Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Carotid Bulb Webs as a Cause of "Cryptogenic" Ischemic Stroke.

BACKGROUND AND PURPOSE: Carotid webs are intraluminal shelf-like filling defects at the carotid bulb with recently recognized implications in patients with recurrent ischemic stroke. We sought to determine whether carotid webs are an under-recognized cause of "cryptogenic" ischemic stroke and to estimate their prevalence in the general population. MATERIALS AND METHODS: A retrospective review of neck CTA studies in young patients with cryptogenic stroke over the past 6 years (n = 33) was performed to determine the prevalence of carotid webs compared with a control group of patients who received neck CTA studies for reasons other than ischemic stroke (n = 63). RESULTS: The prevalence of carotid webs in the cryptogenic stroke population was 21.2% (95% CI, 8.9%-38.9%). Patients with symptomatic carotid webs had a mean age of 38.9 years (range, 30-48 years) and were mostly African American (86%) and women (86%). In contrast, only 1.6% (95% CI, 0%-8.5%) of patients in the control group demonstrated a web. Our findings demonstrate a statistically significant association between carotid webs and ischemic stroke (OR = 16.7; 95% CI, 2.78-320.3; P = .01). CONCLUSIONS: Carotid webs exhibit a strong association with ischemic stroke, and their presence should be suspected in patients lacking other risk factors, particularly African American women.

Heritability of young- and old-onset ischaemic stroke.

BACKGROUND AND PURPOSE: Although the genetic contribution to stroke risk is well known, it remains unclear if young-onset stroke has a stronger genetic contribution than old-onset stroke. This study aims to compare the heritability of ischaemic stroke risk between young and old, using common genetic variants from whole-genome array data in population-based samples. METHODS: This analysis included 4050 ischaemic stroke cases and 5765 controls from six study populations of European ancestry; 47% of cases were young-onset stroke (age < 55 years). To quantify the heritability for stroke risk in these unrelated individuals, the pairwise genetic relatedness was estimated between individuals based on their whole-genome array data using a mixed linear model. Heritability was estimated separately for young-onset stroke and old-onset stroke (age ≥ 55 years). RESULTS: Heritabilities for young-onset stroke and old-onset stroke were estimated at 42% (±8%, P < 0.001) and 34% (±10%, P < 0.001), respectively. CONCLUSIONS: Our data suggest that the genetic contribution to the risk of stroke may be higher in young-onset ischaemic stroke, although the difference was not statistically significant.

Racial/ethnic disparities in mortality by stroke subtype in the United States, 1995-1998.

Healthy People 2010 objectives for improving health include a goal to eliminate racial disparities in stroke mortality. Age-specific death rates by stroke subtype are not well documented among racial/ethnic minority populations in the United States. This report examines mortality rates by race/ethnicity for three stroke subtypes during 1995-1998. National Vital Statistics' death certificate data were used to calculate death rates for ischemic stroke (n = 507,256), intracerebral hemorrhage (n = 97,709), and subarachnoid hemorrhage (n = 27,334) among Hispanics, Blacks, American Indians/Alaska Natives, Asians/Pacific Islanders, and Whites by age and sex. Comparisons with Whites as the referent were made using age-standardized risk ratios and age-specific risk ratios. Age-standardized mortality rates for the three stroke subtypes were higher among Blacks than Whites. Death rates from intracerebral hemorrhage were also higher among Asians/Pacific Islanders than Whites. All minority populations had higher death rates from subarachnoid hemorrhage than did Whites. Among adults aged 25-44 years, Blacks and American Indians/Alaska Natives had higher risk ratios than did Whites for all three stroke subtypes. Increased public health attention is needed to reduce incidence and mortality for stroke, the third leading cause of death. Particular attention should be given to increasing awareness of stroke symptoms among young minority groups.

beta(2)-Glycoprotein 1-dependent anticardiolipin antibodies and risk of ischemic stroke and myocardial infarction: the honolulu heart program.

