Abstract

Background: Migraine is characterized by recurrent moderate to severe headache attacks. It is the most common neurological disorder and the second most disabling human condition, whose pathogenesis is favored by a combination of genetic, epigenetic, and environmental factors. The pathophysiology of migraine includes both vascular and neural mechanisms. As Autotaxin (ATX) may be a link between common mechanisms associated to migraine as neuropeptide release, endothelial dysfunction, and neuroinflammation, we aimed to test its role as a novel biomarker of migraine.

Methods: In this cross-sectional study, healthy controls (n=69), episodic migrainae (EM) patients (n=44), and chronic migraine (CM) patients (n=37) were studied. Clinical symptoms, as well as serum levels of biomarkers for inflammation (interleukin-6, [IL-6], and interleukin-10 [IL-10]), trigeminovascular system activation (calcitonin gene-related peptide, [CGRP]), endothelial dysfunction (pentraxin-3, [PTX-3], cellular fibrinogen [cFn], and soluble tumor necrosis factor-like weak inducer of apoptosis [sTWEAK]), as well as autotaxin (ATX) were investigated. Additionally, spectrometry assays were performed to determine the sphingolipidomic profile.

Results: Serum ATX levels were found significantly (p<0.0001) elevated in both EM (310.7 ± 79.69 ng/mL) and CM (336.7 ± 66.93 ng/mL) compared to controls (212.3 ± 53.19 ng/mL) (p<0.0001). Elevated ATX was associated to migraine pathological variables in CM but not EM. High ATX levels were correlated with CGRP levels in migraine patients, as well as with endothelial dysfunction (PTX3, sTWEAK, and cFn) and IL-6 (all p<0.001). Importantly, high levels of ATX were found in EM patients who do not respond to Onabotulinumtoxin Type A treatment, while patients with lower ATX levels showed an excellent response. Regarding sphingolipidomics, we found a drastic decrease in lysophosphatidylcholine (LPC) levels in migraine patients, which indicates high ATX activity.

Conclusion: Higher serum levels of ATX were found in both EM and CM. Furthermore, ATX levels negatively correlate with the response to treatment with Onabotulinumtoxin Type A. Further studies are necessary to elucidate the potential role of ATX as a therapeutic biomarker for migraine.