Risk Of Migraine Research Articles

Association of rs2651899 Polymorphism in the Positive Regulatory Domain 16 and Common Migraine Subtypes: A Meta-Analysis.

Migraine is a neurovascular disease with recurrent headache attacks. A polymorphism (rs2651899) of the PRDM16 gene, which is associated with migraine, was identified in recent genome-wide association studies. The potential role of the PRDM16 rs2651899 polymorphism in migraine is still unknown. Therefore, we conducted this systematic review and meta-analysis to examine this issue. We performed a comprehensive literature search of the PubMed, Embase, and Google Scholar databases to identify eligible studies published before October 2018. Individual odds ratio and 95% confidence interval was used to estimate the pooled strength of the association between the PRDM16 rs2651899 polymorphism and common migraine subtypes, including migraine with aura (MA) and migraine without aura (MO). Six studies with 2853 cases and 9319 controls that fulfilled the inclusion and exclusion criteria were selected for this meta-analysis. Of the 6 included studies, 4 studies had available data for MWA and another 4 studies had data for MWoA. Overall, significant migraine risks of 1.257, 1.305, and 1.419 were found under allele model (C vs T), dominant model (C/C+T/C vs T/T), and recessive model (C/C vs T/C+T/T), respectively. In the recessive model, significantly increased risks of 1.454 and 1.546 were found for MA and MO, respectively. Our major findings suggest that PRDM16 rs2651899 polymorphism is associated with the risk of migraine. Furthermore, we found that PRDM16 rs2651899 polymorphism is significantly related to common migraine subtypes (MA and MO).

Migraine Genetic Variants Influence Cerebral Blood Flow.

ObjectiveTo investigate the association of migraine genetic variants with cerebral blood flow (CBF).BackgroundMigraine is a common disorder with many genetic and non‐genetic factors affecting its occurrence. The exact pathophysiological mechanisms underlying the disease remain unclear, but are known to involve hemodynamic and vascular disruptions. Recent genome‐wide association studies have identified 44 genetic variants in 38 genetic loci that affect the risk of migraine, which provide the opportunity to further disentangle these mechanisms.MethodsWe included 4665 participants of the population‐based Rotterdam Study (mean age 65.0 ± 10.9 years, 55.6% women). Cross‐sectional area (mm2), flow velocity (mm/s), and blood flow (mL/min) were measured in both carotids and the basilar artery using 2‐dimensional phase‐contrast magnetic resonance imaging. We analyzed 43 previously identified migraine variants separately and calculated a genetic risk score (GRS). To assess the association with CBF, we used linear regression models adjusted for age, sex, and total brain volume. Hierarchical clustering was performed based on the associations with CBF measures and tissue enrichment.ResultsThe rs67338227 risk allele was associated with higher flow velocity and smaller cross‐sectional area in the carotids (P minimum = 3.7 × 10−8). Other variants were related to CBF with opposite directions of effect, but not significantly after multiple testing adjustments (P < 1.4 × 10−4). The migraine GRS was not associated with CBF after multiple testing corrections. Migraine risk variants were found to be enriched for flow in the basilar artery (λ = 2.39).ConclusionsThese findings show that genetic migraine risk is complexly associated with alterations in cerebral hemodynamics.

Health Behaviors and Social Determinants of Migraine in a Canadian Population-Based Sample of Adults Aged 45-85 Years: Findings From the CLSA.

