Subtypes Of Amyotrophic Lateral Sclerosis Research Articles

Examining the complex Interplay between gut microbiota abundance and short-chain fatty acid production in amyotrophic lateral sclerosis patients shortly after onset of disease.

This study aimed to assess differences in the enteral microbiome of relatively recent-onset amyotrophic lateral sclerosis (ALS) patients (< 6-15 months since symptom onset) compared to healthy individuals, focusing on short-chain fatty acids (SCFAs) as potential mediators of host metabolism. We included 28 volunteers (16 ALS, 12 controls) with informed consent. No significant effect of ALS on alpha diversity (measuring the variety and abundance of species within a single sample, and indicating the health and complexity of the microbiome) was observed, but ALS patients had higher abundances of Fusobacteria and Acidobacteria. ALS subtypes influenced specific species, with increased Fusobacteria and Tenericutes in spinal ALS compared to bulbar ALS. ALS patients showed increased Enterobacter, Clostridium, Veillonella, Dialister, Turicibacter, and Acidaminococcus species and decreased Prevotella, Lactobacillus, and Butyricimonas. Correlations between species varied between ALS patients and healthy individuals and among ALS subtypes. No significant differences in SCFA concentrations were found, but spinal ALS samples showed a trend towards decreased propionate content. Relationships between SCFAs and phyla colonization differed by disease status. This study suggests distinct enteral microbiome characteristics in ALS patients, though the implications are unclear. Further research is needed to determine if these differences are causative or consequential and to explore their potential as diagnostic or therapeutic targets. The study also underscores the heterogeneity of microbiome constraints in ALS and the need for more research into ALS and SCFA metabolism.

Graph theory network analysis reveals widespread white matter damage in brains of patients with classic ALS.

Objective: Amyotrophic lateral sclerosis (ALS) exhibits several different presentations and clinical phenotypes. Of these, classic ALS (ALS-Cl), which is the most common phenotype, presents with relatively equal amounts of upper motor neuron and lower motor neuron signs. Magnetic resonance imaging (MRI) provides a noninvasive way to assess central nervous system damage in these patients. To our knowledge no study is available where exploratory whole brain grey matter (GM) and white matter (WM) network analysis is performed considering only the ALS-Cl subgroup of ALS patients. Methods: GM voxel-based morphometry analysis and WM network analysis using graph theory was performed in the MRI dataset of 14 neurologic controls and 25 ALS-Cl patients. Results and Conclusions: No significant GM differences were observed between ALS-Cl and neurologic controls. WM network revealed significant (p < 0.05) reduction and increase in degree measure in several extramotor brain regions of ALS-Cl patients. Both global and local graph metrics revealed significant abnormal values in ALS-Cl patients when compared to neurologic controls. Significant WM changes in ALS-Cl patients with no significant GM changes suggest that neurodegeneration may onset as an "axonopathy" in this ALS subtype.

Exploiting the role of CSF NfL, CHIT1, and miR-181b as potential diagnostic and prognostic biomarkers for ALS.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by relentless and progressive loss of motor neurons. A molecular diagnosis, supported by the identification of specific biomarkers, might promote the definition of multiple biological subtypes of ALS, improving patient stratification and providing prognostic information. Here, we investigated the levels of neurofilament light chain (NfL), chitotriosidase (CHIT1) and microRNA-181b (miR-181b) in the cerebrospinal fluid (CSF) of ALS subjects (N = 210) as well as neurologically healthy and neurological disease controls (N = 218, including N = 74 with other neurodegenerative diseases) from a large European multicentric cohort, evaluating their specific or combined utility as diagnostic and prognostic biomarkers. NfL, CHIT1 and miR-181b all showed significantly higher levels in ALS subjects compared to controls, with NfL showing the most effective diagnostic performance. Importantly, all three biomarkers were increased compared to neurodegenerative disease controls and, specifically, to patients with Alzheimer's disease (AD; N = 44), with NfL and CHIT1 being also higher in ALS than in alpha-synucleinopathies (N = 22). Notably, ALS patients displayed increased CHIT1 levels despite having, compared to controls, a higher prevalence of a polymorphism lowering CHIT1 expression. While no relationship was found between CSF miR-181b and clinical measures in ALS (disease duration, functional disability, and disease progression rate), CSF NfL was the best independent predictor of disease progression and survival. This study deepens our knowledge of ALS biomarkers, highlighting the relative specificity of CHIT1 for ALS among neurodegenerative diseases and appraising the potential diagnostic utility of CSF miR-181b.

