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1.  Prospective comorbidity-matched study of Parkinson's disease and risk of mortality among women 
BMJ Open  2016;6(9):e011888.
Background
Individuals with Parkinson's disease (PD) may have an increased risk of overall mortality compared to the general population. Women may have lower mortality rates from PD than men; however, studies among women on the effect of PD on mortality have been limited and may not have adequately controlled for confounding by comorbidities.
Methods
We conducted a matched cohort study among participants in the Women's Health Study. 396 incident PD cases were identified through self-report. Each PD case was matched by age to a comparator who was alive and had the same modified Charlson comorbidity score as the PD case. The PD cases and matched comparators were followed for all-cause mortality. Cox proportional hazards models adjusted for age at the index date, smoking, alcohol consumption, exercise and body mass index were used to determine the association between PD and mortality.
Results
During a median of 6.2 years of follow-up, 72 women died (47 PD cases and 25 comparators). The multivariable-adjusted HR for mortality was 2.60 (95% CI 1.56 to 4.32).
Conclusions
PD was associated with more than a twofold increased risk of all-cause mortality among women. Results are similar to those observed among men.
doi:10.1136/bmjopen-2016-011888
PMCID: PMC5051400  PMID: 27670518
EPIDEMIOLOGY; mortality
2.  Dietary patterns according to headache and migraine status: A cross-sectional study 
Background
Several potential dietary trigger factors for migraine have been proposed. However, few studies have examined the intake pattern of these dietary items compared to adequate control populations and if intake levels may vary by migraine aura status or attack frequency.
Methods
Cross-sectional study among participants in the Women's Health Study. We used logistic regression to evaluate the association between migraine and headache status and low intake for foods commonly reported to affect migraine.
Results
25,755 women reported no history of migraine or headache; 5573 reported non-migraine headache and 7042 reported any migraine of which 2972 reported migraine without aura and 1974 reported migraine with aura within the past year. Those with non-migraine headache or any migraine were more likely to have low intake of total alcohol (OR=1.22, 95% CI:1.14–1.29 and OR=1.17, 95% CI:1.11–1.24, respectively). Migraineurs with aura were more likely to have low intake of chocolate, ice cream, hot dogs, and processed meats. Those who experience migraine at least once per week were more likely to have low intake of skim/low-fat milk and white and red wine.
Conclusion
Intake of most suggested migraine dietary triggers differs by migraine aura status and attack frequency, a pattern not found for non-migraine headache.
doi:10.1177/0333102414560634
PMCID: PMC4442763  PMID: 25424709
Migraine; diet; epidemiology
3.  Do Physical Activity, Smoking, Drinking, or Depression Modify Transitions from Cognitive Impairment to Functional Disability? 
Journal of Alzheimer's disease : JAD  2015;44(4):1171-1180.
BACKGROUND
Individual-level modifiers can delay onset of limitations in basic activities of daily living (ADLs) among cognitively impaired individuals. We assessed whether these modifiers also delayed onset of limitations in instrumental ADLs (IADLs) among individuals at elevated dementia risk.
OBJECTIVES
To determine whether modifiable individual-level factors delay incident IADL limitations among adults stratified by dementia risk.
METHODS
Health and Retirement Study participants aged 65+ without activity limitations in 1998 or 2000 (N=5,219) were interviewed biennially through 2010. Dementia probability, categorized in quartiles, was used to predict incident IADL limitations with Poisson regression. We estimated relative (risk ratio) and absolute (number of limitations) effects from models including dementia, individual-level modifiers (physical inactivity, smoking, no alcohol consumption, and depression) and interaction terms between dementia and individual-level modifiers.
RESULTS
Dementia probability quartile predicted incident IADL limitations (relative risk for highest versus lowest quartile=0.44; 95% CI: 0.28–0.70). Most modifiers did not significantly increase risk of IADL limitations among the cognitively impaired. Physical inactivity (RR=1.60; 95% CI: 1.16, 2.19) increased the risk of IADL limitations among the cognitively impaired. The interaction between physical inactivity and low dementia probability was statistically significant (p=0.009) indicating that physical inactivity had significantly larger effects on incident IADLs among cognitively normal than among those with high dementia probability.
