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Objective: To investigate changes in immune markers and frequencies throughout disease progression in patients with amyotrophic lateral sclerosis (ALS). Methods: In this longitudinal study, serial blood samples were collected from 21 patients with ALS over a time period of up to 16 months. Flow cytometry was used to quantitate CD14, HLA-DR, and CD16 marker expression on monocyte subpopulations and neutrophils, as well as their cell population frequencies. A Generalized Estimating Equation model was used to assess the association between changes in these immune parameters and disease duration and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Results: CD14 expression on monocyte subpopulations increased with both disease duration and a decrease in ALSFRS-R score in patients with ALS. HLA-DR expression on monocyte subpopulations also increased with disease severity and/or duration. The expression of CD16 did not change relative to disease duration or ALSFRS-R. Finally, patients had a reduction in non-classical monocytes and an increase in the classical to non-classical monocyte ratio throughout disease duration. Conclusion: The progressive immunological changes observed in this study provide further support that monocytes are implicated in ALS pathology. Monocytic CD14 and HLA-DR surface proteins may serve as a therapeutic target or criteria for the recruitment of patients with ALS into clinical trials for immunomodulatory therapies.

IntroductionThe split‐hand concept has highlighted the preferential wasting of the thenar side of the hand in amyotrophic lateral sclerosis (ALS). Our objective is to re‐explore pinch grip strength to assess whether it has the potential to be a practical biomarker of ALS.MethodsWe measured different pinch grip strengths (thumb, index and fifth) using a pinch gauge from both hands of 54 ALS patients and correlated this with the Medical Research Council (MRC) score, the upper‐limb component of the revised ALS functional rating scale (ALSFRS‐R) score, and compound muscle action potentials (CMAPs) that comprise the split‐hand index.ResultsPinch grip strength using any of the three fingers showed a positive correlation with its corresponding CMAP, MRC grading and upper‐limb ALSFRS‐R score. The thumb pinch showed the strongest correlation with the split‐hand index and MRC grading.DiscussionPinch grip strength test using a simple gauge deserves further study as a potentially practical biomarker of ALS.

Immunity has emerged as a key player in neurodegenerative diseases such as amyotrophic lateral sclerosis, with recent studies documenting aberrant immune changes in patients and animal models. A challenging aspect of amyotrophic lateral sclerosis research is the heterogeneous nature of the disease. In this study, we investigate the associations between peripheral blood myeloid cell populations and clinical features characteristic of amyotrophic lateral sclerosis. Peripheral blood leukocytes from 23 healthy controls and 48 patients with amyotrophic lateral sclerosis were analysed to measure myeloid cell alterations. The proportion of monocytes (classical, intermediates and non-classical subpopulations) and neutrophils, as well as the expression of select surface markers, were quantitated using flow cytometry. Given the heterogeneous nature of amyotrophic lateral sclerosis, multivariable linear analyses were performed to investigate associations between patients’ myeloid profile and clinical features, such as the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, bulbar subscore of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale over disease duration and respiratory function. We demonstrate a shift in monocyte subpopulations in patients with amyotrophic lateral sclerosis, with the ratio of classical to non-classical monocytes increased compared with healthy controls. In line with this, patients with greater disease severity, as determined by a lower Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score, had reduced non-classical monocytes. Interestingly, patients with greater bulbar involvement had a reduction in the proportions of classical, intermediate and non-classical monocyte populations. We also revealed several notable associations between myeloid marker expression and clinical features in amyotrophic lateral sclerosis. CD16 expression on neutrophils was increased in patients with greater disease severity and a faster rate of disease progression, whereas HLA-DR expression on all monocyte populations was elevated in patients with greater respiratory impairment. This study demonstrates that patients with amyotrophic lateral sclerosis with distinct clinical features have differential myeloid cell signatures. Identified cell populations and markers may be candidates for targeted mechanistic studies and immunomodulation therapies in amyotrophic lateral sclerosis., Monocyte and neutrophil frequencies and their expression markers were associated with bulbar symptoms, disease severity, rate of disease progression and respiratory impairment in patients with amyotrophic lateral sclerosis. Our study reveals that aberrant peripheral immunity is related to amyotrophic lateral sclerosis patient phenotype and supports the need for tailored therapies to modify the immune profile., Graphical Abstract

Background: The primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers. Methods: In this open-label, dose-escalation trial, IC14 was administered at 2 mg/kg intravenous (IV) followed by 1 mg/kg/d IV × 3 (n = 3) and in subsequent patients at 4 mg/kg IV followed by 2 mg/kg/d IV × 3 (n = 7) (NCT03487263). Disease status was measured using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, Edinburgh Cognitive and Behavioural ALS Screen, and Revised ALS-Specific Quality-of-Life Score. Disease biomarkers included cerebrospinal fluid and serum levels of neurofilament light chain (NfL) and urinary p75 neurotrophin receptor. Results: IC14 was safe and well tolerated. No antidrug antibodies were detected. The drug target saturation of monocyte CD14 receptors was rapid and sustained through day 8. There was no significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, or Revised ALS-Specific Quality-of-Life Score following a single cycle of treatment. Cerebrospinal fluid NfL levels decreased in 6 of 9 patients sampled with declines of 15% to 40% between baseline (not significant [ns]) and day 8 in 3 patients. Serum NfL modestly decreased in 5 of 10 patients (ns) at day 8 and was sustained in 4 (4%-37%, ns) over 33 days of follow up. Conclusion: IC14 quickly and durably saturated its target in all patients. This study demonstrated safety and tolerability in patients with amyotrophic lateral sclerosis. Even though only a single cycle of treatment was given, there were promising beneficial trends in the neurofilament light chain, a disease biomarker. The emerging understanding of the role of systemic inflammation in neurodegenerative diseases, and the potential for IC14 to serve as a safe, potent, and broad-spectrum inhibitor of immune dysregulation merits further clinical study. Clinical Trial Registration: NCT03487263

ObjectiveTo determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival.MethodsFifty-eight patients with clinically definite or probable ALS as defined by El Escorial criteria, and 58 age and sex-matched control participants underwent assessment of energy expenditure. Our primary outcome was the prevalence of hypermetabolism in cases and controls. Longitudinal changes in clinical parameters between hypermetabolic and normometabolic patients with ALS were determined for up to 12 months following metabolic assessment. Survival was monitored over a 30-month period following metabolic assessment.ResultsHypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4; pConclusions and relevanceHypermetabolic patients with ALS have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival. The metabolic index could be important for informing prognosis in ALS.

Background: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. Methods: We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS-relevant variants were cross-checked with population databases and case reports to critically assess whether they were “likely causal,” “uncertain significance,” or “unlikely causal.”. Results: Published ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers. Conclusions: The use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS Refereed/Peer-reviewed

This paper describes an approach to the enhancement of existing software and the development of new applications based upon the premise that advanced software technology is not in itself sufficient to realise high quality usable systems. Development strategies designed to ensure quality must be accompanied by appropriate system architectures and effective implementation tools. We describe a technology and strategy that together enable the efficient development of user and task support systems in a wide variety of contexts.