Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review

The term cerebral small vessel disease (SVD) refers to a group of pathologic processes with various etiologies that affect small arteries, arterioles, venules, and capillaries of the brain. Magnetic resonance imaging (MRI) correlates of SVD are lacunes, recent small subcortical infarcts, white-matter hyperintensities, enlarged perivascular spaces, microbleeds, and brain atrophy. Endothelial dysfunction is thought to have a role in the mechanisms leading to SVD-related brain changes, and the study of endothelial dysfunction has been proposed as an important step for a better comprehension of cerebral SVD. Among available methods to assess endothelial function in vivo, measurement of molecules of endothelial origin in peripheral blood is currently receiving selective attention. These molecules include products of endothelial cells that change when the endothelium is activated, as well as molecules that reflect endothelial damage and repair. This review examines the main molecular factors involved in both endothelial function and dysfunction, and the evidence linking endothelial dysfunction with cerebral SVD, and gives an overview of clinical studies that have investigated the possible association between endothelial circulating biomarkers and SVD-related brain changes.     

Intracranial vessel wall lesions on 7T MRI and MRI features of cerebral small vessel disease: The SMART-MR study

The etiology of cerebral small vessel disease (CSVD) is the subject of ongoing research. Although intracranial atherosclerosis (ICAS) has been proposed as a possible cause, studies on their relationship remain sparse. We used 7 T vessel wall magnetic resonance imaging (MRI) to study the association between intracranial vessel wall lesions—a neuroimaging marker of ICAS—and MRI features of CSVD. Within the SMART-MR study, cross-sectional analyses were performed in 130 patients (68 ± 9 years; 88% male). ICAS burden—defined as the number of vessel wall lesions—was determined on 7 T vessel wall MRI. CSVD features were determined on 1.5 T and 7 T MRI. Associations between ICAS burden and CSVD features were estimated with linear or modified Poisson regression, adjusted for age, sex, vascular risk factors, and medication use. In 125 patients, ≥1 vessel wall lesions were found (mean 8.5 ± 5.7 lesions). ICAS burden (per + 1 SD) was associated with presence of large subcortical and/or cortical infarcts (RR = 1.65; 95%CI: 1.12–2.43), lacunes (RR = 1.45; 95% CI: 1.14–1.86), cortical microinfarcts (RR = 1.48; 95%CI: 1.13–1.94), and total white matter hyperintensity volume (b = 0.24; 95%CI: 0.02–0.46). Concluding, patients with a higher ICAS burden had more CSVD features, although no evidence of co-location was observed. Further longitudinal studies are required to determine if ICAS precedes development of CSVD.     

Assessing cortical cerebral microinfarcts on iron-sensitive MRI in cerebral small vessel disease

Recent studies suggest that a subset of cortical microinfarcts may be identifiable on T2* but invisible on T1 and T2 follow-up images. We aimed to investigate whether cortical microinfarcts are associated with iron accumulation after the acute stage. The RUN DMC – InTENse study is a serial MRI study including individuals with cerebral small vessel disease (SVD). 54 Participants underwent 10 monthly 3 T MRIs, including diffusion-weighted imaging, quantitative R1 (=1/T1), R2 (=1/T2), and R2* (=1/T2*) mapping, from which MRI parameters within areas corresponding to microinfarcts and control region of interests (ROIs) were retrieved within 16 participants. Finally, we compared pre- and post-lesional values with repeated measures ANOVA and post-hoc paired t-tests using the mean difference between lesion and control ROI values. We observed 21 acute cortical microinfarcts in 7 of the 54 participants (median age 69 years [IQR 66–74], 63% male). R2* maps demonstrated an increase in R2* values at the moment of the last available follow-up MRI (median [IQR], 5 [5–14] weeks after infarction) relative to prelesional values (p = .08), indicative of iron accumulation. Our data suggest that cortical microinfarcts are associated with increased R2* values, indicative of iron accumulation, possibly due to microhemorrhages, neuroinflammation or neurodegeneration, awaiting histopathological verification.     

