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1.  Telomere Length and Parkinson's Disease in Men: A Nested Case-Control Study 
Telomere shortening has been implicated in neurodegenerative disorders However, available data on the association between telomere length and Parkinson's disease (PD) are inconclusive.
We used a nested case-control design among men participating in the prospective Physicians Health Study. A large proportion of participants provided blood samples in 1997 and was followed through 2010. Men with self-reported PD were age-matched to controls in a 1:2 ratio. Quantitative PCR was used to determine telomere repeat copy number to single gene copy number ratio (TSR) in genomic DNA extracted from peripheral blood leukocytes. We used TSR as a measure for relative telomere length (RTL) in our analyses. Conditional logistic regression was used to determine the risk of PD associated with RTL.
Data on RTL were available from 408 cases and 809 controls. Median TSR was shorter in controls than in cases (47.7 vs. 50.2; p=0.02). The age-adjusted odds ratio for PD was 0.66 (95% confidence interval [CI] 0.46-0.95; ptrend over quartiles=0.02) comparing the lowest to the highest quartile. The pattern of association was unchanged when comparing RTL below vs. above the median (age-adjusted OR=0.75; 95% CI 0.59-0.96). Associations were similar after additional adjustment for many covariates.
Contrary to the expected, in this large nested case-control study among men shorter telomeres were associated with reduced PD risk. Future research on the nature of this counterintuitive association is warranted.
PMCID: PMC3943750  PMID: 24010387
telomere length; Parkinson's disease; nested case-control study; epidemiology
2.  Structural brain lesions and restless legs syndrome: a cross-sectional population-based study 
BMJ Open  2014;4(11):e005938.
To evaluate the association between white matter lesion (WML) volume, silent infarcts and restless legs syndrome (RLS) in a population-based study of elderly individuals.
Cross-sectional study.
Population-based Three-City study.
1035 individuals from the Dijon, France, centre of the Three-City study who had available information on volume of WMLs from MRIs and who answered questions about the prevalence of RLS.
Primary outcome measure
Prevalence of RLS.
WML volume was measured using an automated tissue segmentation method. Logistic regression was used to evaluate adjusted associations between tertiles of WML volume and RLS and between silent infarcts and RLS. 218 individuals (21.1%) were determined to have RLS. Compared with those in the first tertile of WML volume, individuals in the second tertile (OR=1.09; 95% CI 0.75 to 1.60) or third tertile (OR=1.17; 95% CI 0.79 to 1.74) did not have an increased prevalence of RLS. We also did not observe associations between the volume of deep or periventricular WML and RLS; nor did we observe an association between silent brain infarcts and RLS (OR=0.74; 95% CI 0.40 to 1.39). These findings were not modified by age or gender.
Higher volume of WML and the presence of silent infarcts were not associated with an increased prevalence of RLS in this population-based cohort of elderly individuals.
PMCID: PMC4244423  PMID: 25421338
restless legs syndrome; MRI
3.  Migraine, Headache and the Risk of Depression: Prospective Cohort Study 
While cross-sectional studies have shown associations between migraine and depression, few studies have been able to evaluate the association between migraine and incident depression.
Prospective cohort study among 36,016 women without a history of depression enrolled in the Women’s Health Study who provided information about migraine and headache at baseline. Women were classified as either having non-migraine headache, migraine with aura, migraine without aura, past history of migraine or no history of headache. Cox proportional hazards models were used to evaluate the association between migraine and headache status and incident depression.
At baseline, 5115 women reported a history of non-migraine headache, 1805 reported migraine with aura, 2723 reported migraine without aura and 1896 reported a past history of migraine. During 13.8 mean years of follow-up, 3833 new cases of depression occurred. The adjusted relative risks of incident depression were 1.44 (95% CI: 1.32, 1.56) for non-migraine headache, 1.53 (95% CI: 1.35, 1.74) for migraine with aura, 1.40 (95% CI: 1.25, 1.56) for migraine without aura and 1.56 (95% CI: 1.37, 1.77) for past history of migraine compared to no history of headache.
Middle-aged women with migraine or non-migraine headache are at increased risk of incident depression.
PMCID: PMC3720737  PMID: 23588795
Migraine; depression; epidemiology
4.  Baseline cognitive function, recurrent stroke, and risk of dementia in stroke patients 
Background and purpose
To determine the interrelationships between baseline MMSE and risk of overall dementia, post-recurrent stroke dementia and dementia without recurrent stroke among patients with a history of stroke.
Prospective cohort study among participants enrolled in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) for whom baseline Mini-Mental State Examination (MMSE) score was available. Baseline MMSE was divided into four categories: 30, 29–27, 26–24, or <24. Participants were followed for incident dementia and recurrent stroke. Logistic regression models were used to examine the association between MMSE and dementia.
