Migraine: disease characterisation, biomarkers, and precision medicine

doi:10.1016/S0140-6736(20)32162-0

The Lancet

Volume 397, Issue 10283, 17–23 April 2021, Pages 1496-1504

https://doi.org/10.1016/S0140-6736(20)32162-0 Get rights and content

Summary

Migraine is a disabling neurological disorder, diagnosis of which is based on clinical criteria. A shortcoming of these criteria is that they do not fully capture the heterogeneity of migraine, including the underlying genetic and neurobiological factors. This complexity has generated momentum for biomarker research to improve disease characterisation and identify novel drug targets. In this Series paper, we present the progress that has been made in the search for biomarkers of migraine within genetics, provocation modelling, biochemistry, and neuroimaging research. Additionally, we outline challenges and future directions for each biomarker modality. We also discuss the advances made in combining and integrating data from multiple biomarker modalities. These efforts contribute to developing precision medicine that can be applied to future patients with migraine.

Introduction

Migraine is a highly prevalent neurological disorder, listed as the second leading cause of years lived with disability worldwide.¹ The pathogenesis of migraine has a strong genetic component and involves activation of trigeminovascular pain pathways.2, 3, 4, 5 Migraine is defined solely by clinical criteria, which has fuelled research efforts to establish migraine-specific biomarkers for precision medicine approaches.5, 6 Advances in genetics, provocation models, biochemistry, and neuroimaging hold great promise and have improved our understanding of migraine pathogenesis. In this Series paper, we first evaluate the progress that has been made in the search for migraine-specific biomarkers. Second, we discuss the use of integrating data from multiple biomarker modalities to more accurately assess distinct and unique features of migraine. Finally, we highlight challenges with the current biomarker approaches and provide recommendations to improve research into biomarkers of migraine.

Section snippets

Classification and characterisation of migraine

The diagnosis of migraine is based on clinical criteria provided in the third edition of the International Classification of Headache Disorders (ICHD-3).⁶ Medical history is the main component of diagnosis and typical clinical features include recurrent headache attacks of unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, vomiting, photophobia, and phonophobia.⁶ Although migraine pain often lateralises to

Genetic biomarkers

Migraine often clusters in families, suggesting a strong genetic component to its pathogenesis.² However, identifying the relevant genes remains a challenge. Population-based twin and family studies have shown that migraine is a complex neurological disorder, with its features probably arising from gene–gene and gene–environment interactions, but also other unknown factors.2, 10 A genome-wide association meta-analysis identified 38 genomic loci that affect migraine risk.¹⁰ This meta-analysis

Provocation biomarkers

The pathogenesis of migraine is multifaceted, with a complex interplay between different molecular signalling pathways.⁵ A key feature of migraine is that various trigger factors have been shown to produce migraine attacks (figure 1).²¹ This feature provides a unique opportunity to identify signalling pathways that cause migraine through human provocation models, wherein endogenous signalling molecules or other putative triggers are used to induce migraine in humans.²¹ An important observation

Blood biomarkers

Research into blood biomarkers of migraine has garnered attention over the past 10 years.⁴ This interest is fuelled by the concept that blood biomarkers contribute to the understanding of molecular mechanisms underlying migraine. Efforts have been made to establish blood biomarkers that could predict and monitor treatment response in individual patients. Blood biomarker studies have investigated a multitude of circulating signalling molecules implicated in migraine pathogenesis.⁴ Herein, we

Imaging biomarkers

In studies on biomarkers for migraine, MRI has emerged as useful technology to identify structural and functional changes in individuals with migraine. Alterations in functional connectivity have been investigated in both the interictal and ictal phase of a migraine attack.⁴⁶

Integration of biomarker modalities

Integration of biomarker modalities offers a promising way to combine data from multiple sources and identify novel biomarkers for migraine. Additionally, such approaches might advance our understanding of disease mechanisms underlying migraine and several studies have sought to combine biomarker modalities and establish strategic interdisciplinary research collaborations. We herein summarise the results from studies that have used at least two of the four biomarker modalities.