The genetics of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) has a strong genetic basis, but the genetic landscape of ALS appears to be complex. The purpose of this article is to review recent developments in the genetics of ALS. Large-scale genetic studies have uncovered more than 40 genes contributing to ALS susceptibility. Both rare variants with variable effect size and more common variants with small effect size have been identified. The most common ALS genes are C9orf72 , SOD1 , TARDBP and FUS . Some of the causative genes of ALS are shared with frontotemporal dementia, confirming the molecular link between both diseases. Access to diagnostic gene testing for ALS has to improve, as effective gene silencing therapies for some genetic subtypes of ALS are emerging, but there is no consensus about which genes to test for. Our knowledge about the genetic basis of ALS has improved and the first effective gene silencing therapies for specific genetic subtypes of ALS are underway. These therapeutic advances underline the need for better access to gene testing for people with ALS. Further research is needed to further map the genetic heterogeneity of ALS and to establish the best strategy for gene testing in a clinical setting.

Electrografted Laser-Induced Graphene: Direct Detection of Neurodegenerative Disease Biomarker in Cerebrospinal Fluid.

There are more than 50 neurodegenerative disorders, and amyotrophic lateral sclerosis (ALS) is one of the most common disorders that poses diagnostic and treatment challenges. The poly glycine-proline (polyGP) dipeptide repeat is a toxic protein that has been recognized as a pharmacodynamic biomarker of C9orf72-associated (c9+) ALS, a subtype of ALS that originates from genetic mutation. Early detection of polyGP will help healthcare providers start timely gene therapy. Herein, we developed a label-free electrochemical immunoassay for the simple detection of polyGP in unprocessed cerebrospinal fluid (CSF) samples collected from ALS patients in the National ALS Biorepository. For the first time, an electrografted laser-induced graphene (E-LIG) electrode system was employed in a sandwich format to detect polyGP using a label-free electrochemical impedance technique. The results show that the E-LIG-modified surface exhibited high sensitivity and selectivity in buffer and CSF media with limit of detection values of 0.19 and 0.27 ng/mL, respectively. The precision of the calibration model was better in CSF than in the buffer. The E-LIG immunosensor can easily select polyGP targets in the presence of other dipeptide proteins translated from the c9 gene. Further study with CSF samples from ALS patients demonstrated that the label-free E-LIG-based immunosensor not only quantified polyGP in the complex CSF matrix but also distinguished between c9+ and non-c9- ALS patients.

RNA editing regulates glutamatergic synapses in the frontal cortex of a molecular subtype of Amyotrophic Lateral Sclerosis

BackgroundAmyotrophic Lateral Sclerosis (ALS) is a highly heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons, affecting additional cell types and brain regions. Underlying molecular mechanisms are still elusive, in part due to disease heterogeneity. Molecular disease subtyping through integrative analyses including RNA editing profiling is a novel approach for identification of molecular networks involved in pathogenesis.MethodsWe aimed to highlight the role of RNA editing in ALS, focusing on the frontal cortex and the prevalent molecular disease subtype (ALS-Ox), previously determined by transcriptomic profile stratification. We established global RNA editing (editome) and gene expression (transcriptome) profiles in control and ALS-Ox cases, utilizing publicly available RNA-seq data (GSE153960) and an in-house analysis pipeline. Functional annotation and pathway analyses identified molecular processes affected by RNA editing alterations. Pearson correlation analyses assessed RNA editing effects on expression. Similar analyses on additional ALS-Ox and control samples (GSE124439) were performed for verification. Targeted re-sequencing and qRT-PCR analysis targeting CACNA1C, were performed using frontal cortex tissue from ALS and control samples (n = 3 samples/group).ResultsWe identified reduced global RNA editing in the frontal cortex of ALS-Ox cases. Differentially edited transcripts are enriched in synapses, particularly in the glutamatergic synapse pathway. Bioinformatic analyses on additional ALS-Ox and control RNA-seq data verified these findings. We identified increased recoding at the Q621R site in the GRIK2 transcript and determined positive correlations between RNA editing and gene expression alterations in ionotropic receptor subunits GRIA2, GRIA3 and the CACNA1C transcript, which encodes the pore forming subunit of a post-synaptic L-type calcium channel. Experimental data verified RNA editing alterations and editing-expression correlation in CACNA1C, highlighting CACNA1C as a target for further study.ConclusionsWe provide evidence on the involvement of RNA editing in the frontal cortex of an ALS molecular subtype, highlighting a modulatory role mediated though recoding and gene expression regulation on glutamatergic synapse related transcripts. We report RNA editing effects in disease-related transcripts and validated editing alterations in CACNA1C. Our study provides targets for further functional studies that could shed light in underlying disease mechanisms enabling novel therapeutic approaches.

Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.

TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro

BackgroundThere is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment.MethodsTo identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models.ResultsThrough MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation.ConclusionsOur MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

Differential cortical gray matter changes in early- and late-onset patients with amyotrophic lateral sclerosis.

Age at onset may be an important feature associated with distinct subtypes of amyotrophic lateral sclerosis (ALS). Little is known about the neuropathological mechanism of early-onset ALS (EO-ALS) and late-onset ALS (LO-ALS). Ninety ALS patients were divided into EO-ALS and LO-ALS group, and 128 healthy controls were matched into young controls(YCs) and old controls (OCs). A voxel-based morphometry approach was employed to investigate differences in gray matter volume (GMV). Significant age at onset-by-diagnosis interactions were found in the left parietal operculum, left precentral gyrus, bilateral postcentral gyrus, right occipital gyrus, and right orbitofrontal cortex. Post hoc analysis revealed a significant decrease in GMV in all affected regions of EO-ALS patients compared with YCs, with increased GMV in 5 of the 6 brain regions, except for the right orbitofrontal cortex, in LO-ALS patients compared with OCs. LO-ALS patients had a significantly increased GMV than EO-ALS patients after removing the aging effect. Correspondingly, GMV of the left postcentral gyrus correlated with disease severity in the 2 ALS groups. Our findings suggested that the pathological mechanisms in ALS patients with different ages at onset might differ. These findings provide unique insight into the clinical and biological heterogeneity of the 2 ALS subtypes.

A toxic gain-of-function mechanism in C9orf72 ALS impairs the autophagy-lysosome pathway in neurons

BackgroundMotor neurons (MNs), which are primarily affected in amyotrophic lateral sclerosis (ALS), are a specialized type of neurons that are long and non-dividing. Given their unique structure, these cells heavily rely on transport of organelles along their axons and the process of autophagy to maintain their cellular homeostasis. It has been shown that disruption of the autophagy pathway is sufficient to cause progressive neurodegeneration and defects in autophagy have been associated with various subtypes of ALS, including those caused by hexanucleotide repeat expansions in the C9orf72 gene. A more comprehensive understanding of the dysfunctional cellular mechanisms will help rationalize the design of potent and selective therapies for C9orf72-ALS.MethodsIn this study, we used induced pluripotent stem cell (iPSC)-derived MNs from C9orf72-ALS patients and isogenic control lines to identify the underlying mechanisms causing dysregulations of the autophagy-lysosome pathway. Additionally, to ascertain the potential impact of C9orf72 loss-of-function on autophagic defects, we characterized the observed phenotypes in a C9orf72 knockout iPSC line (C9-KO).ResultsDespite the evident presence of dysfunctions in several aspects of the autophagy-lysosome pathway, such as disrupted lysosomal homeostasis, abnormal lysosome morphology, inhibition of autophagic flux, and accumulation of p62 in C9orf72-ALS MNs, we were surprised to find that C9orf72 loss-of-function had minimal influence on these phenotypes. Instead, we primarily observed impairment in endosome maturation as a result of C9orf72 loss-of-function. Additionally, our study shed light on the pathological mechanisms underlying C9orf72-ALS, as we detected an increased TBK1 phosphorylation at S172 in MNs derived from C9orf72 ALS patients.ConclusionsOur data provides further insight into the involvement of defects in the autophagy-lysosome pathway in C9orf72-ALS and strongly indicate that those defects are mainly due to the toxic gain-of-function mechanisms underlying C9orf72-ALS.

Regional spreading pattern is associated with clinical phenotype in amyotrophic lateral sclerosis.

