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January 31, 2012; 78 (5) Articles

Cerebral microbleeds are associated with worse cognitive function

The Rotterdam Scan Study

M.M.F. Poels, M.A. Ikram, A. van der Lugt, A. Hofman, W.J. Niessen, G.P. Krestin, M.M.B. Breteler, M.W. Vernooij
First published January 18, 2012, DOI: https://doi.org/10.1212/WNL.0b013e3182452928
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Abstract

Objective: Cerebral microbleeds are frequently found in the general elderly population and may reflect underlying vascular disease, but their role in cognitive function is unknown.

Methods: We investigated the association between cerebral microbleeds and performance in multiple cognitive domains in 3,979 persons without dementia (mean age, 60.3 years). Mini-Mental State Examination (MMSE) score and neuropsychological tests were used to assess global cognition and the following cognitive domains: memory, information processing speed, executive function, and motor speed. We used number of microbleeds as continuous variable, and additionally distinguished between persons with no microbleeds, 1 microbleed, 2–4 microbleeds, and ≥5 microbleeds. The association of microbleeds with different cognitive domains was estimated using linear regression models. Additional adjustments were made for vascular risk factors, brain atrophy, and other imaging markers of cerebral small vessel disease. We stratified analyses by location of microbleeds.

Results: A higher number of microbleeds was associated with lower MMSE score and worse performance on tests of information processing speed and motor speed. When analyzed per category, presence of 5 or more microbleeds was associated with worse performance in all cognitive domains, except memory. These associations were most robust in participants with strictly lobar microbleeds, whereas after additional adjustments associations disappeared for deep or infratentorial microbleeds.

Conclusions: Presence of numerous microbleeds, especially in a strictly lobar location, is associated with worse performance on tests measuring cognitive function, even after adjustments for vascular risk factors and other imaging markers of small vessel disease. These results suggest an independent role for microbleed-associated vasculopathy in cognitive impairment.

GLOSSARY

15-WLT=
15-Word Verbal Learning Test;
CAA=
cerebral amyloid angiopathy;
CMB=
cerebral microbleed;
FLAIR=
fluid-attenuated inversion recovery;
GRE=
gradient-recalled echo;
LDST=
Letter-Digit Substitution Task;
MMSE=
Mini-Mental State Examination

Vascular pathology plays a prominent role in cognitive decline and dementia.1,2 Lacunar infarcts and white matter lesions, both markers of cerebral small vessel disease, are important contributors to this relation.3 In recent years, cerebral microbleeds (CMBs), detected by susceptible MRI sequences, have been recognized as an additional marker of cerebral small vessel disease. CMBs are reported to be highly prevalent in memory clinic patients and patients with AD.4,5 Moreover, we have previously shown that microbleeds are very common in the general elderly population.6

Different hypotheses exist about how CMBs may influence cognitive function. Microbleeds may reflect focal damage of brain tissue and when located in strategic areas could interfere with cognitive processes.7 Conversely, CMBs could also be a more general marker for underlying vascular disease, in particular cerebral amyloid angiopathy (CAA) or hypertensive arteriolosclerosis,6,8 and as such may influence cognition.7

The majority of clinical studies did not demonstrate an association between the presence of microbleeds and cognitive function, but all were based on small sample sizes.4,5,9,–,11 Studies investigating this relation in community-dwelling elderly are scarce.12,–,14 Moreover, most studies did not distinguish between different cognitive domains, and did not differentiate between different underlying vascular pathologies.

In a large sample of persons without dementia from the general population, we examined how the presence and location of microbleeds related to various domains of cognitive function. In addition, we investigated whether these associations were independent of vascular risk factors, brain atrophy, and markers of cerebral small vessel disease.

METHODS

Participants.

The study is based on the Rotterdam Scan Study, an ongoing population-based cohort study investigating age-related brain changes on MRI.15 At the time of the present study, we had invited a total of 4,898 participants.8 We excluded individuals who had dementia (n = 30) or had MRI contraindications (n = 389). Of 4,479 eligible persons, 4,082 (91%) participated. Due to physical inability, imaging could not be performed in 44 individuals. Of 4,038 persons with complete MRI examinations, 59 had to be excluded because of motion artifacts or susceptibility artifacts on their scans, leaving 3,979 persons to be analyzed.

Standard protocol approvals, registrations, and patient consents.

The institutional review board approved the study, and written informed consent was obtained from all participants.

Brain MRI.