Of the 6080 participants included in this analysis, 2493 had MMSE=30, 1768 had MMSE=29–28, 1369 had MMSE=26–24 and 450 had MMSE<24. Average follow-up time was 3.8 years. There were 407 cases of dementia, 106 of which were preceded by a recurrent stroke. The risk of overall dementia increased with decreasing MMSE score. However, the impact of MMSE on risk of dementia without recurrent stroke was much stronger than the impact of MMSE on the risk of post-recurrent stroke dementia. For those with MMSE<24, the risk of dementia without recurrent stroke was 47.89 (95% CI: 28.57–80.26) while the risk of post-recurrent stroke dementia was only 7.17 (95% CI: 3.70–13.89). Higher MMSE scores were even less strongly associated with the risk of post-recurrent stroke dementia.
Stroke patients with low MMSE scores are at high risk of dementia over time, even in the absence of a recurrent stroke, and should therefore be followed closely for further cognitive decline.
PMCID: PMC3695012  PMID: 23686974
cerebrovascular disease; cognitive functioning; dementia; epidemiology
5.  Waist to Hip Ratio, Body Mass Index and Subsequent Kidney Disease and Death 
Chronic kidney disease (CKD) and obesity are important public health concerns. We examined the association between anthropomorphic measures and incident CKD and mortality.
Setting and Participants
Individual patient data pooled from the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study
Waist to hip ratio (WHR), body mass index (BMI)
Incident CKD defined as serum creatinine rise of >0.4 mg/dL with baseline creatinine ≤1.4 mg/dL in men and 1.2 mg/dL in women and final creatinine above these levels, and, in separate analyses, as estimated glomerular filtration rate (eGFR) decline ≥15 mL/min/1.73m2 with baseline eGFR ≥60 and final eGFR <60 mL/min/1.73m2.
Multivariable logistic regression to determine the association between waist to hip ratio (WHR), body mass index (BMI) and outcomes. Cox models to evaluate a secondary composite outcome of all-cause mortality and incident CKD.
Among 13,324 individuals, mean WHR was 0.96 in men and 0.89 in women and mean BMI was 27.2 kg/m2 in both men and women. Over 9.3 years, 300 (2.3%) in creatinine-based models and 710 (5.5%) in eGFR-based models developed CKD. In creatinine-based models, each standard deviation increase in WHR was associated with an increased risk of incident CKD [Odds ratio=1.22 (1.05, 1.43)] and the composite outcome [Hazard ratio=1.12 (1.06, 1.18)], while each standard deviation increase in BMI was not associated with CKD [Odds ratio=1.05 (0.93, 1.20)] and appeared protective for the composite outcome [Hazard ratio=0.94 (0.90, 0.99)]. Results of eGFR-based models were similar.
Single measures of creatinine, no albuminuria data.
WHR but not BMI is associated with incident CKD and mortality. Assessment of CKD risk should utilize WHR rather than BMI as an anthropomorphic measure of obesity.
PMCID: PMC4052757  PMID: 18511168
6.  Genome-wide meta-analysis identifies new susceptibility loci for migraine 
Anttila, Verneri | Winsvold, Bendik S. | Gormley, Padhraig | Kurth, Tobias | Bettella, Francesco | McMahon, George | Kallela, Mikko | Malik, Rainer | de Vries, Boukje | Terwindt, Gisela | Medland, Sarah E. | Todt, Unda | McArdle, Wendy L. | Quaye, Lydia | Koiranen, Markku | Ikram, M. Arfan | Lehtimäki, Terho | Stam, Anine H. | Ligthart, Lannie | Wedenoja, Juho | Dunham, Ian | Neale, Benjamin M. | Palta, Priit | Hamalainen, Eija | Schürks, Markus | Rose, Lynda M | Buring, Julie E. | Ridker, Paul M. | Steinberg, Stacy | Stefansson, Hreinn | Jakobsson, Finnbogi | Lawlor, Debbie A. | Evans, David M. | Ring, Susan M. | Färkkilä, Markus | Artto, Ville | Kaunisto, Mari A | Freilinger, Tobias | Schoenen, Jean | Frants, Rune R. | Pelzer, Nadine | Weller, Claudia M. | Zielman, Ronald | Heath, Andrew C. | Madden, Pamela A.F. | Montgomery, Grant W. | Martin, Nicholas G. | Borck, Guntram | Göbel, Hartmut | Heinze, Axel | Heinze-Kuhn, Katja | Williams, Frances M.K. | Hartikainen, Anna-Liisa | Pouta, Anneli | van den Ende, Joyce | Uitterlinden, Andre G. | Hofman, Albert | Amin, Najaf | Hottenga, Jouke-Jan | Vink, Jacqueline M. | Heikkilä, Kauko | Alexander, Michael | Muller-Myhsok, Bertram | Schreiber, Stefan | Meitinger, Thomas | Wichmann, Heinz Erich | Aromaa, Arpo | Eriksson, Johan G. | Traynor, Bryan | Trabzuni, Daniah | Rossin, Elizabeth | Lage, Kasper | Jacobs, Suzanne B.R. | Gibbs, J. Raphael | Birney, Ewan | Kaprio, Jaakko | Penninx, Brenda W. | Boomsma, Dorret I. | van Duijn, Cornelia | Raitakari, Olli | Jarvelin, Marjo-Riitta | Zwart, John-Anker | Cherkas, Lynn | Strachan, David P. | Kubisch, Christian | Ferrari, Michel D. | van den Maagdenberg, Arn M.J.M. | Dichgans, Martin | Wessman, Maija | Smith, George Davey | Stefansson, Kari | Daly, Mark J. | Nyholt, Dale R. | Chasman, Daniel | Palotie, Aarno
Nature genetics  2013;45(8):912-917.
