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Observation |

Lobar Distribution of Cerebral Microbleeds:  The Rotterdam Scan Study FREE

Dymph J. Mesker, MD; Mariëlle M. F. Poels, MD; M. Arfan Ikram, MD, PhD; Meike W. Vernooij, MD, PhD; Albert Hofman, MD, PhD; Henri A. Vrooman, PhD; Aad van der Lugt, MD, PhD; Monique M. B. Breteler, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Epidemiology (Drs Mesker, Poels, Ikram, Vernooij, Hofman, and Breteler), Radiology (Drs Poels, Ikram, Vernooij, Vrooman, and van der Lugt), and Medical Informatics (Dr Vrooman), Erasmus MC University Medical Center, Rotterdam, the Netherlands.


Arch Neurol. 2011;68(5):656-659. doi:10.1001/archneurol.2011.93.
Text Size: A A A
Published online

ABSTRACT

Objective  To investigate the distribution of lobar microbleeds over the different lobes, taking into account lobar volume and clustering effects of multiple microbleeds.

Design  Population-based, cross-sectional analysis.

Setting  The Rotterdam Scan Study.

Participants  A total of 198 persons (age range, 61-95 years) with lobar microbleeds.

Main Outcome Measures  Distribution of microbleeds over different lobes.

Results  We found that lobar cerebral microbleeds occurred significantly more often in the temporal lobe, a region known to be more affected in cerebral amyloid angiopathy.

Conclusion  This study corroborates the presumed association of lobar microbleeds with cerebral amyloid angiopathy.

Figures in this Article

Cerebral microbleeds (CMBs) can be detected with T2*-weighted gradient-echo magnetic resonance imaging (MRI) and are associated with presence and risk of intracerebral hemorrhage.1 Previous articles found that microbleeds in deep or infratentorial regions were associated with hypertension, whereas lobar microbleeds share risk factors with cerebral amyloid angiopathy (CAA).2 Little is known, however, about the spatial distribution of these lobar microbleeds. An imaging study of patients with CAA showed that microbleeds as well as intracerebral hemorrhage occurred more often in the temporal and occipital lobes,3 which fits autopsy studies describing a posterior predilection of vascular pathology in CAA.4,5

Knowledge of the spatial distribution of lobar CMBs in the general population might contribute to our understanding of their pathophysiology and may corroborate the presumed association of lobar microbleeds with CAA.

To date, only 1 population-based study6 of elderly persons examined spatial distribution of lobar bleeds and found that microbleeds occur more often in the parietal lobe. However, merely counting the number of microbleeds per lobe might give a distorted interpretation because volumetric differences between lobes are not taken into account. Furthermore, in persons with multiple microbleeds, consecutive microbleeds tend to occur in proximity of a preceding bleed.3

Therefore, in the population-based Rotterdam Scan Study, we investigated the spatial distribution of lobar microbleeds, taking into account the volume of the separate lobes and clustering effects of multiple microbleeds.

METHODS

SETTING

This study is based on the Rotterdam Scan Study.2 We previously described the prevalence and risk factors of cerebral microbleeds in a population of 1062 persons without dementia.2 Of these, 250 had, in total, 1151 microbleeds. Microbleeds that were located in the deep or infratentorial brain region were discarded from our present analysis, as we aimed to investigate the spatial distribution of lobar microbleeds, leaving 838 lobar microbleeds in 198 persons for the analyses.

BRAIN MRI

We performed a multisequence MRI protocol on a 1.5-T scanner (GE Healthcare, Milwaukee, Wisconsin).2 A custom-made, accelerated, 3-dimensional, T2*-weighted, gradient-recalled echo sequence with high spatial resolution and long echo time was used for microbleed detection. The other sequences in the imaging protocol consisted of 3 high-resolution axial scans, ie, a T1-weighted sequence, a proton density–weighted sequence, and a fluid-attenuated inversion recovery sequence. Slice position of the T1- and T2*-weighted gradient-recalled echo scans was matched.