We performed a multisequence MRI protocol on a 1.5-T scanner (GE Healthcare, Milwaukee, WI). A custom-made accelerated 3D T2*-weighted gradient-recalled echo (GRE) sequence with high spatial resolution and long echo time was used for microbleed detection.16 The other sequences in the imaging protocol consisted of 3 high-resolution axial scans, i.e., a T1-weighted sequence, a proton density–weighted sequence, and a fluid-attenuated inversion recovery (FLAIR) sequence.6

Analyses of brain MRI.

All 3D T2* GRE scans were reviewed by 1 of 5 trained raters who recorded the presence, number, and location of microbleeds.6 All raters were blinded to the clinical data and APOE genotyping. Microbleeds were defined as focal areas of very low signal intensity. Signal voids caused by sulcal vessels, symmetric calcifications in the basal ganglia, choroid plexus, and pineal calcifications, and signal averaging from bone were excluded.17 Intraobserver (n = 500; 1 rater) and interobserver (n = 300) kappa coefficients were κ = 0.87 and κ = 0.85, which corresponds to very good agreement. CMBs were categorized into 1 of 3 locations: lobar, deep, and infratentorial.6

Lacunar and cortical infarcts were rated on FLAIR, proton density–weighted, and T1-weighted sequences by the same raters who had scored cerebral microbleeds according to criteria described previously.6 Tissue classification into CSF, gray matter, normal white matter, and white matter lesions was done with a validated fully automated tissue classification technique.18 Brain tissue volumes were calculated by summing all voxels of a certain tissue across the whole brain. Brain atrophy was defined as total brain tissue volume expressed as percentage of intracranial volume.

Cognitive function.

Cognitive testing was performed at the preceding regular visit of study participants to the research center. Mean interval between cognitive testing and brain MRI was 4.0 ± 5.7 months (SD). The neuropsychological test battery included the Mini-Mental State Examination (MMSE),19 a 15-Word Verbal Learning Test (15-WLT) based on Rey's recall of words,20 the Stroop test,21 the Letter-Digit Substitution Task (LDST),22 the Purdue Pegboard test,23 and a Word Fluency test.24 We generated Z scores (individual test score minus mean test score divided by the SD) for each cognitive test, except for MMSE. To obtain more robust measures, we constructed compound scores for information processing speed, executive function, memory, global cognitive function, and motor speed.25 The Z scores for the Stroop tasks were inverted for use in these compound scores, as higher scores on the Stroop task indicate a worse performance while higher scores on all other tests indicate a better cognitive function. The compound score for memory was the average of the Z scores for the immediate and delayed recall of the 15-WLT. Executive function was constructed by averaging the Z scores for the Stroop interference subtask, the LDST, and the Word Fluency Test. Information processing speed was the average of the Z scores for the Stroop reading and Stroop color naming test and the LDST. For global cognitive function we used the average of the Z scores of the Stroop task (average of all 3 subtasks), the LDST, the Word Fluency test, and the immediate and delayed recall of the 15-WLT. Motor speed was defined by the Z score for the Purdue Pegboard test (both hands).

Assessment of covariates.

During the initial interview at study entry, the attained level of education was assessed according to the standard classification of education.26 In our analysis, we used 7 levels of education: 1) primary education; 2) low-level vocational training; 3) medium-level secondary education; 4) medium-level vocational education; 5) general secondary education; 6) higher-level vocational education; and 7) university-level education.

Cardiovascular risk factors were examined by interview and laboratory and physical examination as previously described.6 Risk factors included in our analyses were systolic and diastolic blood pressure, smoking, diabetes, and serum total cholesterol. The use of lipid-lowering drugs and blood pressure–lowering medication was assessed by interview and house visits during which medication use was registered.

APOE genotyping was performed on coded genomic DNA samples27 and was available for 3,689 participants (93%). The distributions of APOE genotype and allele frequencies in this population were in Hardy-Weinberg equilibrium.

Data analysis.

As number of microbleeds may be a marker of the severity of the underlying disease, we investigated the association of number of microbleeds continuously per SD increase with cognitive function. Furthermore, as microbleeds numbers were highly skewed to the left, we additionally categorized the numbers of microbleeds as follows: no microbleeds, 1 microbleed, 2–4 microbleeds, and ≥5 microbleeds per person.28,29

The association between microbleeds and cognitive function was assessed using linear regression models, with microbleeds as independent and cognitive compound scores as dependent variable. All analyses were adjusted for age, sex, and level of education. Additional adjustments were made for vascular risk factors (i.e., systolic blood pressure, diastolic blood pressure, use of blood pressure–lowering medication, smoking, diabetes, serum total cholesterol, and use of lipid-lowering drugs). To elucidate whether the association of CMBs with cognitive performance is independent of brain atrophy and other imaging markers of small vessel disease, further analyses were also adjusted for brain atrophy, white matter lesion volume, and presence of lacunar infarcts. White matter lesion volume was natural log transformed because of skewness of the untransformed measure.