PMCID: PMC4041123  PMID: 23793025
7.  Selectivity in Genetic Association with Sub-classified Migraine in Women 
PLoS Genetics  2014;10(5):e1004366.
Migraine can be sub-classified not only according to presence of migraine aura (MA) or absence of migraine aura (MO), but also by additional features accompanying migraine attacks, e.g. photophobia, phonophobia, nausea, etc. all of which are formally recognized by the International Classification of Headache Disorders. It remains unclear how aura status and the other migraine features may be related to underlying migraine pathophysiology. Recent genome-wide association studies (GWAS) have identified 12 independent loci at which single nucleotide polymorphisms (SNPs) are associated with migraine. Using a likelihood framework, we explored the selective association of these SNPs with migraine, sub-classified according to aura status and the other features in a large population-based cohort of women including 3,003 active migraineurs and 18,108 free of migraine. Five loci met stringent significance for association with migraine, among which four were selective for sub-classified migraine, including rs11172113 (LRP1) for MO. The number of loci associated with migraine increased to 11 at suggestive significance thresholds, including five additional selective associations for MO but none for MA. No two SNPs showed similar patterns of selective association with migraine characteristics. At one extreme, SNPs rs6790925 (near TGFBR2) and rs2274316 (MEF2D) were not associated with migraine overall, MA, or MO but were selective for migraine sub-classified by the presence of one or more of the additional migraine features. In contrast, SNP rs7577262 (TRPM8) was associated with migraine overall and showed little or no selectivity for any of the migraine characteristics. The results emphasize the multivalent nature of migraine pathophysiology and suggest that a complete understanding of the genetic influence on migraine may benefit from analyses that stratify migraine according to both aura status and the additional diagnostic features used for clinical characterization of migraine.
Author Summary
Migraine is among the most common and debilitating neurological disorders. Diagnostic criteria for migraine recognize a variety of symptoms including a primary dichotomous classification for the presence or absence of aura, typically a visual disturbance phenomenon, as well as others such as sensitivity to light or sound, and nausea, etc. We explored whether any of 12 recently discovered genetic variants associated with common migraine might have selective association for migraine sub-classified by aura status or nine additional migraine features in a population of middle-aged women including 3,003 migraineurs and 18,180 non-migraineurs. Five of the 12 genetic variants met the most stringent significance criterion for association with migraine, among which four had selective association with sub-classified migraine, including one that was selective for migraine without aura. At suggestive significance, all of the remaining genetic variants were selective for sub-classifications of migraine although no two variants showed the same pattern of selectivity. The selectivity patterns suggest very different contributions to migraine pathophysiology among the 12 loci and their implicated genes. Further, the results suggest that future discovery efforts for new migraine susceptibility loci would benefit by considering associations with sub-classified migraine toward the ultimate goals of more specific diagnosis and personalized treatment.
PMCID: PMC4031047  PMID: 24852292
8.  Migraine and cognitive decline: A topical review 
Headache  2013;53(4):589-598.
Migraine has been linked with an increased risk of stroke and an increased prevalence of clinically silent brain lesions and white matter hyperintensities. As it is known that stroke and structural brain lesions are associated with an increased risk of cognitive decline, it has been hypothesized that migraine may be a progressive brain disorder and associated with an increased risk of cognitive impairment. Given the prevalence of migraine in the population, especially among women, and the aging of the population, an association between migraine and cognitive impairment would have substantial public health implications. In this review, we will summarize the existing evidence evaluating the association between migraine and cognitive function. Additionally, we will discuss methodological issues in migraine and cognitive function assessment and elaborate on study design strategies to address this important question.
PMCID: PMC3618490  PMID: 23405909
migraine; cognitive decline; epidemiology
9.  Migraine and Obesity: Epidemiology, Mechanisms, and Implications 
Headache  2009;50(4):631-648.
Adipose tissue is a dynamic neuroendocrine organ that is involved in multiple physiological and pathological processes, and when excessive, results in obesity. Clinical and population-based data suggest that migraine and chronic daily headache are associated with obesity, as estimated by anthropometric indices. In addition, translational and basic science research shows multiple areas of overlap between migraine pathophysiology and the central and peripheral pathways regulating feeding. Specifically, neurotransmittors such as serotonin, peptides such as orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and migraine. In this article, we first review the definition and ascertainment of obesity. This is followed by a review of the clinical and population-based studies evaluating the associations between obesity and chronic daily headache and migraine. We then discuss the central and peripheral pathways involved in the regulation of feeding, where it overlaps with migraine pathophysiology, and where future research may be headed in light of these data.
PMCID: PMC3969571  PMID: 19845784
migraine; obesity; BMI; abdominal obesity; adipocytokines; adiponectin
10.  Vascular risk factors, cardiovascular disease and restless legs syndrome in men 
The American journal of medicine  2013;126(3):228-235.e2.