Social determinants of health are well linked to adverse health outcomes, but less is known about how they relate to migraine. While much attention has been given to the role of modifiable lifestyle factors which may mitigate risk of migraine, the role of physical activity in headache management is not yet understood. The purpose of this study was to explore the relationship between social determinants of health, health behaviors, and migraine prevalence in a sample of the Canadian population aged 45-85years. In this cross-sectional analysis of baseline data from the Canadian Longitudinal Study on Aging, respondents were between 45 and 85years of age and migraine was self-report of physician diagnosis. Analyses were stratified by sex/gender (nwomen =22,176, nmen =21,549). The weighted prevalence of migraine for men and women was 7.5% and 19.6%, respectively. There were relationships between social determinants of health and migraine for both men and women. Notably, higher perceived social status was associated with a 3% reduced odds of migraine among women (OR=0.97, 95% CI: 0.95, 0.98, P<.001). Gay and bisexual men had 50% higher odds of migraine compared to heterosexual men (OR=1.50, 95% CI: 1.13, 1.99, P=.005). Some forms of physical activity were associated with reduced odds of migraine for women: walking for 30minutes but less than 1hour (OR=0.87, 95% CI: 0.78, 0.96, P=.005), light sports for less than 30minutes (OR=0.86, 95% CI: 0.73, 1.00, P=.048), and 1hour but less than 2hours (OR=0.85, 95% CI: 0.74, 0.97, P=.018), strenuous sports for 30minutes but less than 1hour (OR=0.79, 95% CI: 0.71, 0.89, P<.001), and 1hour but less than 2hours (OR=0.82, 95% CI: 0.73, 0.92, P=.001). Men who engaged in daily walking as a form of leisure time physical activity had higher odds of migraine: walking less than 30minutes (OR=1.21, 95% CI: 1.01, 1.45, P=.042), 2hours but less than 4hours (OR=1.42, 95% CI: 1.11, 1.80, P=.005), and 4hours or more (OR=1.65, 95% CI: 1.18, 2.31, P=.004). Social determinants of health are associated with migraine prevalence for both men and women. Physical activity is a modifiable lifestyle factor which merits further exploration as an intervention option for migraine headaches in aging samples, especially among older women. Greater odds of migraine among older men who walked for exercise may be explained by reverse causality.

Cardiovascular fitness and risk of migraine: a large, prospective population-based study of Swedish young adult men

ObjectivesTo examine the longitudinal relationship between cardiovascular fitness in young adult men and future risk of migraine and to estimate eventual differential effects among categories of body mass index (BMI)...

The association between dietary tryptophan intake and migraine.

Migraineurs have been identified to have chronically decreased serotonin levels while its concentrations markedly increase during ictal periods. Regarding the importance of adequate tryptophan intake in regulating serotonin homeostasis and subsequent effect on migraine attacks, we designed the current study. The migraine group (n = 514, diagnosed according to the ICHDIII criteria) was recruited from a tertiary headache clinic. The controls consisted of 582 sex-matched healthy volunteers who were randomly selected from general population. After collecting demographic and anthropometric data, a validated 168-item semi-quantitative food frequency questionnaire (FFQ) was used for dietary intake assessments. Multiple regression models were applied to explore the relationship between migraine and tryptophan intake. The mean (SD) of the age of participants in the controls and migraine group was 44.85 (13.84) and 36.20 (9.78) years, respectively. The multiple regression models were adjusted for age (year), sex, body mass index (BMI) (kg/m2), total daily energy intake (kcal/day), dietary intakes of total carbohydrates (g/day), animal-based protein (g/day), plant-based protein (g/day), total fat (g/day), saturated fat (g/day), and cholesterol (mg/day). It was shown that there is a negative association between tryptophan intake and migraine risk ((OR in the 3rd quartile = 0.46; 95% CI = 0.25-0.85) (OR in the 4th quartile = 0.40; 95% CI = 0.16-0.98) compared with the first quartile; P for trend = 0.045). Therefore, our results showed that subjects who had a median intake of 0.84-1.06g of tryptophan per day had reduced odds of developing migraine by approximately 54-60%, relative to those consumed ≤ 0.56g/day.

Confounding, Mediation, or Independent Effect? Childhood Psychological Abuse, Mental Health, Mood/Psychological State, COPD, and Migraine.

In some settings, it may be difficult to differentiate between a confounder and a mediator. For instance, the observed association of self-reported childhood psychological abuse (CPA) with onset of chronic obstructive pulmonary disease (COPD) and migraine may be confounded by current mood/psychological state (e.g., the subjective evaluation of one's own affective state), as well as mediated by an individual's psychopathological symptoms. In this study, we propose the "independence hypothesis," which could prove meaningful to explore in data that lack prospective or objective indices of CPA. We used cross-sectional data from wave VI (2007-2008) of the Tromsø Study, Norway (N = 12,981). The associations between CPA and COPD and migraine were assessed with Poisson regression models. CPA was associated with a 46% increased risk of COPD (relative risk [RR] = 1.46, 95% confidence interval [CI]: [1.02, 1.90]) and a 28% increased risk of migraine in adulthood (RR = 1.28, 95% CI: [1.04, 1.53]), independent of age, sex, parental history of psychiatric problems/asthma/dementia, smoking, respondent's mood/psychological state, and mental health. These findings suggest that the association between retrospectively reported CPA and COPD and migraine is not driven entirely by respondent's mood/psychological state and mental health. Assessing the independent effect of self-reported CPA on COPD and migraine in retrospective studies may prove more meaningful than exploring the mediating role of mental health. Here, we provide the analytical rationale for assessing the independent effect in settings where it is difficult to differentiate between a confounder and a mediator. Moreover, we provide a theoretical rationale for assessing the independent effect of retrospectively reported childhood adversity on health and well-being.