Analyses were also performed by strata defined by microbleed location (i.e., strictly lobar microbleeds vs deep or infratentorial microbleeds [with or without additional lobar microbleeds]).6 Additionally, we performed analysis stratified according to APOE genotype to investigate whether the association between CMBs and cognition differed between APOE ε4 carriers and noncarriers.

Finally, we repeated all analyses after exclusion of participants with cortical infarcts on MRI.

All analyses were performed using the statistical package SPSS 17.0 for Windows.

RESULTS

Table 1 shows the characteristics of all participants. Mean age was 60.3 years, and 2,164 (54.4%) were women. A total of 609 of 3,979 (15.3%) had 1 or more microbleeds on MRI; 395 (64.9%) persons had 1 CMB, 143 (23.5%) had 2–4 CMBs, and 71 (11.7%) had 5 or more CMBs. Of those with microbleeds, 413 (67.8%) had CMBs in a strictly lobar location. Mean MMSE score was 28.0 ± 1.8.

View this table:
Table 1

Characteristics of the study population (n = 3,979)a

Table 2 shows results for the association between microbleeds and performance on cognitive tests. Per SD increase, a higher microbleed number was significantly associated with lower MMSE score and worse performance on tests of information processing speed and motor speed. When analyzed per category, presence of numerous (≥5) CMBs was significantly associated with lower MMSE score and with worse performance on tests of information processing speed, executive function, global cognition and motor speed, but not with memory performance (model 1 in table 2). Additional adjustment for vascular risk factors did not change these results (model 2 in table 2). Statistical significance remained for the association between (numerous) microbleeds and worse performance on information processing speed and motor speed upon correcting for brain atrophy, white matter lesion volume, and lacunar infarcts (model 3 in table 2).

View this table:
Table 2

Association of categories of microbleeds with cognitive function, using linear regression modelsa

When participants were subdivided into those with strictly lobar CMBs and those with deep or infratentorial CMBs, we found strong associations between strictly lobar microbleeds and information processing speed, and additionally for MMSE score and motor speed when numerous microbleeds were present (model 1 in table 3). When additionally adjusting for vascular risk factors, brain atrophy, and other imaging markers of small vessel disease, the associations attenuated marginally, but number of strictly lobar CMBs per SD increase was still related to information processing speed, whereas presence of 5 or more lobar CMBs remained associated with information processing speed as well as motor speed (model 3 in table 3). In persons with deep or infratentorial microbleeds (with or without additional lobar microbleeds), a higher number of microbleeds was associated with lower MMSE score and worse performance on tests of motor speed, whereas presence of 5 or more microbleeds was related to worse information processing speed, executive function, global cognition, and motor speed, even after adjusting for vascular risk factors (model 1 and 2 in table 4). However, these associations disappeared after additional adjustments for brain atrophy and other imaging markers of small vessel disease; only the association between number of microbleeds per SD increase and motor speed remained significant (model 3 in table 4).

View this table:
Table 3

Association of categories of strictly lobar microbleeds with cognitive function, using linear regression modelsa

View this table:
Table 4

Association of categories of deep or infratentorial microbleeds with cognitive function, using linear regression modelsa

After stratifying the study population for the presence of an APOE ε4 allele, we found that presence of 5 or more microbleeds was associated with MMSE score, information processing speed, executive function, and global cognitive function in APOE ε4 noncarriers, but we found no associations between microbleeds and cognitive function in APOE ε4 carriers (see table e-1 on the Neurology® Web site at www.neurology.org).

Repeating all analyses after excluding persons with a cortical infarct on MRI did not change any of the associations (data not shown).

DISCUSSION

Our finding that microbleed number is associated with worse performance on all domains of cognitive tests except memory suggests that microbleeds reflect vascular pathology that, in addition to and independent of other imaging markers of small vessel disease, contributes to cognitive impairment mainly by affecting nonmemory-related cognitive function.

Strengths of our study are its population-based setting, the large sample size, and use of our custom-made accelerated 3D T2* GRE sequence with proven high sensitivity for microbleed detection.16 We assessed a broad range of cognitive domains and made a distinction between different locations of microbleeds in the brain. In addition, we were able to investigate the role of microbleeds independent of vascular risk factors, brain atrophy, and other imaging markers of small vessel disease. This is especially important as previous published results showed that white matter lesions and lacunar infarcts affect cognitive function.3

A potential limitation is the cross-sectional study design, which restricts our interpretation of cause and consequence, although it is biologically less plausible that cognitive deterioration leads to cerebral microbleeds instead of vice versa.

