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ABSTRACT: AimsThe C677T variant in the methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) enzyme, a key player in the folate metabolic pathway, has been associated with increased risk of migraine with aura. Other genes encoding molecular components of this pathway include methionine synthase (MTR; EC 2.1.1.13) and methionine synthase reductase (MTRR; EC 2.1.1.135) among others. We performed a haplotype analysis of migraine risk and MTHFR, MTR, and MTRR.Methods
Study participants are from a random sub-sample participating in the population-based AGES-Reykjavik Study, including subjects with non-migraine headache (n = 367), migraine without aura (n = 85), migraine with aura (n = 167), and no headache (n = 1347). Haplotypes spanning each gene were constructed using Haploview. Association testing was performed on single SNP and haplotypes using logistic regression, controlling for demographic and cardiovascular risk factors and correcting for multiple testing.ResultsHaplotype analysis suggested an association between MTRR haplotypes and reduced risk of migraine with aura. All other associations were not significant after correcting for multiple testing.Conclusions
These results suggest that MTRR variants may protect against migraine with aura in an older population.
Cephalalgia 02/2013; · 3.43 Impact Factor
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ABSTRACT: Background:Several studies, but not all, of primarily middle-aged or younger adults have suggested that the common MTHFR C677T variant is a genetic risk factor for migraine with aura (MA). Here, we consider whether this variant is associated with MA risk in an older non-clinical population (AGES-Reykjavik cohort).Methods:Participants are a sub-sample (n = 1976) of subjects from the Reykjavik Study (RS; mean age 50) and its continuation, AGES-RS (mean age 76). We estimated the relative odds of MA in TT versus CC carriers using multinomial logistic regression. As both MA and the TT genotype may be linked with modestly reduced longevity, we performed a simple simulation to illustrate the effect that selective survival may have had on our observed gene-disease association.Results:TT versus CC carriers were at marginally reduced odds of MA (OR(TT) 0.55 (0.3-1.0), p = 0.07), significantly for women (OR(TT) 0.45 (0.2-0.9), p = 0.03). Assuming the 'true' (e.g. mid-life) effect of the TT genotype is OR(TT) 1.26, from a recent meta-analysis, our simulation suggested that if 25-year mortality had been (hypothetically) 13% higher in MA subjects with the TT versus CC genotype, the measured effect of the TT genotype on MA would have been attenuated to non-significance (e.g. OR(TT) 1.00). Our observed protective effect was consistent with the most extreme selective mortality scenario, in which essentially all of the previously reported increased mortality in MA subjects was (hypothetically) found in CT or TT carriers.Conclusion:The MTHFR 677TT genotype was associated with marginally reduced risk of MA in our older population. Our simulation illustrated how even modest selective survival might obscure the apparent effect of a genetic or other risk factor in older populations. We speculate that some of the heterogeneity previously observed for this particular genetic variant may be due to age range differences in the studied populations.
Cephalalgia 12/2012; · 3.43 Impact Factor
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Cephalalgia 03/2012; 32(5):355-7. · 3.43 Impact Factor
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ABSTRACT: The well-studied C677T variant in the methylenetetrahydrofolate reductase (MTHFR) enzyme is a biologically plausible genetic risk factor for seizures or epilepsy. First, plasma/serum levels of homocysteine, a pro-convulsant, are moderately elevated in individuals with the homozygote TT genotype. Furthermore, the TT genotype has been previously linked with migraine with aura-a comorbid condition-and with alcohol withdrawal seizures. Finally, several small studies have suggested that the TT genotype may be overrepresented in epilepsy patients. In this study, we consider whether the MTHFR C677T or A1298C variants are associated with risk of epilepsy including post-traumatic epilepsy (PTE) in a representative military cohort. Study subjects were selected from the cohort of military personnel on active duty during the years 2003 through 2007 who had archived serum samples at the DoD Serum Repository, essentially all active duty personnel during this time frame. We randomly selected 800 epilepsy patients and 800 matched controls based on ICD-9-CM diagnostic codes. We were able to isolate sufficient genetic material from the archived sera to genotype approximately 85% of our study subjects. The odds of epilepsy were increased in subjects with the TT versus CC genotype (crude OR=1.52 [1.04-2.22], p=0.031; adjusted OR=1.57 [1.07-2.32], p=0.023). In our sensitivity analysis, risk was most evident for patients with repeated rather than single medical encounters for epilepsy (crude OR=1.85 [1.14-2.97], p=0.011, adjusted OR=1.95 [1.19-3.19], p=0.008), and particularly for PTE (crude OR=3.14 [1.41-6.99], p=0.005; adjusted OR=2.55 [1.12-5.80], p=0.026). Our early results suggest a role for the common MTHFR C677T variant as a predisposing factors for epilepsy including PTE. Further exploration of baseline homocysteine and folate levels as predictors of seizure risk following traumatic brain injury is warranted.
