Silent Lacunar Research Articles

Lack of Association between Periodic Limb Movements during Sleep and Neuroimaging Signatures of Cerebral Small Vessel Disease in Stroke-Free Community-Dwelling Older Adults. The Atahualpa Project

Evidence of the relationship between periodic limb movements during sleep (PLMS) and cerebral small vessel disease (cSVD) is limited and inconsistent. Here, we aimed to assess the independent association between PLMS and the different neuroimaging signatures of cSVD. Atahualpa residents aged more than or equal to 60 years enrolled in the Atahualpa Project undergoing polysomnography and MRI with time intervals less than or equal to 6 months were included. MRI readings focused on white matter hyperintensities (WMH) of presumed vascular origin, deep cerebral microbleeds (CMB), silent lacunar infarcts (LI), and more than 10 enlarged basal ganglia-perivascular spaces (BG-PVS). Data from single-night polysomnograms were interpreted according to recommendations of the American Academy of Sleep Medicine. Associations between the PLMS index and neuroimaging signatures of cSVD (as dependent variables) were assessed by means of logistic regression models, adjusted for relevant confounders. A total of 146 individuals (mean age: 71.4 ± 7.5 years; 64% women) were included. A PLMS index more than or equal to 15 per hour were noted in 48 (33%) participants. Moderate-to-severe WMH were present in 33 individuals (23%), deep CMB in 9 (6%), silent LI in 16 (11%), and more than 10 BG-PVS in 44 (30%). In univariate analyses, silent LI (P = .035) and the presence of more than 10 enlarged BG-PVS (P = .034) were significantly higher among participants with a PLMS index more than or equal to 15 per hour. However, fully-adjusted multivariate models showed no significant association between PLMS index more than or equal to 15 per hour and any of the neuroimaging signatures of cSVD. This study shows no independent association between the PLMS index and neuroimaging signatures of cSVD in stroke-free community-dwelling older adults.

Distinct profiles of cognitive impairment associated with different silent cerebrovascular lesions in hypertensive elderly Chinese

Background/objectivesSilent cerebrovascular lesions (SCLs) and their underlying pathology are now recognized as important causes of cognitive impairment in the elderly. However, the distinct profile of cognitive deficits associated with each type of SCLs remains unclear. MethodsOf 497 otherwise healthy hypertensive elderly Chinese, 398 participants (mean age 72.0, ranging from 65 to 99, SD = 5.1) successfully completed a battery of structured neuropsychological tests and a multi-sequence 3 T MRI scanning. SCLs were rated independently. Correlations between each MRI marker and cognitive function were assessed using a series of linear regression models. ResultsStrictly lobar cerebral microbleeds were linked to impaired language function (B = −0.231, p < 0.05). Silent lacunes were associated with poor executive function, but the association disappeared after additional adjustment for white matter hyperintensities. White matter hyperintensities (especially periventricular hyperintensities) were associated with poor executive function (B = −0.126, p < 0.05) and slower information processing speed (B = −0.149, p < 0.05). ConclusionDifferent SCLs were associated with different patterns of cognitive deficits, indicating that different SCLs may have distinct impacts on cognitive performance.

Basal Ganglia-Cortical Circuit Disruption in Subcortical Silent Lacunar Infarcts.

To investigate the alterations of basal ganglia (BG)-cortical structural and functional connectivity induced by subcortical silent lacunar infarct (SLI), and their associations with cognitive impairment in SLI subjects. All participants were recruited from communities, including 30 subcortical SLIs and 30 age-, gender-, and education-matched healthy controls. The structural and functional connectivity of BG-cortical circuits using diffusion and resting-state functional magnetic resonance imaging data were obtained. Diffusion abnormalities of the white matter tracts connecting the BG and cortical areas were observed in SLI subjects, including the BG-lateral frontal, BG-orbital frontal, and BG-insula tracts. Multiple regions showed a reduced BG-cortical functional connectivity in SLI patients, including direct connectivities with the BG, such as the BG-limbic, BG-insula, and BG-frontal connectivities, and others that showed no direct causation with the BG, such as the insula-limbic, insula-parietal, and frontal-parietal connectivities. Coupling of structural and functional BG-cortical connectivity was observed in healthy controls but not in SLI patients. Significant correlations between structural and functional BG-cortical connectivity and cognitive performance were demonstrated in SLI patients, indicating the potential use of BG-cortical connectivities as MRI biomarkers to assess cognitive impairment. These findings suggest that subcortical SLIs can impair BG-cortical circuits, and these changes may be the pathological basis of cognitive impairment in SLI patients.