CONCLUSION
Physical activity may protect against IADL limitations while smoking, alcohol consumption and depression do not afford substantial protection among the cognitively impaired. Results highlight the need for extra support for IADLs among individuals with cognitive losses.
doi:10.3233/JAD-141866
PMCID: PMC4336575  PMID: 25408214
epidemiology; cognition; disability
4.  Associations Between Lipid Levels and Migraine: Cross-sectional Analysis in the EVA Study 
Cephalalgia  2011;31(14):1459-1465.
Background
Migraine with aura has been associated with increased prevalence of cardiovascular risk factors, including elevated levels of some vascular biomarkers. However, little research has been done on this association among the elderly. We examined the associations of lipid levels with headache and migraine in a cohort of elderly individuals.
Methods
Cross-sectional study among 1155 participants enrolled in the Epidemiology of Vascular Aging Study with available information on headache and blood biomarkers. We used multinomial logistic regression to evaluate the association between biomarker tertiles and headache categories.
Results
925 people had no severe headache, 64 people had non-migraine headache, and 166 people had migraine of whom 23 had aura. Compared to participants without headache, we observed strong associations between increasing tertiles of total cholesterol and migraine with aura. The OR (95% CI) was 4.67 (0.99–21.97) for the 2nd tertile and 5.97 (1.29–27.61) for the 3rd tertile. We also found strong associations between triglycerides and migraine with aura (OR for 3rd tertile:4.42 (1.32–14.77).) We did not see significant associations between increased biomarkers levels and any other headache group.
Conclusions
Elevated levels of total cholesterol and triglycerides are associated with migraine with aura but not other headache forms in the elderly.
doi:10.1177/0333102411421682
PMCID: PMC3303216  PMID: 21926156
migraine; cholesterol; epidemiology
5.  Migraine and Cognitive Decline in the Population-Based EVA Study 
Background
Previous studies on migraine and cognition have shown mixed results. However, many could not assess the relationship between migraine and change in cognitive function or only used a limited number of cognitive tests.
Methods
Prospective cohort study among 1170 participants of the Epidemiology of Vascular Aging Study who provided information about migraine status and completed cognitive testing. Participants were classified as having no severe headache, non-migraine headache and migraine. Cognitive functioning was measured at up to four time points using nine different cognitive functioning tests. Linear mixed effects models were used to evaluate the relationship between migraine status and change in cognitive function.
Results
Of the 1170 participants, 938 had no severe headache, 167 had migraine, and 65 had non-migraine headache. After adjusting for age, gender, education, and smoking status, people with migraine or non-migraine headache did not experience a greater rate of cognitive decline than those without headache or migraine in any domain (for the MMSE, p-values were 0.68 for the non-migraine headache and time interaction and 0.85 for the migraine and time interaction) during 4-5 years of follow-up. For the Wechsler, those with migraine declined less over time (p-value=.02).
Conclusion
Migraine was not associated with faster cognitive decline over time.
doi:10.1177/0333102411417466
PMCID: PMC3175294  PMID: 21816772
Migraine; cognitive function; epidemiology
6.  Non-steroidal anti-inflammatory drug use and functional outcome from ischemic cerebral events among women 
Background
Use of some non-steroidal anti-inflammatory drugs (NSAIDs) has been linked to an increased risk of stroke. However, information on the impact of NSAID use on functional outcomes from stroke is limited.
Methods
Using women enrolled in the Women’s Healthy Study who were free of a history of stroke or TIA at baseline, a prospective cohort study was performed to examine the impact of NSAID use on functional outcomes from stroke. Women were classified as NSAID non-user (<11 days of use in the past month), user (≥11 days of use in the past month), and missing (did not answer the question about NSAID use) during each year of the study. Possible functional outcomes were TIA or ischemic stroke with modified Rankin scale (mRS) score of 0 to1, 2 to 3, or 4 to 6.
Results
After 15.7 mean years of follow-up, 702 TIAs, 292 ischemic strokes with mRS 0-1, 233 ischemic strokes with mRS 2-3 and 98 ischemic strokes with mRS 4-6 occurred. Compared to women who were NSAID non-users, women who were NSAID users had multivariable-adjusted (95% CI) of 1.00 (0.77, 1.29) for TIA, 1.48 (1.04, 2.10) for mRS 0-1, 0.83 (0.52, 1.33) for mRS 2-3, and 1.33 (0.68, 2.59) for mRS 4-6.