There are few previous studies that assessed the relation between microbleeds and cognition in the general elderly population,12,–,14 and most of them only used MMSE as a marker of global cognition and did not investigate other cognitive domains.12,13 Recently, the population-based AGES-Reykjavik study reported on the association between microvascular damage and the association with multiple cognitive domains and dementia.14 Our findings are largely in line with theirs, as they also found an association between multiple CMBs and cognitive dysfunction, in particular slower processing speed and poorer executive function. This study, however, also included individuals with dementia, which makes it difficult to evaluate the role of CMBs on cognitive deterioration in individuals without dementia.14

In a clinical setting, several studies examined in selected groups of patients the relation between microbleeds and cognitive dysfunction. Studies among memory clinic patients and patients with AD, however, yielded conflicting results, and most studies again only used the MMSE score.4,5,9,–,11 In a small neurovascular clinic population, multiple cognitive domains were investigated and a marked difference in the prevalence of executive dysfunction between patients with and without CMBs was found.30 This is in line with our study, though we additionally found associations with other cognitive domains.

We previously found that carriers of the APOE ε4 allele had cerebral microbleeds more often compared to noncarriers.8 Moreover, literature describes poorer performance on neuropsychological tests in individuals without dementia with 1 or 2 APOE ε4 alleles compared to APOE ɛ4 noncarriers.31 In the present study we found, however, associations between 5 or more microbleeds and several cognitive domains in APOE ε4 noncarriers, but a lack of associations in APOE ε4 carriers. Further elucidation is needed for these seemingly paradoxical findings.

The finding of a significant association between a single deep or infratentorial microbleed and better motor speed is seemingly counterintuitive and may be a chance finding in the view of multiple tests that we performed. Analyzed as a continuous variable, number of microbleeds was significantly associated with worse performance on tests of motor speed, underscoring this notion.

The observation that strictly lobar microbleeds and deep or infratentorial microbleeds are related to cognition in a different way may be explained in various ways. On the one hand, microbleeds could be a general marker for (the severity of) underlying vascular disease, in particular CAA or hypertensive arteriolosclerosis, and as such may influence cognition. We found that associations between deep or infratentorial microbleeds and cognition were not only weaker than those for strictly lobar microbleeds, but these were also not independent of brain atrophy and other markers of small vessel disease, while associations for lobar microbleeds and cognition were very robust. This is in line with our previous findings that the location of microbleeds in the brain likely reflects differences in underlying etiology.8 Thus, deep or infratentorial microbleeds are probably associated with cognition through related hypertensive vasculopathy. In contrast, strictly lobar microbleeds are thought to be a marker of pathologies associated with CAA, such as vascular deposition of β-amyloid or neuritic plaques, that in themselves impair cognition.32,33 Along this line of thinking, it could be postulated that microbleeds in various locations differentially relate to specific cognitive domains due to different underlying pathology. Yet which cognitive domains are specifically involved in CAA and hypertensive arteriolosclerosis is, to our knowledge, largely unknown.

An alternative hypothesis relating microbleed location to cognition is that microbleeds reflect focal damage of brain tissue and when located in strategic areas could interfere with cognitive processes, by causing disconnections in functional pathways. For example, there may be more direct or indirect effects of strictly lobar microbleeds to surrounding brain tissue compared to deep or infratentorial microbleeds as the location of these lesions may lead to more disconnection of functionally important cortical and subcortical structures.7,34 Along this line of thinking, it has been suggested that disruption of frontal-basal ganglia connections may provide a plausible mechanism by which microbleeds in frontal and basal ganglia regions cause executive dysfunction.30 In this respect, microbleed location may be of less importance in tasks of speed and attention as these are thought to reflect more widely distributed cognitive skills.30 To further explore this hypothesis, more information on the exact location of microbleeds would be needed, such as in which lobe they occur or even more detailed using voxel-based analysis. Though we (visually) rated microbleed location as being lobar, deep, or infratentorial, we as yet have no further information on their exact location. Advances in automated microbleed detection using computer algorithms will enable the examination of specific regional microbleed distributions in the brain with different cognitive domains in the near future.35

Contrary to our findings, in the AGES-Reykjavik study associations between microbleeds and cognition were found to be strongest for microbleeds located in the deep hemispheric or infratentorial regions.14 Though difficult to explain, it may be that a higher mean age and subsequent more cardiovascular risk factors, brain infarcts, and a higher load of subcortical and periventricular white matter hyperintensities in their study compared to our study has influenced this. Although both their study and our study adjusted for these factors, there may be residual variation in underlying pathology causing these differences between the study samples.

