Whole-blood RNA and plasma NfL correlations identify biomarker candidates and targetable pathways in MS and NMO
2026 ACTRIMS Poster Presentation
Lukasz S. Wylezinski1-2, Guzel I. Shaginurova1, Cheryl L. Sesler1, and Charles F. Spurlock, III1-4
1 Decode Health, Nashville, TN, USA
2 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
3 Thomas F. Frist, Jr. College of Medicine, Belmont University, Nashville, TN, USA
4 Wagner School of Public Service, New York University, New York, NY, USA
Background and Objectives. Neurofilament light chain (NfL) is a quantitative biomarker of neuroaxonal injury used to assess neurological disease activity. Linking peripheral blood RNA expression to plasma NfL levels can reveal immune and metabolic pathways associated with injury and may uncover complementary biomarkers. Our prior work identified distinct whole-blood RNA signatures and molecular subgroups at high versus low plasma NfL concentrations in relapsing-remitting multiple sclerosis (RRMS) and neuromyelitis optica (NMO). This study correlates RNA with plasma NfL in RRMS and NMO to define shared and disease-specific pathway signatures that aid in the identification of biomarker and therapeutic targets.
Methods. Peripheral whole blood was collected in PAXgene Blood RNA tubes from treatment-naive RRMS (n=105) and NMO (n=48). NfL was quantified in matched EDTA plasma. RNA-seq was performed, and gene expression correlations with plasma NfL were calculated within each disease group. NfL-associated genes underwent enrichment analysis across multiple curated pathway libraries. Pathways were ranked by cross-library concordance and disease relevance.
Results. Across diseases, enrichment converged on lipid and lipoprotein biology, including chylomicron and plasma lipoprotein assembly, which aligns with myelin lipid demands and immunometabolic regulation. In RRMS, dominant signals included ABC transporter activity and lipoprotein remodeling (such as ABCA6, ABCA9, APOB), along with junctional and adhesion pathways involving type I hemidesmosome components, supporting blood-brain barrier integrity, leukocyte trafficking, and remyelination. In NMO, correlations highlighted FGFR signaling with downstream PI3K and phospholipase C modules (FGF2), as well as interleukin signaling (IL-18 and IL-1b) and lipoprotein assembly (MTTP), consistent with astrocytopathy and cytokine-driven injury. Shared features included lipid pathways and cytokine, MAPK, and PI3K networks, indicating convergent inflammatory and metabolic processes associated with axonal injury.
Conclusion. Correlating whole-blood RNA expression with plasma NfL reveals clinically relevant biological themes. RRMS shows ABC transporters, lipoprotein remodeling, and junctional programs that may influence blood-brain barrier function and repair. NMO features FGFR-centered signaling with PI3K and phospholipase C branches, interleukin activity, and lipoprotein assembly. Findings identify complementary biomarker candidates and support therapeutic hypotheses consistent with IL-6 and complement activation in NMO, as well as S1P, B-cell, and trafficking mechanisms in MS. Future validation combining these RNA-NfL datasets with imaging and clinical measures could enhance disease activity assessments, enable personalized monitoring, and guide treatment options.