Conclusion
Results from this large cohort study suggest than NSAID use may be associated with an increased risk of ischemic stroke with mild functional outcome.
doi:10.1016/j.ejim.2014.01.013
PMCID: PMC3970177  PMID: 24525385
epidemiology; stroke; non-steroidal anti-inflammatory drugs
7.  Structural brain lesions and restless legs syndrome: a cross-sectional population-based study 
BMJ Open  2014;4(11):e005938.
Objective
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.
Design
Cross-sectional study.
Setting
Population-based Three-City study.
Participants
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.
Results
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.
Conclusions
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.
doi:10.1136/bmjopen-2014-005938
PMCID: PMC4244423  PMID: 25421338
restless legs syndrome; MRI
8.  Migraine, Headache and the Risk of Depression: Prospective Cohort Study 
Background
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.
Methods
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.
Results
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.
Conclusions
Middle-aged women with migraine or non-migraine headache are at increased risk of incident depression.
doi:10.1177/0333102413483930
PMCID: PMC3720737  PMID: 23588795
Migraine; depression; epidemiology
9.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1161/STROKEAHA.111.680728
PMCID: PMC3695012  PMID: 23686974
cerebrovascular disease; cognitive functioning; dementia; epidemiology
10.  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.
doi:10.1111/head.12046
PMCID: PMC3618490  PMID: 23405909
migraine; cognitive decline; epidemiology
11.  Biomarkers and functional outcomes from ischemic cerebral events in women: a prospective cohort study 
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1468-1331.2012.03874.x
PMCID: PMC3538088  PMID: 23034002
stroke; epidemiology; biomarkers
12.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1161/STROKEAHA.112.672451
PMCID: PMC3552068  PMID: 23306328
cerebrovascular disease; epidemiology; aspirin
13.  Dementia and dependence 
Neurology  2014;82(17):1543-1550.
Objective:
To identify modifying factors that preserve functional independence among individuals at high dementia risk.
Methods:
Health and Retirement Study participants aged 65 years or older without baseline activities of daily living (ADL) limitations (n = 4,922) were interviewed biennially for up to 12 years. Dementia probability, estimated from direct and proxy cognitive assessments, was categorized as low (i.e., normal cognitive function), mild, moderate, or high risk (i.e., very impaired) and used to predict incident ADL limitations (censoring after limitation onset). We assessed multiplicative and additive interactions of dementia category with modifiers (previously self-reported physical activity, smoking, alcohol consumption, depression, and income) in predicting incident limitations.
Results:
Smoking, not drinking, and income predicted incident ADL limitations and had larger absolute effects on ADL onset among individuals with high dementia probability than among cognitively normal individuals. Smoking increased the 2-year risk of ADL limitations onset from 9.9% to 14.9% among the lowest dementia probability category and from 32.6% to 42.7% among the highest dementia probability category. Not drinking increased the 2-year risk of ADL limitations onset by 2.1 percentage points among the lowest dementia probability category and 13.2 percentage points among the highest dementia probability category. Low income increased the 2-year risk of ADL limitations onset by 0.4% among the lowest dementia probability category and 12.9% among the highest dementia probability category.
Conclusions:
Smoking, not drinking, and low income predict incident dependence even in the context of cognitive impairment. Regardless of cognitive status, reducing these risk factors may improve functional outcomes and delay institutionalization.
doi:10.1212/WNL.0000000000000357
PMCID: PMC4011462  PMID: 24682970
14.  Changes in Memory Before and After Stroke Differ by Age and Sex, but not by Race 
Background
Post-stroke memory impairment is more common among older adults, women, and blacks. It is unclear whether post-stroke differences reflect differential effects of stroke per se, or differences in pre-stroke functioning. We compare memory trajectories before and after stroke by age, sex and race.
Methods
Health and Retirement Study participants age 50+ (n=17,341) with no stroke history at baseline, were interviewed biennially up to 10 years for first self- or proxy-reported stroke (n=1,574). Segmented linear regression models were used to compare annual rate of memory change before and after stroke among 1,169 stroke survivors, 405 stroke decedents, and 15,767 stroke-free participants. Effect modification was evaluated with analyses stratified by baseline age (≤70 vs. >70), sex and race (white vs. nonwhite), and using interaction terms between age/sex/race indicators and annual memory change.
