Correlation of neurochemical and imaging markers in AU 1 migraine PACAP 38 and DTI measures

Objective To examine whether interictal plasma pituitary adenylate cyclase-activating peptide 38-like immunoreactivity (PACAP38-LI) shows correlation with the microstructural integrity of the white matter in migraine. Methods Interictal plasma PACAP38-LI was measured by radioimmunoassay in 26 patients with migraine (24 women) who underwent diffusion tensor imaging afterward using a 1.5-tesla magnetic resonance scanner. Data were analyzed using tract-based spatial statistics included in FMRIB’s Software Library. Results Interictal plasma PACAP38-LI showed significant correlation with mean diffusivity (p < 0.0179) mostly in the bilateral occipital white matter spreading into parietal and temporal white matter. Axial and radial diffusivity showed positive correlation with interictal PACAP38-LI (p < 0.0432 and p < 0.0418, respectively) in the left optic radiation and left posterior corpus callosum. Fractional anisotropy did not correlate significantly with PACAP38-LI. With disease duration as a nuisance regressor in the model, PACAP38-LI correlated with axial and mean diffusivity in the left thalamus (p < 0.01). Conclusion We report a link between PACAP38, a pathobiologically important neurochemical biomarker, and imaging markers of the disease that may bolster further research into the role of PACAP38 in migraine. From the Departments of Neurology (D.V., N.S., J.T., A.K., P.F., K.K., E.T., B.K., L.V., Z.T.K.) and Radiology (Z.T.K.), Albert Szent-Györgyi Clinical Center, University of Szeged, Hungary; Central European Institute of Technology (N.S., A.K.), Brno, Czech Republic; MTA-SZTE Neuroscience Research Group (B.T., L.V.), Szeged; and Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (T.B., Z.H.), and János Szentágothai Research Centre & Centre for Neuroscience (Z.H.), University of Pécs, Hungary. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. Copyright © 2018 American Academy of Neurology 1 Copyright a 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Pituitary adenylate cyclase-activating peptide 38 (PACAP38) is a neuropeptide of growing importance in migraine literature. There are consistent reports of its migraine-inducing properties, and its blood levels correspond with headache attacks, with decreased blood levels in the interictal term. The exact nature of its connection to migraine, however, remains unclear. Research points to the involvement of PACAP38 in the activation of the trigeminovascular system, and it has been affiliated with headache-related photophobia as well. Alterations of brain function and structure in migraine were identified with various MRI modalities. Magnetic resonance spectroscopy studies demonstrated neurochemical differences mainly in the cingulate and occipital cortices in patients with migraine. Functional MRI studies found altered activation in regions related to pain processing, and the activity of resting-state networks was also shown to be altered in migraine. Several diffusion tensor imaging (DTI) studies found microstructural abnormalities of the white matter in patients with migraine in pathways related to pain sensation and visual processing. Since PACAP38 turns up as a functional molecule in these systems, the question arises whether the peptide’s assumed role in migraine pathophysiology is linked to alterations of the white matter microstructure. A recent study by Yilmaz et al. revealed increased ictal levels of S100B (a marker of glial damage) and neuron-specific enolase (a marker of neuronal damage) in migraineurs without aura. Furthermore, infusion of PACAP38 in migraineurs changed the plasma concentrations of S100B. Combined with decreased interictal levels of PACAP38, these results led us to the hypothesis that PACAP38 may induce degenerative changes in migraineurs that might be detectable with DTI. Alternatively, PACAP38 also exerts neurotrophic and neuroprotective effects, and these effects might also be detected by diffusion MRI. Serum levels of PACAP38 seem to approximately represent intracerebral PACAP38 metabolism in human studies since PACAP38 passes through the blood-brain barrier by way of a saturable transport mechanism, and there are also reports of increased blood-brain barrier permeability in migraine. Since decreased interictal PACAP38 levels could hypothetically be a product of altered PACAP38 metabolism, which might coexist with microstructural changes, we hypothesized that interindividual variation of subnormal interictal PACAP38 levels in patients with migraine might correlate with microstructural characteristics. In this exploratory study, we investigated this correlation in patients with migraine, as measured by DTI.