Special Issue Article
Quantitative assessment and correlation analysis of cerebral microbleed distribution and leukoaraiosis in stroke outpatients Qiong Yang1, Yan Yang1, Chengyu Li1, Jian Li1, Xiangyi Liu1, Aonan Wang1, Jialing Zhao1, Mengyuan Wang1, Xiangzhu Zeng2, Dongsheng Fan*1 1
Department of Neurology, Peking University Third Hospital, Beijing, China, 2Department of Radiology, Peking University Third Hospital, Beijing, China Objective: Cerebral microbleeds (CMBs) are bleeding events associated with cerebral small vessel disease (SVD). Strictly lobar CMBs and strictly deep CMBs are likely caused by cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy, respectively. Leukoaraiosis (LA) reflects an ischaemic change in SVD, and LA severity has been correlated with CMBs. However, whether different locations (aetiologies) of CMBs correlate with LA is unknown. Methods: Patients receiving brain MRI and T2*-weighted gradient-recalled echo scans in a stroke outpatient department were screened for CMBs. The MRI results of the patients with CMBs were sent to investigators for further review and were evaluated using the Microbleed Anatomical Rating Scale. Cerebral microbleed severity was graded using a numerical scale. Leukoaraiosis severity was assessed using the Fazekas scale. Results: Cerebral microbleeds were observed in 14.6% of the 1289 screened patients. The CMB incidence increased with age (in years, v50: 1.3%; 50–59: 10.7%; 60–69: 17.6% and i70: 23.6%; P50.000). The CMB locations were distributed as follows: 23.4% strictly lobar, 12.2% strictly deep, 6.4% strictly infratentorial and 58.0% mixed. Cerebral microbleed severity correlated with the total Fazekas scale score. The numbers of lobar, deep and infratentorial CMBs correlated with the total Fazekas scale score. The mixed CMB group displayed a significantly higher Fazekas scale score than the strictly lobar CMB group (P50.000). Discussion: Cerebral microbleed incidence increased with age. Mixed CMB type displayed the highest incidence. The severity and number of CMBs at any location correlated with LA severity. These results suggested interactions between hypertension and CAA during LA progression.
Keywords: Cerebral amyloid angiopathy, Cerebral microbleeds, Distribution, Gradient-recalled echo, Leukoaraiosis
Introduction Cerebral microbleeds (CMBs) refer to small, rounded, well-defined hypointensities that can be visualised on T2*-weighted gradient-recalled echo (T2* GRE) MRI brain scans.1 The distribution of CMBs reflects the underlying aaetiology: strictly lobar CMBs are likely caused by cerebral amyloid angiopathy (CAA), and deep CMBs are likely caused by hypertensive arteriopathy.1–3 Studies assessing the population-wide CMB prevalence have reported inconsistent results, as have those reporting on the CMB prevalence within various cerebral regions (which represent distinct aetiologies).
*Correspondence to: Dongsheng Fan, Department of Neurology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China. Email: [email protected]
Cerebral microbleeds are bleeding events associated with cerebral small vessel disease (SVD), whereas leukoaraiosis (LA) reflects an ischaemic change in SVD. Leukoaraiosis indicates the presence of patchy hyperintense areas visible in T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI scans.4 Leukoaraiosis is commonly classified into periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMH). The prevalence of LA increases with age and is associated with stroke, hypertension, CAA, dementia, etc.4,5 There are two primary hypotheses regarding LA aetiology: ischaemic (LA is formed as a result of insufficient blood supply to the cerebral white matter because of the vascular pathology) and nonischaemic (LA is formed because of the dilation of the perivascular spaces that surround
ß W. S. Maney and Son Ltd 2015 Received 11 January 2015; Accepted 26 February 2015 DOI 10.1179/1743132815Y.0000000027)
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normal arterioles).4 The clinical significance of LA is not completely defined, and the presence of LA appears to affect cognitive functions.4,6 Leukoaraiosis shares many risk factors, such as hypertension, with lacunes and microbleeds.7 Previous studies have shown that the severity of LA may be related to CMBs.2,8,9 Leukoaraiosis was suggested to be a potential indicator of CMBs. These observations raise the issue of whether different CMB locations (representing distinct aetiologies) correlate with LA. Our study aimed to quantitatively assess the CMB distribution (age and location in the brain) and explore the relationship between CMBs of distinct aetiologies and LA in stroke outpatients.
Methods Participants The authors recruited consecutive patients in the stroke outpatient department of Peking University Third Hospital from June to October 2013. The inclusion criteria included participants w18 years old who had received brain MRI and T2* GRE scans when recruited. The exclusion criteria included tumour, subarachnoid haemorrhage, vascular malformation, cerebral vasculitis and head trauma. The MRI scans of the patients with CMBs were sent to the investigators for further review and were evaluated with respect to CMBs and LA. The review process is shown in Fig. 1. This study was approved by the Ethical Committee of Peking University Third Hospital.