Increasing evidence shows that disease spreading in amyotrophic lateral sclerosis (ALS) follows a preferential pattern with more frequent involvement of contiguous regions from the site of symptom onset. The aim of our study was to assess if: (i) the burden of upper (UMN) and lower motor neuron (LMN) involvement influences directionality of disease spreading; (ii) specific patterns of disease progression are associated with motor and neuropsychological features of different ALS subtypes (classic, bulbar, primary lateral sclerosis, UMN-predominant, progressive muscular atrophy, flail arm, flail leg); and (iii) specific clinical features may help identify ALS subtypes, which remain localized to the site of onset for a prolonged time (regionally entrenching ALS). A single-centre, retrospective cohort of 913 Italian ALS patients was evaluated to assess correlations between directionality of the disease process after symptom onset and motor/neuropsychological phenotype. All patients underwent an extensive evaluation including the following clinical scales: Penn Upper Motor Neuron Score (PUMNS), MRC Scale for Muscle Strength and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The most frequent initial spreading pattern was that towards adjacent horizontal regions (77.3%), which occurred preferentially in patients with lower MRC scores (P = 0.038), while vertical diffusion (21.1%) was associated with higher PUMNS (P < 0.001) and with reduced survival (P < 0.001). Non-contiguous disease spreading was associated with more severe UMN impairment (P = 0.003), while contiguous disease pattern with lower MRC scores. Furthermore, non-contiguous disease spreading was associated with more severe cognitive impairment in both executive and visuospatial ECAS domains. Individuals with regionally entrenching ALS were more frequently female (45.6% versus 36.9%; P = 0.028) and had higher frequencies of symmetric disease onset (40.3% versus 19.7%; P < 0.001) and bulbar phenotype (38.5% versus 16.4%; P < 0.001). Our study suggests that motor phenotypes characterized by a predominant UMN involvement are associated with a vertical pattern of disease progression reflecting ipsilateral spreading within the motor cortex, while those with predominant LMN involvement display more frequently a horizontal spreading from one side of the spinal cord to the other. These observations raise the hypothesis that one of the mechanisms underlying disease spreading in ALS pathology is represented by diffusion of toxic factors in the neuron microenvironment. Finally, it is possible that in our cohort, regionally entrenching ALS forms are mainly observed in patients with atypical bulbar phenotypes, characterized by a slowly progressive course and relatively benign prognosis.

Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival.

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.

Symptoms timeline and outcomes in amyotrophic lateral sclerosis using artificial intelligence

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative motor neuron disease. Although an early diagnosis is crucial to provide adequate care and improve survival, patients with ALS experience a significant diagnostic delay. This study aimed to use real-world data to describe the clinical profile and timing between symptom onset, diagnosis, and relevant outcomes in ALS. Retrospective and multicenter study in 5 representative hospitals and Primary Care services in the SESCAM Healthcare Network (Castilla-La Mancha, Spain). Using Natural Language Processing (NLP), the clinical information in electronic health records of all patients with ALS was extracted between January 2014 and December 2018. From a source population of all individuals attended in the participating hospitals, 250 ALS patients were identified (61.6% male, mean age 64.7 years). Of these, 64% had spinal and 36% bulbar ALS. For most defining symptoms, including dyspnea, dysarthria, dysphagia and fasciculations, the overall diagnostic delay from symptom onset was 11 (6–18) months. Prior to diagnosis, only 38.8% of patients had visited the neurologist. In a median post-diagnosis follow-up of 25 months, 52% underwent gastrostomy, 64% non-invasive ventilation, 16.4% tracheostomy, and 87.6% riluzole treatment; these were more commonly reported (all Ps < 0.05) and showed greater probability of occurrence (all Ps < 0.03) in bulbar ALS. Our results highlight the diagnostic delay in ALS and revealed differences in the clinical characteristics and occurrence of major disease-specific events across ALS subtypes. NLP holds great promise for its application in the wider context of rare neurological diseases.

Molecular subtypes of ALS are associated with differences in patient prognosis

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood clinical heterogeneity, underscored by significant differences in patient age at onset, symptom progression, therapeutic response, disease duration, and comorbidity presentation. We perform a patient stratification analysis to better understand the variability in ALS pathology, utilizing postmortem frontal and motor cortex transcriptomes derived from 208 patients. Building on the emerging role of transposable element (TE) expression in ALS, we consider locus-specific TEs as distinct molecular features during stratification. Here, we identify three unique molecular subtypes in this ALS cohort, with significant differences in patient survival. These results suggest independent disease mechanisms drive some of the clinical heterogeneity in ALS.

Identification of an immune-related gene prognostic index for predicting prognosis, immunotherapeutic efficacy, and candidate drugs in amyotrophic lateral sclerosis.

