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The concreteness effect (CE), namely a better performance with concrete compared to abstract concepts, is a constant feature in healthy people, and it usually increases in persons with aphasia (PWA). However, a reversal of the CE has been reported in patients affected by the semantic variant of Primary Progressive Aphasia (svPPA), a neurodegenerative disease characterized by anterior temporal lobe (ATL) atrophy. The present scoping review aims at identifying the extent of evidence regarding the abstract/concrete contrast in Alzheimer's disease (AD) and svPPA and associated brain atrophy. Five online databases were searched up to January 2023 to identify papers where both concrete and abstract concepts were investigated. Thirty-one papers were selected and showed that while in patients with AD, concrete words were better processes than abstract ones, in most svPPA patients, there was a reversal of the CE, with five studies correlating the size of this effect with ATL atrophy. Furthermore, the reversal of CE was associated with category-specific impairments (living things) and with a selective deficit of social words. Future work is needed to disentangle the role of specific portions of the ATL in concept representation. [ABSTRACT FROM AUTHOR]

Microglia, the innate immune cells of the brain, are activated by damage or disease. In mouse models of amyotrophic lateral sclerosis (ALS), microglia shift from neurotrophic to neurotoxic states with disease progression. It remains unclear how human microglia change relative to the TAR DNA-binding protein 43 (TDP-43) aggregation that occurs in 97% of ALS cases. Here we examine spatial relationships between microglial activation and TDP-43 pathology in brain tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from the Neurological Foundation Human Brain Bank was obtained from 10 control and 10 ALS cases in parallel with brain tissue from a bigenic NEFH-tTA/tetO-hTDP-43∆NLS (rNLS) mouse model of ALS at disease onset, early disease, and late disease stages. The spatiotemporal relationship between microglial activation and ALS pathology was determined by investigating microglial functional marker expression in brain regions with low and high TDP-43 burden at end-stage human disease: hippocampus and motor cortex, respectively. Sections were immunohistochemically labelled with a two-round multiplexed antibody panel against; microglial functional markers (L-ferritin, HLA-DR, CD74, CD68, and Iba1), a neuronal marker, an astrocyte marker, and pathological phosphorylated TDP-43 (pTDP-43). Single-cell levels of microglial functional markers were quantified using custom analysis pipelines and mapped to anatomical regions and ALS pathology. We identified a significant increase in microglial Iba1 and CD68 expression in the human ALS motor cortex, with microglial CD68 being significantly correlated with pTDP-43 pathology load. We also identified two subpopulations of microglia enriched in the ALS motor cortex that were defined by high L-ferritin expression. A similar pattern of microglial changes was observed in the rNLS mouse, with an increase first in CD68 and then in L-ferritin expression, with both occurring only after pTDP-43 inclusions were detectable. Our data strongly suggest that microglia are phagocytic at early-stage ALS but transition to a dysfunctional state at end-stage disease, and that these functional states are driven by pTDP-43 aggregation. Overall, these findings enhance our understanding of microglial phenotypes and function in ALS. [ABSTRACT FROM AUTHOR]

Background: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme in the formation of amyloid-β (Aβ) protein. Increasing evidence suggests that BACE1 concentration is a potential biomarker for Alzheimer's disease (AD). Objective: To evaluate the correlations between plasma BACE1 concentration, cognition, and hippocampal volume at different stages of the AD continuum. Methods: Plasma BACE1 concentrations were measured in 32 patients with probable dementia due to AD (ADD), 48 patients with mild cognitive impairment (MCI) due to AD, and 40 cognitively unimpaired (CU) individuals. Memory function was evaluated using the auditory verbal learning test (AVLT), and voxel-based morphometry was used to analyze bilateral hippocampal volumes. Correlation and mediation analyses were performed to investigate the associations between plasma BACE1 concentration, cognition, and hippocampal atrophy. Results: The MCI and ADD groups exhibited elevated BACE1 concentrations compared with the CU group after adjusting for age, sex, and apolipoprotein E (APOE) genotype. Increased BACE1 concentration was found in AD continuum patients who were APOE ɛ4 carriers (p < 0.05). BACE1 concentration was negatively associated with the scores of the subitems of the AVLT and hippocampal volume (p < 0.05, false discovery rate correction) in the MCI group. Moreover, bilateral hippocampal volume mediated the relationship between BACE1 concentration and recognition in the MCI group. Conclusion: BACE1 expression increased in the AD continuum, and bilateral hippocampal volume mediated the effect of BACE1 concentration on memory function in patients with MCI. Research has indicated that the plasma BACE1 concentration might be a biomarker at the early stage of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-β (Aβ) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aβ-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles. Objective: The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT). Methods: We compared 2,884 subjects with autopsy-confirmed intermediate-high stage ADNC to 208 subjects with definite PART (Braak stage I–IV, Thal phase 0, CERAD NP score "absent") and 178 NT subjects from the National Alzheimer's Coordinating Center dataset. Results: PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ɛ4 alleles than the PART or NT cohort, and less frequent APOE ɛ2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language. Conclusion: Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC. [ABSTRACT FROM AUTHOR]

Transactivation (TAR) DNA binding protein 43 kDa (TDP-43) inclusions frequently occur as a comorbid pathology in several neurodegenerative disorders, including Alzheimer’s disease, Huntington’s disease, Lewy body disease, and progressive supranuclear palsy, and may appear in association with nondegenerative neurological etiology, for example neoplastic, paraneoplastic, traumatic, or infectious. Relationships between various pathological proteins and mechanisms associated with TDP-43-induced neurodegeneration are still not fully understood. Thus, overlap of distinct neuropathological mechanisms frequently leads to greater brain atrophy and a more severe clinical course, suggesting the importance of co-pathologies in ante-mortem diagnosing and treatment. The present review aims to discuss the incidence, morphology, and role of TDP-43 pathology in the context of other dominant, hallmark pathologies, referred to as secondary TDP-43 proteinopathies. The previous part (Part 1) focused on common neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Lewy body disease, while the present part (Part 2) discusses TDP-43 pathology in rare neurodegenerative diseases and neurological diseases with nondegenerative etiology. [ABSTRACT FROM AUTHOR]

Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen identification and prioritization relies on correctly predicting whether the presenting peptide sequence can successfully induce an immune response. Because most somatic mutations are single-nucleotide variants, changes between wild-type and mutated peptides are typically subtle and require cautious interpretation. A potentially underappreciated variable in neoantigen prediction pipelines is the mutation position within the peptide relative to its anchor positions for the patient's specific MHC molecules. Whereas a subset of peptide positions are presented to the T cell receptor for recognition, others are responsible for anchoring to the MHC, making these positional considerations critical for predicting T cell responses. We computationally predicted anchor positions for different peptide lengths for 328 common HLA alleles and identified unique anchoring patterns among them. Analysis of 923 tumor samples shows that 6 to 38% of neoantigen candidates are potentially misclassified and can be rescued using allele-specific knowledge of anchor positions. A subset of anchor results were orthogonally validated using protein crystallography structures. Representative anchor trends were experimentally validated using peptide-MHC stability assays and competition binding assays. By incorporating our anchor prediction results into neoantigen prediction pipelines, we hope to formalize, streamline, and improve the identification process for relevant clinical studies. Taking neoantigen anchors into account: Design of personalized neoantigen vaccines for cancer relies on identification of tumor-specific mutations that can be effectively targeted by autologous T cells. A challenge in the development of computational algorithms for accurate neoantigen prediction is human HLA polymorphisms that influence how well candidate neoantigen peptides will be presented by self HLA class I molecules. Xia et al. report development of a modified computational workflow for neoantigen prediction that factors in which amino acid positions are anchor residues for peptide binding to each patient's HLA class I alleles. Accounting for allele-specific anchor position preferences enhanced neoantigen prediction by avoiding the inadvertent exclusion of candidate neoantigens that could be missed or misclassified by computational approaches not customized for HLA class I allele-associated variations in anchor residue usage. –IRW [ABSTRACT FROM AUTHOR]

Objective: We explored the potential of neurofilament light chain (NfL) in serum and cerebrospinal fluid as a biomarker for neurodestruction in status epilepticus. Methods: In a retrospective analysis, we measured NfL in serum and cerebrospinal fluid samples of patients with status epilepticus using a highly sensitive single-molecule array technique (Simoa). Status epilepticus was diagnosed according to ILAE criteria. Additionally, we employed an alternative classification with more emphasis on the course of status epilepticus. We used data from three large control groups to compare NfL in status epilepticus versus neurologically healthy controls. Results: We included 28 patients (mean age: 69.4 years, SD: 15 years) with a median status duration of 44 h (IQR: 80 h). Twenty-one patients (75%) suffered from convulsive status epilepticus and seven (25%) from non-convulsive status epilepticus. Six patients died (21%). Cerebrospinal fluid and serum NfL concentrations showed a high correlation (r = 0.73, p < 0.001, Pearson). The main determinant of NfL concentration was the status duration. NfL concentrations did not differ between convulsive status epilepticus and convulsive status epilepticus classified according to the ILAE or to the alternative classification without and with adjusting for status duration and time between status onset and sampling. We found no association of NfL concentration with death, treatment refractoriness, or prognostic scores. Conclusion: The results suggest that neurodestruction in status epilepticus measured by NfL is mainly determined by status duration, not status type nor therapy refractoriness. Therefore, our results suggest that regarding neurodestruction convulsive and non-convulsive status epilepticus are both neurological emergencies of comparable urgency. [ABSTRACT FROM AUTHOR]

Road transportation is among the global grand challenges affecting human lives, health, society, and economy, caused due to road accidents, traffic congestion, and other transportation deficiencies. Autonomous vehicles (AVs) are set to address major transportation challenges including safety, efficiency, reliability, sustainability, and personalization. The foremost challenge for AVs is to perceive their environments in real-time with the highest possible certainty. Relatedly, connected vehicles (CVs) have been another major driver of innovation in transportation. In this paper, we bring autonomous and connected vehicles together and propose TAAWUN, a novel approach based on the fusion of data from multiple vehicles. The aim herein is to share the information between multiple vehicles about their environments, enhance the information available to the vehicles, and make better decisions regarding the perception of their environments. TAWUN shares, among the vehicles, visual data acquired from cameras installed on individual vehicles, as well as the perceived information about the driving environments. The environment is perceived using deep learning, random forest (RF), and C5.0 classifiers. A key aspect of the TAAWUN approach is that it uses problem specific feature sets to enhance the prediction accuracy in challenging environments such as problematic shadows, extreme sunlight, and mirage. TAAWUN has been evaluated using multiple metrics, accuracy, sensitivity, specificity, and area-under-the-curve (AUC). It performs consistently better than the base schemes. Directions for future work to extend the tool are provided. This is the first work where visual information and decision fusion are used in CAVs to enhance environment perception for autonomous driving. [ABSTRACT FROM AUTHOR]

The finding of mirror neurons (MNs) has provided a biological substrate to a new concept of cognition, relating data on actions and perceptions not only to integrate perception in action planning and execution but also as a neural mechanism supporting a wide range of cognitive functions. Here we first summarize data on MN localization and role in primates, then we report findings in normal human subjects: functional magnetic resonance imaging and neurophysiological studies sustain that MNs have a role in motor learning and recognizing actions and intentions of others, and they also support an embodied view of language, empathy, and memory. Then, we detail the results of literature searching on MNs and embodied cognition in Parkinson's disease (PD), frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS), and in mild cognitive impairment (MCI)/Alzheimer's disease (AD). In PD the network of MN could be altered, but its hyperactivation might support motor and cognitive performances at least in early stages. In the ALS/FTD continuum, preliminary evidence points out to an involvement of the MN network, which could explain language and inter-subjectivity deficits shown in patients affected by these clinical entities. In the MCI/AD spectrum, a few recent studies suggest a possible progressive involvement from posterior to anterior areas of the MN network, with the brain putting in place compensatory mechanisms in early stages. Reinterpreting neurodegenerative diseases at the light of the new views about brain organization stemming from the discovery of MN could help to better comprehend clinical manifestations and open new pathways to rehabilitation., (© 2020 Wiley Periodicals, Inc.)