Brain MRI MRIs were performed using a 1.5-T superconducting magnet system (Siemens Sonata, Erlangen, Germany). The imaging protocol consisted of T2* GRE (repetition time [TR]/echo time [TE] 720/ 30 ms, flip angle 30uu) with a slice thickness of 5 mm and a 1.5-mm interslice gap, producing 20 axial images. T1-weighted spin echo (TR/TE 1750/27 ms), T2-weighted fast-spin echo (TR/TE 5708/116 ms),
FLAIR (TR/TE 8000/133 ms, inversion time 2500 ms) and diffusion-weighted echo planar (TR/TE 2800/90 ms) imaging series were utilized.
Rating of CMBs Cerebral microbleeds were evaluated using the Microbleed Anatomical Rating Scale (MARS).10 The numbers and locations of the CMBs were recorded according to the MARS, which categorized the CMBs into the deep, lobar and infratentorial regions. The lobar region included the cortical and superficial subcortical white matter. The deep region included the basal ganglia, the thalamus, the internal capsule, the external capsule, the corpus callosum and the deep and periventricular white matter. The infratentorial region included the brainstem and the cerebellum. The CMB severity was defined as follows: Degree 0, 0 CMBs; Degree 1, 1–4 CMBs; Degree 2, 5–9 CMBs and Degree 3, i10 CMBs.
Rating of LA The severity of LA (classified into PVH and DWMH) on FLAIR images was assessed according to the Fazekas scale.11 The grading scale for PVH was defined as follows: Grade 0, absence; Grade 1, ‘caps’ or pencil-thin lining; Grade 2, smooth ‘halo’ and Grade 3, irregular PVH extending into the deep white matter. The grading scale of DWMH was defined as follows: Grade 0, absence; Grade 1, punctate foci; Grade 2, initial confluence of foci and Grade 3, large confluence of foci. The total scores were summed (0–6).11 All MRI scans of the patients with CMBs were reviewed by two trained neurologists to evaluate CMBs and LA.
Statistical analysis SPSS version 19.0 was used for the data analysis. The data were expressed as the mean+ SD. The chi-squared test and the Mann–Whitney test were used to compare the differences between the subgroups of patients with and without CMBs. The Kruskal–Wallis H-test was used for non-parametric analysis to compare the differences between the CMB locations. The correlation between CMB severity and LA was evaluated using the Spearman rank correlation test. Pv0.05 was considered to be significant.
Results Cerebral microbleed incidence Nearly 1289 consecutive patients were screened. Their mean age was 60.49 years old. The proportion of male patients was 53.7%. Among these patients, 188 were found to exhibit CMBs (CMB incidence of 14.6%). The CMB severity was distributed as follows: 59.6% (112/188) with degree 1, 18.6% with degree 2 and 21.8% with degree 3.
Figure 1 MRI review process of the study.
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The proportion of male patients was significantly higher in the CMB group than in the non-CMB group (61.7 vs 52.3%, P50.017). The patients in the CMB group were significantly older on average than those in the non-CMB group (71.20 + 10.68 vs 58.64+ 17.81 years, P50.000) (Table 1).
Age distribution of the patients with CMBs An overview of the age-specific prevalence of CMBs is shown in Table 2. The CMB incidence increased with age (in years, v50: 1.3%; 50–59: 10.7%; 60–69: 17.6% and i70: 23.6%). The between-group comparison revealed significant differences between all groups (P50.000). The severity of CMBs in each age group is shown in Fig. 2, which shows that the incidence of various degrees of CMBs increased with age.
Distribution of CMB location Among the patients, 23.4% exhibited strictly lobar CMBs, 12.2% exhibited strictly deep CMBs, 6.4% exhibited strictly infratentorial CMBs and 58.0%, representing the majority of the patients, exhibited mixed CMBs. The majority of mixed CMB patients exhibited CMBs in the lobar region and another location (Table 3). Figure 3 shows a patient with mixed lobar, deep and infratentorial CMBs.
Association between the severity and distribution of CMBs and the LA grade Association between CMB severity and the LA grade A Spearman rank correlation showed that the numbers of total, lobar, deep and infratentorial CMBs correlated with the Fazekas scale scores (Table 4). Comparison of the Fazekas scale scores in different groups stratified by CMB location Comparing the strictly lobar, strictly deep, strictly infratentorial and mixed CMB patients, the Fazekas scale scores of the mixed CMB patients were significantly higher than those of the strictly lobar CMB patients (P50.000) (Table 5). In addition, the Fazekas scale scores of the mixed CMB patients were higher than those of the strictly deep CMB patients; however, this difference was not significant (P50.062). The remaining
Table 1 Comparison between the groups with and without CMBs No CMBs
CMBs
P-value
n (%) 1101 (85.4%) 188 (14.6%) Gender: male (%) 576 (52.3%) 116 (61.7%) 0.017 Age (years) 58.64z17.81 71.20z10.68 0.000 Severity Degree 1 112 (8.7%) Degree 2 35 (2.7%) Degree 3 41 (3.2%) CMBs: cerebral microbleeds.
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comparisons between each group did not reveal any significant differences.
