Review: molecular genetics and pathology of hereditary small vessel diseases of the brain

Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-β signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.     

Virchow-Robin spaces relate to cerebral small vessel disease severity

BACKGROUND AND PURPOSE: Virchow-Robin spaces (VRs) are perivascular spaces surrounding the deep perforating brain arteries. VRs dilatation is pathologic, and it could be a manifestation of cerebral small vessel disease. In the present study we assessed the relation between VRs and silent ischemic lesions in a cohort of patients with cerebral small vessel disease. METHODS: We divided dilated VRs on MRI (1.5 Tesla) into three semi-quantitative categories in 165 first ever lacunar stroke patients. We counted asymptomatic lacunar infarcts and graded white matter lesions, and compared the prevalence of vascular risk factors in different categories of VRs. We also determined independent predictors of silent ischemic lesions. RESULTS: VRs at basal ganglia level related to age, hypertension, asymptomatic lacunar infarcts, and white matter lesions. VRs at basal ganglia level predicted silent ischemic lesions (odds ratio 10.58 per higher VRs category; 95 %- confidence interval 3.40 - 32.92). CONCLUSION: Dilated VRs in the basal ganglia relate to the severity of cerebral small vessel disease and might be a manifestation of the same small vessel abnormality that causes silent ischemic lesions. This adds a role for VRs as a potential marker for small vessel disease.     

Diffusion tensor MRI correlates with executive dysfunction in patients with ischaemic leukoaraiosis

BACKGROUND: Cerebral small vessel disease is a common cause of vascular dementia. Both discrete lacunar infarcts and more diffuse ischaemic changes, seen as confluent high signal (leukoaraiosis) on T2 weighted magnetic resonance imaging (MRI), occur. However, there is a weak correlation between T2 lesion load and cognitive impairment. Diffusion tensor MRI (DTI) is a new technique that may provide a better index of white matter damage. OBJECTIVES: To determine whether DTI measures are correlated more strongly with cognitive performance than lesion load on T2 weighted images, and whether these correlations are independent of conventional MRI parameters. METHODS: 36 patients with ischaemic leukoaraiosis (leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment. RESULTS: On DTI, diffusivity was increased both within lesions and in normal appearing white matter. Mean diffusivity of normal appearing white matter correlated with full scale IQ (r = -0.46, p = 0.009) and tests of executive function. These correlations remained significant after controlling for age, sex, brain volume, and T1/T2 lesion volumes. No significant correlation was identified between T2 lesion load and IQ or neuropsychological scores. Of conventional measures, brain volume correlated best with cognitive function. CONCLUSIONS: Diffusion tensor measurements correlate better with cognition than conventional MRI measures. They may be useful in monitoring disease progression and as a surrogate marker for treatment trials. The findings support the role of white matter damage and disruption of white matter connections in the pathogenesis of cognitive impairment in cerebral small vessel disease.     

脑小血管病变和抑郁的关系

脑小血管病变是指一组累及脑部小动脉、细动脉和静脉以及毛细血管病变的总称,影像学特点主要包括脑白质病变、腔隙性脑梗死和微出血。脑小血管病变与抑郁的发病及预后相关,其主要的作用机制为小血管病变破坏了皮质-纹状体-苍白球-丘脑皮质环路。本文针对脑小血管病变与抑郁的关系这一热点问题,分别从脑白质病变、腔隙性脑梗死及微出血与抑郁的关系方面对其进行阐述。     

前循环小的深部脑梗死与颅内外大动脉病变

小的深部脑梗死多数被认为与小血管病变有关,常与腔隙性脑梗死划为同一范畴。然而,小的深部脑梗死经常与同侧颅内外大动脉病变同时存在。本文目的即在于探讨二者之间的关系。本文共回顾了21篇国外相关文献,主要涉及前循环大动脉狭窄梗死的类型以及大动脉狭窄所致小的深部脑梗死的发病机制。颅内外大动脉病变能够造成类似“腔隙性梗死”的小的深部脑梗死。     