Results
Older (>70 years) adults experienced faster memory decline before stroke (−0.19 vs. −0.10 points/year for survivors, −0.24 vs. −0.13 points/year for decedents, p<0.001 for both interactions), and among stroke survivors, larger memory decrements (−0.64 vs. −0.26 points, p<0.001) at stroke and faster memory decline (−0.15 vs. −0.07 points/year, p=0.003) after stroke onset, compared to younger adults. Female stroke survivors experienced faster pre-stroke memory decline than male stroke survivors (−0.14 vs. −0.10 points/year, p<0.001). However, no sex differences were seen for other contrasts. Although whites had higher post-stroke memory scores than non-whites, race was not associated with rate of memory decline during any period of time; i.e., race did not significantly modify the rate of decline pre- or post-stroke or the immediate effect of stroke on memory.
Conclusions
Older age and predicted worse memory change before, at and after stroke onset. Sex and race differences in post-stroke memory outcomes might be attributable to pre-stroke disparities, which may be unrelated to cerebrovascular disease.
doi:10.1159/000357557
PMCID: PMC4347666  PMID: 24686293
Memory change; Stroke; Effect Modifier
15.  Headache, migraine and risk of brain tumors in women: prospective cohort study 
Background
While headache is a common symptom among brain tumors patients, often patients with common headache have concerns of being at risk for developing brain tumors. We aimed to disprove that migraine or headache in general is associated with increased risk of developing brain tumors.
Methods
Prospective study among 39,534 middle-aged women, free of any cancer, and who provided information on headache history at baseline. We followed participants for occurrence of medical record-confirmed brain tumors. We ran multivariable-adjusted Cox proportional hazards models to evaluate associations between any headache, migraine, and non-migraine headache with incident brain tumors. We further evaluated whether migraine frequency and updated headache information during follow-up could be linked with brain tumors.
Results
A total of 13,022 (32.9%) women reported headache, of which 5,731 were classified as non-migraine headache and 7,291 as migraine. During a mean follow-up of 15.8 years, 52 brain tumors were confirmed. The multivariable-adjusted hazard ratios (95% confidence interval) for brain tumors were 1.33 (0.76-2.34) for any headache, 1.18 (0.58-2.41) for migraine and 1.53 (0.75-3.12) for non-migraine headache. The association for any headache was further attenuated in time-varying analyses (1.15; 0.58-2.24). Those who experience migraine six times/year were also not at increased risk of brain tumor (0.67; 0.13-3.32).
Conclusions
Results of this large, prospective cohort study in women do not provide evidence that headache in general or migraine in particular are associated with the occurrence of brain tumors. Our data should reassure patients with headache that brain tumor is not a long-term consequence of headache.
Electronic supplementary material
The online version of this article (doi:10.1186/s10194-015-0501-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s10194-015-0501-0
PMCID: PMC4416100  PMID: 25916329
Migraine; Headache; Brain tumor; Epidemiology; Women
16.  Migraine and risk of incident diabetes in women: prospective study 
Background
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.
Methods
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.
Results
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.
Conclusion
Results of this prospective study in women do not support an association between migraine and incident T2D.
doi:10.1177/0333102412453954
PMCID: PMC3460043  PMID: 22807568
migraine; diabetes; epidemiology
17.  Physical Activity and Functional Outcomes from Cerebral Vascular Events in Men 
Background/Purpose
In studies enrolling stroke patients, higher levels of pre-stroke physical activity are associated with better functional outcomes. However, prospective studies evaluating this association are sparse. Using a cohort of initially healthy men, we aimed to prospectively assess the association between physical activity and functional outcomes from cerebral vascular events.
Methods
Prospective cohort study among 21,794 men enrolled in the Physician's Health Study who provided information on physical activity at baseline and who did not have a history of stroke or transient ischemic attack (TIA). Baseline levels of physical activity were categorized as: vigorous exercise <1, 1, 2–4 and ≥5 times/week. Possible functional outcomes included TIA and stroke with mRS score of 0–1, 2–3 or 5–6. Multinomial logistic regression was used to determine the association between physical activity and functional outcomes from cerebral vascular events.