A combination of

Conclusions

Biomarker research has already made great contributions to our understanding of migraine pathogenesis. Advancements in genetics, provocation models, biochemistry, and neuroimaging have shown the potential of biomarker-driven approaches to diagnosis, treatment, and drug discovery. Efforts to combine biomarker modalities have improved understanding of the biological complexity underlying migraine and its subtypes. Building on this foundation, future research should investigate precision medicine

Search strategy and selection criteria

We searched MEDLINE (from database inception to Jan 1, 2020), and Embase (from database inception to Jan 1, 2020). We used the search terms “migraine” in combination with the terms “diagnosis”, “classification”, “genetic”, “provocation”, “human models”, “blood biomarkers”, “serum”, “brain”, “cortical changes”, “imaging”, “data integration”, “biomarker”, “CGRP”, “PACAP” and/or “signaling molecule”. We mainly selected publications from the past 5 years but did not exclude other publications that

Declaration of interests

MA is a consultant, speaker or scientific advisor for AbbVie, Allergan, Amgen, Alder, Biohaven, Eli Lilly, Lundbeck, Novartis, and Teva, and primary investigator for Alder, Amgen, Allergan, Eli Lilly, Lundbeck, Novartis and Teva trials. MA has no ownership interest and does not own stocks of any pharmaceutical company. MA serves as associate editor of Cephalalgia, and associate editor of the Journal of Headache and Pain. MA is president of the International Headache Society. GMT reports grants