BACKGROUND: It has been hypothesized that immunoreactivity to beta(2)-glycoprotein 1 (beta2GP1)-dependent anticardiolipin antibody (aCL), but not beta2GP1-independent aCL, is associated with increased risk of ischemic stroke and myocardial infarction (MI). METHODS: We performed a nested case-control study examining aCL as a risk factor for ischemic stroke and MI by using stored frozen sera obtained from subjects enrolled in the Honolulu Heart Program and followed for up for 20 years. We measured beta2GP1-dependent and beta2GP1-independent aCL and anti-beta2GP1 immunoreactivity in 259 men who developed an ischemic stroke, in 374 men who developed an MI, and in a control group of 1360 men who remained free of both conditions. RESULTS: Only beta2GP1-dependent aCL of the IgG class was significantly associated with both incident ischemic stroke and MI. This association was attenuated in the last 5 years of the 20-year follow-up. For stroke, the risk factor-adjusted relative odds for men with a positive versus a negative beta2GP1-dependent aCL of the IgG class were 2.2 (95% CI 1.5 to 3.4) at 15 years and 1.5 (95% CI 1.0 to 2.3) at 20 years. For MI, the adjusted relative odds were 1.8 (95% CI 1.2 to 2.6) at 15 years and 1.5 (95% CI 1.1 to 2.1) at 20 years. CONCLUSIONS: These data suggest that aCL IgG, particularly the beta2GP1-dependent variety, is an important predictor of future stroke and MI in men.

Alcohol intake, type of beverage, and the risk of cerebral infarction in young women.

BACKGROUND AND PURPOSE: The relationship between alcohol consumption and cerebral infarction remains uncertain, and few studies have investigated whether the relationship varies by alcohol type or is present in young adults. We examined the relationship between alcohol consumption, beverage type, and ischemic stroke in the Stroke Prevention in Young Women Study. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. Case patients (n=224) were aged 15 to 44 years with a first cerebral infarction, and control subjects (n=392), identified by random-digit dialing, were frequency matched by age and region of residence. The interview assessed lifetime alcohol consumption and consumption and beverage type in the previous year, week, and day. ORs were obtained from logistic regression models controlling for age, race, education, and smoking status, with never drinkers as the referent. RESULTS: Alcohol consumption, up to 24 g/d, in the past year was associated with fewer ischemic strokes (<12 g/d: OR 0.57, 95% CI 0. 38 to 0.86; 12 to 24 g/d: OR 0.38, 95% CI 0.17 to 0.86; >24 g/d: OR 0.95, 95% CI 0.43 to 2.10) in comparison to never drinking. Analyses of beverage type (beer, wine, liquor) indicated a protective effect for wine consumption in the previous year (<12 g/wk: OR 0.58, 95% CI 0.35 to 0.97; 12 g/wk to <12 g/d: OR 0.55, 95% CI 0.28 to 1.10; >/=12 g/d: OR 0.92, 95% CI 0.23 to 3.64). CONCLUSIONS: Light to moderate alcohol consumption appears to be associated with a reduced risk of ischemic stroke in young women.

Oral contraceptives and stroke.

Since 1962, more than 25 studies have been devoted to the relationship between oral contraceptives and stroke. They are all case-control or cohort epidemiological studies and thus contain the difficulties and biases that are inherent in these types of studies. The following conclusions can be drawn from these studies: High oestrogen content (> or = 50 microg) increases the risk of stroke, all stroke subtypes, and stroke death. Low oestrogen content (<50 microg) carries a very low or no risk of stroke. There are no data on progestogen only oral contraceptives. Stroke risk is greatly increased if associated risk factors are present, in particular hypertension, cigarette smoking and migraine. Oral contraceptives, even at low doses, significantly increase the risk of cerebral venous thrombosis, which is further enhanced if congenital thrombophilia is present. The attributable risk of stroke in young women using oral contraceptives is about 1 per 200000 woman-years. The contraceptive and non-contraceptive benefits of low dose oral contraceptives vastly outweigh their risks provided that other risk factors are absent or well controlled.

Migraine and stroke in young women.

In this paper we review the evidence that migraine is associated with ischaemic stroke in young women, emphasizing potential biases, factors that may influence the association, potential mechanisms, and potential public health impact. Consistency of case-control findings from several countries and supporting evidence from prospective data suggest that the association is not an artifact of study design or execution, although, due to methodological limitations, none of the studies mentioned can be considered definite proof of the association. However, it is less clear whether migraine without aura is associated with stroke or whether the association is restricted to migraine with aura. Similarly, there are few data examining the magnitude of the association among nonusers of oral contraceptives compared with those who use low oestrogen oral contraceptives. As a consequence, there is a lack of data concurrently stratifying both by the presence vs. the absence of aura and by the use of low oestrogen oral contraceptives vs. non-use of oral contraceptives. Moreover, there is still no convincing evidence on the mechanisms that would be implied and on the groups of migraineurs really at risk of ischaemic stroke. Despite the considerable advances in our understanding of the relationship between migraine and stroke, there are many gaps in the data needed for public health recommendations.