Effects of MTHFR C677T and A1298C Polymorphisms on Migraine Susceptibility: A Meta-Analysis of 26 Studies.

Multiple studies have evaluated the associations between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and migraine risk with conflicting results. Therefore, we conducted a meta-analysis on this theme. We searched the electronic databases of PubMed, EmBase, ScienceDirect, and Cochrane Library for all relevant studies published until April 6, 2018. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) in allelic, dominant, recessive, homozygous, and heterozygous models were calculated using random effects model to assess the strength of associations. We also performed subgroup analyses stratified by ethnicity and migraine subtypes, respectively. Twenty-six studies (20 in Caucasians, 3 in Asians, 2 in Indians, and 1 in Pakistanis) with 10,228 migraineurs and 28,608 controls were included in this meta-analysis. In the overall population, the allele 677T and TT genotype were associated with an increased risk for total migraine and migraine with aura (MA) (total migraine: T vs C: OR=1.19, 95%CI=1.06-1.33, P=.004; TT vs CC: OR=1.32, 95%CI=1.07-1.64, P=.011; MA: T vs C: OR=1.28, 95%CI=1.09-1.51, P=.003; TT vs CC: OR=1.51, 95%CI=1.09-2.08, P=.012), but not for migraine without aura (MO). Subgroup analysis stratified by ethnicity revealed similar findings in Caucasians. In Asians, the association was detected only in recessive model in total migraine (TT vs CT+CC: OR=1.80, 95%CI=1.14-2.85, P=.012). Results in Indians did not suggest any association in either total migraine or its subtypes. Pooled results of 5 studies (4 in Caucasians and 1 in Indians) on A1298C polymorphism indicated a significant association between the CC genotype and migraine risk (CC vs AA: OR=1.78, 95%CI=1.03-3.07, P=.038), which only appeared for MO (CC vs AA: OR=2.83, 95%CI=1.30-6.16, P=.009). Our meta-analysis suggested that allele 677T in MTHFR C677T polymorphism might be a genetic risk factor for MA in Caucasians, and genotype 1298CC might contribute to MO susceptibility.

Examining the National Profile of Chronic Disaster Health Risks in Australia

Introduction:Despite a longstanding focus on examining acute health impacts in disaster research, only limited systematic information is available today to further our understanding of chronic physical health risks of disaster exposure. Heterogeneity of studies and disaster events of varying type and scale compounding this challenge highlight the merit of a consistent approach to examining nationally representative population data to understand distinctive profiles of chronic disaster health risks.Aim:This epidemiological study examined the full spectrum and national profile of chronic physical health risks associated with natural and man-made disaster exposure in Australia.Methods:Nationally-representative population survey data (N=8841) were analyzed through multivariate logistic regression, controlling for sociodemographic variables, exposure to natural and man-made disasters, and other traumatic events. Key outcomes included lifetime national chronic health priority conditions (asthma, cancer, stroke, rheumatism/arthritis, diabetes, heart/circulatory) and other conditions of 6 month or more duration (based on the World Health Organization’s WMH-CIDI chronic conditions module).Results:Natural disaster exposure primarily increased the lifetime risk of stroke (AOR 2.06, 95%CI 1.54-2.74). Man-made disaster exposure increased the lifetime risk of stomach ulcer (AOR 2.21, 95%CI 1.14-4.31), migraine (AOR 1.61, 95%CI 1.02-2.56), and heart/circulatory conditions (AOR 2.01, 95%CI 1.07-3.75). Multiple man-made disaster exposure heightened the risk of migraine (AOR 2.98, 95%CI 1.28-6.92) and chronic back or neck conditions (AOR 1.63, 95%CI 1.02-2.62), while multiple natural disaster exposure heightened the risk of stroke (AOR 3.28, 95%CI 1.90-5.67). No other chronic health risks were elevated. Despite the relatively greater chronic health risks linked to man-made disasters, natural disasters were associated overall with more cases of chronic health conditions.Discussion:The analysis of nationally-representative population data provides a consistent method to examine the unique national imprint of disaster exposure and distinct profile of disaster health risks to inform future detection, prevention measures, disaster health preparedness, and response planning.