Currently, nine polyglutamine (polyQ) expansion diseases are known. They include spinocerebellar ataxias (SCA1, 2, 3, 6, 7, 17), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and Huntington's disease (HD). At the root of these neurodegenerative diseases are trinucleotide repeat mutations in coding regions of different genes, which lead to the production of proteins with elongated polyQ tracts. While the causative proteins differ in structure and molecular mass, the expanded polyQ domains drive pathogenesis in all these diseases. PolyQ tracts mediate the association of proteins leading to the formation of protein complexes involved in gene expression regulation, RNA processing, membrane trafficking, and signal transduction. In this review, we discuss commonalities and differences among the nine polyQ proteins focusing on their structure and function as well as the pathological features of the respective diseases. We present insights from AlphaFold-predicted structural models and discuss the biological roles of polyQ-containing proteins. Lastly, we explore reported protein-protein interaction networks to highlight shared protein interactions and their potential relevance in disease development., (© 2024 The Authors. Proteomics published by Wiley‐VCH GmbH.)

Nerve conduction studies are usually the first diagnostic step in peripheral nerve disorders and their results are the basis for planning further investigations. However, there are some commonplaces in the interpretation of electrodiagnostic findings in peripheral neuropathies that, although useful in the everyday practice, may be misleading: (1) conduction block and abnormal temporal dispersion are distinctive features of acquired demyelinating disorders; (2) hereditary neuropathies are characterized by uniform slowing of conduction velocity; (3) axonal neuropathies are simply diagnosed by reduced amplitude of motor and sensory nerve action potentials with normal or slightly slow conduction velocity. In this review, we reappraise the occurrence of uniform and non-uniform conduction velocity slowing, conduction block and temporal dispersion in demyelinating, dysmyelinating and axonal neuropathies attempting, with a translational approach, a correlation between electrophysiological and pathological features as derived from sensory nerve biopsy in patients and animal models. Additionally, we provide some hints to navigate in this complex field., (© 2024 Peripheral Nerve Society.)

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology., (© 2024 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Barrier-forming olfactory glia cells, termed sustentacular cells, play important roles for immune defense of the olfactory mucosa, for example as entry sites for SARS-CoV-2 and subsequent development of inflammation-induced smell loss. Here we demonstrate that sustentacular cells express ACKR3, a chemokine receptor that functions both as a scavenger of the chemokine CXCL12 and as an activator of alternative signaling pathways. Differential gene expression analysis of bulk RNA sequencing data obtained from WT and ACKR3 conditional knockout mice revealed upregulation of genes involved in immune defense. To map the regulated genes to the different cell types of the olfactory mucosa, we employed biocomputational methods utilizing a single-cell reference atlas. Transcriptome analysis, PCR and immunofluorescence identified up-regulation of NF-κB-related genes, known to amplify inflammatory signaling and to facilitate leukocyte transmigration, in the gliogenic lineage. Accordingly, we found a marked increase in leukocyte-expressed genes and confirmed leukocyte infiltration into the olfactory mucosa. In addition, lack of ACKR3 led to enhanced expression and secretion of early mediators of immune defense by Bowman's glands. As a result, the number of apoptotic cells in the epithelium was decreased. In conclusion, our research underlines the importance of sustentacular cells in immune defense of the olfactory mucosa. Moreover, it identifies ACKR3, a druggable G protein-coupled receptor, as a promising target for modulation of inflammation-associated anosmia., (© 2024 The Authors. GLIA published by Wiley Periodicals LLC.)

Occupational nerve injuries span a broad array of pathologies and contribute toward functional limitation, disability, and economic impact. Early and accurate recognition, treatment, and management of workplace factors rely on a thorough understanding of the anatomic and biomechanical factors that drive nerve injury. This review explores the interplay between anatomy, biomechanics, and nerve pathology common to occupational nerve injury and provides the treating physician with a rational, evidence-based approach to diagnosis and to occupational aspects of management. Assessment of potential occupational nerve injury begins with a detailed understanding of the employee's work duties through a biomechanical lens. One must consider likelihood of occupational causation while accounting for predisposing conditions or preexisting symptoms. Beyond overt crush injury or laceration, potential mechanisms of nerve injury, with effects compounded over time, include compression, stretch, vibration, and repetitive or high-force movements of regional muscles and joints. Injury often occurs at nerve locations that experience higher pressures, changes in pressure over time, or abrupt changes in trajectory, often near a tethered point. This understanding, coupled with condition-specific knowledge presented in this review, equips managing physicians to diagnose occupational nerve injury and enhance treatment recommendations with rational activity modifications or equipment that can protect the nerve or decrease likelihood of continued injury. Long-term management often involves follow-up to assess effectiveness of interventions in the setting of the work environment, with gradual progression of the worker toward return to unrestricted duty or to a point of maximal medical improvement., (© 2024 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Neurological diseases are a major global health challenge, affecting hundreds of millions of people worldwide. Ultrasound therapy plays an irreplaceable role in the treatment of neurological diseases due to its noninvasive, highly focused, and strong tissue penetration capabilities. However, the complexity of brain and nervous system and the safety risks associated with prolonged exposure to ultrasound therapy severely limit the applicability of ultrasound therapy. Ultrasound-sensitive intelligent nanosystems (USINs) are a novel therapeutic strategy for neurological diseases that bring greater spatiotemporal controllability and improve safety to overcome these challenges. This review provides a detailed overview of therapeutic strategies and clinical advances of ultrasound in neurological diseases, focusing on the potential of USINs-based ultrasound in the treatment of neurological diseases. Based on the physical and chemical effects induced by ultrasound, rational design of USINs is a prerequisite for improving the efficacy of ultrasound therapy. Recent developments of ultrasound-sensitive nanocarriers and nanoagents are systemically reviewed. Finally, the challenges and developing prospects of USINs are discussed in depth, with a view to providing useful insights and guidance for efficient ultrasound treatment of neurological diseases., (© 2023 Wiley‐VCH GmbH.)