Post-menopausal hormone replacement therapy and stroke risk.

This paper will review available data bearing on the relationship of post-menopausal hormone replacement therapy to the risk of first or recurrent ischaemic stroke. Although experimental data from both human and animal studies will be briefly mentioned, the bulk of evidence is from observational epidemiological studies. As such, the limitations of observational studies, particularly as applied to the health effects of post-menopausal hormone replacement therapy, will be emphasized. We conclude that there is no compelling consistent evidence that post-menopausal hormone replacement therapy either decreases or increases stroke risk. There are, however, reasons to be concerned that this therapy may contribute to stroke risk.

Lipoprotein (a) and the risk of ischemic stroke in young women.

BACKGROUND AND PURPOSE: lipoprotein (a) (lp (a)) is a lipid-containing particle similar to LDL which has been found in atherosclerotic plaque. The role of lp (a) in ischemic stroke remains controversial, but some studies suggest lp (a) is particularly important as a risk factor for stroke in young adults. We investigated the role of lp (a) as a risk factor for stroke in young women enrolled in the Stroke Prevention in Young Women Study. METHODS: subjects were participants in a population-based, case-control study of risk factors for ischemic stroke in young women. Cases were derived from surveillance of 59 regional hospitals in the central Maryland, Washington DC, Pennsylvania and Delaware area. Lp (a) was measured in 110 cases and 216 age-matched controls. Demographics, risk factors, and stroke subtype were determined by interview and review of medical records. RESULTS: lp (a) values were higher in blacks than whites, but within racial groups, the distribution of lp (a) values was similar between cases and controls. After adjustment for age, race, hypertension, diabetes, cigarette smoking, coronary artery disease, total cholesterol and HDL cholesterol, the odds ratio for an association of lp (a) and stroke was 1.36 (95% CI 0.80-2.29). There was no dose-response relationship between lp (a) quintile and stroke risk. Among stroke subtypes, only lacunar stroke patients had significantly elevated lp (a) values compared to controls. CONCLUSIONS: we found no association of lp (a) with stroke in a population of young women with ischemic stroke. Small numbers of patients limit conclusions regarding risk in ischemic stroke subtypes, but we could not confirm previous suggestions of an association of lp (a) with atherosclerotic stroke in young adults.

Association between total homocyst(e)ine and the likelihood for a history of acute myocardial infarction by race and ethnicity: Results from the Third National Health and Nutrition Examination Survey.

BACKGROUND: Few studies examining the association between total homocyst(e)ine and coronary heart disease have included blacks or Hispanics. METHODS: Data from the third National Health and Nutrition Examination Survey (3173 patients), a nationally representative survey of US adults, were used to examine the relation between total homocyst(e)ine and an electrocardiogram or a physician's diagnosis of acute myocardial infarction (259 patients) among whites, blacks, and Mexican Americans >/=40 years old. RESULTS: Vitamin B(12) and serum folate concentrations were significantly lower among persons with a total homocyst(e)ine concentration >/=15 micromol/L than among those with a total homocyst(e)ine concentration /=15 micromol/L were also older and more likely to be hypertensive, have a higher cholesterol concentration, and smoke. Compared with persons with a total homocyst(e)ine concentration /=15 micromol/L had an odds ratio (OR) for myocardial infarction of 1.8 (95% confidence interval [CI], 1.2-2.9) after adjustment for cardiovascular disease risk factors. Similar associations were noted among whites (OR 1.8, 95% CI, 1.1-3.1) and blacks (OR 1.9, 95% CI, 0.8-4.2); a more modest association was noted among Mexican Americans (OR 1.2, 95% CI, 0.3-5.0). The association between total homocyst(e)ine and myocardial infarction was also more pronounced in persons without hypertension or diabetes. CONCLUSIONS: Almost a 2-fold increased likelihood of myocardial infarction among persons with a total homocyst(e)ine concentration >/=15 micromol/L was noted in this nationally representative survey. The magnitude of the association did not differ by race or ethnicity.