Increased risk of migraine in patients with psoriasis: A longitudinal follow up study using a national sample cohort.

Both psoriasis and migraine are associated with inflammatory diseases. However, few studies have been conducted the increased risk of migraine in psoriasis patients. The aim of this study was to identify whether the psoriasis increases the risk of migraine. This study used the national cohort study data collected by the Korean Health Insurance Review and Assessment from 2002 to 2013. Patients with psoriasis (n = 11,071) and control participants (n = 44,284) were selected and matched 1:4 by age, sex, income, region of residence, and past medical history of hypertension, diabetes, and dyslipidemia. This study used Cox-proportional hazard model for calculating hazard ratio (HR) with crude and adjusted model. Stratification by age and sex was analyzed. Migraines occurred significantly more frequently in psoriasis patients than in control participants (adjusted HR = 1.16, 95% confidence interval (CI) = 1.04-1.31, P <.05). In the stratification analysis, migraines occurred significantly more frequently in psoriasis patients than in control participants only in the group of middle-aged males (adjusted HR = 1.62 95% CI = 1.22-2.13, P = .001). In conclusion, psoriasis might increase the risk of migraine.

Association between PRDM16, MEF2D, TRPM8, LRP1 gene polymorphisms and migraine susceptibility in the She ethnic population in China.

The prevalence of migraines in the She population, a minority in China, is significantly higher than that in Han Chinese and other Asian populations. Two single nucleotide polymorphisms (SNPs) have been found to be associated with migraine susceptibility in the She population. This study investigated four SNPs, identified in genome-wide association studies, within migraine-susceptible loci in Han Chinese for their association with migraine susceptibility in the She population. Two-hundred unrelated migraine patients and 200 healthy controls were recruited. The SNPs examined included rs2651899 (PRDM16 ), rs2274316 (MEF2D ), rs7577262 (TRPM8) and rs11172113 (LRP1). Genotyping of the SNPs was performed by allele-specific polymerase chain reaction and direct sequencing. No significant differences between the participants with migraines and controls (participants without migraines) were demonstrated in genotypes, alleles and allele carriage frequencies for the four SNPs. A subgroup analysis found that migraine with aura had a lower frequency of C allele positivity in rs2651899 than in healthy controls (59.6% vs. 74.5%, respectively; P < 0.034). Univariate analyses indicated that no genotype of the four SNPs had a significant association with migraines. Males had a lower risk of migraines, and advanced age was a significant risk factor for migraines in females. The SNPs in four migraine susceptible loci in Han Chinese were not risk factors for migraines in a relatively small sample of the She population.

Rs2651899 variant is associated with risk for migraine without aura from North Indian population.

Recently a GWAS study had identified 38 genomic variants commonly found in humans that influence migraine risk. For further replicate these findings, we selected two SNPs; rs2651899 on chromosome 1p36.32 in PRDM16 gene and rs10166942 on chromosome 2q37.1 close to TRPM8 gene for their associations with migraine in the North Indian population as much work has not been done on these variants before from this population. In this case-control association study, 300 unrelated subjects, including 150 migraineurs (43 migraine with aura and 107 migraine without aura) and 150 healthy controls were selected to collect genomic DNA. Polymerase chain reaction and restriction-fragment-length polymorphism methods were performed for genotyping of these variants. Univariate and multivariate analyses were done to find the association of different genotypes and alleles of these SNPs with migraine and its subgroups. We found a statistically significant difference in migraineurs with control for PRDM16 rs2651899 polymorphism at genotypic (p < 0.05), allelic (p = 0.022; OR 1.462; 95% CI 1.058-2.022) and for dominant model (p = 0.011; OR 1.957; 95% CI 1.169-3.276). A similar trend was observed both on subgroup and gender analysis in migraine without aura (MO) and females respectively for rs2651899 variant. For the other SNP (rs10166942), statistically non-significant differences were reported in the allelic/genotypic frequencies between migraineurs and controls as p > 0.05. However, on subgroup analysis we found statistically significant differences at genotypic (p < 0.05) and dominant models in migraine with aura (MA) and in males with that of entire controls. But no significant association was found at allelic level in both subgroup and gender analysis for rs10166942. This research study showed that rs2651899 is a potential genetic marker for migraine susceptibility in MO and female subgroup at both genotypic and allelic level in the North Indian population and found that rs10166942 variant may be a potential marker for MA and male subgroup. Further work with large sample size is required for these SNPs to understand their functional mechanisms and to strengthen our results.