Discussion Prevalence of CMBs The participants enrolled in our study included stroke outpatients. Their mean age was 60.5 years and the incidence of CMB was 14.6%. This finding was inconsistent with the results of previous studies.12–17 This discrepancy may be because of the different characteristics of the participants, such as age, comorbidities and mode of MRI scan. In an ageing population, the proportion of patients with CAA, cerebrovascular disease and related risk factors is higher, resulting in more CMBs. Magnetic resonance imaging technology is another important factor that may be responsible for this discrepancy. T2*-weighted gradient-recalled echo and susceptibility-weighted imaging are the most common methods used to identify CMBs. Hypointense signal on GRE sequences is caused by haemosiderin, a blood breakdown product that causes magnetic susceptibility-induced dephasing, thereby leading to T2* signal loss.2 The selected imaging parameters, such as the pulse sequence, the sequence parameters, the spatial resolution, the magnetic field strength and post-processing, can affect the size, clarity and number of lesions identified.2,3,18–20 Variations in these parameters may lead to inconsistent findings, thereby rendering comparisons between studies difficult. The incidence of CMBs in some previous population-based studies ranged from 4 to 12%.12–14,16 For example, the Framingham Heart Study (1965 cases, mean age 66.5 years, using T2* GRE at 1.5 T) found CMBs in 8.8% of the participants, the majority of which were lobar (63%).16 Although the mean age of the participants in this study was higher (66.5 years old) than that in our study, the Framingham Heart Study reported fewer patients with cerebral vascular disease and related risk factors, which may explain why the CMB incidence of this study was lower than that of our study. The Rotterdam Scan Study (3979 cases, mean age of 60.3 years, performing brain MRIs at 1.5 T) reported a CMB incidence of 15.3%, ranging from 6% in participants aged 45–50 years to 36% in those i80 years.15 The mean age of the participants and the examination of a community-based population in this study were similar to the characteristics of our study. However, the Rotterdam Scan Study used 3D T2* GRE technology, which was reported to be able to detect more CMBs than common 2D T2* GRE MRI (35.5 vs 21.0%; Pv0.001).21 This difference may explain why the CMB incidence in this study was slightly higher than that of ours. The prevalence of CMBs in subjects with stroke was 19–83% for ICH and 15–35% for ischaemic stroke.
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Table 2 Age-specific prevalence of CMBs Age range, years
Number of patients examined Number of patients with CMBs
v40
40–49
50–59
60–69
i70
Total
192 1 0.5%
113 3 2.7%
244 26 10.7%
279 49 17.6%
461 109 23.6%
1289 188 14.6%
CMBs: cerebral microbleeds.
Figure 2 Incidence of different degrees of CMBs in each age group.
Table 3 Distribution of CMB locations CMB location
No.
Percentage
Strictly lobar Strictly deep Strictly infratentorial Mixed Lobar and deep Lobar and infratentorial Deep and infratentorial Lobar, deep and infratentorial
44 23 12 109 45 10 12 42
23.4 12.2 6.4 58.0 23.9 5.3 6.4 22.3
CMB: cerebral microbleed.
The CMB prevalence increased in stroke patients treated with intravenous thrombolysis (new CMBs in 40.70% of the patients).16,17,22 These varying results may be associated with differences in the examined populations and MRI modalities.
Prevalence of CMBs by location Our study showed a substantially higher incidence of mixed CMBs than that of other types (58%); most mixed CMBs were composed of the lobar region and another region, followed by strictly lobar and strictly deep CMBs (23.4 and 12.2%, respectively). Studies of community-based populations showed the highest incidence of cortico-subcortical
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CMBs.16,23 For example, the Rotterdam Scan Study found that 58.4% (146/250) of the examined patients exhibited strictly lobar CMBs and that 41.6% (104) exhibited deep or infratentorial CMBs (including 58 instances that were accompanied by lobar CMBs, thereby indicating mixed CMBs).23 A study of Chinese stroke patients reported the basal ganglia contained the highest incidence of CMBs [61.11% (44/72)], followed by the cortico-subcortical region [54.17% (39/72)].17 Another study of ischaemic stroke showed that most patients exhibited strictly subcortical CMBs [40.1% (101/252)] or mixed cortico-subcortical CMBs [34.9% (88/252)]. Only 17.5% (44/252) of the patients exhibited strictly cortical CMBs.24 The reason for the inconsistency between these findings may be because of differences in the study populations (e.g. race, disease status especially hypertension, CAA related to age and other factors), thereby leading to distinct incidences of CMBs, which represent specific aetiologies. Histopathologic analyses have been used to identify two types of vascular pathologies related to CMBs: hypertensive vasculopathy and CAA.3 Strictly lobar CMBs are likely caused by CAA because of their association with known risk factors for CAA, including the e4 genotype of apolipoprotein E.15,23 Non-invasive assessment of amyloid plaques via positron emission tomography (PET) using Pittsburgh Compound B revealed that CMBs in CAA patients occur preferentially in local regions containing concentrated amyloid-b accumulation.25 Deep CMBs are likely caused by hypertensive arteriopathy because of their associations with hypertension and other imaging manifestations of hypertensive SVD.1 However, the aetiology of mixed CMBs is difficult to identify. First, hypertensive arteriopathy preferentially involves the penetrating arterioles and therefore typically produces deep CMBs; however, severe hypertensive arteriopathy, which causes decreased vascular reactivity of the superficial cortical arteries, may be responsible for lobar CMBs.26 Second, CAA can coincide with hypertension-related arteriopathies.1 Thus, mixed CMBs may be caused by hypertension with or without CAA. It is very important to determine whether patients with mixed CMBs
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Figure 3 A 71-year-old man with mixed cerebral microbleeds (CMBs), including CMBs in the lobar, deep and infratentorial regions. Table 4 Association between the numbers of total, lobar, deep and infratentorial CMBs and the Fazekas scale scores Spearman’s r (P-value) Fazekas scale score PVH score DWMH score
r P-value r P-Value r P-value
No. of CMBs
No. of lobar CMBs
No. of deep CMBs
No. of infratentorial CMBs
0.342 0.000 0.296 0.000 0.338 0.000
0.213 0.003 0.175 0.017 0.206 0.005
0.256 0.000 0.221 0.002 0.272 0.000
0.213 0.003 0.173 0.018 0.227 0.002
CMBs: cerebral microbleeds; DWMH: deep white matter hyperintensity; PVH: periventricular hyperintensity.
