all five essential diagnostic criteria. The majority (69%) favored low-dosage dopamine agonists as their first-line treatment, with movement disorder specialists predominantly endorsing this approach, while sleep experts preferred iron supplementation. Regular screening for iron levels was widespread (91%), with supplementation typically guided by serum iron alterations. In cases of ineffective initial treatments, escalating dopamine agonist dosage was the preferred strategy (40%). These findings underscore a lack of a clear conceptualization of RLS, with a widespread misconception of the disorder as solely a movement disorder significantly influencing treatment approaches. Disparities in RLS understanding across neurology subspecialties underscore the necessity for improved diagnostic accuracy, targeted educational initiatives, and management guidelines to ensure consistent and effective RLS management.

Non-Mammalian Models for Understanding Neurological Defects in RASopathies.

RASopathies, a group of neurodevelopmental congenital disorders stemming from mutations in the RAS/MAPK pathway, present a unique opportunity to delve into the intricacies of complex neurological disorders. Afflicting approximately one in a thousand newborns, RASopathies manifest as abnormalities across multiple organ systems, with a pronounced impact on the central and peripheral nervous system. In the pursuit of understanding RASopathies' neurobiology and establishing phenotype-genotype relationships, in vivo non-mammalian models have emerged as indispensable tools. Species such as Danio rerio, Drosophila melanogaster, Caenorhabditis elegans, Xenopus species and Gallus gallus embryos have proven to be invaluable in shedding light on the intricate pathways implicated in RASopathies. Despite some inherent weaknesses, these genetic models offer distinct advantages over traditional rodent models, providing a holistic perspective on complex genetics, multi-organ involvement, and the interplay among various pathway components, offering insights into the pathophysiological aspects of mutations-driven symptoms. This review underscores the value of investigating the genetic basis of RASopathies for unraveling the underlying mechanisms contributing to broader neurological complexities. It also emphasizes the pivotal role of non-mammalian models in serving as a crucial preliminary step for the development of innovative therapeutic strategies.

Identification of potential JNK3 inhibitors through virtual screening, molecular docking and molecular dynamics simulation as therapeutics for Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurological disorder and no effective drug is available for its treatment. Numerous pathological conditions are believed to be responsible for the initiation and development of AD including c-Jun N-terminal kinases (JNKs). The JNKs are one of the enzymes from the mitogen-activated protein kinase (MAPK) family that controls the phosphorylation of various transcription factors on serine and threonine residues, and hold significant responsibilities in tasks like gene expression, cell proliferation, differentiation, and apoptosis. Since, JNK3 is primarily expressed in the brain hence its increased levels in the brain are associated with the AD pathology promoting neurofibrillary tangles, senile plaques, neuroinflammation, and nerve cell apoptosis. The current research work is focused on the development of novel JNK inhibitors as therapeutics for AD employing a structure-based virtual screening (SBVS) approach. The ZINC database (14634052 compounds) was investigated after employing pan assay interference (PAINs), drug-likeness, and diversity picking filter to distinguish molecules interacting with JNK3 by following three docking precision criteria: High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP) & MMGBSA. Five lead molecules showed a better docking score in the range of -13.091 to -14.051kcal/mol better than the reference compound (-11.828kcal/mol). The lead compounds displayed acceptable pharmacokinetic properties and were subjected to molecular dynamic simulations of 100ns and binding free energy calculations. All the lead molecules showed stable RMSD and hydrogen bond interactions throughout the trajectory. The ∆GMM/PBSA_total score for the lead compounds ZINC220382956, ZINC147071339, ZINC207081127, ZINC205151456, ZINC1228819126, and CC-930 was calculated and found to be -31.39, -42.8, -37.04, -39.01, -36.5, -34.16kcal/mol, respectively. Thus, it was concluded that the lead molecules identified in these studies have the potential to be explored as potent JNK3 inhibitors.