Considering the great insufficiency in the survival prediction and therapy of amyotrophic lateral sclerosis (ALS), it is fundamental to determine an accurate survival prediction for both the clinical practices and the design of treatment trials. Therefore, there is a need for more accurate biomarkers that can be used to identify the subtype of ALS which carries a high risk of progression to guide further treatment. The transcriptome profiles and clinical parameters of a total of 561 ALS patients in this study were analyzed retrospectively by analysis of four public microarray datasets. Based on the results from a series of analyses using bioinformatics and machine learning, immune signatures are able to be used to predict overall survival (OS) and immunotherapeutic response in ALS patients. Apart from other comprehensive analyses, the decision tree and the nomogram, based on the immune signatures, were applied to guide individual risk stratification. In addition, molecular docking methodology was employed to screen potential small molecular to which the immune signatures might response. Immune was determined as a major risk factor contributing to OS among various biomarkers of ALS patients. As compared with traditional clinical features, the immune-related gene prognostic index (IRGPI) had a significantly higher capacity for survival prediction. The determination of risk stratification and assessment was optimized by integrating the decision tree and the nomogram. Moreover, the IRGPI may be used to guide preventative immunotherapy for patients at high risks for mortality. The administration of 2MIU IL2 injection in the short-term was likely to be beneficial for the prolongment of survival time, whose dosage should be reduced to 1MIU if the long-term therapy was required. Besides, a useful clinical application for the IRGPI was to screen potential compounds by the structure-based molecular docking methodology. Ultimately, the immune-derived signatures in ALS patients were favorable biomarkers for the prediction of survival probabilities and immunotherapeutic responses, and the promotion of drug development.

Empirical pathological staging and subtyping of TDP‐43 proteinopathies

AbstractBackgroundPathological aggregation of tar DNA‐binding protein 43 (TDP‐43) in the brain is the primary cause of many cases of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). It is therefore imperative to establish empirical staging systems to characterize and distinguish stereotypical patterns and commonplace deviations of different TDP‐43 proteinopathies.MethodWe use ordinal ratings of TDP‐43 burden from 19 brain regions to perform data‐driven disease progression modeling (SuStaIn) to find the most likely trajectories for FTLD‐TDP (n = 108), ALS (n = 137) and LATE (n = 283) from the CNDR Brain Bank at the University of Pennsylvania. Subtype number was defined using cross‐validated information criterion. Each individual was assigned a subtype and stage. Multivariate OLS models tested differences between subtypes. Stages were compared to age and existing staging schemes. Cross‐validated logistic regression was used for 3‐way classification using SuStaIn information only.ResultSuStaIn provided data‐driven staging of TDP‐43 proteinopathies complementing previously described human‐defined staging schema, further providing additional detail (Fig1A‐C; Fig3A‐C). SuStaIn also identified two distinct subtypes within FTLD‐TDP and a further two within ALS (Fig1D). FTLD‐TDP subtypes differed in TDP‐43 type and Alzheimer’s disease pathology (Table1); ALS subtypes were differentiated by age (Table 2) and by antemortem clinical characteristics. No subtypes were observed for the LATE group. Progression along data‐driven stages was positively associated with age in LATE individuals, but negatively associated with age in individuals with FTLD‐TDP (Fig2). Using only regional TDP‐43 severity, our data driven model could distinguish individuals diagnosed with ALS, FTD or LATE with a cross‐validated balanced precision of 0.93 and balanced recall of 0.92, and these metrics improved to 0.95 and 0.96 when combined with a logistic regression model (Fig3). Very little stage overlap was found between FTLD‐TDP and LATE, but stages that did overlap showed subtly different patterns (Fig4)ConclusionWe provide an empirical pathological staging system for ALS, FTLD‐TDP and LATE, which is sufficient for staging and accurate classification. We demonstrate that there is substantial heterogeneity amongst ALS and FTLD‐TDP progression patterns, whilst LATE exhibits a homogeneous progression pattern.

What's Important: Be That Doctor.

What's Important: Be That Doctor.

Forelimb Resistance Exercise Protects Against Neuromuscular Junction Denervation in the SOD1-G93A Rat Model of ALS.

