Complex Neurological Disorder Research Articles

Parkinson’s Disease-Overview

Parkinson’s disease one of the most complex neurological disorder. The disease risk and progression are due to common genetic variants. Approximately 6.2 million cases are reported each year according to the statistics published in 2015 whereas it is expected that this number will be twice by 2040. There are two types of Parkinson’s disease, familial Parkinson’s disease, and sporadic Parkinson’s disease. The disease is characterized by the presence of Lewy bodies. Adult age increases the risk of Parkinson’s disease. In this review, we provide an overview of the disease pathology of Lewy bodies in the occurrence of Parkinson’s disease, in vitro studies to determine the role of iPSCs in treatment of Parkinson’s disease, in vivo studies to determine the role of animal model in studying disease modeling, and future prospective how single-cell RNA sequencing technology is a major advancement in studying and find the treatment for Parkinson’s disease.

Cover Feature: Engineered Human Induced Pluripotent Cells Enable Genetic Code Expansion in Brain Organoids (ChemBioChem 22/2021)

Brain organoids derived from human induced pluripotent stem cells (hiPSC) recapitulate key features of the developing brain and can model complex neurological disorders. Integrating the PylRS/PylT pair into the genome of hiPSCs enables efficient site-directed incorporation of non-canonical amino acids (ncAAs) and allows derivatization of neurons and brain organoids with an expanded genetic code. The cover feature demonstrates how PylT recodes an amber stop codon within a GFP reporter to direct site-specific incorporation of an ncAA, leading to GFP fluorescence throughout the organoid, as visible by light-sheet microscopy. The method will help to implement existing ncAA-based strategies for probing and manipulating proteins in hiPSC-derived complex human disease models. More information can be found in the Full Paper by L. van Husen et al.

Improving rigor and reproducibility in nonhuman primate research.

Nonhuman primates (NHPs) are a critical component of translational/preclinical biomedical research due to the strong similarities between NHP and human physiology and disease pathology. In some cases, NHPs represent the most appropriate, or even the only, animal model for complex metabolic, neurological, and infectious diseases. The increased demand for and limited availability of these valuable research subjects requires that rigor and reproducibility be a prime consideration to ensure the maximal utility of this scarce resource. Here, we discuss a number of approaches that collectively can contribute to enhanced rigor and reproducibility in NHP research.

Relationship Between Oxidative Stress, Tau Level and Antioxidant Mechanisms of the KEAP-1/NRF-2/HO-1 in Children with Hydrocephalus.

Hydrocephalus is a complex neurologic disorder that has a widespread impact on the central nervous system and a multifactor disease which affects the CSF dynamics and causes severe neurological impairments in children. The pathophysiology of hydrocephalus is not fully understood. However, increasing evidence suggests that oxidative stress may be an important factor in the pathogenesis of hydrocephalus. The purpose of this study is to investigate the relationship of the KEAP-1/NRF-2/HO-1 pathway, one of the main regulators of the antioxidant system in the hydrocephalus pathology, on oxidative stress and tau protein level. The study included 32 patients with hydrocephalus and 32 healthy controls. KEAP-1, NRF-2, HO-1, TAU, and MPO levels are measured using ELISA method TAS, TOS, and Total THIOL colorimetric method. KEAP-1, TAS, and Total THIOL levels were found significantly lowerer in the hydrocephalus group than in the control group. Nevertheless, it was identified that in the hydrocephalus group that the NRF-2, HO-1, TAU, MPO, TOS, and OSI levels were significantly elevated. In conclusion, although the KEAP-1/NRF-2/HO-1 pathway is activated in patients with hydrocephalus, it is identified that the antioxidant defense system is insufficient and ultimately leads to elevated oxidative stress. The elevation in the tau level may be an indicator of oxidative stress induced neurodegenerative damage.

Budget Impact of the Vest™ High Frequency Chest Wall Oscillation System for Managing Airway Clearance in Patients with Complex Neurological Disorders: A US Healthcare Payers' Perspective Analysis.