COL4A1 Mutation as a Cause of Familial Recurrent Intracerebral Hemorrhage

The COL4A1 mutation is a very rare monogenic cause of small vessel disease related to recurrent intracerebral hemorrhage. We report a family in which the index case presented with two intracerebral hemorrhages in the basal ganglia with severe periventricular leukoaraiosis and a cataract and vascular tortuosity in the ophthalmological study. His twin brother also had severe leukoaraiosis and multiple subcortical microhemorrhages as well as a congenital cataract and vascular tortuosity in the retina. The older sister had a porencephalic cyst and involvement of the periventricular white matter and intracerebral hemorrhage. In single-gene testing, all three were found to have the same COL4A1 mutation.Intracerebral subcortical hemorrhages or microhemorrhages and severe subcortical leukoaraiosis in familial cases may be related to COL4 mutations.     

Cerebrovascular disease in Saudi Arabia

We studied the pattern and outcome of strokes in 200 Saudi patients. Cerebral infarction constituted 87% of strokes, subarachnoid hemorrhage 4.5%, cerebral hemorrhage 6.5%, and venous infarction 2%. The vessel most commonly involved was part or all of the middle cerebral artery, constituting 52% (90) of the 174 arterial infarcts. Lacunar infarcts were seen in 21% (37) of the patients with arterial infarcts. Among all 200 patients, 8% died and 8% had secondary generalized seizures. Hypertension occurred in 41% of the 174 patients with arterial infarcts and 62% of the 13 with cerebral hemorrhages. The highest incidence of hypertension as a risk factor was among those with lacunar infarcts (81%), ganglionic cerebral hemorrhages (80%), and infarcts of deep branches of the middle cerebral artery (57%). Embolic infarcts due to rheumatic heart disease constituted 11% of all arterial infarcts. We conclude that our pattern of strokes is similar to that of the west rather than that of the Japanese, but with less frequent arteriovenous malformations and aneurysms.     

脑白质疏松和陈旧性腔隙性脑梗死对首发缺血性卒中患者预后的影响

目的 探讨脑白质疏松和陈旧性腔隙性脑梗死对于首发缺血性卒中患者预后的影响。 方法 连续选取791例7 d以内首次发病的非心源性缺血性卒中患者。收集患者的人口学信息和脑血 管病的危险因素,评价患者的头颅磁共振成像包括脑白质疏松的严重程度、无症状性腔隙性脑梗死 的数量、缺血性卒中的病因分型以及急性梗死灶的分布特征,通过多因素Logistic回归分析脑白质疏 松和陈旧性腔隙性脑梗死与缺血性卒中患者预后相关的危险因素。 结果 分别有14例（1.8%）、38例（4.8%）患者在缺血性卒中发病1年内死亡、缺血性卒中或短暂性脑 缺血发作（transient ischemic attack,TIA）复发。多元Logistic回归发现：存在陈旧性腔隙性脑梗死、有 皮层新发脑梗死灶、入院后未给予抗血小板药物、出院时未服用他汀药物是缺血性卒中患者1年内 死亡的危险因素;而脑白质疏松对于缺血性卒中患者1年内的死亡无显著影响。冠状动脉粥样硬化性 心脏病、入院美国国立卫生研究院卒中量表（National Institute of Health stroke scale,NIHSS）评分<4 分、新发梗死灶的责任脑动脉闭塞或狭窄程度≥70%、出院时未给予抗血小板药物是缺血性卒中患 者1年内缺血性卒中或TIA复发的危险因素;而脑白质疏松和陈旧性腔隙性脑梗死对于缺血性卒中患 者1年内缺血性卒中或TIA的复发无显著影响。 结论 陈旧性腔隙性脑梗死是缺血性卒中患者1年内死亡的危险因素。而脑白质疏松和陈旧性腔隙 性脑梗死对于缺血性卒中患者1年内缺血性卒中或TIA的复发无显著影响。     

