Risk Factors, Stroke Prevention Treatments, and Prevalence of Cerebral Microbleeds in the Framingham Heart Study
Background and Purpose—Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB.
Methods—We include 1965 Framingham Original and Offspring participants (age, 66.5±11.0 years; 54% women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (apolipoprotein E [APOE]) risk factors and medication use to the presence of CMB overall and stratified by brain location (deep, lobar, or mixed).
Results—CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age (P<0.0001) and was higher in men (P<0.001). Hypertension increased risk of any CMB, and in deep and mixed locations (P<0.05), and low total cholesterol and APOE ε4 increased risk of lobar CMB (P<0.05). Statin use increased risk of lobar and mixed location CMB (P<0.05). The latter association was not affected by adjustment for cholesterol levels or concomitant medication use.
Conclusions—We observed the expected association of hypertension with deep CMB and low cholesterol and APOE ε4 with lobar CMB. In addition, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.
Cerebral microbleeds (CMB) are subclinical markers of risk of stroke, dementia, and cognitive impairment.1 The pathophysiology of CMB may vary based on their location, with lobar CMB attributed to cerebral amyloid angiopathy and deep CMB to cerebral hypertensive vasculopathy.1 CMB are markers of intracerebral bleeding risk in patients receiving antiplatelet,2 anticoagulant,3 and lipid-lowering4 therapies and in clinical trials of immunotherapy for early Alzheimer disease.5 Traditional vascular risk factors have been related to CMB, especially in deep locations.6,7 The role of risk factors, such as obesity, increased body mass index, metabolic syndrome, and dyslipidemias, is less clear, but they may increase the risk of CMB directly or indirectly, and the associations may also vary according to CMB location. We related vascular risk factors and secondary stroke prevention treatments to the presence and anatomic location of CMB.
Our study sample comprised Framingham Original and Offspring cohort participants (n=1965) who attended a baseline examination between 1998 and 2008 and underwent a brain MRI between 2000 and 2009 with T2*gradient-echo sequences allowing for detection of CMB. Details of sample selection, exclusion criteria, risk factor and covariate definitions, MRI protocol, and data processing are presented in the online-only Data Supplement. The Institutional Review Board of Boston University Medical Center approved the study protocol, and informed consent was obtained from all subjects.
CMBs were defined using recently published guidelines1 and grouped into 4 categories according to their brain location: any CMB, lobar only, deep only, and deep+mixed (later called mixed). Additional details on CMB reading and inter-rater reliability are presented in the online-only Data Supplement.
We used logistic regression models to relate each risk factor to each outcome. All models were adjusted for age (at MRI), sex, and time interval between risk factor measurement and MRI acquisition. In secondary models, we further adjusted for hypertension stage I or higher (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC-7] definition), antiplatelet use, anticoagulant use, statin use, and prevalent cardiovascular disease (online-only Data Supplement). All analyses were performed using Statistical Analyses System software version 9.2 (SAS Institute, Cary, NC). A 2-sided P value <0.05 was considered statistically significant.
CMBs were observed in 8.8% of participants; 62% had a single CMB and 63% were lobar. Sample characteristics related to the primary analysis are presented in Table 1, and results of the primary analyses for vascular risk factors previously reported to be related to CMB risk and for medication use are presented in Table 2. Complete sample characteristics and primary analyses results are shown in Tables I and III in the online-only Data Supplement, respectively. Increased age was a significant predictor of CMB across all locations (P<0.001). Male sex was related to the presence of any CMB and lobar CMB alone (P<0.001). Hypertension was associated with all and deep CMB (P<0.01); hypertensive participants had a >2-fold higher odds of deep CMB. Low total cholesterol levels <10th percentile were associated with any and lobar CMB (P<0.01). No association was observed with the remaining risk factors evaluated (Results in the online-only Data Supplement).
Statin use was related to all CMB (P<0.01), to lobar (P<0.05), and mixed CMB (P<0.05). Antiplatelet therapy use was related to deep and mixed CMB (both P<0.05). Apolipoprotein E (APOE) ε4 status was significantly related to CMB in lobar location only (P<0.05). After multivariable adjustments, hypertension stage 1 or higher, hypertension treatment, statin use, total cholesterol <10th percentile, and APOE status remained associated with CMB presence (online-only Data Supplement).
We confirmed that older age, male sex, low total cholesterol level, APOE status, and statin use were each associated with higher odds of CMB presence, with differential patterns of associations observed depending on the location of the CMB. None of the other risk factors studied were related to risk of CMB, suggesting that vascular risk factors besides hypertension and very low lipid levels may not play a major role in hemorrhage-prone cerebral small vessel disease. Although the association of serum cholesterol to risk of clinical intracerebral hemorrhage is controversial,8,9 our findings, suggest that very low total cholesterol levels are related to risk of CMB, which concurs with a previous report from the Rotterdam study.6 We observed an association of antiplatelet therapy with deep and mixed CMB. Previous population-based studies have related antiplatelet therapy to CMB in any location, with slightly stronger associations for lobar CMB.10 In contrast to our previous report,7 we now use a larger sample and found that APOE ε4 was associated with strictly lobar CMB,11 supporting the hypothesis that cerebral amyloid angiopathy is the predominant vascular pathology underlying lobar CMBs.1 We observed a novel association of statin use with CMB presence, even after adjusting for potential confounders and without significant interactions with antithrombotic medication use, lipid levels, or inflammatory markers (online-only Data Supplement). Only 1 previous study, restricted to patients with intracerebral hemorrhage, has reported an increased risk of deep CMB with statin use although some have related statin use with increased risk of clinical intracerebral hemorrhage.4,12 Statins may increase the risk of CMB by mechanisms other than lipid lowering, such as selective inhibition of platelet-G–coupled α-thrombin protease-associated receptor-1, a cell bound receptor that links platelet activation and thrombin formation.13 In our study, we cannot exclude bias by indication. Our cross-sectional design limits our ability to examine whether the observed associations are causal.
We report, for the first time in a community-based study, an association of statin use with the risk of CMB that does not seem to be explained by the concomitant use of other medications or by very low cholesterol levels. However, our study is hypothesis generating, needs confirmation, and certainly does not negate the benefits of statin use in prevention of ischemic cardiovascular events.
Sources of Funding
This work (design and conduct of the study, collection, and management of the data) was supported by the Framingham Heart Study’s National Heart, Lung, and Blood Institute contract (N01-HC-25195) and by grants from the National Institute of Neurological Disorders and Stroke (R01 NS17950), the National Institute on Aging (R01 AG16495; AG08122; AG033193; AG031287; and K23AG038444) and National Institutes of Health grant (1RO1 HL64753; R01 HL076784; and 1 R01 AG028321).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.004130/-/DC1.
- Received January 8, 2014.
- Revision received March 10, 2014.
- Accepted March 10, 2014.
- © 2014 American Heart Association, Inc.
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