Journal of neurotrauma 07/2011; 28(9):1739-45. · 4.25 Impact Factor
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Ann I Scher,
Yuan Xu,
Esther S C Korf,
Stephen W Hartley,
Menno P Witter,
Philip Scheltens,
Lon R White,
Paul M Thompson,
Arthur W Toga,
Daniel J Valentino,
Lenore J Launer
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ABSTRACT: Hippocampal changes may be a useful biomarker for Alzheimer's disease if they are specific to dementia sub-type. We compare hippocampal volume and shape in population-based incident cases of Alzheimer's disease and vascular dementia (VaD).
Participants are Japanese-American men from the Honolulu Asia Aging Study. The following analysis is based on a sub-group of men with mild incident Alzheimer's disease (n=24: age=82.5 ± 4.6) or incident VaD (n=14: age=80.5 ± 4.5). To estimate hippocampal volume, one reader, blinded to dementia diagnosis, manually outlined the left and right formation of the hippocampus using published criteria. We used 3-D mapping methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal width between dementia groups.
Hippocampal volume was about 5% smaller in the Alzheimer's disease group compared to the VaD group, but the difference was not significant. Hippocampal shape differed between the two case groups for the left (p<0.04) but not right (p<0.21) hippocampus. The specific region of the hippocampus that most consistently differed between the Alzheimer's disease and VaD cases was in the lateral portion of the left hippocampus. Our interpretation of this region is that it intersects the CA1 sub-region to a great extent but also includes the dentate gyrus (and hilar region) and subiculum.
As indicated by shape analysis, there are some differences in atrophy localisation between the Alzheimer's disease and VaD cases, despite the finding that volume of the hippocampi did not differ. These findings suggest hippocampal atrophy in Alzheimer's disease may be more focal than in VaD.
Journal of neurology, neurosurgery, and psychiatry 04/2011; 82(4):373-6. · 4.87 Impact Factor
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Nature Reviews Neurology 03/2010; 6(3):128-9. · 12.46 Impact Factor
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ABSTRACT: To estimate whether migraine in mid-life is associated with mortality from cardiovascular disease, other causes, and all causes.
Population based cohort study.
Reykjavik, Iceland.
18,725 men and women, born 1907-35 and living in Reykjavik and adjacent communities.
Mortality from cardiovascular disease, non-cardiovascular disease, and all causes. Questionnaires and clinical measures were obtained in mid-life (mean age 53, range 33-81) in the Reykjavik Study (1967-91). Headache was classified as migraine without aura, migraine with aura, or non-migraine headache. Median follow-up was 25.9 years (0.1-40.2 years), with 470,990 person years and 10,358 deaths: 4323 from cardiovascular disease and 6035 from other causes. We used Cox regression to estimate risk of death in those with migraine compared with others, after adjusting for baseline risk factors.
People with migraine with aura were at increased risk of all cause mortality (adjusted (for sex and multivariables) hazard ratio 1.21, 95% confidence interval 1.12 to 1.30) and mortality from cardiovascular disease (1.27, 1.13 to 1.43) compared with people with no headache, while those with migraine without aura and non-migraine headache were not. Further examination of mortality from cardiovascular disease shows that people with migraine with aura were at increased risk of mortality from coronary heart disease (1.28, 1.11 to 1.49) and stroke (1.40, 1.10 to 1.78). Women with migraine with aura were also at increased risk of mortality from non-cardiovascular disease (1.19, 1.06 to 1.35).
Migraine with aura is an independent risk factor for cardiovascular and all cause mortality in men and women. The risk of mortality from coronary heart disease and stroke mortality is modestly increased in people with migraine, particularly those with aura.
BMJ (Clinical research ed.). 01/2010; 341:c3966.