Prevalences of vascular risk factors, cardiovascular disease and restless legs syndrome increase with age. Prior studies analyzing the associations between vascular risk factors, cardiovascular disease, and restless legs syndrome found controversial results. We therefore aim to evaluate the association between prevalent vascular risk factors, prevalent cardiovascular disease and restless legs syndrome.
We conducted a cross-sectional study among 22,786 participants of the US Physicians’ Health Studies I and II. Restless legs syndrome was classified according to the four minimal diagnostic criteria. Vascular risk factors and restless legs syndrome symptoms were self-reported. Prevalent cardiovascular disease events including major cardiovascular disease, stroke and myocardial infarction were confirmed by medical record review. Age- and multivariable-adjusted logistic regression models were used to evaluate the association between vascular risk factors, prevalent cardiovascular disease events and restless legs syndrome.
The mean age of the cohort 67.8 years. Restless legs syndrome prevalence was 7.5% and increased significantly with age. Diabetes significantly increased the odds (OR: 1.41, 95%CI: 1.21–1.65), while frequent exercise (OR: 0.78, 95%CI: 0.67–0.91) and alcohol consumption of one or more drinks per day (OR: 0.80, 95%CI: 0.69–0.92) significantly reduced the odds of restless legs syndrome in multivariable-adjusted models. Prevalent stroke showed an increased multivariable-adjusted OR of 1.40 (1.05–1.86) while men with prevalent myocardial infarction had a decreased OR of 0.73 (0.55–0.97) for restless legs syndrome.
The restless legs syndrome prevalence among US male physicians is similar to men of the same age group in other western countries. A history of diabetes is the most consistent risk factor associated with restless legs syndrome. Prevalent stroke and myocardial infarction are related to restless legs syndrome prevalence.
PMCID: PMC3574273  PMID: 23410563
Vascular risk factors; cardiovascular disease; Restless legs syndrome; cohort study
11.  Vascular risk factors, cardiovascular disease and restless legs syndrome in women 
The American journal of medicine  2013;126(3):220-227.e2.
Previous studies evaluating the association between cardiovascular disease and vascular risk factors with restless legs syndrome showed inconsistent results, especially for the potential relation between various vascular risk factors and restless legs syndrome. We therefore aimed to analyze the relationship between vascular risk factors, prevalent cardiovascular disease and restless legs syndrome.
This is a cross-sectional study of 30,262 female health professionals participating in the Women's Health Study (WHS). Restless legs syndrome was defined according to diagnostic criteria of the International Restless Legs Study Group. Information on vascular risk factors (diabetes, hypertension, hypercholesterolemia, body mass index, alcohol, smoking, exercise, family history of myocardial infarction) was self-reported. Cardiovascular disease events (coronary revascularization, myocardial infarction, stroke) were confirmed by medical record review. Prevalent major cardiovascular disease was defined as non-fatal stroke or non-fatal myocardial infarction. Logistic regression models were used to evaluate the association between vascular risk factors, prevalent cardiovascular disease and restless legs syndrome.
Of the 30,262 participants (mean age: 63.6 years), 3,624 (12.0%) reported restless legs syndrome. In multivariable-adjusted models, body mass index (OR for BMI ≥35kg/m2: 1.35, 95% CI: 1.17–1.56), diabetes (OR: 1.19, 95%CI: 1.04–1.35), hypercholesterolemia (OR: 1.17, 95% CI: 1.09–1.26), smoking status (OR for ≥15 cigarettes/day: 1.41, 95%CI: 1.19–1.66) and exercise (OR for exercise ≥ 4 times/week: 0.84, 95%CI: 0.74–0.95) were associated with restless legs syndrome prevalence. We found no association between prevalent cardiovascular disease (major cardiovascular disease, myocardial infarction, stroke) and restless legs syndrome prevalence. Women who underwent coronary revascularization had a multivariable-adjusted OR of 1.39 (1.10–1.77) for restless legs syndrome.
In this large cohort of female health professionals, various vascular risk factors are associated with restless legs syndrome prevalence. We could not confirm results of previous reports indicating an association between prevalent cardiovascular disease and restless legs syndrome.
PMCID: PMC3574635  PMID: 23410562
Vascular risk factors; cardiovascular disease; Restless legs syndrome; cohort study
12.  Biomarkers and functional outcomes from ischemic cerebral events in women: a prospective cohort study 
Several biomarkers have been associated with increased risk of ischemic stroke. However, the association between these biomarkers and functional outcome from cerebral ischemic events is unclear. We aimed to assess the patterns of association between cardiovascular disease biomarkers and functional outcomes after incident ischemic cerebral events in women.
Prospective cohort study among 27,728 women enrolled in the Women’s Health Study who provided information blood samples and were free of stroke or transient ischemic attack (TIA) at baseline. Multinomial logistic regression was used to determine the association between elevated biomarker levels and functional outcomes from ischemic cerebral events. Possible functional outcomes included TIA and ischemic stroke with mRS (modified Rankin scale) score of 0–1, 2–3 or 4–6.
