Brief Report
Population-Based Study of Cerebral Microbleeds
in Stroke-Free Older Adults Living in Rural Ecuador
The Atahualpa Project
Victor J. Del Brutto, MD; Mauricio Zambrano, BS; Robertino M. Mera, MD, PhD;
Oscar H. Del Brutto, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose—Prevalence of cerebral microbleeds (CMB) in white and Asian populations range from 4%
to 15%. However, there is no information from indigenous Latin American people. We aimed to assess prevalence and
cerebrovascular correlates of CMB in stroke-free older adults living in rural Ecuador.
Methods—Of 311 Atahualpa residents aged ≥60 years identified during a door-to-door survey, 258 (83%) underwent brain
magnetic resonance imaging. Twenty-one were further excluded for a diagnosis of overt stroke. Using multivariate
logistic regression models, adjusted for demographics and cardiovascular risk factors, we evaluated whether CMB were
independently associated with silent strokes, white matter hyperintensities, and global cortical atrophy.
Results—Twenty-six (11%) of 237 participants had CMB, which were single in 54% of cases. CMB were deep in 11
patients, cortical in 9, and located both deep and cortical in 6. In univariate analyses, CMB were associated with age,
systolic blood pressure, moderate-to-severe white matter hyperintensities, silent lacunar infarcts, and cortical atrophy.
Mean (±SD) values for systolic blood pressure were 155±27 mm Hg in patients who had CMB versus 142±26 mm Hg in
those who did not (P=0.017). In the adjusted models, moderate-to-severe white matter hyperintensities (P=0.009), silent
lacunar infarcts (P=0.003), and global cortical atrophy (P=0.04) were independently associated with CMB.
Conclusions—Prevalence of CMB in stroke-free older adults living in Atahualpa is comparable with those
reported from other ethnic groups. There is a strong relationship between CMB and increased age, high systolic
(Stroke. 2015;46:00-00.
blood pressure, silent markers of cerebral small vessel disease, and cortical atrophy. DOI: 10.1161/STROKEAHA.115.009594.)
Key Words: cerebral small vessel disease ◼ Ecuador ◼ ethnic groups ◼ microbleed
C
erebral microbleeds (CMB) represent foci of hemosiderinladen macrophages resulting from extravasation of blood
components that have been related to fibrohyalinosis of small
penetrating vessels, amyloid angiopathy, and other vasculopathies.1 CMB are associated with imaging markers of cerebral
small vessel disease and with cognitive decline, stroke recurrence, and vascular mortality.2 Therefore, recognition of CMB
is important for the prompt implementation of preventive strategies. The prevalence of CMB in apparently healthy community
dwellers range from 4% to 15% and is markedly influenced by
age.3–6 These studies have been conducted in white and Asian
populations, but there is no information from indigenous inhabitants of Latin America. We aimed to assess prevalence and correlates of CMB in stroke-free older adults living in rural Ecuador.
village was selected because it is representative of the region. More
than 95% of the population belong to the Native/Mestizo ethnic
group, and their living characteristics are homogeneous, as detailed
elsewhere.7 The neuroimaging substudy enrolled all Atahualpa
residents aged ≥60 years with no contraindications for magnetic
resonance imaging (MRI) who signed the informed consent.8
The Institutional Review Board of Hospital-Clínica Kennedy,
Guayaquil (FWA 00006867), approved the study.
MRIs were performed with a Philips Intera 1.5T machine (Philips
Medical Systems, Best, the Netherlands) at Hospital-Clínica Kennedy,
Guayaquil, after a well-defined protocol detailed elsewhere.8 In brief,
MRI included 2-dimensional multislice turbo spin echo T1-weighted,
fluid attenuated inversion recovery, T2-weighted, and gradient-echo
sequences in the axial plane, as well as a T1-weighted sequence oriented in the sagittal plane. We used the pre-established brain imaging
package delivered by the manufacturer to homogenize applicability
by technicians; slice thickness was 5 mm with 1-mm gap between
slices.