脑小血管病影像标志共识指南解读

脑小血管病(cerebral small vessel disease,CSVD)是老化的常见伴随疾病,并且常与神经退行性疾病并存,可加剧认知障碍和躯体残疾。由于在CSVD影像学特征术语的命名、定义、影像采集和分析以及科学报告等方面均缺乏一致性,因此阻碍了相关研究的发展。2012年,由全球相关领域的专家组成的神经影像研究专家组发布共识指南,确立了代表CSVD 6种关键性损伤的神经影像标志的术语及其定义,并对影像采集及科学报告的一致性提出了指导意见。这6种CSVD神经影像标志包括近期皮质下小梗死、假定血管源性的腔隙灶、假定血管源性的白质高信号、血管周围间隙、脑微出血和脑萎缩。应在临床实践及相关研究中,充分应用这份共识指南,从而促进CSVD的影像学诊断、影像采集和分析以及科学报告的标准化。     

Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials

Detecting treatment efficacy using cognitive change in trials of cerebral small vessel disease (SVD) has been challenging, making the use of surrogate markers such as magnetic resonance imaging (MRI) attractive. We determined the sensitivity of MRI to change in SVD and used this information to calculate sample size estimates for a clinical trial. Data from the prospective SCANS (St George’s Cognition and Neuroimaging in Stroke) study of patients with symptomatic lacunar stroke and confluent leukoaraiosis was used (n = 121). Ninety-nine subjects returned at one or more time points. Multimodal MRI and neuropsychologic testing was performed annually over 3 years. We evaluated the change in brain volume, T2 white matter hyperintensity (WMH) volume, lacunes, and white matter damage on diffusion tensor imaging (DTI). Over 3 years, change was detectable in all MRI markers but not in cognitive measures. WMH volume and DTI parameters were most sensitive to change and therefore had the smallest sample size estimates. MRI markers, particularly WMH volume and DTI parameters, are more sensitive to SVD progression over short time periods than cognition. These markers could significantly reduce the size of trials to screen treatments for efficacy in SVD, although further validation from longitudinal and intervention studies is required.     

Association of autosomal dominant polycystic kidney disease with cerebral small vessel disease

Cilia dysfunction in autosomal-dominant polycystic kidney disease (ADPKD) may impair the integrity of glymphatic system and be implicated in the progression of cerebral small vessel disease (SVD), although the link between the two diseases has not been investigated. We evaluated the association of ADPKD pathology with SVD pattern and severity. Overall, 304 individuals in an ADPKD (chronic kidney disease stage ≤4 and age ≥50 years) cohort and their age, sex, and estimated glomerular filtration rate (eGFR)-matched controls were retrospectively included. ADPKD severity was classified into 1 A-B, 1 C, and 1 D-E, according to age and height-adjusted total kidney volume. SVD parameters included white-matter hyperintensity (WMH) severity scale, enlarged perivascular space (ePVS) score, and degree of lacunes or cerebral microbleeds (CMBs). After adjustments for age, sex, eGFR, and cerebrovascular risk factor parameters, ADPKD was associated with higher ePVS scores (P < 0.001), but not with the WMH severity or degree of lacunes or CMBs. In the ADPKD subgroup, higher ADPKD severity class was associated with higher ePVS scores (P < 0.001), WMH severity (P = 0.003), and degree of lacunes (P = 0.002). ADPKD associated cilia dysfunction may induce chronic cerebral glymphatic system dysfunction, which may contribute to the specific progression of ePVS compared with other SVD markers.     

Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study

Introduction

Small vessel disease (SVD) is a common contributor to dementia. Subtle blood-brain barrier (BBB) leakage may be important in SVD-induced brain damage.