After a mean follow-up of 15.1 years, 461 TIAs and 380 ischemic strokes occurred. Elevated levels of total cholesterol were associated with the highest risk of poor functional outcome (mRS 4–6) after incident cerebral ischemic events (relative risk=2.02 95%CI=1.18–3.46). We observed significant associations between elevated levels of total cholesterol, Lp(a), C-reactive protein, and triglyercides and mild or moderate functional outcomes after ischemic cerebral events. Elevations in all other biomarkers were not significantly associated with functional outcomes.
While total cholesterol was associated with highest risks of poor functional outcome after stroke, we overall observed an inconsistent pattern of association between biomarkers linked with increased risk of vascular events and more impaired functional outcomes from stroke.
PMCID: PMC3538088  PMID: 23034002
stroke; epidemiology; biomarkers
13.  Effect of Low Dose Aspirin on Functional Outcome from Cerebral Vascular Events in Women 
Background and Purpose
While aspirin is effective in prevention of stroke, fewer studies have examined the impact of aspirin on stroke morbidity.
The Women’s Health Study is a completed randomized, placebo-controlled trial designed to test the effect of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer which enrolled 39,876 women. We used multinomial logistic regression to evaluate the relationship between randomized aspirin assignment and functional outcomes from stroke. Possible functional outcomes were no stroke nor TIA, modified Rankin scale (mRS) score 0–1, mRS 2–3 and mRS 4–6.
After a mean of 9.9 years of follow-up, 460 confirmed strokes (366 ischemic, 90 hemorrhagic and 4 unknown type) and 405 confirmed transient ischemic attacks (TIAs) occurred. With regard to total and ischemic stroke, women who were randomized to aspirin had a non-significant decrease in risk of any outcome compared to women not randomized to aspirin. This decrease in risk only reached statistical significance for those experiencing TIA compared to participants without stroke or TIA (OR=0.77; 95% CI: 0.63, 0.94). For hemorrhagic stroke, a non-significant increase in the risk of achieving a modified Rankin Scale (mRS) score 2–3 or mRS 4–6 compared to no stroke or TIA was observed for the women randomized to aspirin compared to those randomized to placebo.
Results from this large randomized clinical trial provide evidence that 100mg of aspirin every other day may reduces the risk of ischemic cerebral vascular events, but does not have differential effects on functional outcomes from stroke.
PMCID: PMC3552068  PMID: 23306328
cerebrovascular disease; epidemiology; aspirin
14.  Migraine and Restless Legs Syndrome in Men 
Previous studies suggest an association between migraine and restless legs syndrome (RLS). Population-based data, however, have been limited to women. The aim of this study is to evaluate the association between migraine and RLS in a male cohort.
Cross-sectional study among 22,926 participants in the Physicians’ Health Study. Migraine and RLS information was self-reported. RLS was classified according to four minimal diagnostic criteria. Age-and multivariable-adjusted logistic regression models were calculated.
Of the 22,926 participants (mean age 67.8), 2,816 (12.3%) reported migraine and 1,717 (7.5%) RLS. Migraine was associated with an increased multivariable-adjusted OR (95% CI) of 1.20 (1.04–1.38) for having RLS. The association remained stable after excluding men with potential mimics of RLS and was not modified by age.
Results of our study indicate an association between migraine and RLS in men. The magnitude of effect is similar to what has been reported in women.
PMCID: PMC3528814  PMID: 23155191
migraine; restless legs syndrome; cross-sectional study; epidemiology
15.  Migraine and Subsequent Risk of Breast Cancer: a Prospective Cohort Study 
Cancer causes & control : CCC  2012;24(1):81-89.
Previous studies have suggested that migraineurs are at decreased risk for developing breast cancer. Further prospective studies are warranted to confirm these results. In addition, studies evaluating migraine characteristics (e.g. migraine subtypes and frequency) are lacking.
We conducted a prospective cohort study among 39,696 participants in the Women's Health Study who were 45 years and older at study entry. Information on migraine was self-reported with good validation rates. Incident breast cancer cases were confirmed by medical record review. We distinguished the following major endpoints: any breast cancer, a combined endpoint of invasive and in situ cases, in situ breast cancer only and invasive breast cancer only. Cox proportional hazards models were used to calculate age- and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CI).
7,318 (18.4%) women reported any migraine. During a mean-follow-up time of 13.6 years, 432 in situ and 1,846 invasive breast cancer cases occurred. Migraine was not associated with breast cancer risk. The multivariable-adjusted HRs (95% CI) were 1.10 (0.99–1.22) for any breast cancer, 1.06 (0.83–1.35) for in situ breast cancer and 1.11 (0.99–1.25) for invasive breast cancer. The risk for developing breast cancer differed according to hormone receptor status with a suggestion of increased risks for hormone receptor negative tumors (HR ER−/PR−: 1.28, 95%CI: 0.96–1.71). We did not observe meaningful differences with regard to histologic subtype or according to migraine aura status or migraine attack frequency.
Results of our study do not support the hypothesis that migraineurs have a decreased risk for breast cancer.
