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Symposium Reports |
1 Clinical Neuroscience, St George's, University of London, London, UK
Abstract
Cerebral small vessel disease results from ischaemia in the perforating arteries supplying the white matter and deep grey matter nuclei. It results in both focal lacunar infarction and more diffuse areas of chronic ischaemia (leukoaraiosis). Two subtypes may exist. One subtype (isolated lacunar infarction) is associated with single or a few larger lacunar infarcts without leukoaraiosis, and may result from microatheroma in the larger perforating arteries. The second subtype (ischaemic leukoaraiosis) results in multiple small lacunar infarcts with leukoaraiosis secondary to a diffuse arteriopathy affecting the smaller perforating arteries, usually occurring in the presence of hypertension. In this subtype, chronic hypoperfusion and impaired cerebral autoregulation have been reported. A number of lines of evidence support a pathogenic role of endothelial activation and dysfunction. Genetic predisposition has also been implicated. Associations with genes involved in endothelial function, including those regulating the renin–angiotensin system, endothelial nitric oxide and homocysteine levels, have been reported. However, not all results have been replicated and there are few robust replicable associations. Larger studies are required to determine definitively which associations represent important risk factors.
(Received 23 July 2007;
accepted after revision 8 October 2007; first published online 12 October 2007)
Corresponding author H. S. Markus: Clinical Neuroscience, St George's, University of London, Cranmer Terrace, London SW17 ORE, UK. Email: hmarkus{at}sgul.ac.uk
Cerebral small vessel disease (SVD) is an important cause of stroke and vascular dementia (dementia resulting from disease of the cerebral circulation). Disease of the small perforating end arteries within the brain results in a combination of small discrete lacunar infarcts and more diffuse areas of chronic ischaemia, seen radiologically as low signal on brain computed tomography (CT) imaging and high signal on T2-weighted magnetic resonance imaging (MRI). This latter appearance is referred to as leukoaraiosis. The neuropathological correlate of leukoaraiosis is gliosis, axonal loss and ischaemic demyelination (Fisher, 1991).
Lacunar stroke accounts for a quarter of ischaemic strokes. It also causes asymptomatic cerebral infarction; this is increasingly common with age. Cerebral SVD is an important cause of age-related cognitive decline and vascular dementia. It is likely that both lacunar infarction and leukoaraiosis contribute to the cognitive impairment. Magnetic resonance imaging white matter hyperintensities (WMH) which, when confluent, appear usually to be caused by cerebral SVD, become increasingly common with age (Garde et al. 2000). Recent clinical trials reported that cerebral SVD was the most common cause of vascular dementia (Erkinjuntti et al. 2002).
For such a common disease there is relatively limited pathological information and this partly reflects the low early mortality rate following lacunar stroke compared with other types of stroke. The most reported abnormality in the cerebral small vessels is a diffuse arteriopathy with hyaline deposition; an appearance described as lipohyalanosis (Fisher, 1991). Atheroma has also been reported in the larger intracerebral arteries at the origin of the perforating arteries and in the proximal portion of the perforating arteries themselves. It was suggested by Miller Fisher in his early neuropathological studies that there may be two types of cerebral SVD: one with single or a few larger lacunar infarcts caused by disease in the larger perforating arteries resulting from atherosclerosis, and the other with multiple smaller lacunar infarcts resulting from a diffuse arteriopathy affecting the smaller perforating vessels, with the underlying pathology being lipohyalinosis usually due to hypertension (Fisher, 1968). This concept was extended into the clinical arena by Lodder and colleagues (Boiten et al. 1993) and has been extended further more recently with the use of MRI, which has shown that the second subtype with multiple lacunar infarcts is usually associated with leukoaraiosis. There are significant risk factor differences between the two subtypes, suggesting that they do indeed represent different pathologies, with hypertension being particularly important for the leukoaraiosis subtype (Khan et al. 2007b). It is this subtype which has been particularly associated with endothelial dysfunction (see below).
Pathogenesis of cerebral SVD
Simplistically, it is hypothesized that acute ischaemia resulting in disruption in a perforating artery results in lacunar infarction, while more chronic ischaemia results in leukoaraiosis. The perforating arteries are end arteries and therefore disruption of flow will result in infarction in the small region supplied by that artery, i.e. a lacunar infarct. Leukoaraiosis first occurs in the periventricular and deep white matter regions, both of which are internal watershed regions. Therefore, perfusion pressure will be lowest in these areas and this will be exacerbated by any diffuse arteriopathy, making them most susceptible to chronic ischaemic damage.
