Characterization of Clinical Phenotype to Glial Fibrillary Acidic Protein Concentrations in Alexander Disease

To determine the concentration of glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and plasma in Alexander disease (AxD) and whether GFAP levels are predictive of disease phenotypes.

CSF and plasma were collected (longitudinally when available) from AxD participants and non-AxD controls. The concentration of GFAP was compared between groups using Wilcoxon rank sum test. The Kruskal-Wallis test was used to compare GFAP concentrations across multiple groups (clinical phenotype or common genetic variants occurring at p.Arg79, p.Arg88, p.Arg239).

GFAP concentrations were significantly elevated at baseline in both AxD CSF (N = 44) compared to controls (N = 46, p < 0.0001) and AxD plasma (N = 96) compared to other leukodystrophy plasma controls (N = 67, p < 0.0001). CSF and plasma GFAP concentrations differed between AxD cerebral, intermediate, and bulbospinal phenotypes (Kruskal-Wallis test, CSF: p = 0.0235, plasma: p < 0.0001). The median GFAP change/year among patients sampled < 8 years of age at baseline was an increase of 91,100 [pg/mL]/year (IQR 136,050) in CSF and 2850 [pg/mL]/year (IQR 9500) in plasma compared to patients > 8 years whose medians decreased over time (-41,000 [pg/mL]/year [IQR 90,300], CSF; -843 [pg/mL]/year [IQR 3900], plasma). The fold change in GFAP from first to last sampling were significantly different before and after 8 years at baseline (Wilcoxon rank sum test, CSF: p = 0.0232, plasma: p = 0.0002). A significant association was not detected between GFAP variant and GFAP levels.

GFAP concentrations are higher in the cerebral phenotype and increase over time in young children. These data can be used to formulate biomarker qualification and context-of-use in AxD.