PMCID: PMC3529745  PMID: 23143336
migraine; migraine subtypes; breast cancer; prospective cohort study; epidemiology
16.  Bi-allelic and tri-allelic 5-HTTLPR polymorphisms and triptan non-response in cluster headache 
Triptans are only effective in terminating cluster headache (CH) attacks in 70-80% of patients. Pharmacogenetic aspects of the serotonin metabolism, specifically variation in the 5-HTTLPR may be involved.
Genetic association study in a well-defined cohort of 148 CH patients with information on drug response to triptans. CH was diagnosed according to the criteria of the International Headache Society. Genotypes of the 43-bp insdel (rs4795541) and A > G (rs25531) polymorphisms in the 5-HTTLPR promoter region were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between bi-allelic and tri-allelic genotypes and triptan non-response with genotype models.
Mean age at study entry among patients was 44.6 ± 10.5 years, 77.7% were men. The genotype distribution both for the bi-allelic and the tri-allelic polymorphism was in Hardy-Weinberg equilibrium. We did not find an association of the bi-allelic polymorphism with triptan non-response. While the effect estimates for the S variant of the tri-allelic polymorphisms suggested increased odds of triptan non-response in CH patients (multivariable-adjusted odds ratio [95% confidence interval]: L*L* genotype—reference; L*S* genotype—1.33 [0.53-3.32]; S*S* genotype—1.46 [0.54-3.98]), the results were not statistically significant.
Data from our study do not indicate a role of bi-allelic and tri-allelic genotypes of the 5-HTTLPR polymorphism in triptan non-response in CH.
PMCID: PMC4112603  PMID: 25043824
5-HTTLPR; SLC6A4; Polymorphism; Cluster headache; Serotonin; Triptans; Triptan response
17.  Migraine and risk of incident diabetes in women: prospective study 
Previous cross-sectional studies evaluating the relationship between diabetes prevalence and migraine status have found conflicting results. We examined the relationship between migraine and incident type 2 diabetes (T2D) in a cohort of adult women.
Prospective cohort study conducted among participants in the Women’s Health Study who provided information on migraine and did not have diabetes at baseline. Our four exposure groups were migraine with aura, migraine without aura, past history of migraine and no history of migraine. Cox proportional hazards models were used to determine the hazard ratio for incident T2D.
Among the 38,620 women included in this study, 5062 (13.1%) women had migraine, of whom 2014 (39.8%) reported migraine with aura, and 2,087 (5.4%) women had a past history of migraine. During a mean of 14.6 years of follow-up, there were 3,032 cases of incident T2D. After adjustment for confounders, the hazard ratio (95% confidence interval) for developing diabetes was 1.06 (0.91–1.24) for women with migraine with aura, 1.01 (0.89–1.16) for women with migraine without aura, 1.13 (0.98–1.30) for women with a past history of migraine compared to women with no history of migraine.
Results of this prospective study in women do not support an association between migraine and incident T2D.
PMCID: PMC3460043  PMID: 22807568
migraine; diabetes; epidemiology
18.  Migraine, weight gain and the risk of becoming overweight or obese: prospective cohort study 
Some cross-sectional studies have suggested an association between migraine and increased body weight. However, prospective data on the association are lacking.
We conducted a prospective cohort study among 19,162 participants in the Women’s Health Study who had a body mass index (BMI) of 18.5–<25kg/m2 at baseline. Migraine was self-reported by standardized questionnaires. Main outcome measures were: incident overweight (BMI ≥25kg/m2), incident obesity (BMI ≥30kg/m2), and mean weight change. Age- and multivariable-adjusted hazard ratios were calculated for the association between migraine and incident overweight and obesity. Differences in weight change were evaluated by ANCOVA.
3,483 (18.2%) women reported any migraine history. After 12.9 years of follow-up, 7,916 incident overweight and 730 incident obesity cases occurred. Migraineurs had multivariable-adjusted HRs (95%CI) of 1.11 (1.05–1.17) for becoming overweight and 1.00 (0.83–1.19) for becoming obese. These associations remained stable after censoring for chronic diseases and were similar according to migraine aura status. Multivariable-adjusted mean weight change from baseline to the end of study was +4.7kg for migraineurs and +4.4kg for women without migraine (P=0.02).
Results of this large prospective study of middle-aged women do not indicate a consistent association between migraine and incident overweight, obesity, or relevant weight gain.
PMCID: PMC3460066  PMID: 22875879
Migraine; body mass index; overweight; obesity; prospective study
19.  Vitamins E and C and Medical Record-Confirmed Age-related Macular Degeneration in a Randomized Trial of Male Physicians 
Ophthalmology  2012;119(8):1642-1649.
To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of the diagnosis of age-related macular degeneration (AMD) in a large-scale randomized trial of male physicians.
Randomized, double-masked, placebo-controlled trial.
We included 14 236 apparently healthy United States male physicians aged ≥50 years who did not report a diagnosis of AMD at baseline.
Participants were randomly assigned to receive 400 international units (IU) of vitamin E or placebo on alternate days, and 500 mg of vitamin C or placebo daily. Participants reported new diagnoses of AMD on annual questionnaires and medical record data were collected to confirm the reports.