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ABSTRACT: It is estimated that nearly half of the global adult population suffers from an active headache disorder, most of whom experience attacks on an episodic basis. The transition from episodic to chronic headache is a poorly understood process. Epidemiological findings demonstrating comorbidity and common risk factors suggest that headache progression or prognosis may be related to the presence of other chronic pain disorders. This review highlights findings from population-based studies on headache and other pain disorders and how they relate to each other, with a focus on understanding headache chronification. We also consider the limitations and methodological challenges in understanding how two different chronic pain disorders may be related.
Current Pain and Headache Reports 09/2009; 13(4):308-13. · 1.66 Impact Factor
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ABSTRACT: Migraine or headache is a common problem in the active duty population, in the recently deployed service members, and is a cardinal symptom of traumatic brain injury. While there is increasing appreciation of the clinical burden of post-traumatic headache (PTHA) in the military traumatic brain injury population, there remain significant research gaps related to the epidemiology of PTHA, including lack of understanding of natural history, whether there are predisposing factors that predict the development or prognosis of headache post trauma and, most basically, the features that distinguish PTHA from other forms of chronic headache. Although diagnostic criteria for PTHA are included in the International Classification of Headache Disorders, 2nd edition, revised, these criteria are somewhat arbitrary and were not empirically defined. This lack of precision about the PTHA phenotype limits the rigor of observational studies of PTH but does not appear to significantly hamper treatment, provided the treatment involves a multi-modality approach.
Headache The Journal of Head and Face Pain 08/2009; 49(7):1089-96. · 2.52 Impact Factor
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ABSTRACT: To evaluate the prevalence of migraine/severe headaches in those with and without general obesity and abdominal obesity (Abd-O) and the effect of gender and age on this relationship.
General, or total body obesity (TBO), as estimated by body mass index, is a risk factor for migraine chronification. However, there are conflicting data as to whether TBO is associated with migraine prevalence. Abd-O has been shown to be a better predictor of various disease states than TBO, but has not been evaluated in general population studies in association with migraine.
Data from a general population survey, the National Health and Nutrition Examination Survey, were used to obtain demographics, self-report of migraine/severe headaches and measured body mass indices, including height, weight, and waist circumference. All analyses were stratified by age and gender and multivariate analyses were determined through use of logistic regression models.
A total of 21,783 participants were included in the analysis. Between 20-55 years of age, the prevalence of migraine was increased in both men and women with TBO as compared with those without, (P <or= .001). Migraine was also more prevalent in those with Abd-O as compared with those without (men: 20.1% vs 15.9%, P < .001; women: 36.9% vs 28.8.2%, P < .001). After 55 years of age, the prevalence of migraine in men was no longer associated with either TBO or Abd-O. Similarly, after 55 years of age, the prevalence of migraine in women was no longer associated with TBO. However, in women older than 55 years, the prevalence of migraine was decreased in those with Abd-O as compared with those without Abd-O (14.4% vs 17.4%, P < .05). After adjusting for demographics, cardiovascular risk factors and Abd-O, results were similar for the association between migraine prevalence and TBO in both younger and older men and women. After adjusting for demographics, cardiovascular risk factors and TBO, migraine prevalence was no longer associated with Abd-O in younger men, but remained associated with an increased odds ratio of having migraine in younger women, as well as a decreased odds ratio in older women.
The relationship between migraine and obesity varies by age, gender, and adipose tissue distribution (eg, TBO vs Abd-O). In men and women <or=55 years old, migraine prevalence is increased in those with TBO, independent of Abd-O. In addition, in men and women <or=55 years old, migraine prevalence is increased in those with Abd-O; and in women this association is independent of TBO. In men older than 55 years, migraine is not associated with either TBO or Abd-O. However, in women older than 55 years, migraine prevalence is decreased in those with Abd-O and is independent of TBO.
Headache The Journal of Head and Face Pain 07/2009; 50(1):52-62. · 2.52 Impact Factor
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ABSTRACT: Migraine is considered to be an episodic condition with no long-term consequences. However, recent studies suggest that migraine attacks may be associated with pathologic changes in the brain, particularly in the cerebellum.
To determine whether individuals not reporting headache compared with individuals reporting migraine symptoms, particularly aura, in midlife are at increased risk of late-life infarct-like lesions found on magnetic resonance imaging (MRI) without consideration of clinical symptoms.