Two readers, blinded to clinical data, independently reviewed
all neuroimaging studies after the standards for research into small
vessel disease proposed by Wardlaw et al.9 In particular, CMB were
identified and rated according to the Microbleed Anatomical Rating
Methods
The Atahualpa Project is a population-based cohort study designed
to reduce the increasing burden of stroke in rural Ecuador. The
Received March 27, 2015; final revision received April 30, 2015; accepted May 5, 2015.
From the Internal Medicine Department, Louis A. Weiss Memorial Hospital, Chicago, IL (V.J.D.B.); Community Center, The Atahualpa Project,
Atahualpa, Ecuador (M.Z.); Gastroenterology Department, University of Vanderbilt, Nashville, TN (R.M.M.); and School of Medicine, Universidad
Espíritu Santo—Ecuador, Guayaquil, Ecuador (O.H.D.B.).
Correspondence to Oscar H. Del Brutto, MD, Air Center 3542, PO Box 522970, Miami, FL 33152. E-mail: [email protected]
© 2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.115.009594
1
2 Stroke July 2015
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Scale,10 white matter hyperintensities (WMH) of presumed vascular
origin were defined as lesions appearing hyperintense on T2-weighted
images that remained bright on fluid attenuated inversion recovery
(without cavitation) and graded according to the modified Fazekas
scale,11 and lacunar infarcts were defined as fluid-filled cavities measuring 3 to 15 mm located in the territory of a perforating arteriole.9
Global cortical atrophy was rated according to Pasquier et al.12
Cardiovascular risk factors—smoking status, physical activity,
body mass index, blood pressure, fasting glucose, and total cholesterol levels—were assessed through interviews and procedures previously described in the Atahualpa Project.7 To recognize—and further
exclude—patients with overt strokes, rural doctors screened all patients with the use of a validated field instrument, and then, certified
neurologists confirmed the diagnosis.
Data analyses are performed using STATA version 13 (College
Station, TX). In the univariate analysis, continuous variables
were compared by linear models and categorical variables by χ2
or Fisher exact test as appropriate. Using multivariate logistic regression models, we evaluated whether CMB were associated with
demographics, cardiovascular risk factors, WMH, silent lacunar infarctions, and global cortical atrophy, after adjusting for the other
variables.
Results
MRIs were performed in 258 (83%) of 311 Atahualpa residents aged ≥60 years identified during a door-to-door survey.
Reasons for not obtaining MRI included refusal to participate
(n=26), severe disability (n=11), claustrophobia (n=8), and
implanted pacemaker (n=1); 7 additional patients had died
or emigrated between the survey and the invitation. Twentyone of the 258 participants were further excluded because of
a diagnosis of overt stroke. Mean age of the 237 individuals
enrolled in this study was 70±8 years, and 140 (59%) were
women. Twenty-six (11%) individuals had CMB, which were
single in 54% of cases; CMB were deep in 11 cases, cortical
in 9, and located both deep and cortical in 6. Moderate-tosevere WMH were noticed in 52 (22%) patients, silent lacunar
infarcts in 28 (12%), and moderate-to-severe global cortical
atrophy in 120 (51%).
Kappa coefficients for inter-rater agreements of MRI
lesions of interest were 0.90 for WMH, 0.76 for deep and
0.53 for cortical CMB, 0.90 for lacunar infarcts, and 0.82 for
cortical atrophy. The modest agreement rate for cortical CMB
was related to the endemicity of calcified neurocysticercosis
in the village because both lesions may appear identical on
MRI. As previously described by our group, inter-rater discrepancies were resolved by consensus and by reviewing CT
findings13 and, for the present study, we only included lesions
that were definitive cortical CMB.