RATING OF CEREBRAL MICROBLEEDS

Microbleeds were defined as focal areas of very low signal intensity.7 All scans were reviewed by 1 of 2 trained raters, as described previously.2 In brief, they recorded the presence, number, and slice location of all microbleeds. Intraobserver and interobserver agreement was good, with κ values of 0.87 and 0.85 respectively.2

Subsequently, all microbleeds were manually labeled by a single trained rater using the Montreal Neurological Institute tool Display.

ASSESSMENT OF LOBAR DISTRIBUTION OF MICROBLEEDS

For assessment of lobar distribution of microbleeds, we first created a template scan in which the lobes were labeled according to a slightly modified version of the segmentation protocol as described by Bodke et al8 into left and right frontal, parietal, temporal, and occipital lobes. Subsequently, we used validated nonrigid registration to map this template to each scan, in which microbleeds were manually labeled.9 By combining this lobar segmentation with the labeled microbleeds, we obtained the microbleed distribution per lobe.

STATISTICAL ANALYSIS

We analyzed the distribution of lobar microbleeds in 4 groups: (1) participants with lobar CMBs (with or without microbleeds located in a deep or infratentorial brain region); (2) participants with multiple lobar CMBs (>1 lobar microbleeds with or without microbleeds located in a deep or infratentorial brain region); (3) participants with strictly lobar CMBs (without microbleeds located in a deep or infratentorial brain region); and (4) multiple, strictly lobar CMBs (>1 lobar microbleeds without CMBs located in a deep or infratentorial brain region). These groups meet with varying degrees the criteria for the presumed underlying CAA pathology.10

Using the null hypothesis, the distribution of CMBs across the lobes would be the same as the volume percentages of each lobe based on the template scan.11 To test whether CMBs were equally distributed throughout the brain, we used the χ2 test. The binomial test was used to examine per lobe whether the microbleeds that occurred in each lobe were in proportion to the mean volume of that specific lobe. We accounted for clustering effects by adding random effects for within subject variation.

RESULTS

Table 1 presents the characteristics of the study population. The mean age was 72.5 years, and 96 (48.5%) were women. The Figure illustrates the spatial distribution of all lobar microbleeds. The CMBs were not uniformly distributed throughout the brain (P = .04). Table 2 shows the distribution of lobar microbleeds in all participants (n = 198) and in participants with multiple lobar (n = 81), strictly lobar (n = 134), and multiple strictly lobar microbleeds (n = 35). Most microbleeds were located in the temporal lobe, ie, 32.6% in participants with lobar microbleeds, 32.9% in participants with multiple lobar microbleeds, 29.9% in participants with strictly lobar microbleeds, and 31.4% in participants with multiple strictly lobar microbleeds (after correction for random effects). Compared with the expected distribution based on the volume of the lobes, lobar cerebral microbleeds occurred significantly more often in the temporal (P < .001) and parietal lobes (P = .04). The CMBs occurred significantly less often than expected in the frontal lobe (P < .001). Moreover, temporal and parietal CMBs (Figure) did not appear to be uniformly distributed in these lobes, but rather appear primarily in the posterior part of the temporal and parietal lobes.

Place holder to copy figure label and caption
Figure.

Sagittal (A) and axial (B) image of the distribution of all lobar microbleeds. Each spot represents a single microbleed (uniform size representation).

Graphic Jump Location
Table Graphic Jump LocationTable 1. Characteristics of the Study Populationa
Table Graphic Jump LocationTable 2. Distribution of Lobar Cerebral Microbleeds

Similar results were found in participants with multiple lobar microbleeds and (multiple) strictly lobar microbleeds.

COMMENT

We found in the general population that lobar microbleeds show a predilection for the posterior brain regions, particularly the temporal lobes.

Some strengths of our study are its population-based setting, high response rate, and large sample size. Moreover, an important strength of our article compared with previous articles is that we took into account lobar volume when analyzing spatial distribution of microbleeds, and thus different a priori probabilities for microbleed occurrence. Furthermore, we also took into consideration the tendency of microbleeds to cluster.