A population-based study of men and women in Reykjavik, Iceland (cohort born 1907-1935; n = 4689; 57% women) were followed up since 1967, examined, and interviewed about migraine symptoms in midlife (mean age, 51 years; range, 33-65 years). Between 2002 and 2006, more than 26 years later, brain MRIs were performed. Participants reporting headaches once or more per month were asked about migraine symptoms including nausea, unilateral location, photophobia, visual disturbance, and numbness. These individuals with headache were classified as having migraine without aura, migraine with aura, or nonmigraine headache. A comprehensive cardiovascular risk assessment was performed at both examinations.
Presence of infarct-like lesions (total) and specifically located in the cortical, subcortical, and cerebellar regions.
Infarct-like lesions were present in 39.3% of men and 24.6% of women. After adjusting for age, sex, and follow-up time, compared with those not reporting headaches once or more per month (n = 3243), those with midlife migraine with aura (n = 361) had an increased risk of late-life infarct-like lesions (adjusted odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8) that specifically reflected an association with cerebellar lesions in women (prevalence of infarcts 23.0% for women with migraine with aura vs 14.5% for women not reporting headaches; adjusted OR, 1.9; 95% CI, 1.4-2.6 vs a 19.3% prevalence of infarcts for men with migraine with aura vs 21.3% for men not reporting headaches; adjusted OR, 1.0; 95% CI, 0.6-1.8; P<.04 for interaction by sex). Migraine without aura and nonmigraine headache were not associated with an increased risk.
Migraine with aura in midlife was associated with late-life prevalence of cerebellar infarct-like lesions on MRI. This association was statistically significant only for women. This is consistent with the hypothesis that migraine with aura in midlife is associated with late-life vascular disease in the cerebellum and in women.
JAMA The Journal of the American Medical Association 06/2009; 301(24):2563-70. · 30.03 Impact Factor
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ABSTRACT: Chronic daily headache (CDH) is a fairly common but disabling disorder that disproportionately affects women and afflicts individuals across all stages of adulthood. It is a dynamic disorder, marked by relatively high rates of remission and incidence. To some extent, this may be due to the accepted, but not empirically supported, cut-point of 15 headache days per month. The purpose of this article is to understand the CDH classification; determine the prevalence and associated demographic profile of CDH as derived from population-based studies; outline identified risk factors for development or persistence of CDH; and understand which risk factors may be more amenable to intervention. Understanding the factors that put people at risk for developing CDH helps to inform possible clinical interventions and also determines which individuals may be most in need of preventive efforts.
Current Pain and Headache Reports 03/2009; 13(1):59-63. · 1.66 Impact Factor
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Neurology 08/2008; 71(5):383-5. · 8.31 Impact Factor
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ABSTRACT: Understanding the variability of the hippocampus in human brain research is essential. The effect of age on the hippocampus has been explored in several studies that have been focused on either normal aging or neural degeneration. Shape analysis of magnetic resonance imaging (MRI) provides morphological measures for brain structures. This study further investigates the age effects on hippocampal morphology in three groups (104 normal controls, 24 Alzheimer's disease (AD) and 14 vascular dementia (VaD) patients). By utilizing a parametric shape analysis of hippocampal MRI scans, each individual distance map is generated and analyzed statistically. Specifically, after eliminating similarity parameters (rotation, translation, and scaling) effects for each hippocampus, an individual distance map is generated from parametric hippocampal surfaces and medial axes. Then statistical methods, including regression, and permutation tests, are applied to detect the differences in hippocampal distance maps and volumes under the effect of age in each group. Statistical analyses reveal that the loss of hippocampal volume and changes in shape are more significantly related to aging in the control group than in AD/VaD. The results also show that the asymmetry of hippocampus in healthy subjects is greater than that in either of the disease groups. Our study shows that 3D statistical shape analysis could enhance the understanding of age effects on local areas of hippocampi. However, the sample sizes of disease groups are relatively low; further studies with more AD/VaD data are needed.
NeuroImage 05/2008; 40(3):1003-15. · 5.89 Impact Factor
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ABSTRACT: About 4% of the adult population and about 1% to 2% of children experience chronic attacks on a daily or near daily basis. While there is uncertainty about the biological mechanisms that lead to headache "chronification," the epidemiologic literature has provided some insight into modifiable and nonmodifiable factors that appear to influence risk of headache progression. This review summarizes the evidence from population-based studies related to the chronic daily headache phenotype, natural history, and risk factors that may influence incidence, prevalence, or prognosis.
