Abstract Details

Title Relationship of Clinical Phenotype to GFAP Concentrations in CSF and Blood of Individuals with Alexander Disease

Topic Child Neurology and Developmental Neurology

Presentation(s) P10 - Poster Session 10 (5:00 PM-6:00 PM)

Poster/Presentation
Number 6-001

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.

Authors/Disclosures
Amy T. Waldman, MD (Children's Hospital of Philadelphia) PRESENTER	Dr. Waldman has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SwanBio. An immediate family member of Dr. Waldman has or had stock in Pfizer. The institution of Dr. Waldman has received research support from Ionis Pharmaceuticals. The institution of Dr. Waldman has received research support from Roche/Genentech. The institution of Dr. Waldman has received research support from Ionis Pharmaceuticals. The institution of Dr. Waldman has received research support from Calico. Dr. Waldman has received publishing royalties from a publication relating to health care. Dr. Waldman has received publishing royalties from a publication relating to health care.
Joshua Joung, Other (Children's Hospital of Philadelphia)	Mr. Joung has nothing to disclose.
Geraldine Liu (Children’s Hospital of Philadelphia)	An immediate family member of Geraldine Liu has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Various. An immediate family member of Geraldine Liu has received publishing royalties from a publication relating to health care.
Asako Takanohashi, PhD, DVM (Children's Hospital of Philadelphia)	Dr. Takanohashi has nothing to disclose.
Walter Faig	Walter Faig has received personal compensation for serving as an employee of Westat.
Sarah Woidill	Sarah Woidill has nothing to disclose.
Sona Narula, MD (CHOP)	Dr. Narula has received personal compensation in the range of $0-$499 for serving as a Consultant for Medscape .
Adeline Vanderver, MD, FAAN (Children'S Hospital of Philadelphia)	An immediate family member of Dr. Vanderver has received personal compensation for serving as an employee of Maryland Physician Care. The institution of Dr. Vanderver has received research support from Takeda. The institution of Dr. Vanderver has received research support from Passage Bio. The institution of Dr. Vanderver has received research support from Homology. The institution of Dr. Vanderver has received research support from Eli Lilly. The institution of Dr. Vanderver has received research support from Myrtelle. The institution of Dr. Vanderver has received research support from SynaptixBio. The institution of Dr. Vanderver has received research support from PMD Foundation. The institution of Dr. Vanderver has received research support from Ionis. The institution of Dr. Vanderver has received research support from ISD . The institution of Dr. Vanderver has received research support from Boehringer-Ingelheim. The institution of Dr. Vanderver has received research support from Biogen. The institution of Dr. Vanderver has received research support from Sana. The institution of Dr. Vanderver has received research support from Affinia. The institution of Dr. Vanderver has received research support from BridgeBio. The institution of Dr. Vanderver has received research support from Orchard. The institution of Dr. Vanderver has received research support from Minoryx. The institution of Dr. Vanderver has received research support from Forge Biologics. The institution of Dr. Vanderver has received research support from Vigil. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care.

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