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Genetics of migraine: complexity, implications, and potential clinical applications
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Migraine is a common neurological disorder with large burden in terms of disability for individuals and costs for society. Accurate diagnosis and effective treatments remain priorities. Understanding the genetic factors that contribute to migraine risk and symptom manifestation could improve individual management. Migraine has a strong genetic basis that includes both monogenic and polygenic forms. Some distinct, rare, familial migraine subtypes are caused by pathogenic variants in genes involved in ion transport and neurotransmitter release, suggesting an underlying vulnerability of the excitatory–inhibitory balance in the brain, which might be exacerbated by disruption of homoeostasis and lead to migraine. For more prevalent migraine subtypes, genetic studies have identified many susceptibility loci, implicating genes involved in both neuronal and vascular pathways. Genetic factors can also reveal the nature of relationships between migraine and its associated biomarkers and comorbidities and could potentially be used to identify new therapeutic targets and predict treatment response.
In vivo visualization of tumor-associated macrophages re-education by photoacoustic/fluorescence dual-modal imaging with a metal-organic frames-based caspase-1 nanoreporter
2024, Journal of Colloid and Interface Science
Tumor-associated macrophages (TAMs) are vital in the tumor microenvironment, contributing to immunosuppression and therapy tolerance. Despite their importance, the precise re-education of TAMs in vivo continues to present a formidable challenge. Moreover, the lack of real-time and efficient methods to comprehend the spatiotemporal kinetics of TAMs repolarization remains a significant hurdle, severely hampering the accurate assessment of treatment efficacy and prognosis. Herein, we designed a metal–organic frameworks (MOFs) based Caspase-1 nanoreporter (MCNR) that can deliver a TLR7/8 agonist to the TAMs and track time-sensitive Caspase-1 activity as a direct method to monitor the initiation of immune reprogramming. This nanosystem exhibits excellent TAMs targeting ability, enhanced tumor accumulation, and stimuli-responsive behavior. By inducing the reprogramming of TAMs, they were able to enhance T-cell infiltration in tumor tissue, resulting in inhibited tumor growth and improved survival in mice model. Moreover, MCNR also serves as an activatable photoacoustic and fluorescent dual-mode imaging agent through Caspase-1-mediated specific enzyme digestion. This feature enables non-invasive and real-time antitumor immune activation monitoring. Overall, our findings indicate that MCNR has the potential to be a valuable tool for tumor immune microenvironment remodeling and noninvasive quantitative detection and real-time monitoring of TAMs repolarization to immunotherapy in the early stage.
Pharmacotherapies for Migraine and Translating Evidence From Bench to Bedside
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Migraine is a ubiquitous neurologic disorder that afflicts more than 1 billion people worldwide. Recommended therapeutic strategies include the use of acute and, if needed, preventive medications. During the past 2 decades, tremendous progress has been made in better understanding the molecular mechanisms underlying migraine pathogenesis, which in turn has resulted in the advent of novel medications targeting signaling molecule calcitonin gene–related peptide or its receptor. Here, we provide an update on the rational use of pharmacotherapies for migraine to facilitate more informed clinical decision-making. We then discuss the scientific discoveries that led to the advent of new medications targeting calcitonin gene–related peptide signaling. Last, we conclude with recent advances that are being made to identify novel drug targets for migraine.
Calcitonin gene-related peptide (CGRP) levels in peripheral blood in patients with idiopathic intracranial hypertension and migraine
2024, Clinical Neurology and Neurosurgery
Calcitonin gene-related peptide (CGRP) plays a dominant role in migraine. This prospective study was designed to investigate CGRP levels in patients with idiopathic intracranial hypertension (IIH) and compare the results of migraine patients and healthy controls (HC). As a second objective, CGRP levels obtained from IIH patients defining sustained headache after the resolution of papilledema were compared with those not defining post-IIH headache.
Thirty-six patients with IIH, 36 with episodic migraine (EM), 18 with chronic migraine (CM), and 36 HC were included in the study. CGRP levels were studied from blood samples obtained from the antecubital vein by using a commercial ELISA kit.
Serum CGRP levels of the patient groups were significantly higher than the HC (p < 0.001). As compared with controls, both CM (p Adj<0.001) and IIH (p Adj=0.039) had significantly increased levels of CGRP. Levels recorded from EM patients did not differ from the HC (p Adj=0.661). In 16 IIH patients, persistent headache was reported after the normalization of intracranial pressure (ICP). Twenty patients did not report post-IIH headaches. Comparison of serum CGRP levels of these two groups revealed significantly higher CGRP levels in patients with sustained headaches obtained from blood samples both at the initial and control visit (p Adj <0.001).
CGRP levels of the patient groups were higher than the HC. High levels recorded in patients with IIH indicates the role of CGRP in IIH related headache and even higher levels in patients with sustained headache after normalization of ICP strengthens this finding.
Somatosensory Profiling of Patients With Cluster Headache: A Systematic Review and Meta-analysis
2024, Journal of Pain
The objectives were 1) to synthesize quantitative sensory testing results in cluster headache (CH) patients and to identify somatosensory differences from healthy subjects (HS), and 2) between symptomatic and asymptomatic sides in CH patients. Two independent reviewers conducted a literature search in MEDLINE, EMBASE, Web of Science, and CINAHL databases. Studies with observational designs were included. Methodological quality and risk of bias were assessed with the Newcastle Ottawa Scale. The selected studies underwent qualitative and quantitative analyses. The qualitative analysis showed inconsistent findings among multiple studies. Meta-analysis showed lower pressure pain thresholds (PPTs) on the symptomatic side of CH patients than HS in V₂ (standardized mean difference [SMD] −1.01 [95% confidence interval (CI) −1.79, −.23], P = .01, I² = 73%, n = 114), V₃ (SMD −1 [95% CI −1.54, .45], P < .01, I² = 82%, n = 354), and cervical region (SMD −1.25 [95% CI −2.07, −.44], P < .01, I² = 84%, n = 194). Furthermore, lower PPTs than those detected in HS were found on the asymptomatic side in V₃ (SMD −.77 [95% CI −1.27, −.27], P < .01, I² = 79%, n = 354) and in the cervical region (SMD −1.13 [95% CI −1.97, −.3], P < .01, I² = 85%, n = 194). However, no differences were found in V₁ or the extratrigeminal points between these groups. No significant changes were found between symptomatic and asymptomatic sides in trigeminal and extratrigeminal regions. Mechanical hyperalgesia in the trigemino-cervical region of patients with CH could suggest the presence of central pain mechanisms. These results are of clinical relevance because their presence could be associated with a poorer prognosis, chronification, and treatment response.
This study provides consistent findings on the somatosensory profile characterizing patients with CH. Clinicians should assess PPTs and other quantitative sensory testing variables in the trigeminal and extratrigeminal (cervical) regions.
The evolving concept of multimorbidity and migraine
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Migraine presents with high prevalence and similar clinical course with different disorders such as neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metabolic-endocrine, and immunological conditions, which can often cooccur themselves. Multifaceted mechanisms subtend these comorbidities with a bidirectional link. First, a shared genetic load can explain the cooccurrence. Second, comorbid pathologies can promote disproportionate energetic needs, thalamocortical network dysexcitability, and systemic transient or persistent proinflammatory state, which may trigger the activation of a broad self-protective network that includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This response results in maintenance of brain homeostasis by modulating subcortical–cortical excitability, energetic balance, osmoregulation, and emotional response. In this process, the CGRP is released in the trigeminovascular system. However, the calcitonin gene-related peptide (CGRP) plays several actions also outside the brain to maintain the homeostatic needs and is involved in the physiological functions of different systems, whose disorders are associated with migraine. This aspect further increases the complexity of migraine treatment, where standard therapies often have systemic adverse effects. On the other hand, some preventives can improve comorbid conditions. In summary, we propose that migraine management should involve a multidisciplinary approach to identify and mitigate potential risk factors and comorbidity and tailor therapies individually.