Headache The Journal of Head and Face Pain 02/2008; 48(1):16-25. · 2.52 Impact Factor
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ABSTRACT: To evaluate the extent to which head and neck injury (HANI) contributes to chronic daily headache (CDH).
In prospective studies, head injury is associated with headache (HA) that remains a problem at 12 to 24 months post-head injury in 20 to 30% of patients. Of these, up to 30 to 50% manifest CDH. The degree to which head injury contributes to CDH has not been evaluated in a non-clinical population. We evaluate the relationship between lifetime occurrence of HANI and CDH in a randomly chosen population sample.
Study participants are from the Frequent Headache Epidemiology Study. Cases with CDH (> or =180 HA/year) and a comparison group with episodic headache (EH, 2 to 102 HA/year) were identified from the general population. Subjects were asked about lifetime occurrence of HANI. HANI were further classified as potentially precipitating injuries (PPI) if they occurred within 2 years of CDH onset for cases or in an equivalent 2-year period for EH controls.
Lifetime occurrence of HANI was more frequent in cases than controls for men (adjusted OR = 3.1 [1.3 to 7.2]), women (OR = 1.5 [0.97 to 2.3]), and overall (OR = 1.7 [1.1 to 2.4]). The attributable risk was 15% (36% men, 11% women). Results were similar for PPI. The odds of CDH increased with the number of lifetime HANI in all groups (p < 0.05 trend).
Results suggest that head and neck injury (HANI) accounts for approximately 15% of chronic daily headache (CDH) cases in this non-clinical population. The relationship between HANI and CDH was not limited to injuries proximate to CDH onset. The lifetime risk of CDH increases with increasing number of HANI.
Neurology 09/2007; 69(11):1169-77. · 8.31 Impact Factor
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ABSTRACT: Comorbidity is defined as an illness that occurs more frequently in association with a specific disorder than would be found as a coincidental association in the general population. Conditions that are frequently comorbid with migraine include depression, anxiety, stroke, epilepsy, sleep disorders, and other pain disorders. In addition, many common illnesses occur concomitantly (at the same time) with migraine and influence the treatment choice. Migraine management, and especially migraine prevention, can be challenging when patients have comorbid or concomitant illnesses. The objectives of this initiative are to review the literature on managing patients who have migraine and common comorbidities, present additional clinical approaches for care of these difficult patients, and evaluate the areas in which research is needed to establish evidence-based guidelines for the management of migraine with associated comorbid conditions.
Headache The Journal of Head and Face Pain 05/2007; 47(4):585-99. · 2.52 Impact Factor
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ABSTRACT: In this article, we consider the possible reasons and supporting evidence for the comorbidity of chronic pain conditions. To simplify the discussion, we primarily focus on the epidemiology of headache with other pain conditions, dividing studies into those based on children or adolescents and those based on adults. We consider exogenous and endogenous factors, and methodological challenges, in understanding whether and how 2 pain conditions may be related.
Headache The Journal of Head and Face Pain 11/2006; 46(9):1416-23. · 2.52 Impact Factor
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Ann I Scher,
Gisela M Terwindt,
W M Monique Verschuren,
Mark C Kruit,
Henk J Blom,
Hisanori Kowa,
Rune R Frants,
Arn M J M van den Maagdenberg,
Mark van Buchem,
Michel D Ferrari,
Lenore J Launer
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ABSTRACT: Migraine with aura is associated with increased risk of stroke. The MTHFR C677T genotype has been associated with increased risk of migraine in selected clinical samples and with elevated homocysteine, a risk factor for stroke. We assessed the association of the MTHFR C677T variant with migraine and the mediating effect of cardiovascular risk factors and metabolic markers of genotype status.
We compared adult migraineurs with aura (MA; n = 187), without aura (MO; n = 226), and nonmigraineurs (n = 1,212) from the population-based Genetic Epidemiology of Migraine study.
Compared with the wild-type genotype, the T/T genotype was associated with increased odds of MA (odds ratio [OR], 2.05; 95% confidence interval, 1.2-3.4; p < 0.006), with a trend of increasing numbers of T alleles (OR, 1.40; 95% confidence interval, 1.1-1.8; p < 0.007). ORs were slightly attenuated after adjusting for homocysteine.
Risk of MA is associated with MTHFR C674T homozygosity, independent of other cardiovascular risk factors.
Annals of Neurology 03/2006; 59(2):372-5. · 11.09 Impact Factor