A possible limitation of our study is misclassification of cerebral microbleeds, as small blood vessels and calcification may resemble cerebral microbleeds. However, mimics of cerebral microbleeds can usually be disregarded based on location and shape.7 Furthermore, as the high spatial resolution of our MRI sequence enabled us to distinguish the linear shape of sulcal vessels from the typical round or ovoid, blind-ending shape of CMBs, we believe that we did not label any more structures than there are microbleeds.12

We found lesions preferentially in the temporal and parietal lobe but not in the occipital lobe, as has been described in previous studies that investigated the distribution of CMBs in patients with CAA and AD.3,13 There may be 3 reasons for the absence of occipital predilection in our study. First, most studies that describe the distribution of CMBs or amyloid burden are done in patients with CAA or AD,3,1315 whereas our study was done in the general elderly population. It may be that CMBs occur preferentially in occipital regions in patients with moderate to severe CAA, whereas persons with mild CAA do not share this predilection. Only one other population-based study assessed the lobar location of microbleeds and suggested that lobar microbleeds show a predilection for the parietal brain area; they also did not find an overrepresentation of CMBs in the occipital brain area.6 Second, although the evidence of the relationship between lobar CMBs and CAA is accumulating,7,16,17 we cannot exclude that some factor other than CAA might account for the distribution of CMBs in this general elderly population.

Lastly, differences across studies in the definition of the border between the occipital, parietal, and temporal lobes may play a role. Because there is no clear sulcal landmark between the 3 lobes except for the parieto-occipital sulcus, the definition between the occipital and parietal lobes is somewhat arbitrary.8 As we especially found a predilection to microbleeds in the surrounding areas of these borders, the setting of the border may influence lobar predilection.

Our finding that microbleeds are found preferentially in the posterior regions of the brain and are underrepresented in the frontal lobes is consistent with previous studies that described the lobar distribution of microbleeds.3,6,18 The only population-based study that studied the lobar location of microbleeds suggested that lobar microbleeds show a predilection for the parietal brain area.6 However, the authors did not correct for lobar volume and therefore their results may have been driven by volume differences between the lobes.6 Only one clinical study in patients with CAA took lobar volume into account in the same way as we did and found lesions preferentially in the temporal and occipital lobes.3

The posterior predilection of microbleeds in CAA has been hypothesized to relate to pattern of β-amyloid accumulation. It is thought that decreased pulse pressure and interstitial fluid pumping may lead to lower clearance of vascular β-amyloid.19 In the posterior lobes, these processes may be most clearly reduced, resulting in more vascular pathology and, consequently, more microbleeds.

Cerebral amyloid angiopathy–related CMBs are thought to be multiple and to occur primarily in lobar brain regions.2,10 In our study, the distribution pattern of lobar CMBs in participants with multiple lobar CMBs was similar to the distribution in participants with multiple, strictly lobar CMBs. Moreover, we found, on average, more CMBs per person in the group with multiple lobar CMBs compared with the group with multiple, strictly lobar CMBs (Table 1). Taken together, this suggests that multiple lobar CMBs might be as indicative of CAA as multiple, strictly lobar CMBs.

In conclusion, our findings show that lobar microbleeds occur more often in the temporal lobe and are underrepresented in the frontal lobe. This corroborates the presumed association of lobar microbleeds with CAA in the general population.

ARTICLE INFORMATION

Correspondence: Monique M. B. Breteler, MD, PhD, Department of Epidemiology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands (m.breteler@erasmusmc.nl).

Accepted for Publication: October 1, 2010.

