Background: Multiple sclerosis (MS) can be difficult to differentiate from other demyelinating diseases, notably neuromyelitis optica spectrum disorder (NMOSD). We previously showed that NMOSD is distinguished from MS by plasma complement biomarkers. Objective: Here, we measure cerebrospinal fluid (CSF) complement proteins in MS, NMOSD and clinically isolated syndrome (CIS), a neurological episode that may presage MS, to test whether these distinguish NMOSD from MS and CIS. Materials and methods: CSF (53 MS, 17 CIS, 11 NMOSD, 35 controls) was obtained; complement proteins (C4, C3, C5, C9, C1, C1q, Factor B (FB)), regulators (Factor I (FI), Factor H (FH), FH-Related Proteins 1, 2 and 5 (FHR125), C1 Inhibitor (C1INH), Properdin) and activation products (terminal complement complex (TCC), iC3b) were quantified by ELISA and results expressed relative to CSF total protein (μg/mg). Results: Compared to control CSF, (1) levels of C4, C1INH and Properdin were elevated in MS; (2) TCC, iC3b, FI and FHR125 were increased in CIS; and (3) all complement biomarkers except TCC, FHR125, Properdin and C5 were higher in NMOSD CSF. A statistical model comprising six analytes (C3, C9, FB, C1q, FI, Properdin) plus age/gender optimally differentiated MS from NMOSD.

Plasma biomarkers to aid the early diagnosis of Alzheimer's disease (AD) or to monitor disease progression have long been sought and continue to be widely studied. Biomarkers that correlate with AD polygenic risk score, a measure of the polygenic architecture of the disease and highly predictive of AD status, would be excellent candidates. Therefore, we undertook a preliminary study to assess the association of plasma inflammatory biomarkers with an overall AD polygenic risk score as well as with an inflammation-specific AD polygenic risk score in a sample set of 93 AD cases. We measured five complement biomarkers [complement receptor 1 (CR1), clusterin, complement component 9 (C9), C1 inhibitor (C1inh), terminal complement complex (TCC)] and the benchmark inflammatory marker C-reactive protein (CRP). Plasma clusterin level showed an association with overall AD polygenic risk score, while clusterin, C1inh, and CRP levels each displayed some association with the inflammatory-specific AD polygenic risk score. The results suggest that elevated plasma levels of inflammatory biomarkers, including complement proteins, associate with polygenic risk scores in AD, further strengthening the link between genetic and biomarker disease predictors and indicating a potential role for these markers in disease prediction and patient stratification in AD.