Aims: The aim of the study was to analyze objective and subjective olfactory/gustatory function in post-COVID-19 infection (PCI)., Materials and Methods: Patients with past PCR-confirmed COVID-19 infection and persistent olfactory/gustatory complaints were investigated. Olfactory threshold and identification, gustatory detection, identification, and magnitude scaling were tested., Results: A total of 42 PCI subjects were compared to 41 age- and gender-matched controls with no COVID-19 history. All PCI tested had mild COVID-19 disease. Mean interval between COVID-19 confirmations to testing was 7.4 ± 3.1 months. PCI subjects complained of combined dysfunction in 85.7%, isolated olfactory or gustatory dysfunction in 7.1% each. Combined complaints were significantly higher in PCI (p < 0.001). Objective testing showed significantly higher prevalence of dysfunction in PCI versus controls for hyposmia (73.8%, 12.2%), anosmia (11.9%, 0%), odor identification (68.5%, 83.0%), hypogeusia (23% and 2.4%, respectively), and impaired magnitude scaling, (p < 0.05). All PCI subjects with hypogeusia had abnormal gustatory magnitude scaling., Conclusions: While most PCI subjects complained of combined gustatory and olfactory dysfunction, objective testing showed in the majority an isolated single sense dysfunction, with a low level of agreement between subjective and objective findings. Abnormal objective results for all olfactory and gustatory functions tested may suggest a central rather than peripheral mechanism, although concomitant mechanisms cannot be excluded., (© 2023 Wiley Periodicals LLC.)

Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD. [ABSTRACT FROM AUTHOR]

We observed a Polish family with familial amyotrophic lateral sclerosis with heterozygous L144S SOD1 mutation, which manifested clinically as flail leg syndrome. Flail leg syndrome is a rare phenotype of amyotrophic lateral sclerosis, with slow progression, long survival, and predominance of lower motor neuron signs at onset, as a triad of distal paresis, muscle atrophy, and hyporeflexia/areflexia, confined to the lower limbs for an extended period of time. Although familial amyotrophic lateral sclerosis is usually associated with a worse prognosis than the sporadic form of the disease, the clinical course of the disease in patients with L144S SOD1 mutation is benign, with slow progression and long survival. This unique case report provides an in-depth clinical analysis of all of the symptomatic members of a family, who were diagnosed with amyotrophic lateral sclerosis in our clinic, including three siblings (two brothers and a deceased sister) with flail leg syndrome and their fraternal aunt, who has been previously misdiagnosed with cervical myelopathy and is living with symptoms of the disease for 15 years. Sanger sequencing of the SOD1 gene was performed in all of the living patients, revealing an L144S (c.434T>C, p.Leu145Ser) heterozygous mutation. The aim of this case report is to increase the physician’s awareness of the atypical phenotypes of amyotrophic lateral sclerosis and hopefully, to encourage further research on the factors responsible for delayed disease progression in patients with L144S SOD1 mutation. [ABSTRACT FROM AUTHOR]

A major function of TAR DNA-binding protein-43 (TDP-43) is to repress the inclusion of cryptic exons during RNA splicing. One of these cryptic exons is in UNC13A, a genetic risk factor for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of cryptic UNC13A in disease is heightened by the presence of a risk haplotype located within the cryptic exon itself. Here, we revealed that TDP-43 extreme N-terminus is important to repress UNC13A cryptic exon inclusion. Further, we found hnRNP L, hnRNP A1, and hnRNP A2B1 bind UNC13A RNA and repress cryptic exon inclusion, independently of TDP-43. Finally, higher levels of hnRNP L protein associate with lower burden of UNC13A cryptic RNA in ALS/FTD brains. Our findings suggest that while TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially function as disease modifiers. This study shows that TDP-43 is the most important repressor of cryptic exon splicing in UNC13A, a risk factor for amyotrophic lateral sclerosis and frontotemporal dementia. While TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially act as disease modifiers. [ABSTRACT FROM AUTHOR]

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neuron function. Although ophthalmic deficits are not considered a classic symptom of ALS, recent studies suggest that changes in retinal cells, similar to those in the spinal cord motor neurons, have been observed in postmortem human tissues and animal models. Methods: In this study, we examined by immunofluorescence analysis the retinal cell layers of sporadic ALS patients in post-mortem retinal slices. We evaluated the presence of cytoplasmic TDP-43 and SQSTM1/p62 aggregates, activation of the apoptotic pathway, and microglia and astrocytes reactivity. Results: We found in the retinal ganglion cell layer of ALS patients the increase of mislocalized TDP-43, SQSTM1/p62 aggregates, activation of cleaved caspase-3, and microglia density, suggesting that retinal changes can be used as an additional diagnostic tool for ALS. Discussion: The retina is considered part of the central nervous system, and neurodegenerative changes in the brain may be accompanied by structural and possibly functional changes in the neuroretina and ocular vasculature. Therefore, using in vivo retinal biomarkers as an additional diagnostic tool for ALS may provide an opportunity to longitudinally monitor individuals and therapies over time in a noninvasive and cost-effective manner. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons. In 10% of patients, the disorder runs in the family. Our aim was to study the impact of ALS-causing gene mutations on cerebral glucose metabolism. Between October 2010 and October 2022, 538 patients underwent genetic testing for mutations with strong evidence of causality for ALS and 18F-2-fluoro-2-deoxy-D-glucose-PET (FDG PET), at University Hospitals Leuven. We identified 48 C9orf72-ALS and 22 SOD1-ALS patients. After propensity score matching, two cohorts of 48 and 21 matched sporadic ALS patients, as well as 20 healthy controls were included. FDG PET images were assessed using a voxel-based and volume-of-interest approach. We observed widespread frontotemporal involvement in all ALS groups, in comparison to healthy controls. The degree of relative glucose metabolism in SOD1-ALS in motor and extra-motor regions did not differ significantly from matched sporadic ALS patients. In C9orf72-ALS, we found more pronounced hypometabolism in the peri-rolandic region and thalamus, and hypermetabolism in the medulla extending to the pons, in comparison to matched sporadic ALS patients. Our study revealed C9orf72-dependent differences in glucose metabolism in the peri-rolandic region, thalamus, and brainstem (i.e., medulla, extending to the pons) in relation to matched sporadic ALS patients. [ABSTRACT FROM AUTHOR]

TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer's disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g., STMN2), as well as being able to modify disease progression (e.g., UNC13A). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease. [ABSTRACT FROM AUTHOR]

In recent years, the number of malicious web pages has increased dramatically, posing a great challenge to network security. While current machine learning-based detection methods have emerged as a promising alternative to traditional detection techniques. However, these methods are commonly based on single-modal features or simple stacking of classifiers built on various features. As a result, these techniques are not capable of effectively fusing features from different modalities, ultimately limiting the detection effectiveness. To address this limitation, we propose a malicious web page detection method based on multi-modal learning and pre-trained models. First, in the input stage, the raw URL and HTML tag sequences of web pages are used as input features. To help the subsequent model learn the relationship between the two modalities and avoid information confusion, modal-type encoding, and positional encoding are introduced. Next, a single-stream neural network based on the ConvBERT pre-trained model is used as the backbone classifier, and it learns the representation of multi-modal features through fine-tuning. For the output part of the model, a linear layer based on large margin softmax is applied to the decision-making. This activation function effectively increases the classification boundary and improves the robustness. In addition, a coarse-grained modal matching loss is added to the model optimization objective to assist the models in learning the cross-modal association features. Experimental results on synthetic datasets show that our proposed method outperforms traditional single-modal detection methods in general, and has advantages over baseline models in terms of accuracy and reliability. [ABSTRACT FROM AUTHOR]

Individuals with amyotrophic lateral sclerosis (ALS) frequently develop speech and communication problems in the course of their disease. Currently available augmentative and alternative communication technologies do not present a solution for many people with advanced ALS, because these devices depend on residual and reliable motor activity. Brain–computer interfaces (BCIs) use neural signals for computer control and may allow people with late-stage ALS to communicate even when conventional technology falls short. Recent years have witnessed fast progression in the development and validation of implanted BCIs, which place neural signal recording electrodes in or on the cortex. Eventual widespread clinical application of implanted BCIs as an assistive communication technology for people with ALS will have significant consequences for their daily life, as well as for the clinical management of the disease, among others because of the potential interaction between the BCI and other procedures people with ALS undergo, such as tracheostomy. This article aims to facilitate responsible real-world implementation of implanted BCIs. We review the state of the art of research on implanted BCIs for communication, as well as the medical and ethical implications of the clinical application of this technology. We conclude that the contribution of all BCI stakeholders, including clinicians of the various ALS-related disciplines, will be needed to develop procedures for, and shape the process of, the responsible clinical application of implanted BCIs. [ABSTRACT FROM AUTHOR]

Purpose of Review: Peripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV. Recent Findings: Progress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Summary: Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV. [ABSTRACT FROM AUTHOR]

Nowadays, phishing attacks have become one of the major security threats that acquire the personal credentials of Internet users via forged websites for committing fraudulent financial transactions. The traditional phishing detection approaches employ single classification method in which the accuracy is more dependent on specific classification algorithm. A particular classifier may well perform on some dataset and less accurately on others. Hence, the framework for combining the complementary information of different classifiers is required to increase the prediction accuracy. This study assesses the performance of various neural network algorithms for selecting the base classifiers and models an ensemble method for detecting phishing websites. Based on the experimental results, Radial Basis Function (RBF), Generalized Radial Basis Function (GRBF), Probabilistic Neural Network (PNN), and Heteroscedastic Probabilistic Neural Network (HPNN) have been chosen as base classifiers for the proposed ensemble method. The proposed approach is focused on improving the performance of base classifiers individually as well as collaboratively for detecting phishing websites. Our proposed ensemble approach, Deep Ensemble Evidential Neural Network (DeepEEviNNet) is obtained by combining the outcome of base classifiers based on their weights for making the final decision. The optimal weight of each classifier is determined by the distance existing between the fusion result that is calculated using Dempster Shafer Theory (DST) and the ground truth. In addition, a novel categorical clustering algorithm named WEighted Fuzzy condense K-Modes (WEFKM) clustering is proposed to determine the RBF centers and Gaussian kernels of the base classifiers. The performance of DeepEEviNNet has been evaluated on various phishing datasets. The results obtained from the experiments reveal that DeepEEviNNet outperforms the stand-alone classification techniques as well as other ensemble methods for detecting phishing attacks. [ABSTRACT FROM AUTHOR]

Several studies using cryogenic electron microscopy (cryo-EM) techniques recently reported the isolation and characterization of novel protein filaments, composed of a C-terminal fragment (CTF) of the endolysosomal transmembrane protein 106B (TMEM106B), from human post-mortem brain tissue with various neurodegenerative conditions and normal aging. Genetic variation in TMEM106B is known to influence the risk and presentation of several neurodegenerative diseases, especially frontotemporal dementia (FTD) caused by mutations in the progranulin gene (GRN). To further elucidate the significance of TMEM106B CTF, we performed immunohistochemistry with antibodies directed against epitopes within the filament-forming C-terminal region of TMEM106B. Accumulation of TMEM106B C-terminal immunoreactive (TMEM-ir) material was a common finding in all the conditions evaluated, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer's disease, tauopathies, synucleinopathies and neurologically normal aging. TMEM-ir material was present in a wide range of brain cell types and in a broad neuroanatomical distribution; however, there was no co-localization of TMEM-ir material with other neurodegenerative proteins in cellular inclusions. In most conditions, the presence and abundance of TMEM-ir aggregates correlated strongly with patient age and showed only a weak correlation with the TMEM106B haplotype or the primary pathological diagnosis. However, all patients with FTD caused by GRN mutations were found to have high levels of TMEM-ir material, including several who were relatively young (< 60 years). These findings suggest that the accumulation of TMEM106B CTF is a common age-related phenomenon, which may reflect lysosomal dysfunction. Although its significance in most neurodegenerative conditions remains uncertain, the consistent finding of extensive TMEM-ir material in cases of FTLD-TDP with GRN mutations further supports a pathomechanistic role of TMEM106B and lysosomal dysfunction in this specific disease population. [ABSTRACT FROM AUTHOR]