Table 5 Fazekas scale scores of different groups stratified by CMB location N
Age (years)
A
44
70.39+ 10.77
3+ 1.463
B
23
70.61+ 11.90
3.39+ 1.994
C
12
73.33+ 11.35
3.92+ 2.021
D
109
71.42+ 10.41
4.14+ 1.536
Group
Fazekas scale score
P-value A vs B 0.354
A vs C 0.099 B vs C 0.401
A vs D 0.000 B vs D 0.062 C vs D 0.670
CMB: cerebral microbleed; A: group of patients with strictly lobar CMBs; B: group of patients with strictly deep CMBs; C: group of patients with strictly infratentorial CMBs; D: group of patients with mixed CMBs.
suffer from some degree of CAA. The diagnostic criteria for CAA (the ‘Boston criteria’), including the presence of strictly lobar ICH or lobar CMBs, are very highly specific. However, the sensitivity of this approach may be low.1 The patients with a mixed deep and lobar distribution of CMBs, who are likely to suffer from CAA, do not fulfil the Boston criteria.1 The use of newly developed technologies such as the assessment of amyloid plaques via PET may contribute to the diagnosis of CAA.5 In addition to neuroimaging processes, an examination of the cerebrospinal fluid can be helpful: the concentration of both Ab 1–42 and Ab 1–40 in the cerebrospinal fluid in patients suffering from CAA is decreased
compared with that in healthy controls and in patients suffering from Alzheimer-type dementia.5 However, because these tests are expensive or invasive, they are not commonly performed on patients with CMBs. In addition, there are other uncommon diseases related to CMBs, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, autoimmune encephalitis, head trauma, etc., rendering the diagnosis more difficult.2 Further research, including the development of novel biomarkers, should be performed to help identify the predictive value of the location of CMBs for CAA, hypertension and other diseases and their prognostic significance.
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Relationship between the severity and distribution of CMBs and LA Our study showed that the numbers of total, lobar, deep and infratentorial CMBs correlated with the Fazekas scale scores. These results were consistent with those of previous studies showing a relationship between the number of CMBs, including deep, mixed (deep and lobar) and strictly lobar CMBs, and the severity of LA (reflecting the severity of SVD).2,8,15 Just as the distribution of CMBs varies according to the aaetiology and severity of SVD, the pattern of LA may also vary.2 Patients with lobar ICH may exhibit a predominantly occipital LA distribution, which would be consistent with the relative predilection towards CAA in posterior brain regions.27 Our study showed that the LA severity of mixed CMBs was significantly higher than that of strictly lobar CMBs (P50.000) and non-significantly higher than that of strictly deep CMBs (P50.062). The limited sample size may have influenced this finding. The results indicated that in patients with mixed CMBs, hypertension and CAA may coincide and mutually exacerbate the development of white matter lesions. In addition, studies have shown that hypertension likely contributes to bleeding in CAA patients and that the control of hypertension (a moderate reduction in systolic/diastolic blood pressure amounting to 9/4 mmHg) reduces CAA-related haemorrhaging in 77% of patients.28 Furthermore, combined with our results, the control of hypertension may help to delay the exacerbation of white matter lesions in CAA patients. Our cross-sectional design limits our ability to examine whether the observed associations are causal. Prospective studies are needed to more thoroughly understand these issues. In conclusion, this study confirmed that the incidence of CMBs increases with age. Among all CMB types, the authors found that mixed CMBs displayed the highest incidence. The severity and number of CMBs at any location correlated with the severity of LA. Furthermore, the study results indicated that there may be an interaction between hypertension and CAA during the progression of LA. Confirmation of this hypothesis requires large-scale studies.
Acknowledgement This study was supported by a grant from the Science and Technology Program of Beijing, China (Grant No. D141100000114005).