Association between arterial stiffness,cerebral small vessel disease and cognitive impairment: A systematic review and meta-analysis

Arterial stiffness may be a cause of cerebral small vessel disease and cognitive impairment. We therefore performed a systematic review and meta-analysis of studies on the association between stiffness, cerebral small vessel disease and cognitive impairment. For the associations between stiffness (i.e. carotid-femoral pulse wave velocity (cfPWV), brachial-ankle PWV (baPWV), carotid stiffness and pulse pressure) on the one hand and cerebral small vessel disease and cognitive impairment on the other, we identified 23 (n = 15,666/20 cross-sectional; 1 longitudinal; 2 combined cross-sectional/longitudinal) and 41 studies (n = 57,671/26 cross-sectional; 11 longitudinal; 4 combined cross-sectional/longitudinal), respectively. Pooled analyses of cross-sectional studies showed that greater stiffness was associated with markers of cerebral small vessel disease with odds ratios, per +1 SD, of 1.29–1.32 (P < .001). Studies on cognitive impairment could not be pooled due to large heterogeneity. Some (but not all) studies showed an association between greater stiffness and cognitive impairment, and the strength of this association was relatively weak. The present study supports the hypothesis that greater arterial stiffness is a contributor to microvascular brain disease.     

Association between hemostatic markers,serum lipid fractions and progression of cerebral small vessel disease: A 2-year follow-up study

Introduction

Little is known if hemostatic markers and serum lipid fractions can predict further radiological progression beyond vascular risk factors in cerebral small vessel disease (SVD). We investigated whether they are associated with SVD radiological progression and if they are related to different SVD clinical manifestations.

脑小血管病与眼底血管网络参数的相关性研究

目的利用计算机辅助的全自动眼底照相分析技术,研究脑小血管病与眼底血管网络参数的相关性。方法连续性纳入能坐位行眼底照相的脑小血管病患者80例,大动脉粥样硬化性脑梗死患者41例,比较两组患者的一般临床资料和眼底血管网络参数。同时行logistic回归分析脑小血管病患者的危险因素。结果脑小血管病组在男性比例、吸烟史发生率、血尿酸水平方面均低于大动脉粥样硬化性脑梗死组[(55%vs.75.6%);(20%vs.39%);(308.33±85.30 vs.367.79±113.60)],差异均有统计学意义(P0.05)。脑小血管病组小静脉分支系数和不对称性指数均小于大动脉粥样硬化性脑梗死组,[(1.37±0.04 vs.1.39±0.05);(0.80±0.02 vs.0.81±0.02)],差异均有统计学意义(P0.05)。Logistic回归分析显示,调整血管危险因素后,减小的小静脉不对称性指数与脑小血管病相关,是其危险因素(OR值=1.16,95%CI:1.05-1.38,P0.05)。结论减小的小静脉不对称性指数与脑小血管病相关,是其危险因素,可作为其早期诊断指标。     

Increased neural progenitors in individuals with cerebral small vessel disease

A. Ekonomou, M. Johnson, R. H. Perry, E. K. Perry, R. N. Kalaria, S. L. Minger and C. G. Ballard (2012) Neuropathology and Applied Neurobiology 38, 344–353 Increased neural progenitors in individuals with cerebral small vessel disease Aims: Recent work has highlighted a significant increase of neural stem/progenitor cells after stroke in humans. In this study, we examined neurogenesis in small vessel disease, a key concurrent pathology in Alzheimer's disease. Methods: We assayed autopsy tissue from 13 vascular dementia patients with small vessel disease and 12 age‐matched subjects without cerebrovascular pathology, undertaking immunohistochemistry in the affected brain area and the subventricular zone with a well‐characterized battery of antibodies to detect neural stem cells/progenitors and immature neurones, as well as choline acetyltransferase immunoreactivity. Results: We showed significant increases ranging from 33% to 92% (P < 0.05) in neural progenitor cells around the areas of microvascular pathology and in the subventricular zone in patients with small vessel disease compared to individuals without cerebrovascular changes, even in patients with severe cerebrovascular disease, as defined by neuropathological assessment. Some of the progenitor cells give rise to immature neurones in the affected areas. These alterations were associated with vascular changes, but were unrelated to the cholinergic deficit observed in the cortex and subventricular zone in these patients, in contrast to other dementias examined such as dementia with Lewy bodies. Conclusions: This study provides evidence for neurogenesis in small vessel disease and may have important implications for the development of new therapies for neurodegenerative diseases.     