Main Outcome Measures
Incident diagnosis of AMD responsible for a reduction in best-corrected visual acuity to ≤20/30.
After 8 years of treatment and follow-up, a total of 193 incident cases of visually significant AMD were documented. There were 96 cases in the vitamin E group and 97 in the placebo group (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.78–1.37). For vitamin C, there were 97 cases in the active group and 96 in the placebo group (HR, 0.99; 95% CI, 0.75–1.31).
In a large-scale, randomized trial of United States male physicians, alternate-day use of 400 IU of vitamin E and/or daily use of 500 mg of vitamin C for 8 years had no appreciable beneficial or harmful effect on risk of incident diagnosis of AMD.
PMCID: PMC3535014  PMID: 22503302
20.  Migraine and Restless Legs Syndrome in Women 
Cephalalgia  2012;32(5):382-389.
Few clinic-based studies report an association between migraine and restless legs syndrome (RLS); however, population-based data are unavailable.
Cohort study among 31,370 women participating in the Women’s Health Study. We had detailed self-reported information on migraine, including aura status, and RLS. RLS was ascertained at the 9-year follow-up. We calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between migraine and RLS. We investigated any indication of migraine until RLS ascertainment as well as migraine with and without aura at baseline, prior migraine before baseline, and new reports of migraine during follow-up.
At baseline or during follow-up 6,857 (21.9%) women reported any migraine. These women had an increased risk for RLS (multivariable-adjusted OR=1.22; 95%CI 1.13–1.32). Further analyses indicated a similar association for migraine with aura (multivariable-adjusted OR=1.27; 95%CI 1.10–1.48) and migraine without aura (multivariable-adjusted OR=1.24; 95%CI 1.09–1.40) as well as for new reports of migraine during follow-up (multivariable-adjusted OR=1.30; 95%CI 1.10–1.54). Prior migraine did not appear to be associated with RLS.
Our data suggest an association between migraine and RLS at the population level. The association is similar for migraine with and without aura and for new reports of migraine during follow-up.
PMCID: PMC3334395  PMID: 22395798
migraine; restless legs syndrome; cohort study; association
21.  Atropine for Critical Care Intubation in a Cohort of 264 Children and Reduced Mortality Unrelated to Effects on Bradycardia 
PLoS ONE  2013;8(2):e57478.
Atropine has is currently recommended to facilitate haemodynamic stability during critical care intubation. Our objective was to determine whether atropine use at induction influences ICU mortality.
Methodology/Principal Findings
A 2-year prospective, observational study of all first non-planned intubations, September 2007–9 in PICU and Intensive Care Transport team of Hôpital Robert Debré, Paris, 4 other PICUs and 5 NICUs in the Paris Region, France. Follow-up was from intubation to ICU discharge. A propensity score was used to adjust for patient specific characteristics influencing atropine prescription. 264/333 (79%) intubations were included. The unadjusted ICU mortality was 7.2% (9/124) for those who received atropine compared to 15.7% (22/140) for those who did not (OR 0.42, 95%CI 0.19–0.95, p = 0.04). One child died during intubation (1/264, 0.4%). Two age sub-groups of neonates (≤28 days) and older children (>28 days, <8 years) were examined. This difference in mortality arose from the higher mortality in children aged over one month when atropine was not used (propensity score adjusted OR 0.22, 95%CI 0.06–0.85, p = 0.028). No effect was seen in neonates (propensity score adjusted OR 1.3, 95%CI 0.31–5.1 p = 0.74). Using the propensity score, atropine maintained the mean heart rate 45.9 bpm above that observed when no atropine was used in neonates (95%CI 34.3–57.5, p<0.001) and 43.5 bpm for older children (95%CI 25.5–61.5 bpm, p<0.001).
Atropine use during induction was associated with a reduction in ICU mortality in children over one month. This effect is independent of atropine’s capacity to attenuate bradycardia during intubation which occurred similarly in neonates and older children. This result needs to be confirmed in a study using randomised methodology.
PMCID: PMC3585379  PMID: 23468997
22.  Relation of Renal Function to Risk for Incident Atrial Fibrillation in Women 
The American Journal of Cardiology  2011;109(4):538-542.
Few prospective studies have explored the association between renal function and risk of incident atrial fibrillation (AF) in apparently healthy populations. A total of 24,746 women participating in the Women’s Health Study who were free of cardiovascular disease (CVD), AF and provided a blood sample at baseline were prospectively followed for incident AF from 1993 to 2010. AF events were confirmed by medical chart review. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine using the Chronic Kidney Disease – Epidemiology equation. Cox models were used to estimate hazard ratios (HR) and 95% CI for incident AF across eGFR categories controlling for AF risk factors. During 15.4 years (median) of follow-up, 786 incident AF events occurred. The multivariable-adjusted HR for incident AF across eGFR categories (<60, 60–74.9, 75–89, and ≥ 90 ml/min/1.73 m2) were:1.36 (1.00–1.84), 0.90 (0.71–1.14), 0.99 (0.84–1.18) and 1.00, respectively, without evidence of a linear association (P for trend, 0.48). Similarly, there was no significant curvilinear association (P quadratic, 0.10) in multivariable analysis across categories. As compared to women with an eGFR ≥ 60 ml/min/1.73 m2, the 1008 women with an eGFR < 60 ml/min/1.73 m2 had a multivariable adjusted HR for AF of 1.39 (1.04–1.86, p value 0.03). In conclusion, no significant linear or curvilinear relationship was observed between incident AF and less severe impairment of renal function in this large prospective cohort of women. However, a significant elevation in AF risk was observed at a threshold eGFR of < 60 ml/min/1.73 m2.