Results
After a mean of 20.2 years of follow-up, 761 TIAs, 1146 ischemic strokes, 221 hemorrhagic strokes and 11 strokes of unknown type occurred. Compared with men who did not experience a stroke or TIA and who exercise vigorously <1 time/week, men who exercise vigorously ≥5 times/week had adjusted relative risk (95% CIs) of 0.67 (0.53–0.86) for TIA, 0.84 (0.61–1.14) for stroke with mRS 0–1, 0.85 (0.67–1.08) for mRS 2–3, and 1.12 (0.78–1.60) for mRS 5–6 after total stroke. Other levels of physical activity did not have a significant impact on the risk of our outcomes.
Conclusions
Physical activity prior to TIA or stroke does not appear to influence functional outcomes after cerebral vascular events.
doi:10.1161/STROKEAHA.111.619544
PMCID: PMC3226877  PMID: 21940956
18.  Tumor Necrosis Factor Gene Polymorphisms and Migraine: A Systematic Review and Meta-Analysis 
Cephalalgia  2011;31(13):1381-1404.
Background
Data on the association between TNF-alpha and TNF-beta gene polymorphisms and migraine are conflicting.
Methods
We performed a systematic review and meta-analysis of studies published until January 2011. We used data from published papers and as provided after contact with the authors. We calculated study specific odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models as well as pooled effect estimates.
Results
Among the ten studies identified the best evidence is available for the TNF-alpha -308G>A and TNF-beta 252A>G polymorphisms indicating no overall association with migraine. Subgroup analyses suggested that the A allele of the TNF-alpha -308G>A variant more than doubles the risk for migraine among populations with a heterogeneous ethnic background, which was driven by associations for MO (additive model: pooled OR=2.87; 95% CI 1.86–4.43). Further, the risk for MA was increased among Asian populations (additive model: pooled OR=1.71; 95% CI 1.07–2.71). Both observed effects were stronger among females than males.
Conclusions
Our results indicate no overall association between TNF-alpha and TNF-beta gene variants. However, associations differed among specific populations. Our findings need to be treated with caution and further targeted research is warranted to evaluate population-specific effects including population stratification.
doi:10.1177/0333102411419022
PMCID: PMC3303222  PMID: 22001640
migraine; tumor necrosis factor; lymphotoxin; polymorphism; meta-analysis
19.  Migraine and Mortality: A Systematic Review and Meta-Analysis 
Objective
To evaluate the evidence on the association between migraine and mortality.
Methods
Systematic review and meta-analysis of studies investigating the association between any migraine (all forms of migraine collectively) or migraine subtypes (e.g. migraine with aura) and mortality published until March 2011.
Results
We identified ten cohort studies. Studies differed regarding the types of mortality investigated and only four presented aura-stratified results, limiting pooled analyses for migraine subtypes and cause-specific mortality. For any migraine pooled analysis does not suggest an association with all-cause (five studies; pooled relative risk [RR]=0.90, 95%CI 0.71–1.16), cardiovascular (CVD; six studies; pooled RR=1.09, 95%CI 0.89–1.32), or coronary heart disease mortality (CHD; three studies; pooled RR=0.95, 95%CI 0.57–1.60). Heterogeneity among studies is moderate to high. Two studies each suggest that migraine with aura increases risk for CVD and CHD mortality.
Conclusion
This meta-analysis does not suggest that any migraine is associated with mortality from all-causes, CVD, or CHD. However, there is heterogeneity among studies and suggestion that migraine with aura increases CVD and CHD mortality. Given the high migraine prevalence a definitive answer to the question if migraine or a subtype alters risk for mortality is of high public health importance; hence, further studies are needed.
doi:10.1177/0333102411415879
PMCID: PMC3175288  PMID: 21803936
migraine; migraine aura; mortality; cardiovascular disease; meta-analysis
20.  Migraine and cognitive decline among women: prospective cohort study 
The BMJ  2012;345:e5027.
Objective To evaluate the association between migraine and cognitive decline among women.
Design Prospective cohort study.
Setting Women’s Health Study, United States.
Participants 6349 women aged 65 or older enrolled in the Women’s Health Study who provided information about migraine status at baseline and participated in cognitive testing during follow-up. Participants were classified into four groups: no history of migraine, migraine with aura, migraine without aura, and past history of migraine (reports of migraine history but no migraine in the year prior to baseline).