Author Contributions: Drs Mesker and Poels contributed equally to the study. Study concept and design: Hofman and Breteler. Acquisition of data: Mesker, Poels, Ikram, and Vrooman. Analysis and interpretation of data: Mesker, Poels, Ikram, Vernooij, van der Lugt, and Breteler. Drafting of the manuscript: Mesker, Poels, and Ikram. Critical revision of the manuscript for important intellectual content: Vernooij, Hofman, Vrooman, van der Lugt, and Breteler. Statistical analysis: Mesker, Poels, and Ikram. Obtained funding: Hofman and Breteler. Administrative, technical, and material support: Vrooman. Study supervision: Vernooij, Hofman, van der Lugt, and Breteler.

Financial Disclosure: None reported.

REFERENCES

Offenbacher  HFazekas  FSchmidt  RKoch  MFazekas  GKapeller  P MR of cerebral abnormalities concomitant with primary intracerebral hematomas. AJNR Am J Neuroradiol 1996;17 (3) 573- 578
PubMed
Vernooij  MWvan der Lugt  AIkram  MA  et al.  Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 2008;70 (14) 1208- 1214
PubMed Link to Article
Rosand  JMuzikansky  AKumar  A  et al.  Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy. Ann Neurol 2005;58 (3) 459- 462
PubMed Link to Article
Vinters  HVGilbert  JJ Cerebral amyloid angiopathy: incidence and complications in the aging brain II: the distribution of amyloid vascular changes. Stroke 1983;14 (6) 924- 928
PubMed Link to Article
Attems  JQuass  MJellinger  KALintner  F Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology. J Neurol Sci 2007;257 (1-2) 49- 55
PubMed Link to Article
Sveinbjornsdottir  SSigurdsson  SAspelund  T  et al.  Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J Neurol Neurosurg Psychiatry 2008;79 (9) 1002- 1006
PubMed Link to Article
Greenberg  SMVernooij  MWCordonnier  C  et al. Microbleed Study Group, Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8 (2) 165- 174
PubMed Link to Article
Bokde  ALTeipel  SJSchwarz  R  et al.  Reliable manual segmentation of the frontal, parietal, temporal, and occipital lobes on magnetic resonance images of healthy subjects. Brain Res Brain Res Protoc 2005;14 (3) 135- 145
PubMed Link to Article
Rueckert  DSonoda  LIHayes  CHill  DLLeach  MOHawkes  DJ Nonrigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging 1999;18 (8) 712- 721
PubMed Link to Article
Knudsen  KARosand  JKarluk  DGreenberg  SM Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 2001;56 (4) 537- 539
PubMed Link to Article
Ikram  MAVrooman  HAVernooij  MW  et al.  Brain tissue volumes in relation to cognitive function and risk of dementia. Neurobiol Aging 2010;31 (3) 378- 386
PubMed Link to Article
Vernooij  MWIkram  MAWielopolski  PAKrestin  GPBreteler  MMvan der Lugt  A Cerebral microbleeds: accelerated 3D T2*-weighted GRE MR imaging versus conventional 2D T2*-weighted GRE MR imaging for detection. Radiology 2008;248 (1) 272- 277
PubMed Link to Article
Pettersen  JASathiyamoorthy  GGao  FQ  et al.  Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol 2008;65 (6) 790- 795
PubMed Link to Article
Johnson  KAGregas  MBecker  JA  et al.  Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol 2007;62 (3) 229- 234
PubMed Link to Article
Ly  JVDonnan  GAVillemagne  VL  et al.  11C-PIB binding is increased in patients with cerebral amyloid angiopathy-related hemorrhage. Neurology 2010;74 (6) 487- 493
PubMed Link to Article
Schrag  MMcAuley  GPomakian  J  et al.  Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study. Acta Neuropathol 2009;119291- 302
PubMed Link to Article
Dierksen  GASkehan  MEKhan  MA  et al.  Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy. Ann Neurol 2010;68 (4) 545- 548
PubMed Link to Article
Lee  SHKwon  SJKim  KSYoon  BWRoh  JK Cerebral microbleeds in patients with hypertensive stroke: topographical distribution in the supratentorial area. J Neurol 2004;251 (10) 1183- 1189
PubMed Link to Article
Auer  RNSutherland  GR Primary intracerebral hemorrhage: pathophysiology. Can J Neurol Sci 2005;32 ((suppl 2)) S3- S12
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Sagittal (A) and axial (B) image of the distribution of all lobar microbleeds. Each spot represents a single microbleed (uniform size representation).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of the Study Populationa
Table Graphic Jump LocationTable 2. Distribution of Lobar Cerebral Microbleeds