Table 1 summarizes clinical and imaging characteristics
of participants and across the categories of CMB. In univariate analyses, CMB were associated with age, systolic blood
pressure, moderate-to-severe WMH, silent lacunar infarcts,
and cortical atrophy. In multivariate adjusted models, moderate-to-severe WMH, silent lacunar infarcts, and global
cortical atrophy were independently associated with CMB
(Table 2).
Discussion
Prevalence of MB in stroke-free older adults living in
Atahualpa (11%) is within the range of that reported from
industrialized nations. Our results provide robust evidence
for an association between CMB and age, high systolic
blood pressure, silent markers of cerebral small vessel disease, and cortical atrophy. Population-based studies conducted in developed countries have presented conflicting
results about the association of CMB with cardiovascular risk factors or with markers of small vessel disease in
individuals without history of cerebrovascular disease.3–6
To our knowledge, no population-based study from Latin
America has addressed the prevalence and cerebrovascular correlates of CMB in patients not consulting for a
vascular disorder. A potential limitation of the present
study is the small sample size, which is counterbalanced
by its population-based design and the unbiased selection
of participants. Additional studies in other regional communities or in Latin American immigrants to the United
States (Hispanics) are needed to confirm our findings, and
longitudinal studies would be of value to address the consequences of CMB in this ethnic group.
Table 1. Characteristics of Stroke-Free Atahualpa Residents Aged ≥60 Years According to the Presence
of Cerebral Microbleeds
Total Series (n=237)
Microbleeds (n=26)
No Microbleeds (n=211)
P Value
70±8
75±9
69±8
0.0001
140 (59)
14 (54)
126 (60)
0.718
2 (1)
…
…
…
Poor physical activity, n (%)
16 (7)
4 (15)
12 (6)
0.082
BMI, kg/m2 (mean±SD)
27±5
26±5
27±5
0.337
Systolic BP, mm Hg, mean±SD
143±26
155±27
142±26
0.017
Diastolic BP, mm Hg, mean±SD
72±11
74±10
72±11
0.378
Fasting glucose, mg/dL, mean±SD
102±40
110±49
101±39
0.282
Total cholesterol, mg/dL, mean±SD
212±40
214±40
212±40
0.810
Moderate-to-severe cortical atrophy, n (%)
Age, y, mean±SD
Women, n (%)
Current smokers, n (%)
120 (51)
19 (73)
101 (48)
0.027
Moderate-to-severe WMH, n (%)
52 (22)
14 (54)
38 (18)
0.0001
Silent lacunar infarcts, n (%)
28 (12)
10 (38)
18 (9)
0.0001
BMI indicates body mass index; BP, blood pressure; and WMH, white matter hyperintensities.
Del Brutto et al Cerebral Microbleeds in Rural Ecuador 3
Table 2. Association of Cerebral Microbleeds With Moderateto-Severe White Matter Hyperintensities of Presumed Vascular
Origin, Silent Lacunar Infarctions, and Moderate-to-Severe
Global Cortical Atrophy in Multivariate Logistic Regression
Models Adjusted for Demographics and Cardiovascular Risk
Factors
Silent lacunar infarction
Odds Ratio
95% CI
P Value
11.82
2.3–60.3
0.003
White matter hyperintensities
5.67
1.6–20.7
0.009
Silent lacunar infarction+white
matter hyperintensities
11.35
2.51–51.5
0.002
2.61
1.04–6.57
0.042
Global cortical atrophy
CI indicates confidence interval.
Sources of Funding
This study was partially supported by Universidad Espíritu Santo—
Ecuador, Guayaquil, Ecuador.
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Disclosures
Dr Mera has stock interests in GlaxoSmithKline. The other authors
report no conflicts.
References
1.Shoamanesh A, Kwok CS, Benavente O. Cerebral microbleeds:
histopathological correlation of neuroimaging. Cerebrovasc Dis.
2011;32:528–534. doi: 10.1159/000331466.
2.Yates PA, Villemagne VL, Ellis KA, Desmond PM, Masters CL,
Rowe CC. Cerebral microbleeds: a review of clinical, genetic, and
neuroimaging associations. Front Neurol. 2014;4:205. doi: 10.3389/
fneur.2013.00205.
