International Journal of Neuroscience, 2014; Early Online: 1–8 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2014.949703
ORIGINAL ARTICLE
The association between leukoaraiosis and carotid atherosclerosis: a systematic review and meta-analysis
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Shao-Qiong Liao,∗ Jing-Cheng Li,∗ Meng Zhang, Yan-Jiang Wang, Bing-Hu Li, Yan-Wei Yin, Yun Liu, Chang-Yue Gao, and Li-Li Zhang Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, P.R. China The association between large-artery atherosclerosis and leukoaraiosis (LA) has been increasingly reported with inconsistent conclusion. This systematic review examines the relationship between LA and carotid atherosclerosis, manifested as atherosclerotic stenosis, plaques and increased intima-media thickness (IMT). PubMed, Embase, and Web of Science were searched for articles published up to February 2014. Thirty-two studies that examined the relationship between LA and carotid atherosclerosis were included. All statistical analysis was conducted with Review Manager 5.2.4. Finally, 32 studies including 17,721 patients were identified. There were 7 (30%) out of 23 studies reporting significant association between LA and carotid stenosis; 11 (79%) out of 14 studies reporting significant association between LA and carotid plaque; all 9 studies reporting significant association between LA and carotid IMT; one study showing an association between LA and CAWT (similar to the role of the IMT). The quantitative meta-analysis of 10 studies showed that carotid atherosclerosis was not associated with LA (OR: 1.10; 95% CI: 0.61–1.98). A significant association was found between LA and carotid plaque (OR = 3.53; 95% CI = 1.83–6.79), and the result of IMT group showed that IMT increased risk of LA (MD = 0.11; 95% CI = 0.01–0.22). This systematic review suggested that LA has a tendency of association with carotid plaques but no association with simple carotid stenosis. KEYWORDS: Carotid atherosclerosis, carotid intima-media thickness, carotid stenosis, leukoaraiosis
Introduction Leukoaraiosis (LA), also known as white matter changes, is revealed as hyperintensities in T2 sequences and fluid-attenuated inversion recovery (FLAIR) in magnetic resonance imaging (MRI) or hypodensity with ill-defined margins in computed tomography (CT) in the areas of cerebral white matter, predominantly in aging brains [1,2]. LA is associated with cognitive impairment [3], gait abnormalities, falls, and late-onset depression [4]. Moreover, LA also represents an independent risk factor to predict future stroke [5,6], and stroke outcome in patients with LA is poor [7].
Received 19 April 2014; revised 6 July 2014; accepted 24 July 2014. ∗ These authors contribute equally to this article. Correspondence: Li-Li Zhang, Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, P.R. China. Tel: (01186) 23-68757842. Fax: (01186) 23-68757841. E-mail:
[email protected] The major pathological of LA is myelin pallor, enlargement of perivascular spaces, gliosis, and axonal loss [8]. It has been considered to be a consequence from cerebral small vessel disease [9], but impact of large-artery disease on LA is not yet clear. Large-artery atherosclerosis, especially carotid atherosclerosis, has been demonstrated to be closely related with ischaemic stroke. LA have been most often interpreted as “incomplete infarction”—tissue injury consistent with ischaemia not severe enough to produce frank infarction [4]. In fact, insufficient cerebral perfusion due to largevessel atherosclerosis may affect the severity of LA and an increased frequency of LA has been reported in patients with carotid atherosclerosis [10,11]. Moreover, LA could be partially reversible in patients with carotid artery stenosis [12]. Recently, increasing evidence indicate a relationship between carotid atherosclerosis and LA [13], although this remains controversial [14,15]. Herein, we performed a systematic review of published data to provide an overview of the association of carotid atherosclerosis and LA, hoping that this would throw light on the pathomechanism of LA. 1
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Methods
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Searches The aim of this meta-analysis was to evaluate all published or reported studies investigating the influence of extracranial or carotid atherosclerosis on LA. In accordance with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement [16], two investigators (Liao SQ and Li JC) independently conducted a search of the PubMed, Embase, and Web of Science databases supplemented by manual search of included articles’ reference lists. The language was restricted to English. To identify potentially relevant articles and abstracts, we used the terms LA or white matter changes/lesion/hyperintensity and matched with the terms carotid/extracranial atherosclerosis or carotid artery stenosis/disease searching for original articles published before February 2014.