Disclaimer Statements Contributors DF conceived this study and provided financial support. DF and QY designed the study. YY, CL, JL, XL, AW, JZ, MW, and XZ took part in the design of the study and in sample collection. DF, QY, and XZ conducted data management and
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analysis. DF was responsible for project management. QY and DF were responsible for preparing and revising the manuscript. Funding This study was supported by a grant from the Science and Technology Program of Beijing, China (Grant No. D141100000114005). Conflict of interest The authors report no conflicts of interest. Ethics approval
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Quantitative assessment and correlation analysis of cerebral microbleed distribution and leukoaraiosis in stroke outpatients Qiong Yang1, Yan Yang1, Chengyu Li1, Jian Li1, Xiangyi Liu1, Aonan Wang1, Jialing Zhao1, Mengyuan Wang1, Xiangzhu Zeng2, Dongsheng Fan*1 1
Department of Neurology, Peking University Third Hospital, Beijing, China, 2Department of Radiology, Peking University Third Hospital, Beijing, China Objective: Cerebral microbleeds (CMBs) are bleeding events associated with cerebral small vessel disease (SVD). Strictly lobar CMBs and strictly deep CMBs are likely caused by cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy, respectively. Leukoaraiosis (LA) reflects an ischaemic change in SVD, and LA severity has been correlated with CMBs. However, whether different locations (aetiologies) of CMBs correlate with LA is unknown. Methods: Patients receiving brain MRI and T2*-weighted gradient-recalled echo scans in a stroke outpatient department were screened for CMBs. The MRI results of the patients with CMBs were sent to investigators for further review and were evaluated using the Microbleed Anatomical Rating Scale. Cerebral microbleed severity was graded using a numerical scale. Leukoaraiosis severity was assessed using the Fazekas scale. Results: Cerebral microbleeds were observed in 14.6% of the 1289 screened patients. The CMB incidence increased with age (in years, v50: 1.3%; 50–59: 10.7%; 60–69: 17.6% and i70: 23.6%; P50.000). The CMB locations were distributed as follows: 23.4% strictly lobar, 12.2% strictly deep, 6.4% strictly infratentorial and 58.0% mixed. Cerebral microbleed severity correlated with the total Fazekas scale score. The numbers of lobar, deep and infratentorial CMBs correlated with the total Fazekas scale score. The mixed CMB group displayed a significantly higher Fazekas scale score than the strictly lobar CMB group (P50.000). Discussion: Cerebral microbleed incidence increased with age. Mixed CMB type displayed the highest incidence. The severity and number of CMBs at any location correlated with LA severity. These results suggested interactions between hypertension and CAA during LA progression.
Keywords: Cerebral amyloid angiopathy, Cerebral microbleeds, Distribution, Gradient-recalled echo, Leukoaraiosis
Introduction Cerebral microbleeds (CMBs) refer to small, rounded, well-defined hypointensities that can be visualised on T2*-weighted gradient-recalled echo (T2* GRE) MRI brain scans.1 The distribution of CMBs reflects the underlying aaetiology: strictly lobar CMBs are likely caused by cerebral amyloid angiopathy (CAA), and deep CMBs are likely caused by hypertensive arteriopathy.1–3 Studies assessing the population-wide CMB prevalence have reported inconsistent results, as have those reporting on the CMB prevalence within various cerebral regions (which represent distinct aetiologies).
*Correspondence to: Dongsheng Fan, Department of Neurology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China. Email: [email protected]
Cerebral microbleeds are bleeding events associated with cerebral small vessel disease (SVD), whereas leukoaraiosis (LA) reflects an ischaemic change in SVD. Leukoaraiosis indicates the presence of patchy hyperintense areas visible in T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI scans.4 Leukoaraiosis is commonly classified into periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMH). The prevalence of LA increases with age and is associated with stroke, hypertension, CAA, dementia, etc.4,5 There are two primary hypotheses regarding LA aetiology: ischaemic (LA is formed as a result of insufficient blood supply to the cerebral white matter because of the vascular pathology) and nonischaemic (LA is formed because of the dilation of the perivascular spaces that surround
ß W. S. Maney and Son Ltd 2015 Received 11 January 2015; Accepted 26 February 2015 DOI 10.1179/1743132815Y.0000000027)
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normal arterioles).4 The clinical significance of LA is not completely defined, and the presence of LA appears to affect cognitive functions.4,6 Leukoaraiosis shares many risk factors, such as hypertension, with lacunes and microbleeds.7 Previous studies have shown that the severity of LA may be related to CMBs.2,8,9 Leukoaraiosis was suggested to be a potential indicator of CMBs. These observations raise the issue of whether different CMB locations (representing distinct aetiologies) correlate with LA. Our study aimed to quantitatively assess the CMB distribution (age and location in the brain) and explore the relationship between CMBs of distinct aetiologies and LA in stroke outpatients.
Methods Participants The authors recruited consecutive patients in the stroke outpatient department of Peking University Third Hospital from June to October 2013. The inclusion criteria included participants w18 years old who had received brain MRI and T2* GRE scans when recruited. The exclusion criteria included tumour, subarachnoid haemorrhage, vascular malformation, cerebral vasculitis and head trauma. The MRI scans of the patients with CMBs were sent to the investigators for further review and were evaluated with respect to CMBs and LA. The review process is shown in Fig. 1. This study was approved by the Ethical Committee of Peking University Third Hospital.
