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Background:  In progressive multiple sclerosis (MS), glial activation is thought to be a relevant mechanism of disability progression. Therefore,  in vivo  assessment of the glial cell activity is, in the emerging treatment era of primary progressive MS (PPMS), more important than ever.   Objectives:  To test the association of cerebrospinal fluid (CSF) and serum markers of glial activation in PPMS patients; including glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (CHI3L1), soluble variant of triggering receptor expressed on myeloid cells 2 (sTREM2), and marker of neuroaxonal damage (Neurofilament light chain, NfL) as well as clinical severity.   Methods:  CSF and serum samples from PPMS patients were collected in the MS-centers at Universities of Freiburg ( n  = 49), Ulm ( n  = 27), Muenster ( n  = 11), and Rostock ( n  = 6). sTREM2 and CHI3L1 levels were measured using the previously reported ELISA assays, while NfL and GFAP were measured using SIMOA assays. Clinical data included age, gender, disease duration, treatment status, and Expanded Disability Status Scale (EDSS).   Results:  93 CSF samples and 71 matching serum samples were analyzed. The median age of patients was 49 years and disease duration 4.5 years. GFAP serum  correlated with EDSS after correction for age (β = 0.3,  p  = 0.001). Furthermore, EDSS was higher in patients with a GFAP serum  level ≥ 151.7 pg/ml compared to patients with GFAP serum  below this cut-off (5.5 vs. 4.0,  p  = 0.009). Other markers did not correlate with the clinical severity. Moreover, we found a correlation between NfL CSF  and GFAP CSF , sTREM2 and CHI3L1 (ρ = 0.4 for GFAP CSF  and sTREM2, ρ = 0.3 for CHI3L1,  p  < 0.01 for sTREM2 and CHI3L1 and <0.001 for GFAP CSF ). CHI3L1 did not correlate with GFAP CSF  but with sTREM2 (ρ = 0.4,  p  < 0.01).   Discussion:  The correlation between the glial activation markers in CSF with the markers of neuroaxonal demise supports the notion of the glial involvement in PPMS. The positive correlation between GFAP CSF  with disease duration and GFAP serum  with the clinical severity of the disease may highlight a particular role of the astrocytes in PPMS and mark the potential of GFAP serum  as a disease severity marker.

frontiers in neurology

Glial Activation Markers in CSF and Serum From Patients With Primary Progressive Multiple Sclerosis: Potential of Serum GFAP as Disease Severity Marker?