Inclusion criteria Inclusion criteria for the studies included : (1) published case-control studies, cohort studies or cross-sectional studies; (2) the patients of case group suffered from LA (also known as white matter lesions, white matter hyperintensity, white matter ischaemia); (3) all the patients underwent effective imaging diagnosis such as magnetic resonance angiography (MRA), digital subtraction angiography (DSA), computed tomography angiography (CTA), carotid duplex ultrasound (CDUS) [17]. The atherosclerosis including: diameter stenosis demonstrated by DSA, MRA, and CTA; plaque or plaque composition demonstrated by MRA, CTA, and CDUS, even endarterectomy specimen; increased intima-media thickness (IMT) demonstrated by CDUS; (4) the full text of report was published. Papers in which the relationship between LA and carotid atherosclerosis was unclear or could not be determined were excluded. White matter changes resulting from multiple sclerosis, history of acute anoxia, radiation, and other known nonvascular causes were excluded. For the studies with the same or overlapping data, the most recent or largest population was selected (e.g. Streifler, Eliasziw [18] and Streifler, Eliasziw [19]). The decision to include or exclude studies was conducted independently by two of the investigators (Liao SQ and Li JC), with disagreements resolved by discussion.
Data extraction The following data were collected from each study: first author’s name, publication year, country, total number of participants of each study or number of patients
of case and control group, percentage of males, mean age and atherosclerosis assessment method. Information was carefully extracted from all included studies independently by two of the authors (Liao SQ and Li JC) according to the inclusion criteria listed above. Any disagreements about the data were resolved by the consensus with another author Zhang LL.
Statistical analysis The Microsoft Excel software was used in the tabulation and analysis of the abstracted data. Mean differences (MDs) and their 95% confidence intervals (95%CIs) were calculated for continuous variables. Odd ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated for dichotomous variables. The heterogeneity among studies was assessed by the Q-test and I2 statistic, and p < 0.10 and I2 > 50% indicated the evidence of significant heterogeneity. Pooled ORs were calculated with a fixed effects model, using the Mantel–Haenszel approach when no significant heterogeneity was observed among the studies. Otherwise, when significant heterogeneity among the studies was detected, a random effects model was adopted. Subgroup analyses were performed based on different appearances of atherosclerosis, including stenosis, plaques, and IMT. Sensitivity analysis was performed to investigate the influence of each included study on the pooled ORs, by repeating the fixed effects model or random effects model meta-analysis with each of the studies being individually removed. All above statistical analysis were performed using Review Manager 5.2.4. All statistical tests were two-sided, and p-values of 0.05 were considered to be statistically significant.
Results A total of 617 citations were identified by the electronic search. Based on the titles and abstracts, 33 studies were included for reviewing the full text and other 584 studies were excluded. In these 33 studies, one study was excluded because its patient population was also reported in another publication [18,19], only the more completed study was included [19]. Finally, 17 crosssectional studies[17,20–35] and 15 case-control studies [10,13,19,36–47] were included in this systematic review (Figure 1). Table 1 describes the characteristics of the included studies. Out of the included 32 studies, 22 were conducted in the Western and 10 were conducted in Asia. The studies’ sample sizes ranged from 23 to 3491. Total 17,721 participants were included. The minimum mean age is 56.2 and the maximum is 75.1 among all studies. In half of studies, mean age of the participants more International Journal of Neuroscience
Leukoaraiosis and carotid atherosclerosis Table 1.
Characteristics of included studies.