Superficial white matter microstructure affects processing speed in cerebral small vessel disease

White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD), which contributes to about 50% of dementias worldwide. Microstructural alterations in deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In 141 CSVD patients, processing speed was assessed using Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (volume on T2‐FLAIR) and diffusion MRI measures. SWM imaging measures had a large contribution to processing speed, despite a relatively low SWM WMH burden. Across all imaging measures, SWM free water (FW) had the strongest association with processing speed, followed by SWM mean diffusivity (MD). SWM FW was the only marker to significantly increase between two subgroups with the lowest WMH burdens. When comparing two subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Mediation analysis revealed that SWM FW fully mediated the association between WMH volume and processing speed, while no mediation effect of MD or DWM FW was observed. Overall, results suggest that the SWM has an important contribution to processing speed, while SWM FW is a sensitive imaging marker associated with cognition in CSVD. This study extends the current understanding of CSVD‐related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes.     

脑小血管病认知障碍与影像特征分析

目的观察分析脑小血管病(CSVD)认知障碍与磁共振影像特征,为早期发现及治疗依据。方法选取脑小血管病患者86例,另选取80例健康志愿者为对照组。应用MMSE、临床记忆量表、WAIS-RC对86例脑小血管病患者进行认知评估,并分析其磁共振影像特征。结果脑小血管病患者MMSE评分、记忆商数MQ、语言智商VIQ、作业智商PIQ、总智商FIQ与对照组比较下降明显(P0.05);LI组无意义图形再认、人像特点回忆、算术、数字广度、木块图、数字符号的等值量表分下降更显著(P0.01);WML组数字广度、算术、图画填充、木块图、数字符号、图形拼凑、图片排列测试的等值量表分下降更显著(P0.01);CMB组在图像自由回忆、无意义图形再认、数字广度、图画填充、木块图、图片排列测试的等值量表分下降更显著(P0.01);LI、CMB、WML共存组各项测试分值均显著下降(P0.01)。结论脑小血管病存在认知障碍,且磁共振特征可以提示其认知障碍特点,早期发现其磁共振异常表现可以早期进行CSVD防治,延缓及改善CSVD认知障碍。     

脑小血管病变与临床诊治

随着对脑血管病临床研究的不断深入和核磁共振成像各项检测功能的开发和利用,脑小血管病变（SVD）正日益受到人们的关注。由于SVD是隐匿性渐进发展的,所以以往人们对它往往认识不足。血管性认知损害和痴呆与SVD有着密切的关系,SVD的后期可对患者造成不可逆性损害。本文就SVD的病理生理变化、相关危险因素以及临床治疗中的一些注意事项作一综述。     

Hhcy对脑小血管病患者认知功能的影响

目的探讨高同型半胱氨酸血症(Hhcy)对脑小血管病(SVD)患者认知功能的影响。方法 142例SVD患者根据认知功能分为痴呆组、认知功能障碍非痴呆组、认知功能正常组,测定研究对象血浆同型半胱氨酸(Hcy)水平及MMSE、画钟测验评分。结果 (1)Hcy水平痴呆组明显高于认知功能障碍非痴呆组(P<0.05),认知功能障碍非痴呆组高于认知功能正常组。(2)Logistic回归分析得出Hcy水平升高是小血管病患者认知功能损害的独立危险因素。(3)Hhcy对MMSE总评分、定向功能、语言功能以及反应视空间功能、动作的计划性和执行功能画钟测验均有独立的危险性,其OR值分别为1.044、1.057、1.040、1.251。结论 Hcy水平升高是脑小血管病认知功能损伤的独立危险因素,对总体认知功能、定向功能、语言功能以及视空间功能、动作的计划性和执行功能有独立影响作用。