Neuroimaging signatures of cerebral small vessel disease and risk of falls in stroke-free older adults living in rural Ecuador. The Atahualpa Project

PurposeThis study aimed to assess the association between neuroimaging signatures of cerebral small vessel disease (cSVD) and the risk of falls in stroke-free older adults living in rural Ecuador. MethodsRisk of falls was evaluated by the Downton Fall Risk Index (DFRI). MRI readings focused on white matter hyperintensities (WMH) of presumed vascular origin, deep cerebral microbleeds (CMB), silent lacunar infarcts (LI), and > 10 enlarged basal ganglia-perivascular spaces (BG-PVS). Logistic regression models were fitted to evaluate whether these neuroimaging signatures were associated with the DFRI, after adjusting for relevant confounders. ResultsWe included 288 participants. The DFRI was positive in 69 (24%). Moderate-to-severe WMH were noticed in 55 individuals (19%), deep CMB in 18 (6%), LI in 23 (8%), and > 10 BG-PVS in 65 (23%). Multivariate models showed a significant association between moderate-to-severe WMH and the DFRI (p = .016). There were no associations between other neuroimaging signatures of cSVD and the DFRI. Age was the single covariable remaining significant in all models. ConclusionsWMH is associated with the DFRI in stroke-free older adults living in a remote rural setting. A target for fall prevention should include the control of factors favoring the development of diffuse subcortical damage of vascular origin.

Serum alkaline phosphatase level is correlated with the incidence of cerebral small vessel disease.

Vascular calcification is one of the mechanisms underlying the pathogenesis of cerebral small vessel disease (CSVD). Whether higher levels of serum alkaline phosphatase (ALP), a predictor of vascular calcification, are independently associated with CSVD remains inconclusive. The present study explored the link between levels of circulating ALP and CSVD in a Chinese population. A total of 568 participants were recruited from the healthcare center at the affiliated Zhongshan Hospital of Dalian University and the Fifth People Hospital of Dalian between January 2010 and December 2016. The subjects were divided into three groups based on the infarct and severity of white matter hyper-intensities (WMH) as categorized by brain magnetic resonance imaging (MRI) analysis and Fazekas rating scales: no/mild cerebral WMH (nm-WMH); moderate-to-severe WMH (MS-WMH); and silent lacunar infarct (SLI). The subjects were also divided into three tertiles based on circulating levels of ALP: ≤64, 65-105 and ≥106 (IU/L). Information regarding the risk factors, such as coronary artery disease, diabetes mellitus, hypertension and serum ALP level, C-reactive protein, homocysteine (HCY), and other laboratory results, were collected. The associations of ALP with WMH and SLI were evaluated using logistic regression analysis. After adjustment for vascular risk factors, subjects with MS-WMH and SLI were more likely to have ALP levels ≥106 IU/L than ≤64 IU/L. The mean circulating level of ALP was substantially increased in patients with MS-WMH or SLI compared with patients with nm-WMH. The multivariate model revealed that this significant difference remained when MS-WMH or SLI was added to the model, after adjustment for confounding factors. The circulating level of ALP was positively correlated with a high risk of silent lacunar infarct and white matter hyperintensity; important indicators of small vessel disease.