View all citing articles on Scopus

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SeriesMigraine: disease characterisation, biomarkers, and precision medicine

Summary

Introduction

Section snippets

Classification and characterisation of migraine

Genetic biomarkers

Provocation biomarkers

Blood biomarkers

Imaging biomarkers

Integration of biomarker modalities

Conclusions

Search strategy and selection criteria

Declaration of interests

Lancet Neurol

Neuron

Lancet

Lancet

Pain

Lancet Neurol

Prog Neurobiol

Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Lancet Neurol

Meta-analysis of the heritability of human traits based on fifty years of twin studies

Nat Genet

Pathophysiology of migraine: a disorder of sensory processing

Physiol Rev

Migraine

N Engl J Med

The international classification of headache disorders, 3rd edn

Cephalalgia

A population-based analysis of the diagnostic criteria of the International Headache Society

Cephalalgia

Neuroimaging for migraine: the American Headache Society systematic review and evidence-based guideline

Headache

Migraine headache is present in the aura phase: a prospective study

Neurology

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Nat Genet

Shared genetic basis for migraine and ischemic stroke: a genome-wide analysis of common variants

Neurology

Genetic analysis for a shared biological basis between migraine and coronary artery disease

Neurol Genet

Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

Nat Genet

Advance in genetics of migraine

Curr Opin Neurol

Linking migraine frequency with family history of migraine

Cephalalgia

Genome-wide DNA methylation profiling in whole blood reveals epigenetic signatures associated with migraine

BMC Genomics

Increased familial risk and evidence of genetic factor in migraine

BMJ

Migraine polygenic risk score associates with efficacy of migraine-specific drugs

Neurol Genet

Mendelian randomization

JAMA

Human models of migraine—short-term pain for long-term gain

Nat Rev Neurol

Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain

Neuroreport

Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine

Brain

PACAP38 induces migraine-like attacks in patients with migraine without aura

Brain

Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura

Cephalalgia

Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase

Brain

Migraine can be induced by sildenafil without changes in middle cerebral artery diameter

Brain

Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache

Cephalalgia

W. P. A randomised, single-blind, placebo-controlled, adaptive clinical trial of GW274150, a selective iNOS inhibitor, in the treatment of acute migraine

Cephalalgia

Vasoactive peptide release in the extracerebral circulation of humans during migraine headache

Ann Neurol

Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally

Cephalalgia

No increase of calcitonin gene-related peptide in jugular blood during migraine

Ann Neurol

Series
Migraine: disease characterisation, biomarkers, and precision medicine