ObjectiveAs a recognized therapy to improve airway clearance, high-frequency chest wall oscillation (HFCWO) is used to manage reduced vital capacity in patients with complex neuromuscular disorders (cNMD). This study aimed to investigate the budget impact of HFCWO versus chest wall physical therapy (CWPT) from a US-commercial payer perspective.MethodsIn combination with a previously developed cost-effectiveness model, a budget impact model was developed to evaluate the incremental budgetary impact associated with introducing a HFCWO device over a 5-year time horizon. The model compared the cost implications associated with the commonly used CWPT procedure, as the current scenario, with a new scenario consisting of 80% of market share for HFCWO. The resource use and costs included in the analyses were costs associated with the HFCWO device (Vest™ System) and its consumables, patient training, and medical services such as hospitalization, medications, emergency room, and outpatient visits. The primary outcome measures included total and incremental budgetary impact per member per year (PMPY).ResultsIn a hypothetical plan of 1,000,000 members (men: 49.2%), 2099 patients with cNMD were estimated to be eligible to receive airway clearance services over 5 years. The new scenario (HFCWO and CWPT [US$24 PMPY]) was cost-saving compared with the current scenario (CWPT only [$34 PMPY]) with a cost reduction of US$9.46 PMPY. The model estimated a net cost-saving of US$1,594,131 and US$9,591,343 over 1 and 5 years, respectively.ConclusionThis study suggests the HFCWO technique to manage the reduction in vital capacity in patients with cNMD would lead to favorable budget impact results.

PRATEEK: Integration of Multimodal Neuroimaging Data to Facilitate Advanced Brain Research

Background: In vivo neuroimaging modalities such as magnetic resonance imaging (MRI), functional MRI (fMRI), magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), and quantitative susceptibility mapping (QSM) are useful techniques to understand brain anatomical structure, functional activity, source localization, neurochemical profiles, and tissue susceptibility respectively. Integrating unique and distinct information from these neuroimaging modalities will further help to enhance the understanding of complex neurological diseases. Objective: To develop a processing scheme for multimodal data integration in a seamless manner on healthy young population, thus establishing a generalized framework for various clinical conditions (e.g., Alzheimer’s disease). Methods: A multimodal data integration scheme has been developed to integrate the outcomes from multiple neuroimaging data (fMRI, MEG, MRS, and QSM) spatially. Furthermore, the entire scheme has been incorporated into a user-friendly toolbox- “PRATEEK”. Results: The proposed methodology and toolbox has been tested for viability among fourteen healthy young participants. The data-integration scheme was tested for bilateral occipital cortices as the regions of interest and can also be extended to other anatomical regions. Overlap percentage from each combination of two modalities (fMRI-MRS, MEG-MRS, fMRI-QSM, and fMRI-MEG) has been computed and also been qualitatively assessed for combinations of the three (MEG-MRS-QSM) and four (fMRI-MEG-MRS-QSM) modalities. Conclusion: This user-friendly toolbox minimizes the need of an expertise in handling different neuroimaging tools for processing and analyzing multimodal data. The proposed scheme will be beneficial for clinical studies where geometric information plays a crucial role for advance brain research.

Investigating Migraine-Like Behavior using Light Aversion in Mice

Migraine is a complex neurological disorder characterized by headache and sensory abnormalities, such as hypersensitivity to light, observed as photophobia. Whilst it is impossible to confirm that a mouse is experiencing migraine, light aversion can be used as a behavioral surrogate for the migraine symptom of photophobia. To test for light aversion, we utilize the light/dark assay to measure the time mice freely choose to spend in either a light or dark environment. The assay has been refined by introducing two critical modifications: pre-exposures to the chamber prior to running the test procedure and adjustable chamber lighting, permitting the use of a range of light intensities from 55 lux to 27,000 lux. Because the choice to spend more time in the dark is also indicative of anxiety, we also utilize a light-independent anxiety test, the open field assay, to distinguish anxiety from light-aversive behavior. Here, we describe a modified test paradigm for the light/dark and open field assays. The application of these assays is described for intraperitoneal injection of calcitonin gene-related peptide (CGRP) in two mouse strains and for optogenetic brain stimulation studies.

Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications.

Spinocerebellar ataxias (SCAs) represent a large group of hereditary degenerative diseases of the nervous system, in particular the cerebellum, and other systems that manifest with a variety of progressive motor, cognitive, and behavioral deficits with the leading symptom of cerebellar ataxia. SCAs often lead to severe impairments of the patient's functioning, quality of life, and life expectancy. For SCAs, there are no proven effective pharmacotherapies that improve the symptoms or substantially delay disease progress, i.e., disease-modifying therapies. To study SCA pathogenesis and potential therapies, animal models have been widely used and are an essential part of pre-clinical research. They mainly include mice, but also other vertebrates and invertebrates. Each animal model has its strengths and weaknesses arising from model animal species, type of genetic manipulation, and similarity to human diseases. The types of murine and non-murine models of SCAs, their contribution to the investigation of SCA pathogenesis, pathological phenotype, and therapeutic approaches including their advantages and disadvantages are reviewed in this paper. There is a consensus among the panel of experts that (1) animal models represent valuable tools to improve our understanding of SCAs and discover and assess novel therapies for this group of neurological disorders characterized by diverse mechanisms and differential degenerative progressions, (2) thorough phenotypic assessment of individual animal models is required for studies addressing therapeutic approaches, (3) comparative studies are needed to bring pre-clinical research closer to clinical trials, and (4) mouse models complement cellular and invertebrate models which remain limited in terms of clinical translation for complex neurological disorders such as SCAs.

Neuroprotective Effect of Fisetin Through Suppression of IL-1R/TLR Axis and Apoptosis in Pentylenetetrazole-Induced Kindling in Mice.

Epilepsy is a complex neurological disorder, characterized by frequent electrical activity in brain regions. Inflammation and apoptosis cascade activation are serious neurological sequelae during seizures. Fisetin (3, 3′,4′,7-tetrahydroxyflavone), a flavonoid molecule, is considered for its effective anti-inflammatory and anti-apoptotic properties. This study investigated the neuroprotective effect of fisetin on experimental epilepsy. For acute studies, increasing current electroshock (ICES) and pentylenetetrazole (PTZ)-induced seizure tests were performed to evaluate the antiseizure activity of fisetin. For the chronic study, the kindling model was established by the administration of PTZ in subconvulsive dose (25 mg/kg, i.p.). Mice were treated with fisetin (5, 10, and 20 mg/kg, p.o.) to study its probable antiseizure mechanism. The kindled mice were evaluated for seizure scores. Their hippocampus and cortex were assessed for neuronal damage, inflammation, and apoptosis. Histological alterations were observed in the hippocampus of the experimental mice. Levels of high mobility group box 1 (HMGB1), Toll-like receptor-4 (TLR-4), interleukin-1 receptor 1 (IL-1R1), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed in the hippocampus and cortex by ELISA. The immunoreactivity and mRNA expressions of nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), cytochrome C, and caspase-3 were quantified by immunohistochemical analysis and real-time PCR. Phosphorylation ELISA was performed to evaluate AkT/mTOR (mammalian target of rapamycin) activation in the hippocampus and cortex of the kindled mice. The results showed that fisetin administration increased the seizure threshold current (STC) in the ICES test. In PTZ-induced seizures, fisetin administration increased the latency for myoclonic jerks (MJs) and generalized seizures (GSs). In the PTZ-induced kindling model, fisetin administration dose-dependently suppressed the development of kindling and the associated neuronal damage in the experimental mice. Further, fisetin administration ameliorated kindling-induced neuroinflammation as evident from decreased levels of HMGB1, TLR-4, IL-1R1, IL-1β, IL-6, and TNF-α in the hippocampus and cortex of the kindled mice. Also, the immunoreactivity and mRNA expressions of inflammatory molecules, NF-κB, and COX-2 were decreased with fisetin administration in the kindled animals. Decreased phosphorylation of the AkT/mTOR pathway was reported with fisetin administration in the hippocampus and cortex of the kindled mice. The immunoreactivity and mRNA expressions of apoptotic molecules, cytochrome C, and caspase-3 were attenuated upon fisetin administration. The findings suggest that fisetin shows a neuroprotective effect by suppressing the release of inflammatory and apoptosis molecules and attenuating histological alterations during experimental epilepsy.