Atypical phenotype of an old disease or typical phenotype of a new disease: deficiency of adenosine deaminase 2

Çakan M, Aktay-Ayaz N, Karadağ ŞG, Tahir-Turanlı E, Stafstrom K, Bainter W, Geha RS, Chou J. Atypical phenotype of an old disease or typical phenotype of a new disease: deficiency of adenosine deaminase 2. Turk J Pediatr 2019; 61: 413-417. Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder caused by mutations in CECR1 (cat eye syndrome chromosome region, canditate 1) gene, which encodes the enzyme adenosine deaminase 2 necessary for endothelial cell survival and function. The diversity of the clinical phenotypes associated with DADA2 include polyarteritis nodosa-like vasculitic features, early-onset stroke, mild to severe immunodeficiency and cytopenias. The diagnosis of the disease may be difficult due to complex clinical phenotype. Herein, we present a case of DADA2 presenting with vasculitis, amarousis fugax, gastrointestinal bleeding and silent lacunar infarct successfully treated with etanercept.

25-Hydroxy vitamin D level is associated with total MRI burden of cerebral small vessel disease in ischemic stroke patients

Background: Decreased 25-hydroxyvitamin D [25(OH)D] has been reported to be related to increased risk of cerebrovascular disease. We aimed to investigate whether an association exists between 25(OH)D levels and cerebral small vessel disease (cSVD).Method: Patients with first-ever minor ischemic stroke or transient ischemic attack were recruited prospectively during Jan 2017 to December 2017. Serum 25(OH)D levels were measured at admission in all patients. Magnetic resonance imaging (MRI) was performed to determine the presence of cSVD, including silent lacunar infarcts (SLIs), white matter lesions (WMLs), cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVs). The severity of cSVD was evaluated by total MRI cSVD burden, an ordinal score from 0 to 4. The association between the baseline 25(OH)D level and cSVD was analyzed by multiple logistic regression models.Results: Of 234 patients included, the median 25(OH)D level was 39.2 nmol/L. The proportions of patients with 0 to 4 cSVD features were 8.5%, 29.1%, 42.3%, 16.2%, and 3.8%, respectively. After adjusting for potential confounders, multiple logistic regression analysis demonstrated that patients with 25(OH)D level in its first quartile, compared with those in its fourth quartile, were more likely to have severe WMLs [odds ratio (OR), 3.31; 95% confidence interval (CI) 1.74–9.67; p = .004], severe EPVs (OR, 2.35; 95% CI 1.11–6.02, p = .046] and increasing total MRI cSVD burden (OR, 3.00; 95% CI 1.36–6.53, p = .006).Conclusions: Lower levels of 25(OH)D are associated with greater total MRI cSVD burden in ischemic stroke patients.

Hemispheric Asymmetry of White Matter Hyperintensity in Association With Lacunar Infarction.

BackgroundWhite matter hyperintensities (WMHs) are commonly asymmetric between hemispheres but for unknown reasons. We investigated asymmetric WMHs associated with lacunar infarcts.Methods and ResultsA total of 267 consecutive patients with small first‐ever supratentorial infarcts (≤20 mm) were included. None had a relevant vascular stenosis. WMH asymmetry was measured based on the hemispheric difference of a modified Scheltens scale score (≥3 defined as asymmetric). We analyzed the association of the hemispheric WMH asymmetry with old silent lacunar infarcts or acute lacunar infarcts. We compared lesion frequency maps between groups and generated t‐statistics maps. The mean age of patients was 64 years, and 63% were men. Asymmetric WMH was more than 3‐fold as frequent (P<0.001) in the group with old silent lacunar infarcts (42%, 43/102) than in the group without old silent lacunar infarcts (15%, 24/165). In patients with left hemispheric dominance of WMHs, an acute lacunar infarct was more likely to be located in the left (versus right) hemisphere (74% versus 26%, P<0.001). In patients with right hemispheric dominance of WMHs, an acute lacunar infarct was more likely to be located on the right (versus left) hemisphere (81% versus 19%, P<0.001). Mapping studies showed that the side of hemispheric dominance of WMHs was associated with acute and silent lacunes on the same side.ConclusionsThese are the first data to show that asymmetric WMHs are associated with both old silent lacunar infarcts and acute lacunar infarcts ipsilateral to the greatest WMH burden. This suggests that the hemisphere with relatively large WMHs is more vulnerable to ischemia.