Brain MRI MRIs were performed using a 1.5-T superconducting magnet system (Siemens Sonata, Erlangen, Germany). The imaging protocol consisted of T2* GRE (repetition time [TR]/echo time [TE] 720/ 30 ms, flip angle 30uu) with a slice thickness of 5 mm and a 1.5-mm interslice gap, producing 20 axial images. T1-weighted spin echo (TR/TE 1750/27 ms), T2-weighted fast-spin echo (TR/TE 5708/116 ms),
FLAIR (TR/TE 8000/133 ms, inversion time 2500 ms) and diffusion-weighted echo planar (TR/TE 2800/90 ms) imaging series were utilized.
Rating of CMBs Cerebral microbleeds were evaluated using the Microbleed Anatomical Rating Scale (MARS).10 The numbers and locations of the CMBs were recorded according to the MARS, which categorized the CMBs into the deep, lobar and infratentorial regions. The lobar region included the cortical and superficial subcortical white matter. The deep region included the basal ganglia, the thalamus, the internal capsule, the external capsule, the corpus callosum and the deep and periventricular white matter. The infratentorial region included the brainstem and the cerebellum. The CMB severity was defined as follows: Degree 0, 0 CMBs; Degree 1, 1–4 CMBs; Degree 2, 5–9 CMBs and Degree 3, i10 CMBs.
Rating of LA The severity of LA (classified into PVH and DWMH) on FLAIR images was assessed according to the Fazekas scale.11 The grading scale for PVH was defined as follows: Grade 0, absence; Grade 1, ‘caps’ or pencil-thin lining; Grade 2, smooth ‘halo’ and Grade 3, irregular PVH extending into the deep white matter. The grading scale of DWMH was defined as follows: Grade 0, absence; Grade 1, punctate foci; Grade 2, initial confluence of foci and Grade 3, large confluence of foci. The total scores were summed (0–6).11 All MRI scans of the patients with CMBs were reviewed by two trained neurologists to evaluate CMBs and LA.
Statistical analysis SPSS version 19.0 was used for the data analysis. The data were expressed as the mean+ SD. The chi-squared test and the Mann–Whitney test were used to compare the differences between the subgroups of patients with and without CMBs. The Kruskal–Wallis H-test was used for non-parametric analysis to compare the differences between the CMB locations. The correlation between CMB severity and LA was evaluated using the Spearman rank correlation test. Pv0.05 was considered to be significant.
Results Cerebral microbleed incidence Nearly 1289 consecutive patients were screened. Their mean age was 60.49 years old. The proportion of male patients was 53.7%. Among these patients, 188 were found to exhibit CMBs (CMB incidence of 14.6%). The CMB severity was distributed as follows: 59.6% (112/188) with degree 1, 18.6% with degree 2 and 21.8% with degree 3.
Figure 1 MRI review process of the study.
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The proportion of male patients was significantly higher in the CMB group than in the non-CMB group (61.7 vs 52.3%, P50.017). The patients in the CMB group were significantly older on average than those in the non-CMB group (71.20 + 10.68 vs 58.64+ 17.81 years, P50.000) (Table 1).
Age distribution of the patients with CMBs An overview of the age-specific prevalence of CMBs is shown in Table 2. The CMB incidence increased with age (in years, v50: 1.3%; 50–59: 10.7%; 60–69: 17.6% and i70: 23.6%). The between-group comparison revealed significant differences between all groups (P50.000). The severity of CMBs in each age group is shown in Fig. 2, which shows that the incidence of various degrees of CMBs increased with age.
Distribution of CMB location Among the patients, 23.4% exhibited strictly lobar CMBs, 12.2% exhibited strictly deep CMBs, 6.4% exhibited strictly infratentorial CMBs and 58.0%, representing the majority of the patients, exhibited mixed CMBs. The majority of mixed CMB patients exhibited CMBs in the lobar region and another location (Table 3). Figure 3 shows a patient with mixed lobar, deep and infratentorial CMBs.
Association between the severity and distribution of CMBs and the LA grade Association between CMB severity and the LA grade A Spearman rank correlation showed that the numbers of total, lobar, deep and infratentorial CMBs correlated with the Fazekas scale scores (Table 4). Comparison of the Fazekas scale scores in different groups stratified by CMB location Comparing the strictly lobar, strictly deep, strictly infratentorial and mixed CMB patients, the Fazekas scale scores of the mixed CMB patients were significantly higher than those of the strictly lobar CMB patients (P50.000) (Table 5). In addition, the Fazekas scale scores of the mixed CMB patients were higher than those of the strictly deep CMB patients; however, this difference was not significant (P50.062). The remaining
Table 1 Comparison between the groups with and without CMBs No CMBs
CMBs
P-value
n (%) 1101 (85.4%) 188 (14.6%) Gender: male (%) 576 (52.3%) 116 (61.7%) 0.017 Age (years) 58.64z17.81 71.20z10.68 0.000 Severity Degree 1 112 (8.7%) Degree 2 35 (2.7%) Degree 3 41 (3.2%) CMBs: cerebral microbleeds.
Quantitative assessment and correlation analysis
comparisons between each group did not reveal any significant differences.
