Relationship of Clinical Phenotype to GFAP Concentrations in CSF and Blood of Individuals with Alexander Disease
Amy Waldman1, Joshua Joung2, Geraldine Liu3, Asako Takanohashi1, Walter Faig2, Sarah Woidill2, Sona Narula1, Adeline Vanderver1
1Pediatrics, Children's Hospital of Philadelphia, 2Children's Hospital of Philadelphia, 3Children’s Hospital of Philadelphia
Objective:
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.
Background:
In AxD, a gain of function pathologic variant in GFAP leads to the accumulation of GFAP in astrocytes and Rosenthal fibers. This study explores initial concepts towards GFAP biomarker qualification and context-of-use in AxD.
Design/Methods:
CSF and plasma were collected (longitudinally when available) from AxD subjects 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 genetic variant [for common genetic variants occurring at p.Arg79, p.Arg88, p.Arg239]).
Results:
GFAP concentrations were significantly elevated at baseline in the CSF of AxD subjects (N=42) compared to controls (N=46, p<0.0001) and AxD plasma (N=80) compared to other leukodystrophy controls (N=66, p<0.0001). CSF and plasma GFAP concentrations differed between AxD Cerebral, Intermediate, and Bulbospinal subtypes (Kruskal-Wallis test, CSF p=0.0419, plasma p<0.0001). In subjects sampled prior to 8 years at baseline, the median change in GFAP was an increase of 108,000 [pg/ml]/year (IQR=147,000 [pg/ml]/year) in CSF and 6,580 [pg/ml]/year (IQR=8,310 [pg/ml]/year) in plasma. In the subjects sampled after 8 years at baseline, the median change in GFAP was -41,000 [pg/ml]/year (IQR=90,300 [pg/ml]/year) in CSF and -678 [pg/ml]/year (IQR=3,930 [pg/ml]/year) in 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=0.014, plasma: p<0.001). A relationship was not detected between GFAP variant and GFAP levels.
Conclusions:
GFAP concentrations are higher in the cerebral phenotype of AxD and increase over time in young children. These data can be used to formulate biomarker qualification in AxD.
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