SyNC, a Computationally Extensive and Realistic Neural Net to Identify Relative Impacts of Synaptopathy Mechanisms on Glutamatergic Neurons and Their Networks in Autism and Complex Neurological Disorders.

Synaptic function and experience-dependent plasticity across multiple synapses are dependent on the types of neurons interacting as well as the intricate mechanisms that operate at the molecular level of the synapse. To understand the complexity of information processing at synaptic networks will rely in part on effective computational models. Such models should also evaluate disruptions to synaptic function by multiple mechanisms. By co-development of algorithms alongside hardware, real time analysis metrics can be co-prioritized along with biological complexity. The hippocampus is implicated in autism spectrum disorders (ASD) and within this region glutamatergic neurons constitute 90% of the neurons integral to the functioning of neuronal networks. Here we generate a computational model referred to as ASD interrogator (ASDint) and corresponding hardware to enable in silicon analysis of multiple ASD mechanisms affecting glutamatergic neuron synapses. The hardware architecture Synaptic Neuronal Circuit, SyNC, is a novel GPU accelerator or neural net, that extends discovery by acting as a biologically relevant realistic neuron synapse in real time. Co-developed ASDint and SyNC expand spiking neural network models of plasticity to comparative analysis of retrograde messengers. The SyNC model is realized in an ASIC architecture, which enables the ability to compute increasingly complex scenarios without sacrificing area efficiency of the model. Here we apply the ASDint model to analyse neuronal circuitry dysfunctions associated with autism spectral disorder (ASD) synaptopathies and their effects on the synaptic learning parameter and demonstrate SyNC on an ideal ASDint scenario. Our work highlights the value of secondary pathways in regard to evaluating complex ASD synaptopathy mechanisms. By comparing the degree of variation in the synaptic learning parameter to the response obtained from simulations of the ideal scenario we determine the potency and time of the effect of a particular evaluated mechanism. Hence simulations of such scenarios in even a small neuronal network now allows us to identify relative impacts of changed parameters and their effect on synaptic function. Based on this, we can estimate the minimum fraction of a neuron exhibiting a particular dysfunction scenario required to lead to complete failure of a neural network to coordinate pre-synaptic and post-synaptic outputs.

Interleukin-6 induces spatially dependent whole-body hypersensitivity in rats: implications for extracephalic hypersensitivity in migraine

