Determination of CSF GFAP, CCN5, and vWF Levels Enhances the Diagnostic Accuracy of Clinically Defined MS From Non-MS Patients With CSF Oligoclonal Bands

Abstract

BackgroundInclusion of cerebrospinal fluid (CSF) oligoclonal IgG bands (OCGB) in the revised McDonald criteria increases the sensitivity of diagnosis when dissemination in time (DIT) cannot be proven. While OCGB negative patients are unlikely to develop clinically definite (CD) MS, OCGB positivity may lead to an erroneous diagnosis in conditions that present similarly, such as neuromyelitis optica spectrum disorders (NMOSD) or neurosarcoidosis.ObjectiveTo identify specific, OCGB-complementary, biomarkers to improve diagnostic accuracy in OCGB positive patients.MethodsWe analysed the CSF metabolome and proteome of CDMS (n=41) and confirmed non-MS patients (n=64) comprising a range of CNS conditions routinely encountered in neurology clinics.ResultsOCGB discriminated between CDMS and non-MS with high sensitivity (85%), but low specificity (67%), as previously described. Machine learning methods revealed CCN5 levels provide greater accuracy, sensitivity, and specificity than OCGB (79%, +5%; 90%, +5%; and 72%, +5% respectively) while glial fibrillary acidic protein (GFAP) identified CDMS with 100% specificity (+33%). A multiomics approach improved accuracy further to 90% (+16%).ConclusionThe measurement of a few additional CSF biomarkers could be used to complement OCGB and improve the specificity of MS diagnosis when clinical and radiological evidence of DIT is absent.

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis

“…Astrocytes at the edge of MS chronic active lesions as well as in the glia limitans and ependyma show high expression of GFAP and may reflect sources of increased levels associated with smoldering injury in the context of focal lesions, as well as in the subpial cortex and periventricular regions, respectively. Elevated CSF GFAP has also been reported in early MS, supporting its potential utility across the disease continuum . We identified only a moderate correlation between serum and CSF GFAP levels and did not detect an association between serum GFAP levels and progressive disease outcomes (consistent with other similarly sized studies).…”

Proteomics in Multiple Sclerosis: The Perspective of the Clinician

“…CCN5 measurement increased both by 5%, while measurement of GFAP increased the specificity to 100% [154]. According to them, combining CCN5, vWF, GFAP with OGP is able to accurately discriminate between OGP positive MS and other neurological conditions with OGP positivity [154].…”

“…In a very recent, high quality evaluation, Probert et al investigated different CNS biomarkers that can help distinguish MS from non-MS controls as compared to OGP positivity. They found that the measurement of connective tissue growth factor/cysteine-rich protein/nephroblastoma overexpressed-5 (CCN5), von Willebrand factor (vWF) and glial fibrillary acidic protein (GFAP) increased the specificity and sensitivity level of the diagnosis as compared to solely identifying OGP [154]. CCN5 measurement increased both by 5%, while measurement of GFAP increased the specificity to 100% [154].…”

“…They found that the measurement of connective tissue growth factor/cysteine-rich protein/nephroblastoma overexpressed-5 (CCN5), von Willebrand factor (vWF) and glial fibrillary acidic protein (GFAP) increased the specificity and sensitivity level of the diagnosis as compared to solely identifying OGP [154]. CCN5 measurement increased both by 5%, while measurement of GFAP increased the specificity to 100% [154]. According to them, combining CCN5, vWF, GFAP with OGP is able to accurately discriminate between OGP positive MS and other neurological conditions with OGP positivity [154].…”

“…They found GFAP to be rather specific to NMOSD, its level being elevated as compared to both MS and controls samples, while fibronectin seemed to be more specific to MS [164]. The finding on GFAP seems a bit surprising considering other evaluations; however, it probably shows that GFAP may be an even more important marker in NMOSD than in MS [154,164]. Two interesting assessments evaluated the urine proteome trying to differentiate between MS and NMOSD.…”