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Background: IL-26 is a key mediator of pulmonary host defense given its abundant expression in human airways and its established antibacterial properties. Moreover, recent studies indicate that IL-26 can also inhibit viral replication. Along these lines, we have previously reported an increase in the plasma concentration of IL-26 among patients with acute COVID-19 that is linked to harmful hyperinflammation. Nevertheless, it is still unclear whether this systemic increase in IL-26 relates to disease severity, sex, comorbidities, viral load, or the innate immune response in acute COVID-19., Methods: IL-26 was quantified using ELISA in plasma samples from a large cohort of well-characterized patients with acute COVID-19 (n=178) and healthy controls (n=30). The plasma concentrations of SARS-CoV-2 nucleocapsid and spike protein, as well as those of IFN-α2a, IFN-β, and IFN-γ, were determined using electrochemiluminescence immunoassay. The concentration of double-stranded DNA was determined using fluorometry., Results: The plasma concentration of IL-26 was increased in patients with severe/critical COVID-19, particularly among males and patients with comorbid obstructive lung disease. Moreover, the concentration of IL-26 displayed positive correlations with length of hospital stay, as well as with systemic markers of viral load, antiviral immunity, and extracellular DNA., Conclusions: Systemic IL-26 is involved in severe COVID-19, especially in males and patients with comorbid obstructive lung disease. These findings argue that systemic IL-26 has pathogenic and antiviral relevance, as well as biomarker potential., Competing Interests: Authors SM, JB, MW, MS, GS, and JW are employed by Meso Scale Diagnostics, LLC., Rockville, MD, USA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cardenas, Robertson, Misaghian, Brown, Wang, Stengelin, Sigal, Wohlstadter, Gisslén and Lindén.)