Relationship of MTHFR and ACE gene Variations with Migraine Susceptibility: A Case-Control Study in the Population of North India (Jammu)

Disturbance in vascular functioning pathways has been related to pathophysiology of migraine. The present study investigated the role of MTHFR C677T and ACE I/D gene polymorphisms in migraine susceptibility within the population of Jammu province of J&amp;K state. A sum of 252 subjects including 102 migraine patients and 150 non-migrainous unrelated healthy controls were enrolled for the present study. PCR-RFLP was performed for determining MTHFR gene variations. For detecting insertion/deletion in ACE gene PCR was performed. In case of MTHFR, ‘T’ allele (variant allele) and TT genotype (variant) was found to be present only in migraine patients but not in controls thereby suggesting its positive role in migraine pathophysiology. For ACE I/D polymorphism, higher frequency of DD genotype (32.35 % vs 15.3 %) and D allele (0.51 vs 0.4) were observed in patients than in controls. Logistic regression analysis revealed a significant association of ACE I/D polymorphism with risk of migraine. However, a direct link of MTHFR C677T polymorphism with migraine risk was not found.

Quantitative assessment of the association between GRIA1 polymorphisms and migraine risk.

Purpose: The association between GRIA1 rs548294 G>A and rs2195450 C>T polymorphisms and migraine risk has been reported in several case–control studies. However, the results of studies are inconsistent. Thus, we conducted a meta-analysis to more precisely estimate the association of the two polymorphisms with migraine risk.Methods: Eligible studies were retrieved and screened from the online databases (EMBASE, PubMed, Web of Science, Wanfang, and Chinese National Knowledge Infrastructure). The pooled odds ratio (OR) with corresponding 95.0% confidence intervals (CIs) was assessed using random- or fixed-effects model.Results: A total of 1233 cases and 1374 controls from four eligible studies were included. The pooled analysis showed that GRIA1 rs548294 G>A polymorphism was not significantly associated with migraine risk. GRIA1 rs2195450 C>T polymorphism was significantly associated with migraine risk under heterozygous model (CT vs. CC, OR = 1.23, 95%CI = 1.02–1.48, PZ = 0.03). Further subgroup analysis based on ethnicity showed a significant association of GRIA1 rs2195450 C>T polymorphism with migraine risk in Asian population, but not in Caucasian population.Conclusions: Our results indicates that GRIA1 rs2195450 C>T polymorphism is significantly associated with migraine risk. However, the number of studies included in the meta-analysis was small. Thus, more high quality case–control studies with a large sample size are still required to confirm these findings.

Editors' note: Body composition status and the risk of migraine: A meta-analysis

In “Body composition status and the risk of migraine: A meta-analysis,” Gelaye et al. reported that a meta-analysis of 12 studies revealed that the risk of migraine is increased in persons who are underweight. Dr. Gupta attributes the fact that this finding was statistically significant to the methodology of the meta-analysis, rather than to a true relationship, noting that he does not believe uncomplicated low body mass index (BMI) is associated with migraine. In support of this conclusion, he remarks that (1) Addison disease, a disorder that causes low body weight, is not associated with migraine; and (2) thyrotoxicosis, which also leads to low body weight, is associated with cephalgias of unclear etiology. Gelaye et al. respond that they were unsurprised by the relationship they observed between low BMI and migraine. They support the validity of their finding by noting that migraine is associated with altered levels of adipocytokines and that, correspondingly, their meta-analysis also showed an association between obesity and migraine. In “Body composition status and the risk of migraine: A meta-analysis,” Gelaye et al. reported that a meta-analysis of 12 studies revealed that the risk of migraine is increased in persons who are underweight. Dr. Gupta attributes the fact that this finding was statistically significant to the methodology of the meta-analysis, rather than to a true relationship, noting that he does not believe uncomplicated low body mass index (BMI) is associated with migraine.

Reader response: Body composition status and the risk of migraine: A meta-analysis.

I read with interest the article by Gelaye et al.1 regarding influence of body mass index (BMI), at both ends of the spectrum, on incidence of migraine. Meta-analyses are susceptible to all intrinsic biases of all observational studies and have spurred a quest for statistical truth that risks drawing clinicians away from clinical reality or common sense.2,3 In addition, there is no requirement for a generalized robust overarching theoretical matrix to conduct a meta-analysis, pooling—as they do—data from several studies that frequently do not ask the same research question.