PMCID: PMC3402228  PMID: 22100025
atrial fibrillation; renal function
23.  α-Methylacyl-CoA racemase expression and lethal prostate cancer in the Physicians’ Health Study and Health Professionals Follow-up Study 
The Prostate  2011;72(3):301-306.
α-Methylacyl-CoA racemase (AMACR) is an enzyme that serves as a diagnostic biomarker of prostate cancer in clinical practice. Recent studies suggest that low AMACR expression is associated with biochemical recurrence and the development of fatal disease.
We conducted a prospective cohort study among 920 men aged 47–84 years, who were diagnosed with prostate cancer in the Physicians’ Health Study and the Health Professionals Follow-up Study cohorts, and whose resected tissue specimens were available for immunohistochemical analysis. We used Cox proportional hazards regression to evaluate the association of AMACR expression with lethal prostate cancer over a 20-year follow-up period.
In total, 68 men died from prostate cancer, and an additional 18 developed bony metastases during follow-up. We found that lower AMACR intensity was associated with higher prostate-specific antigen levels (p=0.003) and more advanced clinical stage (p=0.06) at diagnosis, and a non-significant trend for higher risk of lethal outcomes. The hazard ratio comparing the lowest to the highest quartile of AMACR expression intensity was 1.53 ((95% CI: 0.86, 2.73), p-for-trend across quartiles=0.07); this trend was further attenuated after adjustment for age, Gleason score, stage and cohort with a hazard ratio of 1.24 (95% CI 0.69, 2.22), p-for-trend=0.23.
Low AMACR expression in primary tumor specimens was not independently associated with the development of metastatic and lethal prostate cancer after treatment over a 20-year follow-up period, after adjustment for important clinical covariates at diagnosis.
PMCID: PMC3267640  PMID: 21713964
24.  Migraine Mutations Increase Stroke Vulnerability by Facilitating Ischemic Depolarizations 
Circulation  2011;125(2):335-345.
Migraine is an independent risk factor for stroke. Mechanisms underlying this association are unclear. Familial hemiplegic migraine (FHM), a migraine subtype that also carries an increased stroke risk, is a useful model for common migraine phenotypes because of shared aura and headache features, trigger factors, and underlying glutamatergic mechanisms.
Methods and Results
Here, we show that FHM type 1 (FHM1) mutations in CaV2.1 voltage-gated Ca2+ channels render the brain more vulnerable to ischemic stroke. Compared to wild-type, two FHM1 mutant mouse strains developed earlier onset of anoxic depolarization and more frequent peri-infarct depolarizations, associated with rapid expansion of infarct core on diffusion-weighted MRI and larger perfusion deficits on laser speckle flowmetry. Cerebral blood flow required for tissue survival was higher in the mutants, leading to infarction with milder ischemia. As a result, mutants developed larger infarcts and worse neurological outcomes after stroke, which were selectively attenuated by a glutamate receptor antagonist.
We propose that enhanced susceptibility to ischemic depolarizations akin to spreading depression predisposes migraineurs to infarction during mild ischemic events, thereby increasing the stroke risk.
PMCID: PMC3276214  PMID: 22144569
stroke; spreading depression; migraine; calcium channels
25.  Associations of socioeconomic status with migraine and non-migraine headache 
Cephalalgia  2011;32(2):159-170.
Migraine has been linked with several measures of socioeconomic status (SES). However, results are inconsistent and data on the association between SES and non-migraine headache, migraine subtypes and migraine frequency are sparse.
We conducted a cross-sectional study among 36,858 participants in the Women’s Health Study. As proxy for SES, we calculated an SES index using annual household income and education. Migraine, migraine aura, and non-migraine headache were self-reported with good validation rates. Multinomial logistic regression models were used to evaluate the association between SES index and the various headache forms.
12,140 (32.9%) women reported any history of headache, 6,801 women (18.4%) reported any history of migraine and 5,339 (14.5%) reported non-migraine headache. Women with low SES had an increased risk for all headache forms. The multivariable-adjusted OR (95% CI) were 1.22 (1.10–1.36) for non-migraine headache, 1.40 (1.28–1.54) for any migraine, 1.44 (1.23–1.69) for migraine with aura, and 1.38 (1.21–1.58) for migraine without aura. Among active migraineurs, low SES was associated with an increased OR for ≥weekly attack frequency (1.77, 1.26–2.49).
In this large cohort of female health professionals, low SES was associated with an increased prevalence for all headache forms and an increased migraine attack frequency.
PMCID: PMC3266434  PMID: 22174348
Migraine; non-migraine headache; migraine frequency; socioeconomic status

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