What triggers lacunar infarction remains uncertain. Thrombus in a perforating artery on MRI, which subsequently resolved, has been demonstrated in patients presenting with lacunar stroke (Wardlaw et al. 2001). However, this was hours or days after stroke onset, and the initiating event remains uncertain. There is considerable evidence that chronic hypoperfusion is important in the pathogenesis of leukoaraiosis. Cerebral blood flow studies using a variety of techniques, including positron emission tomography and MRI, have shown hypoperfusion. Using endogenous contrast MRI perfusion, it has been shown that perfusion is reduced in the white matter but not in the grey matter (Markus et al. 2000) and that within the white matter it is reduced not only within regions of radiological leukoaraiosis but also in normal appearing white matter, although to a lesser extent (O'Sullivan et al. 2002). This would support a causal role rather than a reduction in perfusion merely secondary to reduced demands of damaged tissue. Some studies have also demonstrated impaired cerebral autoregulation in patients with leukoaraiosis, although measuring this in the white matter presents technical challenges (Terborg et al. 2000). This has led to the suggestion that the diffuse arteriopathy results in a reduction in cerebral perfusion and impaired cerebral autoregulation, which can lead to chronic ischaemia, possibly exacerbated during episodes of systemic hypoperfusion.
Endothelial dysfunction as a risk factor for cerebral SVD
Inhibition studies using the nitric oxide inhibitor NG-monomethyl-L-arginine have demonstrated that endothelial nitric oxide release plays an important role in maintaining normal cerebral blood flow (White et al. 1998, 1999) and mediating dynamic autoregulation (White et al. 2000) in man. Therefore, the reduction in cerebral blood flow and autoregulation reported in cerebral SVD raises the possibility that endothelial dysfunction may be present. Considerable evidence now supports this hypothesis. Neuropathologically, increased expression of endothelial markers such as intracellular adhesion molecule 1 (ICAM-1) can be demonstrated (Fernando et al. 2006). Elevated levels of circulating markers of endothelial cell activation/dysfunction such as ICAM-1 and thrombomodulin are found in symptomatic cerebral SVD (Hassan et al. 2003). Support for a causal rather than a secondary role comes from prospective data from the Austrian Stroke Prevention Study (ASPS), which is looking at progression of asymptomatic WMH in a community population. In this study, ICAM-1 levels correlated with leukoaraiosis progression after controlling for both conventional risk factors and baseline lesion load (Markus et al. 2005). Blood levels of the endogenous non-isoform-specific inhibitor of nitric oxide synthase asymmetric dimethylarginine (ADMA) are elevated in lacunar stroke and correlate with the degree of leukoaraiosis (Khan et al. 2007a). Further support, although not always consistent, has come from candidate gene association studies (see below). Impairment of endothelial function in systemic vessels has also been associated with lacunar stroke (Pretnar-Oblak et al. 2006), raising the possibility that cerebral SVD is part of a systemic endotheliopathy but that symptoms are most pronounced in the brain, possibly due to the unique characteristics of the blood–brain barrier or secondary to features of the cerebral perforating vessels. Experience with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) may be relevant. This autosomal dominant cause of cerebral SVD results in recurrent lacunar strokes and dementia. It is caused by mutations in the notch-3 gene. A systemic arteriopathy is found even though the pathology is more severe, and clinical symptoms confined to, the brain. Deposition of the extracellular portion of notch 3 in the arterial wall of both cerebral and systemic arteries can be identified adjacent to granular osmiophilic material, a deposition of unknown composition. However, the mechanisms linking the mutation to arterial damage, and whether this relates to a toxic gain of function or deposition of the aberrant notch 3, are not understood. Within the brain, diffusely abnormal vessels without severe stenoses are found (Okeda et al. 2002). In notch-3 transgenic mice, early abnormalities in endothelium-mediated vasodilatation and cerebral vessel reactivity have been reported prior to the onset of typical neuropathological changes (Lacombe et al. 2005; Dubroca et al. 2005).
Homocysteine may represent an important endothelial toxin in cerebral SVD. A number of studies have demonstrated elevated serum homocysteine levels in cerebral SVD, particularly in the leukoaraiosis subtype (Fassbender et al. 1999; Hassan et al. 2004b). In vitro studies have shown that homocysteine is an endothelial toxin. The association between homocysteine and cerebral SVD was no longer significant after controlling for the endothelial markers ICAM-1 and thrombomodulin (Hassan et al. 2004b), supporting the hypothesis that elevated homocysteine mediates its effect via endothelial damage.
Two major mechanisms have been proposed by which endothelial dysfunction could cause leukoaraiosis. The first is chronic hypoperfusion, as outlined above. The second is increased blood–brain barrier permeability, with leakage of plasma components into the vessel wall and surrounding brain parenchyma (Wardlaw et al. 2003). Blood–brain barrier permeability is supported by studies demonstrating leakage of albumin into the cerebrospinal fluid in patients with vascular dementia (Wardlaw et al. 2003). More recently, it has been shown that the intravenously injected magnetic resonance contrast agent gadolinium leaks into the brain in patients with cerebral SVD and also in diabetics who are predisposed to the condition (Hanyu et al. 2002; Starr et al. 2003). In the diabetic population, more leakage was seen in individuals with leukoaraiosis (Starr et al. 2003).