Author response: Body composition status and the risk of migraine: A meta-analysis.

We thank Dr. Gupta for the interest in our article,1 in which we evaluated the relationship between body composition and migraine. The commentary raised an interesting point about biological plausibility and how observed association between low body mass index (BMI) and migraine might be attributable to underlying illness such as thyrotoxicosis. Biologically, it is well-known that there are several potential mechanisms for the BMI–migraine association.2 Adipose tissue is a neuroendocrine organ. Like the thyroid gland, too much or too little can both be associated with medical symptoms or disorders. Adipose tissue is centrally regulated by the hypothalamus and its connections, and peripherally participates in modulation of hormones, immune cells, and inflammatory-related proteins (e.g., adipocytokines).2,3 With adipose tissue expansion, or reduction, changes in macrophage recruitment, receptor expression, and the secretion of cytokines and adipokines occur.2,4 As such, it is not surprising that low BMI is associated with migraine. Is it possible that undetected illness could lead to low BMI? Yes, it is possible. However, as noted in our article, most of the studies included for meta-analysis are population-based studies.1 It is highly unlikely these rare complications can introduce bias in population-based studies. Finally, we would like to clarify that our meta-analysis was not a data-driven exercise. Rather, it was guided by a fundamental biological question with priori set procedures and consistent operational definitions of exposure and outcome variables. The details are summarized in the Methods of our article.1

Impact of migraine on health care utilization and expenses in obese adults: a US population-based study.

PurposeMigraine prevalence increases in people with obesity, and obesity may contribute to migraine chronicity. Yet, few studies examine the effect of comorbid migraine on health care utilization and expenses in obese US adults. This study aimed to identify risk factors for migraine and compare the use of health care services and expenses between migraineurs and non-migraineurs in obese US adults.Subjects and methodsThis 7-year retrospective study used longitudinal panel data from 2006 to 2013 from the Household Component of the Medical Expenditure Panel Survey to identify obese adults reporting migraines. Outcomes compared in migraineurs vs non-migraineurs were as follows: annualized per-person medical care, prescription drug, and total health expenses.ResultsIn 23,596 obese adults, 4.7% reported migraine (n=1,025) approximating 3 million civilian noninstitutionalized US individuals. Logistic regression showed that the following sociodemographic characteristics increased migraine risk: age (18–45 years), females, White race, poor perceived health status, and greater Charlson comorbidity index. Migraineurs showed US$1,401 (P=0.007), US$813 (P<0.001), and US$2,213 (P=0.001) greater annual medical, prescription drug, and total health expenses than non-migraineurs, respectively. After adjustment, total health expenses increased by 31.6% in migraineurs vs non-migraineurs.ConclusionIn this US adult obese population, migraineurs showed greater total health care utilization and expenses than non-migraineurs. Treatment plans that address risk factors associated with migraine and comorbidities may help reduce the utilization of health care services and costs.

Exaggerated systemic oxidative-inflammatory-nitrosative stress in chronic mountain sickness is associated with cognitive decline and depression.

Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. We examined if exaggerated oxidative-inflammatory-nitrosative stress (OXINOS) and corresponding decrease in vascular nitric oxide bioavailability in patients with CMS (CMS+) is associated with impaired cerebrovascular function and adverse neurological outcome. Systemic OXINOS was markedly elevated in CMS+ compared to healthy HA (CMS-) and low-altitude controls. OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. These findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced systemic OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of more specialist neurological assessment and targeted support. Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. The present cross-sectional study examined to what extent exaggerated systemic oxidative-inflammatory-nitrosative stress (OXINOS), defined by an increase in free radical formation and corresponding decrease in vascular nitric oxide (NO) bioavailability, is associated with impaired cerebrovascular function, accelerated cognitive decline and depression in CMS. Venous blood was obtained from healthy male lowlanders (80m, n= 17), and age- and gender-matched HA dwellers born and bred in La Paz, Bolivia (3600m) with (CMS+, n= 23) and without (CMS-, n= 14) CMS. We sampled blood for oxidative (electron paramagnetic resonance spectroscopy, HPLC), nitrosative (ozone-based chemiluminescence) and inflammatory (fluorescence) biomarkers. We employed transcranial Doppler ultrasound to measure cerebral blood flow (CBF) and reactivity. We utilised psychometric tests and validated questionnaires to assess cognition and depression. Highlanders exhibited elevated systemic OXINOS (P< 0.05vs. lowlanders) that was especially exaggerated in the more hypoxaemic CMS+ patients (P< 0.05 vs. CMS-). OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. Collectively, these findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of specialist neurological assessment and support.