With the origin of smart homes, smart cities, and smart everything, smart phones came up as an area of magnificent growth and development. These devices became a part of daily activities of human life. This impact and growth have made these devices more vulnerable to attacks than other devices such as desktops or laptops. Text messages or SMS (Short Text Messages) are a part of smartphones through which attackers target the users. Smishing (SMS Phishing) is an attack targeting smartphone users through the medium of text messages. Though smishing is a type of phishing, it is different from phishing in many aspects like the amount of information available in the SMS, the strategy of attack, etc. Thus, detection of smishing is a challenge in the context of the minimum amount of information shared by the attacker. In the case of smishing, we have short text messages which are often in short forms or in symbolic forms. A single text message contains very few smishing-related features, and it consists of abbreviations and idioms which makes smishing detection more difficult. Detection of smishing is a challenge not only because of features constraint but also due to the scarcity of real smishing datasets. To differentiate spam messages from smishing messages, we are evaluating the legitimacy of the URL (Uniform Resource Locator) in the message. We have extracted the five most efficient features from the text messages to enable the machine learning classification using a limited number of features. In this paper, we have presented a smishing detection model comprising of two phases, Domain Checking Phase and SMS Classification Phase. We have examined the authenticity of the URL in the SMS which is a crucial part of SMS phishing detection. In our system, Domain Checking Phase scrutinizes the authenticity of the URL. SMS Classification Phase examines the text contents of the messages and extracts some efficient features. Finally, the system classifies the messages using Backpropagation Algorithm and compares results with three traditional classifiers. A prototype of the system has been developed and evaluated using SMS datasets. The results of the evaluation achieved an accuracy of 97.93% which shows the proposed method is very efficient for the detection of smishing messages. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the progressive neurological diseases which affect around 10 million population worldwide. The clinical manifestation of motor symptoms in PD patients appears later when most dopaminergic neurons have degenerated. Thus, for better management of PD, the development of accurate biomarkers for the early prognosis of PD is imperative. The present work will discuss the potential biomarkers from various attributes covering biochemical, microRNA, and neuroimaging aspects (α-synuclein, DJ-1, UCH-L1, β-glucocerebrosidase, BDNF, etc.) for diagnosis, recent development in PD management, and major limitations with current and conventional anti-Parkinson therapy. This manuscript summarizes potential biomarkers and therapeutic targets, based on available preclinical and clinical evidence, for better management of PD. [ABSTRACT FROM AUTHOR]

This work presents detailed anatomic labels for a spatiotemporal atlas of fetal brain Diffusion Tensor Imaging (DTI) between 23 and 30 weeks of post‐conceptional age. Additionally, we examined developmental trajectories in fractional anisotropy (FA) and mean diffusivity (MD) across gestational ages (GA). We performed manual segmentations on a fetal brain DTI atlas. We labeled 14 regions of interest (ROIs): cortical plate (CP), subplate (SP), Intermediate zone‐subventricular zone‐ventricular zone (IZ/SVZ/VZ), Ganglionic Eminence (GE), anterior and posterior limbs of the internal capsule (ALIC, PLIC), genu (GCC), body (BCC), and splenium (SCC) of the corpus callosum (CC), hippocampus, lentiform Nucleus, thalamus, brainstem, and cerebellum. A series of linear regressions were used to assess GA as a predictor of FA and MD for each ROI. The combination of MD and FA allowed the identification of all ROIs. Increasing GA was significantly associated with decreasing FA in the CP, SP, IZ/SVZ/IZ, GE, ALIC, hippocampus, and BCC (p <.03, for all), and with increasing FA in the PLIC and SCC (p <.002, for both). Increasing GA was significantly associated with increasing MD in the CP, SP, IZ/SVZ/IZ, GE, ALIC, and CC (p <.03, for all). We developed a set of expert‐annotated labels for a DTI spatiotemporal atlas of the fetal brain and presented a pilot analysis of developmental changes in cerebral microstructure between 23 and 30 weeks of GA. [ABSTRACT FROM AUTHOR]

Adolescence is characterized by significant brain development and marks a period of the life span with an increased incidence of mood disorders, especially in females. The risk of developing mood disorders is also higher in individuals scoring high on neuroticism, a personality trait characterized by a tendency to experience negative and anxious emotions. We previously found in a cross‐sectional study that neuroticism is associated with microstructural left–right asymmetry of the fronto‐limbic white matter involved in emotional processing, with opposite effects in female and male adolescents. We now have extended this work collecting longitudinal data in 76 typically developing children and adolescents aged 7–18 years, including repeated MRI sampling up to 11 times. This enabled us, for the first time, to address the critical question, whether the association between neuroticism and frontal‐limbic white matter asymmetry changes or remains stable across late childhood and adolescence. Neuroticism was assessed up to four times and showed good intraindividual stability and did not significantly change with age. Conforming our cross‐sectional results, females scoring high on neuroticism displayed increased left–right cingulum fractional anisotropy (FA), while males showed decreased left–right cingulum FA asymmetry. Despite ongoing age‐related increases in FA in cingulum, the association between neuroticism and cingulum FA asymmetry was already expressed in females in late childhood and remained stable across adolescence. In males, the association appeared to become more prominent during adolescence. Future longitudinal studies need to cover an earlier age span to elucidate the time point at which the relationship between neuroticism and cingulum FA asymmetry arises. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the effects of flywheel squat training on lower body muscle function adaptations and sport-specific performance in collegiate club water polo players. Methods: Thirteen collegiate club water polo athletes (5 women, 8 men) performed flywheel squat training for 4 weeks. Isokinetic knee extension (KE) peak power (PP) and peak torque (PT), flywheel squat peak power (FPP) and mean power (FMP), countermovement jump (CMJ), in-water jump height (WJH) and foot speed were assessed at baseline (Pre1), 4 weeks (Pre2), and 8 weeks (Post) with the first 4 week block being a control period and the second 4 week block being the experimental training. Throughout the training period muscle soreness was assessed using a VAS scale, and FPP and FMP were assessed during every other session. Results: Isokinetic KE PP and PT increased from Pre1 to Post, and FPP and FMP increased between Pre1 and Post, and Pre2 and Post. CMJ and foot speed were unchanged. WJH displayed a change between Pre1 and Post. FPP increased 19% from session 2 to 4 and FMP increased 27% from session 2 to 6, and each remained elevated through session 8. Conclusion: 4 weeks of flywheel squat training in collegiate club water polo players elicited large gains (47–52%) in flywheel-specific squat power, but did not influence sport-specific performance measures including CMJ, WJH, and foot speed. Water-based exercises and stretch-shortening cycle movements (plyometrics) in combination with effective resistance training programs, which may include flywheel-based training, are likely needed for marked sport skill improvements. [ABSTRACT FROM AUTHOR]

