BARCELONA, Spain — Genetics and brain inflammation play a role in the pathogenesis of migraine, but precise diagnosis and effective treatment are hampered by a lack of reliable biomarkers. Experts at the 17th European Headache Congress in Barcelona examined the latest knowledge on the pathophysiology of migraine and how improved understanding could lead to new diagnostic and therapeutic approaches.
Calcitonin Gene-Related Peptide
Calcitonin gene-related peptide (CGRP) plays a pivotal role in the pathophysiology of migraine and is an important therapeutic target. Monoclonal antibodies that inhibit CGRP binding to its receptor are one of the few classes of medications developed specifically for migraine.
Human CGRP levels are typically measured using enzyme-linked immunosorbent assays (ELISAs), but the kits used for the measurements cannot distinguish between the closely related peptide sequences found in the alpha and beta isoforms of the peptide.
The results from these assays can, therefore, be highly ambiguous; therefore, despite the interest in CGRP, its reliability as a biomarker for migraine is still uncertain. Numerous other neuropeptide systems are also implicated in migraine, but assays designed to measure them would have the same problems as CGRP ELISA kits.
"If we could reliably measure CGRP, there could be great value in the results," Professor Debbie Hay of the University of Otago, New Zealand, told Medscape Medical News. "It could help us identify those who may or may not respond to different CGRP-targeted therapies. It could help us to stratify patients or help us to understand the transition from episodic to chronic migraine."
The Complex Genetics of Migraine
Although the pathophysiology of migraine is still not fully understood, genetic analyses have identified dozens of key proteins, novel therapeutic targets, and more potential diagnostic biomarkers.
The heritability of migraine is estimated to be about 40%, but the genetics of the condition is extremely complex. More than 180 migraine-associated gene variants have been identified to date, all of which promote "pro-migraine" molecular abnormalities within neurons or cerebral vasculature, with many having variable functional effects.
One recent genome-wide analysis of more than 100,000 migraine cases identified 123 loci, the majority of which were previously unknown. All of the variants were enriched in central nervous system and vascular tissues and cell types, confirming that neurovascular mechanisms underlie migraine pathophysiology.
Familial hemiplegic migraine (FHM) is rare and is characterized by motor weakness as a manifestation of aura at the time of migraine attack. FHM has well characterized monogenetic causes, with each of its four subtypes associated with a specific gene.
FHM type 1 is caused by mutations in the CACNA1A gene, which encodes a calcium channel. Type 2 is caused by a missense mutation in ATP1A2, which encodes a sodium-potassium ATPase pump. Type 3 is caused by gain-of-function mutations in SCN1A, which encodes a neuronal sodium channel. Finally, type 4 is associated with loss-of-function mutations in PRRT2, which encodes a neuronal transmembrane signaling protein.
"These mutations are only found in a few FHM patients," said Professor Anne Ducros of the University of Montpellier, France. "Other mutations in the same genes are responsible for many conditions, such as ataxias and epileptic syndromes."
Some migraine-associated variants are rare but have large effect sizes; in other words, they have a large contribution to the condition. Many others have smaller effect sizes, such as variants linking migraine to neurological and psychiatric conditions like attention-deficit/hyperactivity disorder, major depressive disorder, and Tourette syndrome, which often present as comorbidities.
Brain Inflammation
Migraine with aura is associated with neuroimmune activation and inflammation, which can be imaged in humans with integrated PET/MRI. Neuroimaging shows that visual cortical areas involved in motion processing are thickened in people who experience migraines with and without auras. Whether these changes are a cause or a consequence of migraine remains unclear.
Patients with migraine also exhibit changes in brain structure and functional connectivity. Reductions in migraine day frequency in response to erenumab treatment are associated with changes in resting state functional connectivity that differ from those seen in nonresponders.
"Migraine has different phases, and the interictal phase is the most widely studied. But each phase may potentially have its own imaging biomarkers," said Professor Hülya Karataş of Hacettepe University, Turkey.
Imaging can be useful for research and may have diagnostic potential in the future. Currently, however, it is not widely used in the clinic for diagnosing or managing migraine.
"Higher-resolution imaging and more sophisticated data analysis techniques are on the horizon," said Karataş. "These techniques may deepen our understanding of migraine etiology and improve our ability to treat it, so it is important to integrate imaging into routine clinical practice."
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