Gallbladder Stone Disease Is Associated with an Increased Risk of Migraines.

Background: Several pathophysiological mechanisms are shared in both gallbladder stone disease (GSD) and migraines. We assessed the migraine risk for patients diagnosed with GSD. Methods: We identified 20,427 patients who were diagnosed with GSD between 2000 and 2011 from Taiwan’s National Health Insurance Research Database (NHIRD) as the study cohort. We randomly selected 81,706 controls from the non-GSD population with frequency matching by age and index year for the control cohort. All patient cases were followed until the end of 2011 to measure the incidence of migraines. Results: The cumulative incidence of migraines was greater in patients with GSD than in those without GSD (log-rank test: p < 0.001). The risk of migraine (3.89 vs. 2.30 per 10,000 person-years, adjusted hazard ratio (aHR) = 1.56, 95% confidence interval (CI) = 1.41–1.73) was greater for the GSD cohort than that for the non-GSD cohort. The risk of migraine increased with the time of follow-up after a diagnosis of GSD. The risk of migraine contributed by GSD was greater for all age groups. The risk of migraine for GSD patients with depression (aHR = 2.89, 95% CI = 2.21–3.77), anxiety (aHR = 2.07, 95% CI = 1.58–2.70), and coronary artery disease (CAD) (aHR = 2.05, 95% CI = 1.69–2.48) tended to be greater than that for GSD patients without depression (aHR = 1.54, 95% CI = 1.39–1.72), anxiety (aHR = 1.62, 95% CI = 1.46–1.81), and CAD (aHR = 1.65, 95% CI = 1.47–1.85), respectively. Compared with the patients without GSD, the risk of developing migraines was greater in those GSD patients either with (aHR = 1.39, 95% CI = 1.19–1.63) or without (aHR = 1.67, 95% CI = 1.48–1.88) cholecystectomy. Compared with the GSD patients that have not had a cholecystectomy, the risk of developing migraines was lower in the GSD patients that had a cholecystectomy (aHR = 0.83, 95% CI = 0.69–0.99). Conclusions: GSD is associated with an increased risk of migraines in the Taiwanese population, but the risk diminishes after a cholecystectomy. Furthermore, in the development of migraines, GSD is synergic with some migraine-associated comorbidities, such as CAD, depression, and anxiety. Further study is necessary to clarify whether GSD is a causal risk factor for migraine.

Implications for the migraine SNP rs1835740 in a Swedish cluster headache population

BackgroundCluster headache is a severe headache disorder with unknown aetiology. The pathophysiology and symptoms present certain common features with migraine. Specifically, activation of the trigeminal vascular system seems to be involved in both disorders, which is hypothesized to result in neurogenic inflammation and vasodilation of the cerebral vessels. In addition, genetic factors have been implicated in both migraine and cluster headache.ObjectiveIn order to determine whether or not migraine and cluster headache share genetic risk factors, we screened two genetic variants known to increase the risk of migraine in Sweden in a Swedish cluster headache case-control study population.MethodsIn all, 541 patients and 581 control subjects were genotyped for rs1835740 in close proximity to MTDH (metadherin) and rs2651899 in the PRDM16 (PR/SET domain 16) gene, using TaqMan® real-time PCR and pyrosequencing. In addition, we analyzed MTDH gene expression in a subset of the material, using reverse transcription real-time PCR to determine relative mRNA levels in primary fibroblast cell lines from patients and controls.ResultsWe found a trend for association between rs1835740, which is reported to affect MTDH mRNA levels, and cluster headache in our Swedish case-control material (p = 0.043, Χ2 = 4.102). This association was stronger in a subgroup of patients suffering from both cluster headache and migraine (p = 0.031, Χ2 = 6.964). We could further confirm that rs1835740 has an effect on the transcriptional activity of MTDH. In this Swedish cluster headache cohort we did not find an association with the rs2651899 variant.ConclusionsWe conclude that rs1835740 is a potential risk factor for cluster headache in Sweden. Our data indicates that rs1835740 and MTDH might be involved in neurovascular headaches in general whilst rs2651899 is specifically related to migraine.