BackgroundMigraine is a complex neurological disorder that is characterized by throbbing head pain, increased sensitivity to light, sound, and touch, as well as nausea and fatigue. It is one of the most common and most disabling disorders globally but mechanisms causing migraine are poorly understood. While head pain is a typical feature of attacks, they also often present with cutaneous hypersensitivity in the rest of the body. In contrast, primary pain conditions in the lower parts of the body are less commonly associated with cephalic hypersensitivity. Previous studies indicate that application of stimuli to the meninges of rodents causes cutaneous facial as well as hindpaw hypersensitivity. In the present study, we asked whether widespread hypersensitivity is a unique feature of dural stimulation or whether body-wide responses occur similarly when the same stimulus is given in other locations.MethodsRats were given the same dose of IL-6 either via dural, intraplantar, subcutaneous, intramuscular, intracisternal, or intrathecal injection. Cutaneous facial and hindpaw allodynia was assessed using Von Frey following injection into each location.ResultsHindpaw allodynia was observed following dural and intraplantar injection of IL-6 in both males and females. Hindpaw allodynia was only observed in females following intracisternal and intrathecal IL-6 injections. In contrast, facial allodynia was only observed in either sex following dural and intracisternal injections, which would activate meningeal afferents and the trigeminal nucleus caudalis (TNC), respectively.ConclusionsHere we show that while stimulation of upper body regions with IL-6 including the meninges and brainstem can cause widespread hypersensitivity spreading to the paws, similar stimulation of the lower body does not cause the spread of hypersensitivity into the head. These data are consistent with the observations that whole body hypersensitivity is specific to conditions such as migraine where pain is present in the head and they may provide insight into co-morbid pain states associated with migraine.

Phenome-wide analysis highlights putative causal relationships between self-reported migraine and other complex traits

BackgroundMigraine is a complex neurological disorder that is considered the most common disabling brain disorder affecting 14 % of people worldwide. The present study sought to infer potential causal relationships between self-reported migraine and other complex traits, using genetic data and a hypothesis-free approach.MethodsWe leveraged available summary statistics from genome-wide association studies (GWAS) of 1,504 phenotypes and self-reported migraine and inferred pair-wise causal relationships using the latent causal variable (LCV) method.ResultsWe identify 18 potential causal relationships between self-reported migraine and other complex traits. Hypertension and blood clot formations were causally associated with an increased migraine risk, possibly through vasoconstriction and platelet clumping. We observed that sources of abdominal pain and discomfort might influence a higher risk for migraine. Moreover, occupational and environmental factors such as working with paints, thinner or glues, and being exposed to diesel exhaust were causally associated with higher migraine risk. Psychiatric-related phenotypes, including stressful life events, increased migraine risk. In contrast, ever feeling unenthusiastic / disinterested for a whole week, a phenotype related to the psychological well-being of individuals, was a potential outcome of migraine.ConclusionsOverall, our results suggest a potential vascular component to migraine, highlighting the role of vasoconstriction and platelet clumping. Stressful life events and occupational variables potentially influence a higher migraine risk. Additionally, a migraine could impact the psychological well-being of individuals. Our findings provide novel testable hypotheses for future studies that may inform the design of new interventions to prevent or reduce migraine risk and recurrence.

Study on the removal of amyloid plaque by nano-gold in the treatment of neurodegenerative disease-alzheimer’s disease

As a complex neurological disease, the treatment of Alzheimer’s disease (AD) is a global challenge. Compared with traditional drug therapy, a novel therapeutic tool, inorganic nanoparticles combined with photothermal therapy (PTT) can decompose amyloid β-protein (Aβ) fibrils and inhibit Aβ aggregation, alleviating AD symptoms. In this study, MoS2@Au NPs composite nanoparticles were constructed by combining sulfhydryl-modified Au NPs and MoS2 nanosheets. In vitro experiments showed that the composite nanoparticles could degrade insoluble Aβ fibers to soluble monomers and alleviate neurotoxicity. Additionally, the excellent biocompatibility and biosafety of MoS2@Au NPs reduced the damaging effects on nerve cells, and the AD model mice benefited from the treatment with MoS2@Au NPs, which significantly improved their learning and cognitive abilities and thus reduced the disease. More importantly, MoS2@Au NPs combined with PTT effectively curbed the inflammatory response and slowed down the course of AD.

Voluntary Wheel Running Partially Attenuates Early Life Stress-Induced Neuroimmune Measures in the Dura and Evoked Migraine-Like Behaviors in Female Mice.