Background: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer's disease (AD) pathology. Multiple p-tau biomarkers on several analytical platforms are poised for clinical use. The Alzheimer's Association Global Biomarker Standardisation Consortium plasma phospho-tau Round Robin study engaged assay developers in a blinded case-control study on plasma p-tau, aiming to learn which assays provide the largest fold-changes in AD compared to non-AD, have the strongest relationship between plasma and cerebrospinal fluid (CSF), and show the most consistent relationships between methods (commutability) in measuring both patient samples and candidate reference materials (CRM)., Methods: Thirty-three different p-tau biomarker assays, built on eight different analytical platforms, were used to quantify paired plasma and CSF samples from 40 participants. AD biomarker status was categorised as "AD pathology" (n=25) and "non-AD pathology" (n=15) by CSF Aβ42/Aβ40 (US-FDA; CE-IVDR) and p-tau181 (CE-IVDR) methods. The commutability of four CRM, at three concentrations, was assessed across assays., Findings: Plasma p-tau217 consistently demonstrated higher fold-changes between AD and non-AD pathology groups, compared to other p-tau epitopes. Fujirebio LUMIPULSE G, UGOT IPMS, and Lilly MSD p-tau217 assays provided the highest median fold-changes. In CSF, p-tau217 assays also performed best, and exhibited substantially larger fold-changes than their plasma counterparts, despite similar diagnostic performance. P-tau217 showed the strongest correlations between plasma assays (rho=0.81 to 0.97). Plasma p-tau levels were weakly-to-moderately correlated with CSF p-tau, and correlations were non-significant within the AD group alone. The evaluated CRM were not commutable across assays., Interpretation: Plasma p-tau217 measures had larger fold-changes and discriminative accuracies for detecting AD pathology, and better agreement across platforms than other plasma p-tau variants. Plasma and CSF markers of p-tau, measured by immunoassays, are not substantially correlated, questioning the interchangeability of their continuous relationship. Further work is warranted to understand the pathophysiology underlying this dissociation, and to develop suitable reference materials facilitating cross-assay standardisation., Funding: Alzheimer's Association (#ADSF-24-1284328-C)., Competing Interests: CONFLICTS OF INTEREST All biomarker measurements were performed by the assay developers in-house without cost. ALZpath p-tau217 was performed at the University of Gothenburg (UGOT) and Lilly immunoassays were performed at the University of Lund. C2N Diagnostics declined to participate in the study. N.J.A. has given lectures in symposia sponsored by Eli-Lilly, Roche Diagnostics, and Quanterix. NJA has declined paid opportunities from ALZpath. A.K. has no conflicts of interest. W.S.B. has no conflicts of interest. L.G. has no conflicts of interest. U.A. has no conflicts of interest. B.A. has no conflicts of interest. M.D. is an employee of AbbVie and holds stock or stock options. S.B. is an employee of AbbVie and holds stock or stock options. J.V. is employee of ADx NeuroSciences. C.L. is an employee of ADx NeuroSciences. M.V.L. is an employee of ADx NeuroSciences. E.S. is an employee of ADx NeuroSciences. S.I. is an employee of Alamar Biosciences H.Y.J. is an employee of Alamar Biosciences X.Y. is an employee of Alamar Biosciences A.F-H. is an employee of Alamar Biosciences B.Z. is an employee of Alamar Biosciences Y.L. is an employee of Alamar Biosciences A.Jeromin is an employee of ALZpath, Inc., and has stock options. M.V. is an employee of Fujirebio Europe N.V. N.L.B. is an employee of Fujirebio Europe N.V H.K. is a former employee of Janssen R&D D.B. has no conflicts of interest. G.T-B. is an employee of Janssen R&D and has stock options. D.B. has no conflicts of interest. S.J. has no conflicts of interest. S-Y.Y is an employee of MagQu Co., Ltd.C.D. C.D. is employee of Meso Scale Diagnostics, LLC D.R. is an employee of Meso Scale Diagnostics, LLC G.S. is an employee of Meso Scale Diagnostics, LLC J.W. is an employee of Meso Scale Diagnostics, LLC K.M. is an employee of Quanterix M.K. is an employee of Quanterix A.Jethwa is a full-time employee of Roche Diagnostics GmbH, Penzberg, Germany. L.S. is a full-time employee of Roche Diagnostics GmbH, Penzberg, Germany. O.H. has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. R.R has no conflicts of interest. J.G. has no conflicts of interest. P.K. has no conflicts of interest. F.G-O. has no conflicts of interest. L.M-G. has no conflicts of interest. L.M.S. has served as a consultant or on advisory boards for Biogen, Roche Diagnostics, Fujirebio; receives grant support from NIA/ADNI with QC oversight responsibilities and in-kind support from Fujirebio and Roche Diagnostics automated immunoassay platforms and reagents. K.B. has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. J.M.S. has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly); consulted for Roche Pharmaceuticals, Biogen, Merck, and Eli Lilly; given educational lectures sponsored by GE Healthcare, Eli Lilly, and Biogen; and is Chief Medical Officer for ARUK. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work).

Background: Gliomas are aggressive malignant tumors, with poor prognosis. There is an unmet need for the discovery of new, non-invasive biomarkers for differential diagnosis, prognosis, and management of brain tumors. Our objective is to validate four plasma biomarkers - glial fibrillary acidic protein (GFAP), neurofilament light (NEFL), matrix metalloprotease 3 (MMP3) and fatty acid binding protein 4 (FABP4) - and compare them with established brain tumor molecular markers and survival., Methods: Our cohort consisted of patients with benign and malignant brain tumors (GBM = 77, Astrocytomas = 26, Oligodendrogliomas = 23, Secondary tumors = 35, Meningiomas = 70, Schwannomas = 15, Pituitary adenomas = 15, Normal individuals = 30). For measurements, we used ultrasensitive electrochemiluminescence multiplexed immunoassays., Results: High plasma GFAP concentration was associated with GBM, low GFAP and high FABP4 were associated with meningiomas, and low GFAP and low FABP4 were associated with astrocytomas and oligodendrogliomas. NEFL was associated with progression of disease. Several prognostic genetic alterations were significantly associated with all plasma biomarker levels. We found no independent associations between plasma GFAP, NEFL, FABP4 and MMP3, and overall survival. The candidate biomarkers could not reliably discriminate GBM from primary or secondary CNS lymphomas., Conclusions: GFAP, NEFL, FABP4 and MMP3 are useful for differential diagnosis and prognosis, and are associated with molecular changes in gliomas., (© 2024. The Author(s).)