Relation of leukoaraiosis to lesion type in stroke patients

Nonspecific periventricular white matter lucencies on computed tomograms (leukoaraiosis) were found in 141 (38%) of 367 patients with ischemic or hemorrhagic strokes. Patients with leukoaraiosis were significantly older than those without it and were significantly more likely to have hypertension, diabetes mellitus, general vascular disease, and lacunar infarcts on computed tomograms but were less likely to have cortical infarcts. Because many of these variables may be mutually dependent, we performed a logistic regression analysis examining all clinical and computed tomographic variables. The analysis demonstrated that increasing age, lacunar infarcts, and hemorrhages were significant determinants of leukoaraiosis; cortical infarcts were also significantly, but negatively, correlated with leukoaraiosis. In patients with hemorrhages, leukoaraiosis occurred significantly more often when aneurysms or arteriovenous malformations were not demonstrated. These findings suggest that in patients with cerebrovascular disorders leukoaraiosis is associated with small-vessel disease.     

Acute vestibular syndrome in a patient with cerebral autosomal dominant leukoencephalopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary form of small vessel disease in which the pons may show lacunar infarcts and leukoaraiosis. Acute pure vestibular syndrome may be due to caudal pontine lesions and is probably underestimated. We describe a case of CADASIL with acute vestibular syndrome mimicking peripheral vestibulopathy, and evidence of focal infarction in the ponto-medullary junction at gadolinium-enhanced MRI including diffusion-weighted imaging, involving the area of the right vestibular nucleus and root entry zone of the ipsilateral vestibular nerve bundle. In CADASIL, both focal brainstem lesions and leukoaraiosis may parallel supratentorial white matter changes and may be related to poor outcome. Their actual extent should be evaluated in longitudinal studies that might predict clinical outcome and progression of disability.     

MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited, autosomal dominant condition caused by mutations of the Notch3 gene. Affected individuals have migraine, mood disturbance, and recurrent strokes, often progressing to subcortical dementia and premature death. MRI findings include focal lacunar infarcts and diffuse T2-weighted hyperintensity, or leukoaraiosis. However, such findings are seen much more commonly in patients with cardiovascular risk factors, particularly hypertension, where they are believed to represent cerebral small vessel disease. No previous study has sought to identify specific radiologic markers of CADASIL. METHODS: MRI scans from 20 consecutive patients with CADASIL and 20 patients with sporadic leukoaraiosis due to presumed small-vessel disease were compared using the previously validated semiquantitative MRI rating scale devised by Scheltens et al. Analysis was blinded to clinical category. RESULTS: Scores for hyperintensities of the temporal white matter and external capsule-insula region were significantly higher in patients with CADASIL. Hyperintensity confined to the pole of the temporal lobe was a characteristic finding in CADASIL, occurring in 19 patients with CADASIL but no patients with ischemic leukoaraiosis. Involvement of the external capsule, though less specific, was seen early in the disease course. In a few patients with CADASIL, involvement of the corpus callosum was observed. CONCLUSIONS: Temporal pole hyperintensity is a radiologic marker of CADASIL. Involvement of the external capsule and corpus callosum are also characteristic findings that may help to distinguish the disease.     

