Plasma versus serum: which is better for proteomic blood biomarker analysis? Evaluation of the novel NULISA platform

Abstract

INTRODUCTION The NULISASeq™ CNS Disease Panel has high potential for AD diagnosis, but the comparability of serum vs. plasma remains unclear. METHODS We compared its performance on 43 matched serum-plasma pairs from a memory clinic cohort. RESULTS The panel reproducibly quantified 124 targets (mean CV=4.9%) with high detectability (mean=95.7%). Serum-plasma correlations were strong (ρ>0.7) for 79 targets. 48 targets had significant NPQ differences, with 32 higher in plasma. Plasma had more erythrocyte-enriched proteins (HBA1, PGK1, SOD1, PRDX6), while serum had more platelet-derived proteins (CD40LG, BDNF, VEGFA, Aβ40). For classical AD biomarkers, serum-plasma correlations were stronger for p-tau, GFAP, and NfL (ρ>0.9) than for Aβ targets (ρ=0.594– 0.785). Tau levels were higher in plasma; GFAP and NfL were similar, and Aβ peptides were mixed. Twelve targets, along with p-tau217/Aβ42, were linked to AD diagnosis, with plasma generally showing stronger effects. DISCUSSION Our results support serum use but suggest plasma performs better for AD using this panel. ### Competing Interest Statement XZ, YC and TKK are listed inventors on the University of Pittsburgh provisional patent #63/672,952. XZ is also an inventor on the University of Pittsburgh provisional patents on anti-tau antibodies. TKK has consulted for Quanterix Corporation, SpearBio Inc., and Alzheon, and has served on advisory boards for Siemens Healthineers and Neurogen Biomarking LLC., outside the submitted work. Over the last two years, he has received in-kind research support from Janssen Research Laboratories, SpearBio Inc., and Alamar Biosciences, as well as meeting travel support from the Alzheimer Association and Neurogen Biomarking LLC., outside the submitted work. TKK has received royalties from Bioventix for the transfer of specific antibodies and assays to third party organizations. TKK is an inventor on patents and provisional patents regarding biofluid biomarker methods, targets and reagents/compositions, that may generate income for the institution and/or self should they be licensed and/or transferred to another organization. The other authors report no conflict of interest. ### Funding Statement The Pitt-ADRC is funded by P30 AG066468. This study used biomarker testing infrastructure established with support from NIH/NIA R01AG083874 awarded to TKK. TKK and the Karikari Laboratory were further supported by NIH/NIA (U24AG082930, P30AG066468, RF1AG077474, R01AG083156, R01AG025516, R01AG073267, R01AG075336, P01AG025204), NIH/NINDS (U01NS131740, U01NS141777), NIH/NIMH (R01MH108509), Aging Mind Foundation (DAF2255207), the Department of Defense (HT94252320064), the Anbridge Charitable Fund, and a professorial endowment from the Department of Psychiatry, University of Pittsburgh. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ADRC study was reviewed and approved by the University of Pittsburgh Institutional Review Board (MOD19110245-023). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors from qualified investigators for the purpose of replicating the results in this manuscript, provided all applicable legal, ethical and institutional regulations are followed.