This paper critically examines how senior figures in the UK Labour Party and wider labour movement discussed the topic of immigration in the immediate aftermath of the UK's vote to leave the European Union in 2016. Influenced by the Discourse Historical Approach, the paper is based on an analysis of 86 public interventions by Labour figures, over a 6-month period, delivered in speeches, articles and essays. The paper examines argumentative strategies adopted by Labour figures – including Members of Parliament, advisors and trade union leaders – who called for stronger immigration controls from an avowedly 'left-wing' perspective. Foregrounding their commitment to progressive politics, Labour politicians argued that restricting the number of migrants entering Britain was democratic, anti-racist and an expression of the Labour Party's commitment to the interests of working-class people. Nevertheless, it is the contention of this paper that the Labour Party's rhetoric tapped into right-wing populist discourses which constructed immigration as a threat to the racialised privileges of a 'white' working class. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively attacks motor neurons, and leads to progressive muscle weakness and death. A common pathological feature is the misfolding, aggregation, and cytoplasmic mislocalization of TAR DNA‐binding protein 43 (TDP‐43) proteins in more than 95% of ALS patients, suggesting a universal role TDP‐43 proteinopathy in ALS. Mutations in SQSTM1/p62 have been identified in familial and sporadic cases of ALS. MicroRNAs (miRNAs) are small non‐coding RNAs that post‐transcriptionally regulate their target genes. Emerging evidence indicates that miRNA dysregulation is associated with neuronal toxicity and mitochondrial dysfunction, and also plays a pivotal role in ALS pathogenesis. Here, we report the first evidence that miR‐183‐5p is aberrantly upregulated in spinal cords of patients with ALS. Using luciferase reporter assays and miR‐183‐5p agomirs, we demonstrate that miR‐183‐5p regulates the SQSTM1/p62 3′‐untranslated region to suppress expression. A miR‐183‐5p agomir attenuated SOSTM1/p62 expression and led to an increase in TDP‐43 protein levels in neuronal and non‐neuronal cells. In contrast, a miR‐183‐5p antagomir decreased TDP‐43 but increased SQSTM1/p62 protein levels. The antagomir repressed formation of stress granules and aggregated TDP43 protein in neuronal cells under stress‐induced conditions and protected against cytotoxicity. Knockdown of SQSTM1/p62 decreased total ubiquitination and increased TDP‐43 protein aggregation, indicating that SQSTM1/p62 may play a protective role in cells. In summary, our study reveals a novel mechanism of TDP‐43 proteinopathy mediated by the miR‐183‐5p and provides a molecular link between aberrant RNA processing and protein degradation, two major pillars in ALS pathogenesis. [ABSTRACT FROM AUTHOR]

Objectives: To compare the utility of conventional amplitude measurements of short-interval intracortical inhibition (A-SICI) with two threshold-tracking (T-SICI) methods, as aids to early diagnosis of amyotrophic lateral sclerosis (ALS). The new parallel threshold-tracking method (T-SICIp) was compared with the previously used serial tracking method (T-SICIs). Methods: 112 consecutive patients referred with the suspicion of ALS and 40 healthy controls were prospectively included. Based on clinical follow-up, patients were divided into 67 patients with motor neuron disease (MND) comprising progressive muscular atrophy (PMA) as well as ALS, and 45 patient controls. SICI was recorded from first dorsal interosseus muscle using the three different protocols. Results: MND patients had significantly reduced T-SICIp, T-SICIs and A-SICI, compared with healthy controls and patient controls, while healthy and patient controls were similar. Paradoxically, T-SICIp was least affected in MND patients with the most upper motor neuron (UMN) signs (Spearman ρ = 0.537, P < 0.0001) whereas there was no correlation for T-SICIs or A-SICI. T-SICIp also provided the best discrimination between patient controls and MND as determined by the receiver operating characteristic (ROC) curves. For patients with no UMN signs, area under ROC curve for 2-3ms inter-stimulus intervals was 0.931 for T-SICIp, 0.771 for T-SICIs and 0.786 for A-SICI. Conclusions: SICI is a sensitive measure for detection of cortical involvement in ALS patients. T-SICIp has higher sensitivity and specificity than T-SICIs and A-SICI, particularly in patients without any upper motor neuron signs. [ABSTRACT FROM AUTHOR]