Study
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Country
Participants
Male (%)
Mean age
Imaging
Saba (2013) Chutinet (2012) Kandiah (2012) Potter (2012) Scherr (2012) Kwee (2011) Lee (2011) Enzinger (2010) Kearney (2009) Patterson (2009) Romero (2009) Shrestha (2009) Altaf (2006) De Leeuw (2000) Manolio (1999) Adachi (1997) Lindgren (1994)
Italy USA Singapore UK Austria Netherlands South Korea Austria France UK USA Japan UK Netherlands USA Japan Sweden
CTA CTA DUS DUS DUS MRI MRA DUS/MRA DUS DUS DUS DUS HS DUS DUS DUS DUS
Turkey China USA China Israel Italy China Italy South Korea France Canada Switzerland Netherlands Austria Switzerland
78.0 64.2 77.0 59.6 56.1 60.0 56.7 70.1 48.0 90.0 47.0 52.5 50.7 48.5 41.7 73.4 50.6 Control 92 478 256 68 98 22 148 44 287 531 2125 2140 81 11 31
71.0 62.5 56.2 68.5 70.2 67.7 67.0 69.1 69.3 73.5 58.0 66.0 69.2 72.2 75.1 68.2 65.1
Demirtas (2013) Li (2013) Schulz (2013) Shu (2013) Ben (2012) Saba (2011) Pu (2009) Saba (2009) Lee (2008) Pico (2002) Streifler (2002) Wisznicwsha (2000) Bots (1993) Fazekas (1988) Bogousslavsky (1987)
50 201 100 500 212 50 268 97 198 40 1971 179 57 1077 3491 323 77 LA 102 188 415 294 72 76 37 103 307 109 493 149 30 12 31
64.4 70.9 55.7 56.6 61.2 66.3 85.9 69.4 57.6 42.0 69.6 61.6 45.9 / 48.4
63.5 72.4 71.1 72.0 66.4 74.8 57.3 74.4 66.8 65.2 65.7 63.4 73.8 58.5 68.0
Stenosis
Plaque
IMT
Y Y YN N N Y Y
N
Y N Y
Y N N CTA DSA MRA US DUS CTA MRA CTA MRA DUS DUS DUS DUS DUS DUS
Y Y YN
Y N N
N N Y N N N N N N
Y Y YY
Y
Y Y Y
Y Y Y
Y Y
Y
Y
Y
CTA = computed tomography angiography; DUS = duplex ultrasound; MRI = magnetic resonance imaging; MRA = magnetic resonance angiography; HS = Histologic section; Y = Association, Y- = only association with periventricular or subcortical; LA N = No association.
than 65. The populations of included studies are various, such as patients with carotid stenosis and ischaemic symptoms, patients with/without ischemic stroke or patients retrospectively recruited from population-based studies.
Qualitative Analysis
Figure 1. Flow diagram of the study selection process.
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Table 1 also summarizes the findings (See Data Supplement) related to the association between LA and carotid atherosclerosis. Stenosis and plaque were studied most frequently, and stenosis, plaques and/or IMT were assessed together in some studies. A statistically significant association was found in all 9 papers [13,27,28,30,32,33,36,40,45] reporting on the relationship of IMT and LA. In addition, one study [41] showed an association between CAWT (similar to the role of the IMT) and LA. The relationship between LA and the presence of plaque or plaque characteristics
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Figure 2. Forest plot for carotid atherosclerosis (including stenosis and plaque) and LA.
were assessed. Seven studies out of the 14 exhibited positive relationship between LA and the presence of plaque [13,27,32,36,39,40,45]. Seven studies assessed the relationship between LA and unstable plaques, and positive results were found in 4 studies (including one unstable plaques [31], 3 fatty plaques [17,41,42]). In total, most studies (11 out of 14) showed a relationship between LA and carotid plaque. A total of 23 studies evaluated the relationship between carotid stenosis and LA. Seven [22,23,26,28,33,39,42] out of 23 studies found a relationship between LA and carotid stenosis. However, the majority of the studies (16 out of 23) showed no relationship between LA and carotid stenosis. Among these, 11 showed no relationship between LA and degree of carotid stenosis (the grading methods were varied) [10,13,21,24,25,34,38,41,43,44,47]. Five showed no relationship between LA and severe stenosis (≥50%) [19,20,35,37,46]. In addition, 6 studies evaluated the relationship between LA and carotid plaque and stenosis. Among the 6 studies, 4 showed a relationship between LA and carotid plaque, only 3 showed an relationship between LA and carotid stenosis (2 studies showed LA associated with plaques but not stenosis [13,41], 1 showed LA associ-
ated with stenosis but not plaques [33], 2 studies [39,42] showed both were related to and one neither [25]).