Cerebral small vessel disease in pseudoxanthoma elasticum: three cases

BACKGROUND: Cerebral small vessel disease is rarely described in association with pseudoxanthoma elasticum (PXE), a hereditary connective tissue disorder with skin, eye and vascular manifestations. This autosomally inherited elastic tissue disease has been attributed to mutations in the ABCC6 gene located on chromosome 16p13.1. Different stroke mechanisms are suggested in PXE patients, arterial hypertension and accelerated atherosclerosis being the leading ones. CASE DESCRIPTIONS: Case 1: A 49-year-old man with history of mild hypertension presented with recurrent transient ischemic attacks. At the age of 42, evaluation for progressive visual loss and skin changes led to diagnosis of PXE. Brain magnetic resonance imaging (MRI) disclosed multiple lacunar infarctions and confluent periventricular white matter lesions (WML). Case 2: A 71-year-old woman with history of mild hypertension suffered right-sided stroke. Diagnosis of PXE was made at the age of 48 due to severe visual loss and skin changes. Brain MRI revealed multiple lacunar infarctions and subcortical ischemic leukoencephalopathy. Case 3: A 47-year-old woman with prominent skin changes and bilateral amblyopia developed right-sided weakness. Skin biopsy confirmed PXE. Several lacunar infarcts in deep white matter and pons were revealed on MRI. DISCUSSION: We present three patients with clinical and histopathological features of PXE who presented with multiple lacunar strokes, two with extensive confluent WML. These cases illustrate that PXE is a rare but significant risk factor for small vessel disease and stroke in patients of all age groups. Occlusive small vessel disease and subsequent lacunar infarcts and WML represent important PXE manifestations.     

Angiotensin converting enzyme insertion/deletion genotype is associated with leukoaraiosis in lacunar syndromes

OBJECTIVES: Pathological and clinical data suggest that patients presenting with ischaemic lacunar syndromes may be a heterogenous group. Those with isolated lacunar infarction are thought to have localised atherosclerosis whereas in those with coexisting leukoaraiois a distinct diffuse small vessel vasculopathy may be the predominant underlying pathology. The ACE insertion/deletion (I/D) polymorphism is an important candidate gene in ischaemic cerebrovascular disease but, where lacunar stroke specifically has been examined, there have been discrepant reports concerning a possible association. It was hypothesised that the influence of the ACE gene may be different among the two subgroups of ischaemic lacunar stroke reflecting the heterogeneity of the small vessel disease phenotype. METHODS: Eighty four consecutive patients presenting with classic lacunar syndromes were studied. All had acute cranial CT to exclude primary intracerebral haemorrhage and these were subsequently assessed for the presence and extent of leukoaraiosis. All patients were genotyped for the ACE insertion/deletion polymorphism. RESULTS: There was a significant difference in the distribution of ACE genotype with the DD genotype occurring more often in patients with leukoaraiosis and the II and ID genotypes occurring more often among those in whom this was absent (chi(2)=9.06, p=0.01). In a logistic regression model the ACE DD genotype remained as an independent predictor for the presence of leukoaraiosis (p=0.02) in patients presenting with classic lacunar syndromes. CONCLUSION: This study supports the hypothesis that there may be different types of small vessel disease in patients with classic lacunar syndromes and that the influence of the ACE DD genotype may be relevant in mediating the diffuse form of vessel injury.     

Risk factor profile of cerebral small vessel disease and its subtypes

Background

The mechanisms of cerebral small vessel disease (SVD) are unclear. Both atherosclerosis and a non‐atherosclerotic diffuse arteriopathy have been reported pathologically. Two pathological and radiological subtypes have been suggested: localised atherosclerotic disease in larger perforating arteries causing larger lacunar infarcts without leukoaraiosis, and diffuse disease in smaller arterioles causing multiple smaller lacunar infarcts with leukoaraiosis. If atherosclerosis were important in SVD as a whole or in one particular subtype, one would expect the risk factor profile to be similar to that of cerebral large vessel disease (LVD).

Methods

Risk factor profiles were compared in Caucasian stroke patients with SVD (n = 414), LVD (n = 471) and 734 stroke‐free Caucasian population controls. Patients with SVD were subdivided according to the presence or absence of confluent leukoaraiosis, into isolated lacunar infarction (ILI) and ischaemic leukoaraiosis (ILA).