Genetics, endothelial function and SVD
Genetic predisposition is important for cerebral SVD. A twin study in healthy individuals quantifying MRI WMH reported a heritability of 71% (Carmelli et al. 1998). Family history of stroke is a risk factor for lacunar stroke, particularly at younger ages (Polychronopoulos et al. 2002; Jerrard-Dunne et al. 2003).
A number of phenotypes have been used to examine associations between a variety of endothelial candidate genes and cerebral SVD. These include symptomatic lacunar stroke with or without leukoaraiosis, and asymptomatic WMH either in community populations or in at risk populations, such as hypertensive individuals. Confluent, although not punctate, WMH in community populations appears to correlate neuropathologically with cerebral SVD (Fazekas et al. 1993).
The renin–angiotensin system has received most attention. An early study reported an association between an angiotensin-converting enzyme (ACE) insertion–deletion (I/D) polymorphism and lacunar stroke but much less or no association with other types of ischaemic stroke (Markus et al. 1995). This polymorphism is associated with elevated plasma ACE levels. Similar findings have been shown in some but not all other studies in Caucasian populations (Ueda et al. 1995; Catto et al. 1996; Hassan et al. 2002; Szolnoki et al. 2002). In most studies, the ACE I/D polymorphism has been studied alone, as a marker in linkage disequilibrium with an unidentified nearby functional variant. Haplotype analysis allows improved characterization of genetic variation in the ACE gene (Keavney et al. 1998). In a recent study in which eight ACE polymorphisms were studied and haplotype analysis performed, in 300 well-phenotyped SVD cases and 600 control subjects no association was found (Gormley et al. 2006). When these data were included in a meta-analysis of all studies in Caucasian populations (Fig. 1A), no significant association was reported (Gormley, 2007). A number of studies have also been performed in Asian, predominantly Chinese, populations. In this ethnic group, cerebral SVD appears more common. Most have been relatively small studies, but a meta-analysis (Fig. 1B) did suggest a significant association (odds ratio 1.79, 95% confidence interval 1.39–2.31; Gormley, 2007). There may, however, be significant publication bias in genetic association studies which can lead to errors in meta-analysis, and larger studies are required to confirm whether this is a real association.
Genetic variation in the angiotensinogen (AGT) gene has also been associated with cerebral SVD. Owing to its effects on cardiac and vascular function, the AGT gene has been widely studied in essential hypertension. In the ASPS, the promoter –20C polymorphism was associated with leukoaraiosis. When further single nucleotide polymorphisms (SNPs) in the promoter region were examined, homozygotes with a particular haplotype (ACGG at the loci –6G > A, –20 A > C, –153G > A and –218G > A) had a higher rate of asymptomatic SVD (63.6 versus 19%), but this was in a small number of individuals (Schmidt et al. 2001). The AGT –20C polymorphism has been associated with increased basal promoter activity (Zhao et al. 1999). In 300 well-phenotyped symptomatic SVD cases and 600 control subjects, three promoter (–18G > A, –20 A > C and –6G > A) and two coding exonic SNPs (174T > M and 235 M > T) were genotyped. No differences were found in genotype or haplotype distribution between cases and control subjects (Gormley et al. 2006). Amongst hypertensives, however, only the –20 A > C polymorphism was associated with the leukoaraiosis subtype of SVD (odds ratio 1.716, 95% confidence interval 1.073–2.746, P = 0.024). This would potentially be consistent with the ASPS data in that the leukoaraiosis subtype of symptomatic lacunar stroke is likely to be the equivalent of asymptomatic leukoaraiosis detected in a community population.
In addition to vasodilatory substances, such as nitric oxide, the cerebral endothelium secretes the vasoconstrictive endothelins (ETs). Investigation of associations with circulating ET levels is problematic because these may not reflect vascular production of endothelin-1, most of which is abluminal. Therefore, study of the genetic associations, particularly of functional polymorphisms that alter ET system activity, is an attractive method of determining whether ET does indeed play a role in SVD pathogenesis. This is an area of potential clinical importance because drugs that modulate ET function are becoming available. Polymorphisms in the ET1 gene (K198N), the ET receptor type A (ETa) (–231G > A, +122C > T) and the ET type B (ETb) receptor (G57S and L277L) were studied individually and as haplotypes in 300 SVD patients (Gormley et al. 2005). No association was found with any polymorphism or haplotype, either in SVD as a whole or in the isolated lacunar infarction or leukoaraiosis subtypes.