Quantitative synthesis Ten studies were included in quantitative synthesis. Figure 2 shows the results of meta-analysis on the relationship between carotid atherosclerosis (including diameter stenosis and plaque) and LA compared with no- LA. Random effects models were adopted to perform metaanalysis as there was a significant heterogenity (I2 = 91%, p ≤ 0.00001). The combined OR was 1.10 (95% CI: 0.61–1.98), which showed that carotid atherosclerosis was not associated with LA.
Subgroup analyses In the subgroup analyses, significant associations were found between LA and carotid plaque (OR = 3.53; 95% CI = 1.83–6.79; Figure 3), and the result of IMT group showed that increased IMT increased risk of LA (MD = 0.11; 95% CI = 0.01–0.22; Figure 4). Interestingly, the result of stenosis group showed that carotid stenosis was a protective factor for LA (OR = 0.53; 95% CI = 0.32–0.87; Figure 5).
Figure 3. Forest plot for carotid plaque and LA.
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Figure 4. Forest plot for carotid IMT and LA.
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Sensitivity analyses and publication bias The sensitivity analyses that omitted one study at a time and calculated the combined OR for the remaining studies yielded consistent results. In addition, no single study substantially contributed to the heterogeneity across studies. The funnel plots of the studies included quantitative synthesis were almost symmetrical (Figure 6). This may reflect that publication bias of our metaanalysis was little.
Discussion LA is a big public health problem, which increases the risk of stroke and dementia. Although the pathophysiology of LA remains speculative, epidemiologic studies have shown that LA is correlated with age, hypertension, arteriosclerosis, smoking, and diabetes [46,48]. Previously, LA is thought to be caused by pathologic thickening or necrosis of the vessel wall, and microatheromasin small cerebral endarteries [49]. However, there is increasing evidence for a close relationship between largeartery atherosclerosis and LA, but the conclusion is inconsistent. We use systematic review and meta-analysis, which has been widely used [50,51] to evaluate their relationship. This systematic review identified 32 studies focusing on the relationship between carotid atherosclerosis and LA. Only 18 out of 32 studies reported that carotid
Figure 5. Forest plot for carotid stenosis and LA.
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atherosclerosis (including diameter stenosis, plaque, and IMT) was associated with LA. The result of quantitative synthesis showed that carotid atherosclerosis (including diameter stenosis and plaque) was no associated with LA (OR = 1.10; 95% CI: 0.61–1.98). Eleven (79%) out of 14 studies reported that carotid plaque was associated with LA, and an association between LA and IMT was observed in all 10 studies. In order to better analyze the relationship between LA and carotid atherosclerosis, we did a subgroup analysis based on different appearances of atherosclerosis. Plaque was found to be a strong risk factor for LA, with an odds ratio of 3.53 (95% CI = 1.83–6.79), and increased IMT also is a risk factor for LA (MD = 0.11; 95% CI = 0.01–0.22). The average thickness of the combined media and intima is considered to be “normal” ranges between 0.5 and 1.2 mm [52], therefore, a carotid IMT of >1.1–1.2 mm is typically used to define the presence of a plaque [53–55]. In some studies, plaques were defined as a focal structure that encroached more than 0.5 mm into the arterial lumen (induce stenosis), or 50% of the surrounding intima-media thickness (IMT) value, or demonstrated a thickness of >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface, which shows that plaque and IMT are interacting and influencing each other. The possible explanation for the significant association between LA and carotid plaque and IMT was that embolic events from unstable carotid plaques might contribute to the development
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Figure 6. Funnel plot for carotid atherosclerosis (including
stenosis and plaque) and LA.
