2025 American Academy of Neurology Abstract Website

Giulia Porcari¹, Asako Takanohashi¹, Sona Narula¹, Joshua Joung¹, Geraldine Liu¹, Walter Faig², Mix Wannasarnmetha³, Arastoo Vossough⁴, Adeline Vanderver¹, Amy Waldman¹
¹Department of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, ²Biostatistics and Data Management Core, Children's Hospital of Philadelphia, ³Department of Radiology, Khon Kaen University, ⁴Department of Radiology, University of Pennsylvania - Children's Hospital of Philadelphia

Objective:

To examine whether levels of growth differentiation factor 15 (GDF15) are elevated in Alexander disease (AxD).

Background:

AxD is a rare heritable astrocytopathy characterized by accumulation of mutant glial fibrillary acidic protein in white matter, striatal and brainstem structures. Medullary involvement, and particularly the development of medullary mass-like lesions, is hypothesized to mediate the intractable emesis distinctive of this leukodystrophy. GDF15 is an inflammatory cytokine involved in emesis and cachexia via binding to its receptor in the medulla. This mechanism suggests a possible pathophysiologic role of GDF15 in centrally-mediated emesis in AxD.

Design/Methods:

Plasma GDF15 levels were assessed in AxD patients (n=67) and age-matched leukodystrophy controls (n=47). Cerebrospinal fluid (CSF) GDF15 levels were evaluated in AxD patients (n=44) and age-matched controls (n=27) enrolled in an institutional biorepository. Longitudinal samples were available in a subset of AxD patients. Generalized estimating equations compared GDF15 levels between AxD and controls, and further evaluated the relationship between emesis, medullary mass-like lesions and GDF15 levels in AxD patients, controlling for age. Spearman correlation assessed relationship between plasma and CSF GDF15 levels.

Results:

Median GDF15 levels were significantly elevated in CSF of patients with AxD compared to controls (medians 286, IQR 184-378 vs 18, IQR 9-34, p<0.001). There was no difference in plasma levels. Age was inversely associated with GDF15 level in CSF (p=0.009) but not in plasma (p=0.08). In AxD patients with both samples (n=36), plasma and CSF GDF15 levels were not correlated (rho=-0.10, p=0.6). Accounting for age, presence of emesis (p=0.3) and medullary lesions (p=0.8) was not associated with CSF GDF15 level in this cohort of AxD patients.

Conclusions:

GDF15 levels are elevated more than 10-fold in CSF of AxD patients compared to controls, and do not correlate with plasma levels. CSF GDF15 levels are inversely correlated with age, possibly reflecting differences in disease activity by age.