Migraine is a complex neurological disorder that affects three times more women than men and can be triggered by endogenous and exogenous factors. Stress is a common migraine trigger and exposure to early life stress increases the likelihood of developing chronic pain disorders later in life. Here, we used our neonatal maternal separation (NMS) model of early life stress to investigate whether female NMS mice have an increased susceptibility to evoked migraine-like behaviors and the potential therapeutic effect of voluntary wheel running. NMS was performed for 3 h/day during the first 3 weeks of life and initial observations were made at 12 weeks of age after voluntary wheel running (Exercise, -Ex) or sedentary behavior (-Sed) for 4 weeks. Mast cell degranulation rates were significantly higher in dura mater from NMS-Sed mice, compared to either naïve-Sed or NMS-Ex mice. Protease activated receptor 2 (PAR2) protein levels in the dura were significantly increased in NMS mice and a significant interaction of NMS and exercise was observed for transient receptor potential ankyrin 1 (TRPA1) protein levels in the dura. Behavioral assessments were performed on adult (>8 weeks of age) naïve and NMS mice that received free access to a running wheel beginning at 4 weeks of age. Facial grimace, paw mechanical withdrawal threshold, and light aversion were measured following direct application of inflammatory soup (IS) onto the dura or intraperitoneal (IP) nitroglycerin (NTG) injection. Dural IS resulted in a significant decrease in forepaw withdrawal threshold in all groups of mice, while exercise significantly increased grimace score across all groups. NTG significantly increased grimace score, particularly in exercised mice. A significant effect of NMS and a significant interaction effect of exercise and NMS were observed on hindpaw sensitivity following NTG injection. Significant light aversion was observed in NMS mice, regardless of exercise, following NTG. Finally, exercise significantly reduced calcitonin gene-related peptide (CGRP) protein level in the dura of NMS and naïve mice. Taken together, these findings suggest that while voluntary wheel running improved some measures in NMS mice that have been associated with increased migraine susceptibility, behavioral outcomes were not impacted or even worsened by exercise.

Multi-Target-Directed Ligands as an Effective Strategy for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurological disorder and multiple pathological factors are believed to be involved in the genesis and progression of the disease. A number of hypothesis including Acetylcholinesterase, Monoamine oxidase, β- Amyloid, Tau protein etc. have been proposed for the initiation and progression of the disease. At present, acetylcholine esterase inhibitors and memantine (NMDAR antagonist) are the only approved therapy for the symptomatic management of AD. Most of these single-target drugs have miserably failed in the treatment or halting the progression of the disease. Multi-factorial diseases like AD require complex treatment strategies that involve simultaneous modulation of a network of interacting targets. Since last few years, Multi-Target-Directed Ligands (MTDLs) strategy, drugs that can simultaneously hit multiple targets, is being explored as an effective therapeutic approach for the treatment of AD. In the current review article, the authors have briefly described various pathogenic pathways associated with the AD. Importance of Multi-Target-Directed Ligands and their design strategies in recently reported articles have been discussed in detail. Potent leads identified through various structure-activity relationship studies and their drug like characteristics are described. Recently developed promising compounds have been summarized in the article. Some of these MTDLs with balanced activity profile against different targets have the potential to be developed as drug candidates for the treatment of AD.

Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease

Transcriptional dysregulation in Huntington's disease (HD) causes functional deficits in striatal neurons. Here, we performed Patch-sequencing (Patch-seq) in an in vitro HD model to investigate the effects of mutant Huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. In support of a pivotal role for epigenetic mechanisms in HD pathophysiology, we found that inhibiting histone deacetylase 1/3 activities rectified several functional and morphological deficits and alleviated the aberrant transcriptional profiles in mutant Htt neurons. With this study, we demonstrate that Patch-seq technology can be applied both to better understand molecular mechanisms underlying a complex neurological disease at the single-cell level and to provide a platform for screening for therapeutics for the disease.

Nanotherapeutics in Neuropathologies: Obstacles, Challenges and Recent Advancements in CNS Targeted Drug Delivery Systems.