We especially found numerous strictly lobar microbleeds to be related to worse cognitive function. Studies in patients with AD found a mainly lobar distribution of microbleeds that corresponds with the distribution described in sporadic CAA cases.10,36 Therefore, it is suggested that CMBs in patients with AD are more likely to be related to CAA rather than due to hypertensive vasculopathy.7 Both the Honolulu-Asia Aging Study and the MRC Cognitive Function and Ageing Study found associations of CAA with cognition even after controlling for age and AD pathology.37,38 More recently, the Religious Orders Study found moderate to very severe CAA, but not mild to moderate CAA, to be associated with lower performance in specific cognitive domains, most notably perceptual speed.39 Our results thus corroborate the suggestion that high numbers of strictly lobar microbleeds may be one of the manifestations of CAA in a certain stage. Furthermore, microbleeds were recently postulated as the potential “missing link” in the interaction between CAA and hypertensive arteriolosclerosis in the pathogenesis of AD.40 The robust associations we assessed between numerous strictly lobar microbleeds and cognitive function further support this notion.

AUTHOR CONTRIBUTIONS

Dr. Poels: drafting the manuscript for content, analysis or interpretation of data, acquisition of data, statistical analysis. Dr. Ikram: revising the manuscript for content, acquisition of data. Dr. van der Lugt: revising the manuscript for content. Dr. Hofman: revising the manuscript for content, study concept or design, obtaining funding. Dr. Niessen: revising the manuscript for content. Dr. Krestin: revising the manuscript for content, obtaining funding. Dr. Breteler: revising the manuscript for content, study concept or design, obtaining funding. Dr. Vernooij: revising the manuscript for content, analysis or interpretation of data, acquisition of data, study supervision or coordination. Dr. Poels and Dr. Vernooij had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the statistical data analysis.

Study Funding

The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam, the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), the Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Dr. Meike W. Vernooij was supported by a grant from the Alzheimer's Association (NIRG-09-13168). This study was also supported by the Netherlands Organization for Scientific Research (NWO) grants 948-00-010 and 918-46-615 and an Erasmus MC grant for translational research. The funding sources had no role in the design or conduct of the study, data collection, data analysis, data interpretation, or in writing or approval of this report.

DISCLOSURE

Dr. Poels reports no disclosures. Dr. Ikram has received research support from the Nederlandse Hartstichting and the Internationaal Parkinson Fonds and serves on the editorial board for Neuroepidemiology. Dr. Van der Lugt receives research support from Bayer Schering Pharma, the Dutch Heart Foundation, and the Alzheimer's Association USA and has served as a consultant for GE Healthcare. Dr. Hofman has received funding for travel from GlaxoSmithKline; serves as Editor-in-Chief for the European Journal of Epidemiology; receives publishing royalties for Grondslagen der epidemiologie (Elsevier, 2008), Klinische epidemiologie (Elsevier, 2000), and Investigating Neurological Disease (Cambridge University Press, 1996); and receives research support from the Netherlands Genomics Initiative for the Rotterdam Study and from the Ministry of Health for the Generation R study. Dr. Niessen serves as an Associate Editor for IEEE Transactions on Medical Imaging and Associate Editor for Medical Image Analysis. Dr. Krestin serves on the editorial boards of MagMa, Abdominal Imaging, European Radiology, Investigative Radiology, Radiologica Medica, Contrast Media, and Molecular Imaging; serves as a consultant for GE Healthcare; has received honoraria from Bayer Schering Pharma, GE Healthcare, and Siemens Medical Solutions; and receives/has received research support from Bayer Schering Pharma, GE Healthcare, Philips Healthcare, Siemens Medical Solutions, the European Commission FP6 and FP7, the Dutch Science Organization, Cancer Foundation Netherlands, and Heart Foundation Netherlands. Dr. Breteler serves on editorial advisory boards for Neuroepidemiology, Alzheimer's & Dementia, and Stroke; and receives research support from Pfizer Inc, the Netherlands Organization for Scientific Research, the Alzheimer's Association USA, the NIH, the Internationale Stichting Alzheimer Onderzoek (ISAO), the Dutch Cancer Society, the Dutch Parkinsonfonds, and the Netherlands Brain Foundation. Dr. Vernooij receives research support from the Alzheimer's Association.

Footnotes

  • Study funding: Funding information is provided at the end of the article.

  • Supplemental data at www.neurology.org

  • Received June 23, 2011.
  • Accepted September 23, 2011.

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