Genetic and Imaging Markers in Migraine: Ready for Prime Time?

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Markers of migraine could potentially also be used to confirm the diagnosis in patients in whom migraine is suspected but who fail to meet clinical criteria.
Markers of migraine could potentially also be used to confirm the diagnosis in patients in whom migraine is suspected but who fail to meet clinical criteria.

Advancements in research have led to the identification of a growing number of genetic and neuroimaging markers of migraine. The application of neuroimaging technology in migraine research has provided valuable insights into the pathophysiologic mechanisms responsible for migraine symptoms during and between attacks.1 Similarly, the application of large-scale, genome-wide association studies — a methodology that uses both microarray technology and statistical analysis to compare the DNA of different individuals to find common genetic variants associated with a given trait or disease — has facilitated the identification of genetic variants associated with the risk for migraine. Despite the invaluable insights that neuroimaging and genetic studies have provided regarding the neurobiology of migraine, the markers that have been identified have had little impact on the diagnosis or treatment of individual people with migraine.

In an interview, Paul Durham, PhD, distinguished professor of cell biology at Missouri State University, who researches the cellular and molecular mechanisms in models of migraine, told Neurology Advisor that the potential value of validated genetic and imaging markers for migraine would be enormous both to the patient and to society. “If markers or imaging technology could allow for more personalized medicine by knowing more about a patient's underlying pathology, then the treatment could be tailored to address the specific pathology. It would be very valuable to be able to have better predictive ability when choosing which therapy would be most appropriate.”

Other benefits of migraine markers include facilitating diagnosis, monitoring treatment, and discovering more about the pathogenesis of the disorder, thus potentially providing the basis for the development of new classes of antimigraine therapies. Andrew Charles, MD, wrote in a recent review of the pathophysiology of migraine, “neuromodulation approaches could enable physicians to specifically target novel central and peripheral migraine mechanisms, such as alterations in thalamocortical circuits, or contributions of cervical nerve roots to migraine headache.”2 Markers of migraine might also be used to confirm the diagnosis in patients in whom migraine is suspected but whose headaches fail to meet clinical criteria stipulated in the third edition of the International Classification of Headache Disorders.3

Genetics

Based on observations of significantly increased familial risk for migraine and higher pairwise concordance rates in monozygotic vs dizygotic twin pairs, migraine is widely understood to have a strong genetic component.4 Two competing theories on the etiology of migraine have been proposed. The vasogenic theory maintains that migraine is a disease of vascular dysfunction, and the neurogenic theory holds that migraine is a disease of neuronal dysfunction with secondary vascular changes.5,6

In a meta-analysis of 22 studies previously conducted on migraine, 44 independent single-nucleotide polymorphisms significantly associated with migraine risk were identified in 38 distinct genomic loci. The migraine-associated genes were found to be involved both in arterial and smooth muscle function, providing support for the vasogenic theory.7 This finding is consistent with observations that patients with migraine are at elevated risk for cardiovascular disease and ischemic stroke. Nine of the migraine-associated genes that have been identified have known associations with vascular disease (PHACTR1, TGFBR2, LRP1, PRDM16, RNF213, JAG1, HEY2, GJA1, and ARMS2.)7,8

Imaging

The use of a variety of types of advanced structural and functional neuroimaging techniques in patients with migraine have evinced abnormal function of key brain areas and networks, including cortical hyperexcitability, derangements in brain chemistry, and alterations in gray and white matter structure.6 Results from a recent meta-analysis that evaluated the association between grey matter changes and migraine in 13 studies involving 579 patients suggest that gray matter volume reductions in the bilateral inferior frontal gyri, the right precentral gyrus, the left middle frontal gyrus, and the left cingulate gyrus may be implicated in pain processing. Additionally, gray matter volume decreases in the right claustrum, left cingulated gyrus, right anterior cingulate, amygdala, and left parahippocampal gyrus were negatively correlated with the estimated frequency of headache attack.9

“The ultimate aim of these studies is to translate the variety of clinical phenotypes of migraine (for example, sensory sensitivity, nausea, cognitive and emotional dysfunction) into brain phenotypes that are identifiable with neuroimaging markers,” wrote Dale Nyholt, PhD, and colleagues in a recent review.8

Imaging and genetic markers of migraine need to have high reliability and predictive function to be clinically useful, however, “we are not there yet,” Dr Durham noted. “[It] most likely will require DNA and protein biomarkers as well as imaging techniques to ensure a higher degree of confidence,” he said. “So many ‘biomarkers' for other diseases are actually not that useful and in many instances lead to a lot of stress for the patient due to false positive results.”

References

  1. Li DW. Genome-Wide Association Study. In: Dubitzky W, Wolkenhauer O, Cho K-H, Yokota H, eds. Encyclopedia of Systems Biology. New York, NY: Springer; 2013:834.
  2. Charles A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 2018;17(2):174-182.
  3. No authors listed. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
  4. Eising E, de Vries B, Ferrari MD, Terwindt GM, van den Maagdenberg AM. Pearls and pitfalls in genetic studies of migraine. Cephalalgia. 2013;33(8):614-625.
  5. Parsons AA, Strijbos PJ. The neuronal versus vascular hypothesis of migraine and cortical spreading depression. Curr Opin Pharmacol. 2003;3(1):73-77.
  6. Cutrer FM, Smith JH. Human studies in the pathophysiology of migraine: genetics and functional neuroimaging. Headache. 2013;53(2):401-412.
  7. Gormley P, Anttila V, Winsvold BS, et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet. 2016;48(8):856-866.
  8. Nyholt DR, Borsook D, Griffiths LR. Migrainomics - identifying brain and genetic markers of migraine. Nat Rev Neurol. 2017;13(12):725-741.
  9. Jia Z, Yu S. Grey matter alterations in migraine: A systematic review and meta-analysis. NeuroImage Clin. 2017;14:130-140.
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