Discussion Prevalence of CMBs The participants enrolled in our study included stroke outpatients. Their mean age was 60.5 years and the incidence of CMB was 14.6%. This finding was inconsistent with the results of previous studies.12–17 This discrepancy may be because of the different characteristics of the participants, such as age, comorbidities and mode of MRI scan. In an ageing population, the proportion of patients with CAA, cerebrovascular disease and related risk factors is higher, resulting in more CMBs. Magnetic resonance imaging technology is another important factor that may be responsible for this discrepancy. T2*-weighted gradient-recalled echo and susceptibility-weighted imaging are the most common methods used to identify CMBs. Hypointense signal on GRE sequences is caused by haemosiderin, a blood breakdown product that causes magnetic susceptibility-induced dephasing, thereby leading to T2* signal loss.2 The selected imaging parameters, such as the pulse sequence, the sequence parameters, the spatial resolution, the magnetic field strength and post-processing, can affect the size, clarity and number of lesions identified.2,3,18–20 Variations in these parameters may lead to inconsistent findings, thereby rendering comparisons between studies difficult. The incidence of CMBs in some previous population-based studies ranged from 4 to 12%.12–14,16 For example, the Framingham Heart Study (1965 cases, mean age 66.5 years, using T2* GRE at 1.5 T) found CMBs in 8.8% of the participants, the majority of which were lobar (63%).16 Although the mean age of the participants in this study was higher (66.5 years old) than that in our study, the Framingham Heart Study reported fewer patients with cerebral vascular disease and related risk factors, which may explain why the CMB incidence of this study was lower than that of our study. The Rotterdam Scan Study (3979 cases, mean age of 60.3 years, performing brain MRIs at 1.5 T) reported a CMB incidence of 15.3%, ranging from 6% in participants aged 45–50 years to 36% in those i80 years.15 The mean age of the participants and the examination of a community-based population in this study were similar to the characteristics of our study. However, the Rotterdam Scan Study used 3D T2* GRE technology, which was reported to be able to detect more CMBs than common 2D T2* GRE MRI (35.5 vs 21.0%; Pv0.001).21 This difference may explain why the CMB incidence in this study was slightly higher than that of ours. The prevalence of CMBs in subjects with stroke was 19–83% for ICH and 15–35% for ischaemic stroke.
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Table 2 Age-specific prevalence of CMBs Age range, years
Number of patients examined Number of patients with CMBs
v40
40–49
50–59
60–69
i70
Total
192 1 0.5%
113 3 2.7%
244 26 10.7%
279 49 17.6%
461 109 23.6%
1289 188 14.6%
CMBs: cerebral microbleeds.
Figure 2 Incidence of different degrees of CMBs in each age group.
Table 3 Distribution of CMB locations CMB location
No.
Percentage
Strictly lobar Strictly deep Strictly infratentorial Mixed Lobar and deep Lobar and infratentorial Deep and infratentorial Lobar, deep and infratentorial
44 23 12 109 45 10 12 42
23.4 12.2 6.4 58.0 23.9 5.3 6.4 22.3
CMB: cerebral microbleed.
The CMB prevalence increased in stroke patients treated with intravenous thrombolysis (new CMBs in 40.70% of the patients).16,17,22 These varying results may be associated with differences in the examined populations and MRI modalities.
Prevalence of CMBs by location Our study showed a substantially higher incidence of mixed CMBs than that of other types (58%); most mixed CMBs were composed of the lobar region and another region, followed by strictly lobar and strictly deep CMBs (23.4 and 12.2%, respectively). Studies of community-based populations showed the highest incidence of cortico-subcortical
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CMBs.16,23 For example, the Rotterdam Scan Study found that 58.4% (146/250) of the examined patients exhibited strictly lobar CMBs and that 41.6% (104) exhibited deep or infratentorial CMBs (including 58 instances that were accompanied by lobar CMBs, thereby indicating mixed CMBs).23 A study of Chinese stroke patients reported the basal ganglia contained the highest incidence of CMBs [61.11% (44/72)], followed by the cortico-subcortical region [54.17% (39/72)].17 Another study of ischaemic stroke showed that most patients exhibited strictly subcortical CMBs [40.1% (101/252)] or mixed cortico-subcortical CMBs [34.9% (88/252)]. Only 17.5% (44/252) of the patients exhibited strictly cortical CMBs.24 The reason for the inconsistency between these findings may be because of differences in the study populations (e.g. race, disease status especially hypertension, CAA related to age and other factors), thereby leading to distinct incidences of CMBs, which represent specific aetiologies. Histopathologic analyses have been used to identify two types of vascular pathologies related to CMBs: hypertensive vasculopathy and CAA.3 Strictly lobar CMBs are likely caused by CAA because of their association with known risk factors for CAA, including the e4 genotype of apolipoprotein E.15,23 Non-invasive assessment of amyloid plaques via positron emission tomography (PET) using Pittsburgh Compound B revealed that CMBs in CAA patients occur preferentially in local regions containing concentrated amyloid-b accumulation.25 Deep CMBs are likely caused by hypertensive arteriopathy because of their associations with hypertension and other imaging manifestations of hypertensive SVD.1 However, the aetiology of mixed CMBs is difficult to identify. First, hypertensive arteriopathy preferentially involves the penetrating arterioles and therefore typically produces deep CMBs; however, severe hypertensive arteriopathy, which causes decreased vascular reactivity of the superficial cortical arteries, may be responsible for lobar CMBs.26 Second, CAA can coincide with hypertension-related arteriopathies.1 Thus, mixed CMBs may be caused by hypertension with or without CAA. It is very important to determine whether patients with mixed CMBs
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Figure 3 A 71-year-old man with mixed cerebral microbleeds (CMBs), including CMBs in the lobar, deep and infratentorial regions. Table 4 Association between the numbers of total, lobar, deep and infratentorial CMBs and the Fazekas scale scores Spearman’s r (P-value) Fazekas scale score PVH score DWMH score
r P-value r P-Value r P-value
No. of CMBs
No. of lobar CMBs
No. of deep CMBs
No. of infratentorial CMBs
0.342 0.000 0.296 0.000 0.338 0.000
0.213 0.003 0.175 0.017 0.206 0.005
0.256 0.000 0.221 0.002 0.272 0.000
0.213 0.003 0.173 0.018 0.227 0.002
CMBs: cerebral microbleeds; DWMH: deep white matter hyperintensity; PVH: periventricular hyperintensity.