Background: Certain demyelinating disorders, such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) exhibit serum autoantibodies against aquaporin-4 (αAQP4) and myelin oligodendrocyte glycoprotein (αMOG). The variability of the autoantibody presentation warrants further research into subtyping each case., Methods: To elucidate the relationship between astroglial and neuronal protein concentrations in the peripheral circulation with occurrence of these autoantibodies, 86 serum samples were analyzed using immunoassays. The protein concentration of glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL) and tau protein was measured in 3 groups of subcategories of suspected NMOSD: αAQP4 positive (n = 20), αMOG positive (n = 32) and αMOG/αAQP4 seronegative (n = 34). Kruskal-Wallis analysis, univariate predictor analysis, and multivariate logistic regression with ROC curves were performed., Results: GFAP and NFL concentrations were significantly elevated in the αAQP4 positive group (p = 0.003; p = 0.042, respectively), and tau was elevated in the αMOG/αAQP4 seronegative group (p < 0.001). A logistic regression model to classify serostatus was able to separate αAQP4 seropositivity using GFAP + tau, and αMOG seropositivity using tau. The areas under the ROC curves (AUCs) were 0.77 and 0.72, respectively. Finally, a combined seropositivity versus negative status logistic regression model was generated, with AUC = 0.80., Conclusion: The 3 markers can univariately and multivariately classify with moderate accuracy the samples with seropositivity and seronegativity for αAQP4 and αMOG., (© 2024. The Author(s).)

A growing literature suggests that plasma levels of tau phosphorylated at amino acid 217 (pTau217) performs similarly to cerebrospinal fluid (CSF) biomarkers and PET imaging to detect amyloid pathology and to provide diagnostic and prognostic information in Alzheimer's disease (AD), but a significant limiting factor thus far has been a lack of widely available immunoassays. We evaluated a novel pTau217 S-PLEX® assay developed by Meso Scale Discovery (MSD; Rockville, MD) in plasma from 131 individuals with AD confirmed by CSF biomarkers and controls. Technical performance of the assay was excellent with an LLOQ of 1.84 pg/mL and intra/interplate CVs of 5.5% (0.3-15.0%) and 5.7% (range 0.3-13.4%), respectively. The pTau217 plasma assay differentiated AD and controls with an AUC of 0.98 (95% CI 0.96-1.0) and pTau217 levels were 3.9-fold higher in individuals with AD. This performance was significantly better than what was observed for plasma pTau181, performed in parallel, and comparable to published data on existing pTau217 assays. While further clinical validation and head-to-head comparisons are needed to fully establish the role for the novel pTau217 S-PLEX assay, these data demonstrate the utility of the assay to detect AD pathology., (© 2024. The Author(s).)

Convenient and widespread serology testing may alter the trajectory of the COVID-19 pandemic. This study seeks to leverage high-throughput, multiplexed serologic assays, which have been adopted as benchmarks for vaccine efficacy, to support large-scale surveys of SARS-CoV-2 immunity using finger-stick blood and/or saliva. Specifically, we optimized MSD's serology assays, which were analytically validated for serum, to test self-collected finger-stick blood and saliva samples to identify prior infection. We show that these assays can be used with FDA-registered specimen collection devices to obtain quantitative measurements for self-collected samples. First, we show that salivary antibodies are stable without refrigeration or preservatives for at least 5 days. We selected classification thresholds for antibodies against SARS-CoV-2 N, RBD and Spike in finger-stick blood and saliva that provided 98% specificity in a set of individuals without known COVID-19 exposure. Using matched samples, we show that testing of saliva and finger-stick blood equivalently identified individuals with humoral responses to CoV-2 antigens. Moreover, we piloted a simple saliva collection kit that can be used to safely send samples through the mail using written instructions only. This work establishes key parameters to robustly assay self-collected finger-stick blood and saliva using quantitative immunoassays that could support large-scale serology testing., (© 2022. The Author(s).)