Background: The UNC13A gene is an established susceptibility locus for amyotrophic lateral sclerosis (ALS) and a determinant of shorter survival after disease onset, with up to 33.0 months difference in life expectancy for carriers of the rs12608932 risk genotype. However, its overall effect on other clinical features and ALS phenotypic variability is controversial. Methods: Genotype data of the UNC13A rs12608932 SNP (A-major allele; C-minor allele) was obtained from a cohort of 972 ALS patients. Demographic and clinical variables were collected, including cognitive and behavioral profiles, evaluated through the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) - Italian version and the Frontal Behavioral Inventory (FBI); upper and lower motor neuron involvement, assessed by the Penn Upper Motor Neuron Score (PUMNS) and the Lower Motor Neuron Score (LMNS)/Medical Research Council (MRC) scores, respectively; the ALS Functional Rating Scale Revised (ALSFRS-R) score at evaluation and progression rate; age and site of onset; survival. The comparison between the three rs12608932 genotypes (AA, AC, and CC) was performed using the additive, dominant, and recessive genetic models. Results: The rs12608932 minor allele frequency was 0.31 in our ALS cohort, in comparison to 0.33-0.41 reported in other Caucasian ALS populations. Carriers of at least one minor C allele (AC + CC genotypes) had a shorter median survival than patients with the wild-type AA genotype (-11.7 months, p = 0.013), even after adjusting for age and site of onset, C9orf72 mutational status and gender. Patients harboring at least one major A allele (AA + AC genotypes) and particularly those with the wild-type AA genotype showed a significantly higher PUMNS compared to CC carriers (p = 0.015 and padj = 0.037, respectively), thus indicating a more severe upper motor neuron involvement. Our analysis did not detect significant associations with all the other clinical parameters considered. Conclusion: Overall, our findings confirm the role of UNC13A as a determinant of survival in ALS patients and show the association of this locus also with upper motor neuron involvement. [ABSTRACT FROM AUTHOR]

Clinical exome sequencing (ES) is the most comprehensive genomic test to identify underlying genetic diseases in Canada. We performed this retrospective cohort study to investigate the diagnostic yield of clinical ES in adulthood. Inclusion criteria were: (1) Adult patients ≥18 years old; (2) Patients underwent clinical ES between January 1 and December 31, 2021; (3) Patients were seen in the Department of Medical Genetics. We reviewed patient charts. We applied American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification guidelines for interpretation of variants. Non‐parametric Fisher's exact statistical test was used. Seventy‐seven patients underwent clinical ES. Fourteen different genetic diseases were confirmed in 15 patients: FBXO11, MYH7, MED13L, NSD2, ANKRD11 (n = 2), SHANK3, RHOBTB2, CDKL5, TRIO, TCF4, SCN1, SMAD3, POGZ, and EIF2B3 diseases. The diagnostic yield of clinical ES was 19.5%. Patients with a genetic diagnosis had a significantly higher frequency of neurodevelopmental disorders than those with no genetic diagnosis (p = 0.00339). The diagnostic yield of clinical ES was the highest in patients with seizures (35.7%), and with progressive neurodegenerative diseases (33.3%). Clinical ES is a helpful genomic test to provide genetic diagnoses to the patients who are referred to medical genetic clinics due to suspected genetic diseases in adulthood to end their diagnostic odyssey. Targeted next generation sequencing panels for specific phenotypes may decrease the cost of genomic test in adulthood. [ABSTRACT FROM AUTHOR]

Gresham's law popularly states that "bad money drives out good". It originates from monetary policy involving coinage, but it has for years been applied in a number of areas with various degrees of thoroughness and thoughtfulness. Although most applications are paraphrasing, and not scientific usage of analogy, Gresham's law fits remarkably well in many cases, and therefore deserves study. Analogies are used extensively throughout the history of science, but it requires a deep understanding of a phenomenon and a subsequent generic description that can be transferred to other domains. We believe that Gresham's law can be described using systems theory since most real-life systems fit within systems theory. We therefore review of Gresham's law to develop a simple, generic model. Through a simple simulation, to ascertain whether it makes sense or not, we find the generic model useful and we people that it can serve well in system-related, qualitative research. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) has been overwhelmingly applied to motor regions to date and our understanding of frontotemporal metabolic signatures is relatively limited. The association between metabolic alterations and cognitive performance in also poorly characterised. Material and Methods: In a multimodal, prospective pilot study, the structural, metabolic, and diffusivity profile of the hippocampus was systematically evaluated in patients with ALS. Patients underwent careful clinical and neurocognitive assessments. All patients were non-demented and exhibited normal memory performance. 1H-MRS spectra of the right and left hippocampi were acquired at 3.0T to determine the concentration of a panel of metabolites. The imaging protocol also included high-resolution T1-weighted structural imaging for subsequent hippocampal grey matter (GM) analyses and diffusion tensor imaging (DTI) for the tractographic evaluation of the integrity of the hippocampal perforant pathway zone (PPZ). Results: ALS patients exhibited higher hippocampal tNAA, tNAA/tCr and tCho bilaterally, despite the absence of volumetric and PPZ diffusivity differences between the two groups. Furthermore, superior memory performance was associated with higher hippocampal tNAA/tCr bilaterally. Both longer symptom duration and greater functional disability correlated with higher tCho levels. Conclusion: Hippocampal 1H-MRS may not only contribute to a better academic understanding of extra-motor disease burden in ALS, but given its sensitive correlations with validated clinical metrics, it may serve as practical biomarker for future clinical and clinical trial applications. Neuroimaging protocols in ALS should incorporate MRS in addition to standard structural, functional, and diffusion sequences. [ABSTRACT FROM AUTHOR]

This decade has seen the beginning of ground-breaking conceptual shifts in the research of Alzheimer's disease (AD), which acknowledges risk elements and the evolving wide spectrum of complicated underlying pathophysiology among the range of diverse neurodegenerative diseases. Significant improvements in diagnosis, treatments, and mitigation of AD are likely to result from the development and application of a comprehensive approach to precision medicine (PM), as is the case with several other diseases. This strategy will probably be based on the achievements made in more sophisticated research areas, including cancer. PM will require the direct integration of neurology, neuroscience, and psychiatry into a paradigm of the healthcare field that turns away from the isolated method. PM is biomarker-guided treatment at a systems level that incorporates findings of the thorough pathophysiology of neurodegenerative disorders as well as methodological developments. Comprehensive examination and categorization of interrelated and convergent disease processes, an explanation of the genomic and epigenetic drivers, a description of the spatial and temporal paths of natural history, biological markers, and risk markers, as well as aspects about the regulation, and the ethical, governmental, and sociocultural repercussions of findings at a subclinical level all require clarification and realistic execution. Advances toward a comprehensive systems-based approach to PM may finally usher in a new era of scientific and technical achievement that will help to end the complications of AD. [ABSTRACT FROM AUTHOR]