Table 5 Fazekas scale scores of different groups stratified by CMB location N
Age (years)
A
44
70.39+ 10.77
3+ 1.463
B
23
70.61+ 11.90
3.39+ 1.994
C
12
73.33+ 11.35
3.92+ 2.021
D
109
71.42+ 10.41
4.14+ 1.536
Group
Fazekas scale score
P-value A vs B 0.354
A vs C 0.099 B vs C 0.401
A vs D 0.000 B vs D 0.062 C vs D 0.670
CMB: cerebral microbleed; A: group of patients with strictly lobar CMBs; B: group of patients with strictly deep CMBs; C: group of patients with strictly infratentorial CMBs; D: group of patients with mixed CMBs.
suffer from some degree of CAA. The diagnostic criteria for CAA (the ‘Boston criteria’), including the presence of strictly lobar ICH or lobar CMBs, are very highly specific. However, the sensitivity of this approach may be low.1 The patients with a mixed deep and lobar distribution of CMBs, who are likely to suffer from CAA, do not fulfil the Boston criteria.1 The use of newly developed technologies such as the assessment of amyloid plaques via PET may contribute to the diagnosis of CAA.5 In addition to neuroimaging processes, an examination of the cerebrospinal fluid can be helpful: the concentration of both Ab 1–42 and Ab 1–40 in the cerebrospinal fluid in patients suffering from CAA is decreased
compared with that in healthy controls and in patients suffering from Alzheimer-type dementia.5 However, because these tests are expensive or invasive, they are not commonly performed on patients with CMBs. In addition, there are other uncommon diseases related to CMBs, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, autoimmune encephalitis, head trauma, etc., rendering the diagnosis more difficult.2 Further research, including the development of novel biomarkers, should be performed to help identify the predictive value of the location of CMBs for CAA, hypertension and other diseases and their prognostic significance.
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Relationship between the severity and distribution of CMBs and LA Our study showed that the numbers of total, lobar, deep and infratentorial CMBs correlated with the Fazekas scale scores. These results were consistent with those of previous studies showing a relationship between the number of CMBs, including deep, mixed (deep and lobar) and strictly lobar CMBs, and the severity of LA (reflecting the severity of SVD).2,8,15 Just as the distribution of CMBs varies according to the aaetiology and severity of SVD, the pattern of LA may also vary.2 Patients with lobar ICH may exhibit a predominantly occipital LA distribution, which would be consistent with the relative predilection towards CAA in posterior brain regions.27 Our study showed that the LA severity of mixed CMBs was significantly higher than that of strictly lobar CMBs (P50.000) and non-significantly higher than that of strictly deep CMBs (P50.062). The limited sample size may have influenced this finding. The results indicated that in patients with mixed CMBs, hypertension and CAA may coincide and mutually exacerbate the development of white matter lesions. In addition, studies have shown that hypertension likely contributes to bleeding in CAA patients and that the control of hypertension (a moderate reduction in systolic/diastolic blood pressure amounting to 9/4 mmHg) reduces CAA-related haemorrhaging in 77% of patients.28 Furthermore, combined with our results, the control of hypertension may help to delay the exacerbation of white matter lesions in CAA patients. Our cross-sectional design limits our ability to examine whether the observed associations are causal. Prospective studies are needed to more thoroughly understand these issues. In conclusion, this study confirmed that the incidence of CMBs increases with age. Among all CMB types, the authors found that mixed CMBs displayed the highest incidence. The severity and number of CMBs at any location correlated with the severity of LA. Furthermore, the study results indicated that there may be an interaction between hypertension and CAA during the progression of LA. Confirmation of this hypothesis requires large-scale studies.
Acknowledgement This study was supported by a grant from the Science and Technology Program of Beijing, China (Grant No. D141100000114005).
Disclaimer Statements Contributors DF conceived this study and provided financial support. DF and QY designed the study. YY, CL, JL, XL, AW, JZ, MW, and XZ took part in the design of the study and in sample collection. DF, QY, and XZ conducted data management and
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analysis. DF was responsible for project management. QY and DF were responsible for preparing and revising the manuscript. Funding This study was supported by a grant from the Science and Technology Program of Beijing, China (Grant No. D141100000114005). Conflict of interest The authors report no conflicts of interest. Ethics approval
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