3. Jeerakathil T, Wolf PA, Beiser A, Hald JK, Au R, Kase CS, et al. Cerebral
microbleeds: prevalence and associations with cardiovascular risk factors
in the Framingham Study. Stroke. 2004;35:1831–1835. doi: 10.1161/01.
STR.0000131809.35202.1b.
4.Sveinbjornsdottir S, Sigurdsson S, Aspelund T, Kjartansson O,
Eiriksdottir G, Valtysdottir B, et al. Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J
Neurol Neurosurg Psychiatry. 2008;79:1002–1006. doi: 10.1136/
jnnp.2007.121913.
5. Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der
Lugt A, et al. Prevalence and risk factors of cerebral microbleeds: an
update of the Rotterdam scan study. Stroke. 2010;41(10 suppl):S103–
S106. doi: 10.1161/STROKEAHA.110.595181.
6. Mok V, Srikanth V, Xiong Y, Phan TG, Moran C, Chu S, et al. Raceethnicity and cerebral small vessel disease–comparison between Chinese
and White populations. Int J Stroke. 2014;9(Suppl A100):36–42. doi:
10.1111/ijs.12270.
7. Del Brutto OH, Peñaherrera E, Ochoa E, Santamaría M, Zambrano M,
Del Brutto VJ; Atahualpa Project Investigators. Door-to-door survey of
cardiovascular health, stroke, and ischemic heart disease in rural coastal
Ecuador–the Atahualpa Project: methodology and operational definitions. Int J Stroke. 2014;9:367–371. doi: 10.1111/ijs.12030.
8. Del Brutto OH, Mera RM, Del Brutto VJ, Zambrano M, Lama J. White
matter hyperintensities of presumed vascular origin: a populationbased study in rural Ecuador (The Atahualpa Project). Int J Stroke.
2015;10:372–375. doi: 10.1111/ijs.12417.
9. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne
R, et al; STandards for ReportIng Vascular changes on nEuroimaging
(STRIVE v1). Neuroimaging standards for research into small vessel
disease and its contribution to ageing and neurodegeneration. Lancet
Neurol. 2013;12:822–838. doi: 10.1016/S1474-4422(13)70124-8.
10. Gregoire SM, Chaudhary UJ, Brown MM, Yousry TA, Kallis C, Jäger
HR, et al. The Microbleed Anatomical Rating Scale (MARS): reliability
of a tool to map brain microbleeds. Neurology. 2009;73:1759–1766. doi:
10.1212/WNL.0b013e3181c34a7d.
11. Pantoni L, Basile AM, Pracucci G, Asplund K, Bogousslavsky J, Chabriat
H, et al. Impact of age-related cerebral white matter changes on the transition to disability – the LADIS study: rationale, design and methodology. Neuroepidemiology. 2005;24:51–62. doi: 10.1159/000081050.
12. Pasquier F, Leys D, Weerts JG, Mounier-Vehier F, Barkhof F, Scheltens
P. Inter- and intraobserver reproducibility of cerebral atrophy assessment
on MRI scans with hemispheric infarcts. Eur Neurol. 1996;36:268–272.
13. Del Brutto OH, Lama J, Zambrano M, Del Brutto VJ. Neurocysticercosis
is a neglected microbleed mimic. a cautionary note for stroke neurologists. Eur Neurol. 2014;72:306–308. doi: 10.1159/000365847.
Population-Based Study of Cerebral Microbleeds in Stroke-Free Older Adults Living in
Rural Ecuador: The Atahualpa Project
Victor J. Del Brutto, Mauricio Zambrano, Robertino M. Mera and Oscar H. Del Brutto
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Stroke. published online May 28, 2015;
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2015 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/early/2015/05/28/STROKEAHA.115.009594
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Stroke is online at:
http://stroke.ahajournals.org//subscriptions/