Utilization of multiple imperfect assessments of the dependent variable in a logistic regression analysis.

Often, in biomedical research, there are multiple sources of imperfect information regarding a dichotomous variable of interest. For example, in a study we are conducting on the relationship between cocaine use and stroke risk, information on the cocaine use of each study patient is available from three fallible sources: patient interviews; urine toxicology testing, and medical record review. Regression analyses based on a rule for classifying patients from this information can result in biased estimation of associations and variances due to the misclassification of some subjects and to the assumption of certainty. We describe a likelihood-based method that directly incorporates multiple sources of information regarding an outcome variable into a regression analysis and takes into account the uncertainty in the classification. The method can be applied when some sources of information are missing for some subjects. We show how the availability of multiple sources can be exploited to generate estimates of the quality (for example, sensitivity and specificity) of each source and to model the degree to which missing data are informative. A fitting algorithm and issues of identifiability are discussed. We illustrate the method using data from our study.

Clinical features of cardioembolic strokes identified by transesophageal echocardiography.

Clinical and CT scan features predictive of a cardiac source of embolism (CSOE) are helpful in planning appropriate investigations in ischaemic strokes. The currently described predictors of CSOE were determined before the availability of trans esophageal echocardiography (TEE). After the advent of TEE, many new CSOE were discovered. The present study was planned to investigate if the previously described predictors of CSOE are also valid for patients with CSOE detectable only with TEE (TEE-detected CSOE). From 1992-1995, 485 consecutive patients of ischemic stroke were enrolled in the Maryland Stroke Data Bank (MSDB). Patients with CSOE identified only by TEE and not by clinical, electrocardiographic or transthoracic echocardiographic (TTE) examination were compared to patients with a CSOE with respect to the features of the history, neurologic examination and CT scan. Of 485 patients with cerebral infarction, 132 (27%) patients had CSOE. In 21/132 (16%), diagnosis of high risk CSOE could be established only by TEE. The most discriminating clinical findings in TEE-detected CSOE patients were visual field deficit (OR 2.9; 95% CI, 1.1-7.4) and neglect (OR 3.4; 95% CI,1.2-9.3). Less strong associations were also found with other clinical features described previously for CSOE. No significant differences were found for features of the initial CT scan. In summary, presence of visual field defect and hemineglect may suggest a higher likelihood of finding a CSOE by TEE, even if the clinical cardiac examination and TTE are normal.

Stroke location is not associated with return to work after first ischemic stroke.

BACKGROUND AND PURPOSE: In prior studies, age, race, job category, disability, and cortical functions such as praxis, language, and memory have been associated with vocational outcome, but the influence of stroke location on return to work has never been critically examined. METHODS: We examined the influence of stroke location on vocational outcome in patients with clinically confirmed acute ischemic stroke from the National Institute of Neurological Disorders and Stroke Stroke Data Bank. RESULTS: Of 143 patients working full time at the time of first ischemic stroke, 23 patients were dead and 120 were alive at 1 year. Employment status was known in 109 (mean age, 55 years; 51 [47%] were white, and 82 [75%] were male). Fifty-eight (53%) had returned to work; most (85%) worked full time. Younger age was positively associated with return to work (P<0.05). In an age-adjusted analysis, stroke severity as measured by the Barthel Index 7 to 10 days after stroke was negatively associated with return to work (P<0.001). Higher household income and absence of cortical neurological dysfunction 7 to 10 days after stroke were positively but less strongly associated with return to work (P<0.08). Stroke location, sex, and depression at time of stroke were not associated with vocational outcome. CONCLUSIONS: Our data suggest that stroke location may be less important than other more easily measured factors in predicting vocational outcome.

Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women.