References

Offenbacher  HFazekas  FSchmidt  RKoch  MFazekas  GKapeller  P MR of cerebral abnormalities concomitant with primary intracerebral hematomas. AJNR Am J Neuroradiol 1996;17 (3) 573- 578
PubMed
Vernooij  MWvan der Lugt  AIkram  MA  et al.  Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 2008;70 (14) 1208- 1214
PubMed Link to Article
Rosand  JMuzikansky  AKumar  A  et al.  Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy. Ann Neurol 2005;58 (3) 459- 462
PubMed Link to Article
Vinters  HVGilbert  JJ Cerebral amyloid angiopathy: incidence and complications in the aging brain II: the distribution of amyloid vascular changes. Stroke 1983;14 (6) 924- 928
PubMed Link to Article
Attems  JQuass  MJellinger  KALintner  F Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology. J Neurol Sci 2007;257 (1-2) 49- 55
PubMed Link to Article
Sveinbjornsdottir  SSigurdsson  SAspelund  T  et al.  Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location. J Neurol Neurosurg Psychiatry 2008;79 (9) 1002- 1006
PubMed Link to Article
Greenberg  SMVernooij  MWCordonnier  C  et al. Microbleed Study Group, Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8 (2) 165- 174
PubMed Link to Article
Bokde  ALTeipel  SJSchwarz  R  et al.  Reliable manual segmentation of the frontal, parietal, temporal, and occipital lobes on magnetic resonance images of healthy subjects. Brain Res Brain Res Protoc 2005;14 (3) 135- 145
PubMed Link to Article
Rueckert  DSonoda  LIHayes  CHill  DLLeach  MOHawkes  DJ Nonrigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging 1999;18 (8) 712- 721
PubMed Link to Article
Knudsen  KARosand  JKarluk  DGreenberg  SM Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 2001;56 (4) 537- 539
PubMed Link to Article
Ikram  MAVrooman  HAVernooij  MW  et al.  Brain tissue volumes in relation to cognitive function and risk of dementia. Neurobiol Aging 2010;31 (3) 378- 386
PubMed Link to Article
Vernooij  MWIkram  MAWielopolski  PAKrestin  GPBreteler  MMvan der Lugt  A Cerebral microbleeds: accelerated 3D T2*-weighted GRE MR imaging versus conventional 2D T2*-weighted GRE MR imaging for detection. Radiology 2008;248 (1) 272- 277
PubMed Link to Article
Pettersen  JASathiyamoorthy  GGao  FQ  et al.  Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol 2008;65 (6) 790- 795
PubMed Link to Article
Johnson  KAGregas  MBecker  JA  et al.  Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol 2007;62 (3) 229- 234
PubMed Link to Article
Ly  JVDonnan  GAVillemagne  VL  et al.  11C-PIB binding is increased in patients with cerebral amyloid angiopathy-related hemorrhage. Neurology 2010;74 (6) 487- 493
PubMed Link to Article
Schrag  MMcAuley  GPomakian  J  et al.  Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study. Acta Neuropathol 2009;119291- 302
PubMed Link to Article
Dierksen  GASkehan  MEKhan  MA  et al.  Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy. Ann Neurol 2010;68 (4) 545- 548
PubMed Link to Article
Lee  SHKwon  SJKim  KSYoon  BWRoh  JK Cerebral microbleeds in patients with hypertensive stroke: topographical distribution in the supratentorial area. J Neurol 2004;251 (10) 1183- 1189
PubMed Link to Article
Auer  RNSutherland  GR Primary intracerebral hemorrhage: pathophysiology. Can J Neurol Sci 2005;32 ((suppl 2)) S3- S12
PubMed

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