Variation in the endothelial nitric oxide synthase (eNOS) gene has also been studied. A promoter (T-786C) polymorphism and a 27 bp deletion polymorphism (A insertion, B deletion) within intron 4 have been associated with alterations in promoter activity (Wang et al. 2002). In addition, a variant located in exon 7 (G894T) which encodes an amino acid change from Glu to Asp is believed to render the enzyme more susceptible to proteolytic cleavage (Tesauro et al. 2000). In the French GÉNIC study, the 894GG genotype was found to be a risk factor for lacunar stroke but not for other stroke subtypes (Elbaz et al. 2000). A later study in SVD cases found no association with the 894 polymorphism, but the intron 4a allele was found to be protective against cerebral SVD, an effect which was confined to the isolated lacunar infarct (without leukoaraiosis) subtype (Hassan et al. 2004a). Associations were stronger when this was included in a haplotype also including the T-786C and G894T polymorphisms, although the predominant association came from the variable number tandem repeat (VNTR) polymorphism. Fasting plasma nitrate levels measured after a period of controlled nitrate intake were associated with the T-786C locus, although only in the presence of the intron 4a allele, but were not associated with the 894 polymorphism. An earlier study also found no association with the 894 polymorphism (Markus et al. 1998). The intron 4a allele has also been associated with all stroke subtypes (Hou et al. 2001), but this is at variance with the above study, which showed it to be protective in SVD (Hassan et al. 2004a).
The nitric oxide synthase interacting protein (NOSIP) appears to be involved in eNOS trafficking and to play a role in translocating eNOS from the plasma membrane to intracellular compartments. An analysis of eight SNPs in the NOSIP gene and a subsequent haplotype analysis found no association with cerebral SVD or its subtypes in 300 SVD cases and 600 control subjects (Gormley, 2007).
The reported association between elevated homocysteine levels with SVD, and particularly with the leukoaraiosis subtype (Hassan et al. 2004b), could either be causal or could be secondary to established disease. For example, if cerebral SVD is a systemic arteriopathy and there is also renal microvascular disease, this could lead to impaired clearance of homocysteine and secondary elevation of plasma serum levels. Examination of a genetic variant associated with increased homocysteine levels throughout life allows causality to be explored, an approach referred to as ‘Mendelian randomization’. The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with elevated homocysteine levels. A number of studies have shown no, or only weak, associations between a common MTHFR polymorphism and stroke as a whole. In contrast, an association was found in a well-phenotyped group of patients with lacunar stroke and, interestingly, this association was present only in the ischaemic leukoaraiosis subtype (Hassan et al. 2004b). This supports a causal role for homocysteine in this specific subtype.
Conclusions
As can be seen from this review, genetic association studies have implicated a number of genes involved in endothelial function and cerebral SVD. However, results have been inconsistent and often not replicated in larger well-phenotyped studies. Interpretation is further complicated by incomplete phenotyping in many studies, which sometimes does not even allow accurate separation of lacunar stroke from other subtypes of stroke, and in few studies is sufficient to allow division of SVD into its different subtypes. Accurate phenotyping of cerebral SVD requires brain imaging, ideally MRI, and also imaging of the heart and extracerebral vessels to exclude other causes of small deep infarcts. However, perhaps the most important limitation has been the small sample sizes in many studies. This has been a problem in genetic studies in stroke as a whole, not only those in cerebral SVD. It has led to methodological recommendations for stroke genetics studies (Dichgans & Markus, 2005).
Increasingly, studies are being performed with larger sample sizes, and the importance of primary replication in a second population is being appreciated. Large collaborative DNA banks are being established, such as the UK Stroke Genetics Group's Young Lacunar Stroke Resource (http://www.strokegenetics.co.uk). This is recruiting 1100 younger patients (65 years or less) presenting with a lacunar stroke, all of whom will have MRI and other appropriate imaging. A corresponding control cohort of 2000 individuals is also being recruited. With the revolution in genotyping technology, it is likely that these will be primarily used for genome-wide association studies. This approach has shown recent promising results in other complex genetic diseases, such as diabetes, obesity and myocardial infarction.
In conclusion, considerable evidence suggests that endothelial dysfunction may play an important role in cerebral SVD, particularly the leukoaraiosis subtype. This could result in cerebral hypoperfusion and impaired autoregulation and/or increased blood–brain barrier permeability. There is evidence that genetic factors are important in cerebral SVD, particularly in younger individuals. A number of genes involved in endothelial regulation have been implicated as risk factors, but many associations have been found to be inconsistent and not replicable. The importance of these genetic influences is likely to be answered only by much larger collaborative studies.
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