BACKGROUND: Many previous investigations of cobalamin and folate status were performed in white populations. OBJECTIVE: Our objective was to determine whether there are racial differences in the prevalence of cobalamin and folate deficiency. DESIGN: The study was a cross-sectional comparison of baseline serum cobalamin, folate, methylmalonic acid (MMA), total homocysteine (tHcy), and creatinine concentrations, complete blood count, and vitamin supplementation in 550 white and 212 African American subjects from a cohort of physically disabled older women. RESULTS: The mean (+/-SD) serum MMA concentration was significantly higher in whites than in African Americans: 284 +/- 229 compared with 218 +/- 158 nmol/L (P = 0.0001). tHcy concentration was higher in African Americans than in whites: 12.4 +/- 7.0 compared with 10.9 +/- 4.6 micromol/L (P = 0.001). Serum cobalamin was lower in whites (P = 0.0002). Cobalamin deficiency (serum cobalamin <258 pmol/L and MMA >271 nmol/L) was more frequent in the white women (19% compared with 8%; P < 0.0003). Folate deficiency (serum folate <11.4 nmol/L, tHcy >13.9 micromol/L, and MMA <271 nmol/L) was more prevalent in African Americans than in whites (5% compared with 2%; P = 0.01). Multivitamin use was associated with lower tHcy but not with MMA concentrations. Regression models showed that age >85 y, African American race, serum creatinine >90 micromol/L, and high MMA concentration were all significantly correlated with higher tHcy. Creatinine > 90 micromol/L, white race, and folate concentration were positively associated with MMA concentration. CONCLUSIONS: Cobalamin deficiency with elevated serum MMA concentration is more prevalent in elderly white than in African American women and elevated serum tHcy and folate deficiency are more prevalent in elderly African American than in white women.

Homocyst(e)ine and risk of cerebral infarction in a biracial population : the stroke prevention in young women study.

BACKGROUND AND PURPOSE: Genetic enzyme variation and vitamin intake are important determinants of blood homocyst(e)ine levels. The prevalence of common genetic polymorphisms influencing homocyst(e)ine levels varies by race, and vitamin intake varies by socioeconomic status. Therefore, we examined the effect of vitamin intake, race, and socioeconomic status on the association of homocyst(e)ine with stroke risk. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. One hundred sixty-seven cases of first ischemic stroke among women aged 15 to 44 years were compared with 328 controls identified by random-digit dialing from the same region. Risk factor data were collected by standardized interview and nonfasting phlebotomy. Plasma homocyst(e)ine was measured by high-performance liquid chromatography and electrochemical detection. RESULTS: Blacks and whites did not differ in median homocyst(e)ine levels, nor did race modify the association between homocyst(e)ine and stroke. After adjustment for cigarettes per day, poverty status, and regular vitamin use, a plasma homocyst(e)ine level of >/=7.3 micromol/L was associated with an odds ratio for stroke of 1.6 (95% CI, 1.1 to 2.5). CONCLUSIONS: The association between elevated homocyst(e)ine and stroke was independent not only of traditional vascular risk factors but also of vitamin use and poverty status. The degree of homocyst(e)ine elevation associated with an increased stroke risk in young women is lower than that previously reported for middle-aged men and the elderly and was highly prevalent, being present in one third of the control group.

Oral anticoagulation in patients with atrial fibrillation: adherence with guidelines in an elderly cohort.

PURPOSE: To determine adherence with practice guidelines in a population-based cohort of elderly persons aged 70 years or older with atrial fibrillation. SUBJECTS AND METHODS: This was a cross-sectional analysis of a subgroup of participants in the Cardiovascular Health Study, a prospective observational study involving four communities in the United States. Subjects were participants with atrial fibrillation on electrocardiogram at one or more yearly examinations from 1993 to 1995. The outcome measure was self-reported use of warfarin in 1995. RESULTS: In 1995, 172 (4.1%) participants had atrial fibrillation together with information regarding warfarin use and no preexisting indication for its use. Warfarin was used by 63 (37%) of these participants. Of the 109 participants not reporting warfarin use, 92 (84%) had at least one of the clinical risk factors (aside from age) associated with stroke in patients with atrial fibrillation. Among participants not taking warfarin, 47% were taking aspirin. Several characteristics were independently associated with warfarin use, including age [odds ratio (OR) = 0.6 per 5-year increment, 95% CI 0.5-0.9], a modified mini-mental examination score <85 points [OR = 0.3, 95% confidence interval (CI) 0.1-0.9], and among patients without prior stroke, female sex (OR = 0.5, 95% CI 0.2-1.0). CONCLUSIONS: Despite widely publicized practice guidelines to treat patients who have atrial fibrillation with warfarin, most participants who had atrial fibrillation were at high risk for stroke but were not treated with warfarin. More studies are needed to determine why elderly patients with atrial fibrillation are not being treated with warfarin.