Neurology and associated nanotherapeutics are a complex field in terms of therapeutics and neurological disorder complexity. The brain is an intricate appendage and requires more precise embattled treatment for the particular diseases and hence it is a broad scale for developing more targeted drug deliveries. The brain is one of the most inaccessible tissues of the body due to the existence of the blood-brain barrier (BBB), thus delivery of drugs inside the brain is a striking dare and it is also tricky to treat central nervous system (CNS) complications pharmacologically. The therapeutic aspiration is to accomplish the lowest drug meditation in the brain tissues so as to gain favoured therapeutic results. To devastate this obstacle, nanotechnology is engaged in the field of targeted brain drug delivery and neuropathology targeting. These carriers hold myriad abilities as they may augment the drug delivery into the brain by shielding them from degradation and prolonging their transmission in the blood, as well as promoting their transport through the BBB. Nanopharmaceuticals are quickly sprouting as a new avenue that is engaged with the drug-loaded nanocarriers to demonstrate unique physicochemical properties and tiny size range for penetrating the central nervous system. The enchantment behind their therapeutic achievement is the condensed drug dose and inferior toxicity, whereby restricting the therapeutic compound to the specific site. Therefore, in this article, we have tried to recapitulate the advances of the novel scopes for the brain targeted drug delivery for complex neurological disorders.

Next-Generation Sequencing Technologies and Neurogenetic Diseases.

Next-generation sequencing (NGS) technology has led to great advances in understanding the causes of Mendelian and complex neurological diseases. Owing to the complexity of genetic diseases, the genetic factors contributing to many rare and common neurological diseases remain poorly understood. Selecting the correct genetic test based on cost-effectiveness, coverage area, and sequencing range can improve diagnosis, treatments, and prevention. Whole-exome sequencing and whole-genome sequencing are suitable methods for finding new mutations, and gene panels are suitable for exploring the roles of specific genes in neurogenetic diseases. Here, we provide an overview of the classifications, applications, advantages, and limitations of NGS in research on neurological diseases. We further provide examples of NGS-based explorations and insights of the genetic causes of neurogenetic diseases, including Charcot–Marie–Tooth disease, spinocerebellar ataxias, epilepsy, and multiple sclerosis. In addition, we focus on issues related to NGS-based analyses, including interpretations of variants of uncertain significance, de novo mutations, congenital genetic diseases with complex phenotypes, and single-molecule real-time approaches.

Advances in Proteomics Allow Insights Into Neuronal Proteomes.

Protein–protein interaction networks and signaling complexes are essential for normal brain function and are often dysregulated in neurological disorders. Nevertheless, unraveling neuron- and synapse-specific proteins interaction networks has remained a technical challenge. New techniques, however, have allowed for high-resolution and high-throughput analyses, enabling quantification and characterization of various neuronal protein populations. Over the last decade, mass spectrometry (MS) has surfaced as the primary method for analyzing multiple protein samples in tandem, allowing for the precise quantification of proteomic data. Moreover, the development of sophisticated protein-labeling techniques has given MS a high temporal and spatial resolution, facilitating the analysis of various neuronal substructures, cell types, and subcellular compartments. Recent studies have leveraged these novel techniques to reveal the proteomic underpinnings of well-characterized neuronal processes, such as axon guidance, long-term potentiation, and homeostatic plasticity. Translational MS studies have facilitated a better understanding of complex neurological disorders, such as Alzheimer’s disease (AD), Schizophrenia (SCZ), and Autism Spectrum Disorder (ASD). Proteomic investigation of these diseases has not only given researchers new insight into disease mechanisms but has also been used to validate disease models and identify new targets for research.

Symptom amelioration in 798 patients with complex neurological disorders following a 5-day intensive multimodal neurorehabilitation program: Chart review (5240)

Symptom amelioration in 798 patients with complex neurological disorders following a 5-day intensive multimodal neurorehabilitation program: Chart review (5240)