Main outcome measures Cognitive testing was carried out at two year intervals up to three times using the telephone interview for cognitive status, immediate and delayed recall trials of the east Boston memory test, delayed recall trial of the telephone interview for cognitive status 10 word list, and a category fluency test. All tests were combined into a global cognitive score, and tests assessing verbal memory were combined to create a verbal memory score.
Results Of the 6349 women, 853 (13.4%) reported any migraine; of these, 195 (22.9%) reported migraine with aura, 248 (29.1%) migraine without aura, and 410 (48.1%) a past history of migraine. Compared with women with no history of migraine, those who experienced migraine with or without aura or had a past history of migraine did not have significantly different rates of cognitive decline in any of the cognitive scores: values for the rate of change of the global cognitive score between baseline and the last observation ranged from −0.01 (SE 0.04) for past history of migraine to 0.08 (SE 0.04) for migraine with aura when compared with women without any history of migraine. Women who experienced migraine were also not at increased risk of substantial cognitive decline (worst 10% of the distribution of decline). When compared with women without a history of migraine, the relative risks for the global score ranged from 0.77 (95% confidence interval 0.46 to 1.28) for women with migraine without aura to 1.17 (0.84 to 1.63) for women with a past history of migraine.
Conclusion In this prospective cohort of women, migraine status was not associated with faster rates of cognitive decline.
doi:10.1136/bmj.e5027
PMCID: PMC3414433  PMID: 22875950
21.  Migraine, Migraine Aura, and Cervical Artery Dissection: A Systematic Review and Meta-Analysis 
Cephalalgia  2011;31(8):886-896.
Objective
We evaluated the current evidence on the association between migraine including aura status and cervical artery dissection.
Methods
We performed a systematic review and meta-analysis of studies investigating the association between migraine or migraine subtypes (e.g. migraine with aura) and cervical artery dissection published until October 2010.
Results
We identified five case-control studies investigating the association between migraine and cervical artery dissection. In pooled analysis, migraine doubled the risk of cervical artery dissection (pooled odds ratio [OR]=2.06, 95% CI 1.33–3.19). All studies allowed evaluation of migraine aura status. While the effect estimate for migraine without aura (pooled OR=1.94, 95% CI 1.21–3.10) was similar to overall migraine, the association was weaker for migraine with aura (pooled OR=1.50, 95% CI 0.76–2.96) However, there is no evidence that aura status significantly modifies the association between migraine and cervical artery dissection (meta-regression on aura status p=0.58). The risk does not appear to differ between women and men; however, only few studies presented gender-specific data. Heterogeneity among studies was low to moderate.
Conclusion
In this meta-analysis migraine is associated with a two-fold increased risk of cervical artery dissection. This risk does not appear to significantly differ by migraine aura status or gender.
doi:10.1177/0333102411401634
PMCID: PMC3303220  PMID: 21511950
migraine; migraine aura; cervical artery dissection; carotid artery dissection; vertebral artery dissection; meta-analysis
22.  Migraine and Functional Outcome from Ischemic Cerebral Events in Women 
Circulation  2010;122(24):2551-2557.
Background
Studies have linked migraine with aura to an increased risk of ischemic stroke, particularly among women. Data on the relationship of migraine and functional outcome from ischemic cerebral events are sparse.
Methods and Results
Prospective cohort study among 27,852 women enrolled in the Women’s Health Study for whom we had information on migraine and measured cholesterol values and who had no prior stroke or transient ischemic attack (TIA). Migraine was classified into no history of migraine, active migraine with aura, active migraine without aura, and past history of migraine. Possible functional outcomes were no stroke or TIA, TIA, and stroke with modified Rankin Scale (mRS) score 0–1, mRS 2–3, and mRS 4–6. We used multinomial logistic regression to evaluate the relationship of migraine with functional outcomes after ischemic stroke. During a mean of 13.5 years of follow-up, 398 TIAs and 345 ischemic strokes occurred. Compared with women without history of migraine and who did not experience a TIA or stroke, women who reported migraine with aura had adjusted relative risk (95% confidence interval) of 1.56 (1.03–2.36) for TIA, 2.33 (1.37–3.97) for stroke with mRS 0–1, 0.82 (0.30–2.24) for mRS 2–3, and 1.18 (0.28–4.97) for mRS 4–6. The risk of any outcome was not significantly elevated for women who experienced migraine without aura or who had a past history of migraine.