Results

Hypertension was commoner in SVD than LVD (odds ratio (OR) 3.43 (2.32 to 5.07); p<0.001) whereas hypercholesterolaemia (OR 0.34 (0.24 to 0.48); p<0.001), smoking (OR 0.63 (0.44 to 0.91); p = 0.012), myocardial infarction (OR 0.35 (0.20 to 0.59); p<0.001) and peripheral vascular disease (OR 0.32 (0.20 to 0.50); p<0.001) were commoner in LVD. Among SVD patients, age (OR 1.11 (1.09 to 1.14); p<0.001) and hypertension (OR 3.32 (1.56 to 7.07); p = 0.002) were associated with ILA and hypercholesterolaemia (OR 0.45 (0.28 to 0.74); p = 0.002), diabetes (OR 0.42 (0.21 to 0.84); p = 0.014) and myocardial infarction (OR 0.18 (0.06 to 0.52); p = 0.001) with ILI.

Conclusion

SVD has a different risk factor profile from the typical atherosclerotic profile found in LVD, with hypertension being important. There are differences in the risk factor profile between the SVD subtypes; the association of ILI with hypercholesterolaemia, diabetes and myocardial infarction may be consistent with a more atherosclerotic aetiology.The pathogenesis of cerebral small vessel disease (SVD) is incompletely understood. Hypertension is a major risk factor but fails to account for all of the risk.¹ Neuropathological data, particularly soon after a lacunar stroke, are limited because of low case fatality. Pathological vascular abnormalities reported include both a diffuse arteriopathy of the perforating arteries with hyaline deposition, an appearance referred to as lipohyalinosis, and microatheroma.²Based on pathological studies, it has been suggested that there may be two types of SVD that can be differentiated on brain imaging.³ The first involves atheroma at the origins or proximal portions of the larger (200–800 μm diameter) perforating arteries. This is associated with single or a few larger lacunar infarcts without leukoaraiosis. The second involves a diffuse arteriopathy of the smaller perforating arteries, 40–200 μm in diameter, resulting in multiple smaller lacunar infarcts with leukoaraiosis. Endothelial dysfunction may play an important role in the pathogenesis of this SVD subtype. A reduction in white matter cerebral blood flow⁴ and autoregulation,⁵ both dependent on nitric oxide released from the endothelium, has been reported in lacunar infarction with leukoaraiosis. Furthermore, circulating markers of endothelial activation are elevated in lacunar infarction with leukoaraiosis,⁶ and specific associations have been reported with homocysteine, which is toxic to the endothelium.⁷One way of obtaining information on pathogenesis is to compare the risk factor profile between different stroke subtypes. If atherosclerosis plays an important role in SVD, one would expect the risk factor profile to be similar to that seen in patients with large artery atherosclerotic stroke. Furthermore, as suggested by pathological studies in SVD, if atherosclerosis is more important in lacunar infarction without leukoaraiosis compared with lacunar infarction with leukoaraiosis, one might expect differences in the risk factor profile between the two proposed subtypes of lacunar stroke, with a more atherosclerotic profile seen in lacunar infarction without leukoaraiosis.A meta‐analysis of four community based clinical studies demonstrated that there are differences in the risk factor profile between ischaemic stroke subtypes.⁸ Large vessel disease (LVD) stroke was associated with male sex, smoking and raised cholesterol, while SVD was associated with hypertension. However, there were several limitations to these studies, including small SVD and LVD sample sizes, lack of MRI imaging in all studies, variability in risk factor definition between studies, inclusion of hypertension and diabetes in the SVD definition by some studies which may result in biased risk factor–stroke subtype associations, and failure to prospectively subtype patients using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria in one large stroke cohort used in the meta‐analysis. In this same cohort, a significant proportion of patients did not have carotid imaging. It has been shown that subtyping based on clinical presentation alone without imaging of the large arteries cannot reliably distinguish SVD from LVD.⁹ Studies have also suggested there may be differences in the risk factor profile between the two subtypes of cerebral SVD but data are limited and most studies have been small,^{3,10,11,12,13,14} and this was not covered in the meta‐analysis above.In this study, we used a large well‐phenotyped group of patients with SVD and LVD to determine differences in the risk factor profile between the two groups. All patients had brain imaging and imaging of the extracranial cerebral arteries. In addition, differences in the risk factor profile between the two proposed subtypes of SVD were determined.     

COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy

Type IV collagen α1 and α2 chains form heterotrimers that constitute an essential component of basement membranes. Mutations in COL4A1, encoding the α1 chain, cause a multisystem disease with prominent cerebrovascular manifestations, including porencephaly, bleeding-prone cerebral small vessel disease, and intracranial aneurysms. Mutations in COL4A2 have only been reported in a few porencephaly families so far. Herein, we report on a young adult patient with recurrent intracerebral hemorrhage, leukoencephalopathy, intracranial aneurysms, nephropathy, and myopathy associated with a novel COL4A2 mutation. We extensively investigated a 29-year-old male patient with recurrent deep intracerebral hemorrhages causing mild motor and sensory hemisyndromes. Brain MRI showed deep intracerebral hemorrhages of different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally. Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase. Genetic testing found a de novo glycine mutation within the COL4A2 triple helical domain. The presented case completes the spectrum of cerebral and systemic manifestations of COL4A2 mutations that appears to be very similar to that in COL4A1 mutations. Therefore, we emphasize the importance of screening both COL4A1 and COL4A2 in patients showing recurrent intracerebral hemorrhage of unknown etiology, particularly if associated with leukoencephalopathy.     

症状性小动脉硬化脑小血管病患者脑微出血的危险因素分析

目的 应用头颅MRI 的SWI序列检测症状性小动脉硬化脑小血管病（cerebral small vessel disease,CSVD）患者脑微出血（cerebral microbleeds,CMBs）灶,分析不同部位CMBs的临床特征差异及CMBs的危险因素。方法 回顾性纳入2017年3月—2018年10月就诊于新疆昌吉州中医院神经内科的小动脉硬化的CSVD患者。根据有无微出血分为CMBs组与无CMBs组。应用二元logistic回归分析CMBs的独立危险因素;判断CMBs数量分级与独立危险因素的相关性。根据CMBs的位置分为脑叶区亚组、深部区亚组、幕下区亚组。比较脑叶区CMBs与非脑叶区CMBs、深部CMBs与非深部CMBs、幕下区CMBs与非幕下区CMBs亚组之间的临床特征差异。 结果 共纳入144例CSVD患者,CMBs组42例（29.2%）,无CMBs组102例（70.8%）,其中脑叶区18例,深部白质区23例,幕下区9例。二元logistic回归分析显示,低载脂蛋白b水平（OR 0.308,95%CI 0.099～0.957,P=0.042）及高空腹血糖值（OR 1.128,95%CI 1.015～1.254,P=0.026）、舒张压、脑梗死灶及假定血管源性腔隙灶是CMBs的独立危险因素。CMBs分级与载脂蛋白b呈负相关（r=-0.212,P=0.011）,与脑梗死灶分级（r=0.378,P＜0.001）、假定血管源性腔隙灶分级（r=0.411,P＜0.001）呈正相关。脑叶区CMBs与非脑叶区CMBs相比：脑叶区CMBs组BMI（24.4 kg/m2 vs. 23.5 kg/m2,P=0.045）、射血分数（61.0% vs. 60.0%,P=0.012）高于非脑叶CMBs组,心率（75.0次/分 vs. 83.0次/分,P=0.017）低于非脑叶CMBs组,文化程度分布组间差异有统计学意义（P=0.004）。深部CMBs组的男性比例（78.3% vs. 47.4%,P=0.038）高于非深部CMBs组,梗死灶（P=0.002）数量多于非深部CMBs组。结论 低载脂蛋白b水平及高空腹血糖值、舒张压、脑梗死灶及假定血管源性的腔隙灶是CMBs独立危险因素;CMBs分级与载脂蛋白b呈负相关,与脑梗死灶分级、假定血管源性腔隙灶分级呈正相关;BMI、射血分数、心率、文化程度与脑叶CMBs相关,性别、梗死灶分级与深部CMBs相关。     