The symptoms of Amyotrophic Lateral Sclerosis (ALS) include muscle weakness and eventual paralysis. These symptoms result from denervation of the neuromuscular junction (NMJ) and motor neuron cell death in the brain and spinal cord. Due to the "dying back" pattern of motor neuron degeneration, protecting NMJs should be a therapeutic priority. Although exercise has the potential to protect against NMJ denervation, its use in ALS has been controversial. Most preclinical studies have focused on aerobic exercise, which report that exercise can be beneficial at moderate intensities. The effects of resistance exercise on NMJ preservation in limb muscles have not been explored. We trained male SOD1-G93A rats, which model ALS, to perform a unilateral isometric forelimb resistance exercise task. This task allows within-animal comparisons of trained and untrained forelimbs. We then determined the effects of isometric resistance exercise on NMJ denervation and AMP kinase (AMPK) activation in forelimb muscles. Our results revealed that SOD1-G93A rats were able to learn and perform the task similarly to wildtype rats, even after loss of body weight. SOD1-G93A rats exhibited significantly greater NMJ innervation in their trained vs their untrained forelimb biceps muscles. Measures of activated (phosphorylated) AMPK (pAMPK) were also greater in the trained vs untrained forelimb triceps muscles. These results demonstrate that isometric resistance exercise may protect against NMJ denervation in ALS. Future studies are required to determine the extent to which our findings generalize to female SOD1-G93A rats and to other subtypes of ALS.

Pseudopolyneuritic form of amyotrophic lateral sclerosis: Marie-Patrikios type

Introduction: Amyotrophic lateral sclerosis (ALS), also called motor neuron disease (MND), is a progressive, neurodegenerative, and inexorable disease that affects the neurons of the anterior horn of the spinal cord, as well as the lateral funiculus. A rare variant of ALS was first described in 1918 by Patrikios and Marie, called the pseudopolyneuritic form or Marie-Patrikios disease. It is characterized by an initial manifestation with melting of the feet, distal weakness of the muscles of the anterior compartment of the leg, and absence of the Achilles tendon reflex. We present an atypical case of ALS, marked by polyneuropathy and involvement of upper and lower motor neurons. Case Report: A 70-year-old man reported that approximately four years ago he started having pain in the thoracic region with subsequent paresis in the lower limbs. Initially, compressive myelopathy, transverse myelitis, and spastic paraparesis of various causes were thought to be the cause. However, the non-impairment of the superficial and deep sensibility, obviously, with absence of sensorial level, associated to the absence of specific imaging findings in the thoracic and lumbar spine, a normal complete laboratory, ruled out such hypotheses. Conclusion: We highlight that the pseudopolyneuritic form presented in this study has a better prognosis and survival rate when compared to other subtypes of ALS. Thus, a detailed investigation including physical, neurological, and electrophysiological examination is essential to establish the diagnosis and increase the scarce knowledge about this condition.

MRI Clustering Reveals Three ALS Subtypes With Unique Neurodegeneration Patterns.

The purpose of this study was to identify subtypes of amyotrophic lateral sclerosis (ALS) by comparing patterns of neurodegeneration using brain magnetic resonance imaging (MRI) and explore their phenotypes. We performed T1-weighted and diffusion tensor imaging in 488 clinically well-characterized patients with ALS and 338 control subjects. Measurements of whole-brain cortical thickness and white matter connectome fractional anisotropy were adjusted for disease-unrelated variation. A probabilistic network-based clustering algorithm was used to divide patients into subgroups of similar neurodegeneration patterns. Clinical characteristics and cognitive profiles were assessed for each subgroup. In total, 512 follow-up scans were used to validate clustering results longitudinally. The clustering algorithm divided patients with ALS into 3 subgroups of 187, 163, and 138 patients. All subgroups displayed involvement of the precentral gyrus and are characterized, respectively, by (1) pure motor involvement (pure motor cluster [PM]), (2) orbitofrontal and temporal involvement (frontotemporal cluster [FT]), and (3) involvement of the posterior cingulate cortex, parietal white matter, temporal operculum, and cerebellum (cingulate-parietal-temporal cluster [CPT]). These subgroups had significantly distinct clinical profiles regarding male-to-female ratio, age at symptom onset, and frequency of bulbar symptom onset. FT and CPT revealed higher rates of cognitive impairment on the Edinburgh cognitive and behavioral ALS screen (ECAS). Longitudinally, clustering remained stable: at 90.4% of their follow-up visits, patients clustered in the same subgroup as their baseline visit. ALS can manifest itself in 3 main patterns of cerebral neurodegeneration, each associated with distinct clinical characteristics and cognitive profiles. Besides the pure motor and frontotemporal dementia (FTD)-like variants of ALS, a new neuroimaging phenotype has emerged, characterized by posterior cingulate, parietal, temporal, and cerebellar involvement. ANN NEUROL 2022;92:1030-1045.