of LA. This supports the notion that the association between large-vessel disease and white matter ischemia may be indirect through the shared vascular risk factors. The possible mechanisms may include artery-to-artery thromboembolization and impaired hemodynamics caused by carotid atherosclerotic plaque [56]. Seven (30%) out of 23 studies reported that carotid stenosis was associated with LA. Interestingly, the result of stenosis subgroup showed that carotid stenosis was a protective factor for LA (OR = 0.53, 95% CI = 0.32–0.87). Stenosis of the carotid arteries is believed to decrease cerebral blood flow (CBF). If hypoperfusion was a mechanism of LA, we should have found an association between LA and increasing stenosis. However, the majority of the studies showed no relationship between LA and carotid stenosis. In fact, Patankar et al. [57] have found there was no evidence of a direct relationship between severity of LA and CBF, even some patients with severe reductions in CBF exhibited minimal LA. They suggested that reductions in global perfusion pressure are of minimal importance in the genesis of LA. Furthermore, in some patients with a severe carotid stenosis, the normal ICA distal to the stenosis is narrowed or collapsed [58–60], indicating particularly low poststenotic intraluminal pressure. Rothwell and Warlow [61] have demonstrated that low flow alone is not usually sufficient to cause ischemic event distal to symptomatic carotid stenosis, and poststenotic narrowing may be protective because blood flow distal to the stenosis is insufficient to carry emboli to the brain. Although some LA may be caused by insufficient blood supply to the cerebral white matter [62–64], others are not. In the brains of older individuals, whenever cortical atrophy and rarefaction of axons in the whitematter has led to significant widening of a large number of the perivascular spaces, the increased quantity of CSF
in these channels may result in the appearance of hypodense lucencies of the periventricular white matter on CT or MRI images [65]. So some “non-ischemic” LA may simply be a CT or MRI manifestation of the dilation of the perivascular spaces which were filled with CSF or atrophic changes that include gliosis or the loss of the myelinated axons seen in the normal-aging brain [66,67]. Several limitations should be acknowledged. First, most of the studies included in this study come from patients with symptomatic ischemic stroke or TIA, due to paucity of data on asymptomatic stroke and non-neuroimaging evidence. Considering that the development and progression of LA are associated with occurrence of strokes [68], and LA is more common in patients with symptomatic cerebrovascular disease, the evidence generated by this systematic review needs to be considered in the context of indirectness due to differences in population and setting. Second, there is heterogeneity in the techniques for the assessment of the LA and carotid atherosclerosis. Most studies used visual rating scales rather than quantitative volumetric measurement to assess the LA, while the latter may give a more sensitive measure of LA. Detecting carotid stenosis by DUS in some studies may introduce bias due to limited accuracy especially for evaluating mild carotid stenosis ≤50% [69].
Conclusion This systematic review suggests that LA has a tendency of association with carotid plaques which have the potential to cause artery-to-artery thromboembolization. This information could be used to optimize prevention strategies for LA and their consequences on the risk of stroke and dementia. However, LA was not association with simple carotid stenosis, although stenosis led to cerebral hypoperfusion and chronic ischemia. LA formation probably involves ischemic and nonischemic. Further exploration is necessary to distinguish “ischemic” and “non-ischemic” LA in order to initiate adequate preventive medication for future stroke, or to avoid unnecessary treatment of healthy individuals.
Declaration of Interest No competing interest declared. The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper. This work was supported by the Natural Science Foundation Project of CQ CSTC (CSTC2012 JJJQ10003 to Li-li Zhang) and the National Natural International Journal of Neuroscience
Leukoaraiosis and carotid atherosclerosis
Science Foundation of China (NSFC 81271282 to Jing-cheng Li).
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