Cerebral small vessel disease and C-reactive protein: results of a cross-sectional study in community-based Japanese elderly

BACKGROUND AND PURPOSE: Inflammatory processes are involved in the pathogenesis of atherosclerosis. Inflammation has been known as a risk factor for coronary heart disease, whereas inflammation as a risk for cerebrovascular disease is less well established. Whether inflammatory processes, excluded from their involvement in large-vessel disease, are implicated in the pathogenesis of cerebral small vessel disease remains unclear. We assessed whether higher C-reactive protein (CRP) levels were associated with an increased number of lacunar infarcts or severity of white matter lesions. METHODS AND RESULTS: In a community-based group of Japanese elderly (n=689), CRP concentrations were measured using a highly sensitive assay. All participants underwent magnetic resonance imaging (MRI), and cerebral small vessel disease-related lesions (lacunar infarcts and white matter hyperintensity) were subsequently evaluated. Furthermore, carotid atherosclerosis was also assessed with ultrasonography. As the grades of white matter hyperintensity and the numbers of lacunes were considered small vessel disease-related lesions, we evaluated the relationships between CRP levels and small vessel disease-related brain lesions. Interestingly, the median CRP concentration of our participants was remarkably lower, being approximately one third or one quarter of the value of Western populations. Subjects with higher CRP levels tended to have more small vessel disease-related lesions; however, these associations were not seen after adjustment for cardiovascular risk factors and carotid atherosclerosis. CONCLUSIONS: The relationship between CRP levels and small vessel disease-related lesions was not apparent in the community-based Japanese elderly. The impact of inflammation in the pathogenesis of small vessel disease-related brain lesions seems to be weak among the Japanese elderly.     

Is type 2 diabetes related to leukoaraiosis? an updated review

A significantly increased interest has been dedicated to the study of the effects of diabetes mellitus (DM) on the brain. DM is associated with an increased risk of stroke and cognitive decline. In patients with DM, neuroimaging discloses with high‐frequency structural changes, such as cerebral atrophy, infarcts and white matter lesions, also called leukoaraiosis (LA), an expression of small vessel disease. A previous review showed a relation between DM and both cerebral atrophy and lacunar infarcts, while the question about the relation between DM and LA remained unanswered. In this review, we provide an update on data on this last association. In the reviewed studies, we examined the presence of DM, other disease characteristics, such as duration and complications, and laboratory markers of the disease such as blood glycated hemoglobin (HbA1c), insulin resistance, insulin concentrations and their association with LA. About 40% of the reviewed studies reported a statistically significant association between DM and LA. Long‐standing DM and a poor glycemic control were associated with severe LA. Studies using innovative MRI techniques, such as diffusion tensor imaging (DTI), reported a significant association between microstructural white matter alterations and DM. This review highlights more firmly than previously reported the existence of a relation between DM and both presence and severity of LA. These results are possibly due to more sensitive and advanced imaging techniques recently used to study the extent of LA. However, because of the heterogeneous methodology used in the reviewed studies, a definitive conclusion cannot be drawn.     

Cognitive performance after lacunar stroke correlates with leukoaraiosis severity

BACKGROUND: This study investigates the effect of leukoaraiosis on patients presenting with cognitive impairment after lacunar stroke. METHODS: Fourty-six patients with cognitive impairment and newly discovered lacunar stroke detected by brain magnetic resonance imaging underwent neuropsychological testing. RESULTS: Patients with both lacunar infarct and leukoaraiosis performed less well on cognitive measures, compared to those with lacunar infarcts alone. Additionally, leukoaraiosis severity inversely correlated with cognitive performance. CONCLUSIONS: In patients with lacunar stroke, presence of leukoaraiosis is associated with worse performance in multiple cognitive domains. These findings suggest lacunar infarcts plus leukoaraiosis is a common etiology for vascular dementia.