Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies

Abstract

Objectives: Neurodegeneration is considered a relevant pathophysiologic feature in neurologic disorders associated with antibodies against glutamic acid decarboxylase 65 (GAD65). In this study, we investigate surrogates of neuroaxonal damage in relation to disease duration and clinical presentation.

Methods: In a multicentric cohort of 50 patients, we measured serum neurofilament light chain (sNfL) in relation to disease duration and disease phenotypes, applied automated MRI volumetry, and analyzed clinical characteristics.

Results: In patients with neurologic disorders associated with GAD65 antibodies, we detected elevated sNfL levels early in the disease course. By contrast, this elevation of sNfL levels was less pronounced in patients with long-standing disease. Increased sNfL levels were observed in patients presenting with cerebellar ataxia and limbic encephalitis, but not in those with stiff person syndrome. Using MRI volumetry, we identified atrophy predominantly of the cerebellar cortex, cerebellar superior posterior lobe, and cerebral cortex with similar atrophy patterns throughout all clinical phenotypes.

Discussion: Together, our data provide evidence for early neuroaxonal damage and support the need for timely therapeutic interventions in GAD65 antibody-associated neurologic disorders.

Figure. Analysis of Serum Biomarkers Reveals Elevated Levels of sNfL Early in the Disease Course

(A) Flowchart of the study cohort; * 2 patients additionally showed no intrathecal synthesis of GAD65-Abs, and 4 other patients had missing parameters to calculate the latter; ** criteria for intrathecal GAD65-Ab synthesis—CA, LE: GAD65 antibody index >4 (CBA, IIFT), >1.4 (RIA, ELISA); SPS: GAD65-Ab positive in serum and CSF in CBA, IIFT, RIA, or ELISA; in 2 patients additionally, no serum was sampled; *** in one patient additionally no serum was sampled. (B) Association of sNfL levels and age in patients with GAD65-Ab-SD and age-matched and sex-matched HCs. (C) Association of sNfL levels with disease duration in GAD65-Ab-SD patients. Both (B) and (C) show a linear regression model adjusted for age and sex with 95% confidence intervals depicted in gray. Spearman's R is given. The Shapiro-Wilk test was applied to test for normality and was significant; thus, log transformation (base 10) was used to achieve normal distribution in (B) and (C). (D) sNfL levels were compared in patients with different clinical phenotypes (CA, LE, and SPS) to age-matched and sex-matched controls by the Kruskal-Wallis test followed by Dunn's multiple comparisons test. CA = cerebellar ataxia; HC = healthy controls; LE = limbic encephalitis; NfL = neurofilament light chain; SPS = stiff person syndrome.