Conclusion
Results of this large prospective cohort suggest that women with migraine with aura are at increased risk of experiencing TIA or ischemic stroke with good functional outcome.
doi:10.1161/CIRCULATIONAHA.110.977306
PMCID: PMC3058846  PMID: 21126968
Migraine; stroke; epidemiology; women
23.  Sex Hormone Receptor Gene Polymorphisms and Migraine: A Systematic Review and Meta-Analysis 
Data on the association between sex hormone receptor polymorphisms and migraine are conflicting. We performed a systematic review and meta-analysis on this topic searching for studies published until August 2009. For each study we calculated odds ratios (ORs) and 95% confidence intervals (CIs) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. Among the 7 genes targeted 4 variants were investigated in multiple studies. Effect estimates from an additive model suggest that the ESR-1 594 G>A (pooled OR 1.37; 95% CI 1.02–1.83) and ESR-1 325 C>G (pooled OR 1.16; 95% CI 1.03–1.32) variants are associated with any migraine. This pattern does not differ between migraine with and without aura. In contrast the ESR-1 Pvu II C>T and PGR PROGINS insert polymorphism do not appear to be associated with migraine. Results were driven by studies among Caucasians and may differ in other ethnic groups.
doi:10.1177/0333102410364155
PMCID: PMC3055237  PMID: 20959426
migraine; sex hormone receptors; polymorphisms; meta-analysis
24.  5-HTTLPR Polymorphism in the Serotonin Transporter Gene and Migraine: A Systematic Review and Meta-Analysis 
Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published until September 2009. For each study with genotype information we calculated odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. Among the ten studies identified there was no overall association between the polymorphism and any migraine for Europeans or Asians. However, European women carrying the S allele had an increased risk for any migraine (dominant model: pooled OR=2.02; 95%CI 1.24–3.28). Results among Europeans further suggested an increased risk for migraine with aura among carriers of the S/S genotype (recessive model: pooled OR=1.41; 95%CI 0.83–2.40). While our results indicate no overall association between the SLC6A4 5-HTTLPR polymorphism and migraine among Europeans and Asians, gender and migraine aura status may have modifying roles among Europeans.
doi:10.1177/0333102410362929
PMCID: PMC3055240  PMID: 20959425
migraine; serotonin transporter gene; SLC6A4; 5-HTTLPR; meta-analysis
25.  STin2 VNTR Polymorphism in the Serotonin Transporter Gene and Migraine: A Pooled and Meta-Analysis 
The journal of headache and pain  2010;11(4):317-326.
Data on the association between the SLC6A4 STin2 VNTR polymorphism and migraine are conflicting. To perform a pooled and meta-analysis, we searched for studies published until September 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies. Assessment for eligibility and extraction of data was performed by two independent investigators. We extracted allele and genotype frequencies for each study. We then calculated study-specific and pooled odds ratios (OR) and 95% confidence intervals (CI) assuming allele and genotype models. We also calculated pooled ORs and 95% CIs based on study-specific effect estimates for the allele model. We included five studies investigating the association between the STin2 VNTR polymorphism and migraine. Results from the allele model suggested a protective effect against migraine for the STin2.9 and STin2.10 alleles compared to the STin2.12 allele among populations of European descent, which however, was not significant. Results from the genotype model indicated a significant ~25% reduced risk for migraine among carriers of the 10/12 genotype compared with carriers of the 12/12 genotype among all study populations (OR=0.76, 95% CI 0.60–0.97) for any migraine, which was more pronounced among populations of European descent (OR=0.68, 95% CI 0.53–0.87). Results for migraine with and without aura were of similar magnitude, however not statistical significant. Our results suggest a protective effect of non-STin2.12 alleles compared to STin2.12 alleles, respectively 10/12 and 10/10 genotypes compared to the 12/12 genotype against migraine among populations of European descent. Associations in non-European populations may differ.
doi:10.1007/s10194-010-0230-3
PMCID: PMC3026586  PMID: 20585826
migraine; serotonin transporter; SLC6A4; STin2 VNTR; meta-analysis

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