Serum glial fibrillary acid protein associates with TSPO-expressing lesions in multiple sclerosis brain
Tanja Sjöros1,2, Maija Saraste3,4,5,6, Markus Matilainen3,4,5
1Turku PET Centre, University of Turku, Åbo Akademi University, Turku University Hospital, P.O. Box 52, Turku 20521, Finland.
Background:
Serum glial fibrillary acidic protein (sGFAP) is a promising biomarker for multiple sclerosis (MS) disease progression. Elevated sGFAP levels are considered to reflect ongoing astrocyte-related pathology in the central nervous system.
Objectives:
To study whether sGFAP levels associate with 18 kDa translocator protein (TSPO) availability in MS brain. TSPO is a mitochondrial molecule that is expressed by activated microglia and astrocytes.
Design:
Cross-sectional multimodal biomarker correlation study.
Methods:
We included 80 people with MS (66 relapsing-remitting and 14 progressive MS, 69% women), and 11 healthy control participants (73% women). sGFAP was measured using single molecule array (Simoa®) technology in combination with 3T magnetic resonance imaging and positron emission tomography (PET) using a TSPO-binding [11C]PK11195 radioligand.
Results:
sGFAP was higher among people with progressive MS (median 122 pg/ml) compared to healthy controls (median 59 pg/ml, p = 0.0002) or participants with relapsing-remitting MS (median 77 pg/ml, p = 0.0056). Among people with MS, higher sGFAP associated with higher volume of chronic lesions with increased TSPO activity (r = 0.36, p = 0.0011) and with thalamic TSPO activity (r = 0.30, p = 0.0069), as well as with T1 and T2 lesion loads (r = 0.38, 0.41, p = 0.0005, 0.0002, respectively). Smaller normal-appearing white matter (r = -0.36, p = 0.0009), cortical gray matter, and thalamus volumes (r = -0.39, p = 0.0003 for both) correlated with higher sGFAP. In regression analyses, the volume of TSPO-expressing lesions, together with age and MS disease-modifying treatment status, explained 27% of the variation in sGFAP.
Conclusion:
sGFAP associates with adverse magnetic resonance imaging and PET imaging outcomes. The association between a high prevalence of TSPO-expressing white matter lesions and high sGFAP suggests that lesion-associated glial activity promotes MS progression partially via astrocyte-driven mechanisms. A combination of various soluble biomarkers and PET ligands for specific cell types may add to the understanding of progression-promoting cellular mechanisms in the brain.
Trial Registration:
ClinicalTrials.gov NCT03134716, NCT03368677, NCT04126772, NCT04239820, https://clinicaltrials.gov.