Cognitive Deficits and Related Brain Lesions in Patients With Chronic Heart Failure

ObjectivesThis study sought to determine the spectrum of brain lesions seen in heart failure (HF) patients and the extent to which lesion type contributes to cognitive impairment. BackgroundCognitive deficits have been reported in patients with HF. MethodsA total of 148 systolic and diastolic HF patients (mean age 64 ± 11 years; 16% female; mean left ventricular ejection fraction 43 ± 8%) were extensively evaluated within 2 days by cardiological, neurological, and neuropsychological testing and brain magnetic resonance imaging (MRI). A total of 288 healthy, sex- and age-matched subjects sampled from the Austrian Stroke Prevention Study served as MRI controls. ResultsDeficits in reaction times were apparent in 41% of patients and deficits in verbal memory in 46%. On brain MRI, patients showed more advanced medial temporal lobe atrophy (MTA) (Scheltens score) compared to controls (2.1 ± 0.9 vs. 1.0 ± 0.6; p < 0.001). The degree of MTA was strongly associated with the severity of cognitive impairment, whereas the extent of white matter hyperintensities was similar in patients and controls. Moreover, patients had a 2.7-fold increased risk for presence of clinically silent lacunes. ConclusionsHF patients exhibit cognitive deficits in the domains of attention and memory. MTA but not white matter lesion load seems to be related to cognitive impairment.

Cerebral Microbleeds Are Associated With Mild Cognitive Impairment in Patients With Hypertension.

BackgroundCerebral microbleeds (CMBs) are hypothesized downstream markers of brain damage caused by vascular and amyloid pathologic mechanisms. The aim of this study was to determine whether CMB count and location are associated with an increased risk for mild cognitive impairment (MCI) in patients with essential hypertension without a history of transient ischemic attack or stroke.Methods and ResultsIn this cross‐sectional study, patients were prospectively enrolled from consecutive outpatients with essential hypertension 50 years and older at 3 centers in northern China. Generalized linear Poisson models were used to determine the association between the number and location of CMBs and MCI in patients with hypertension. The association of microbleeds with different cognitive domains was estimated using linear mixed models. The presence, number, and distribution of CMBs were greater in patients with hypertension who had MCI (P<0.001). The presence of any CMBs, strictly lobar CMBs, and deep or infratentorial CMBs were all related to MCI after adjusting for age, sex, education, cardiovascular risk factors, body mass index, intima‐media thickness, the presence of silent lacunar infarctions, white matter lesion grade, and brain atrophy. Furthermore, the presence of multiple microbleeds (≥5) was associated with lower Montreal Cognitive Assessment total scores and worse performance on specific domains of cognitive tests, such as global cognitive function, information processing speed, and motor speed.ConclusionsThis study suggests that the presence of and a greater number of cerebral CMBs independently correlate with MCI in patients with essential hypertension without a history of transient ischemic attack or stroke.

Subclinical hypothyroidism and risk of cerebral small vessel disease: A hospital‐based observational study

Subclinical hypothyroidism (SCH) has been associated with atherosclerosis and increased risk of ischaemic stroke. However, whether SCH is associated with cerebral small vessel disease (cSVD) remains largely unexplored. This study aimed to investigate the relationship between SCH and total cSVD burden, a composite measurement detected with magnetic resonance imaging (MRI), in patients with minor ischaemic stroke or transient ischaemic attack (TIA). This was a prospective observational cohort study conducted in a tertiary referral hospital. Subclinical hypothyroidism (SCH) was defined as with mildly or moderately increased thyroid-stimulating hormone levels (TSH, 4.5-10.0mIU/L), but with normal free thyroxine levels. Brain MRI presence of silent lacunar infarcts (LIs), white matter lesions (WMLs), cerebral microbleeds (CMBs) and enlarged perivascular spaces (EPVs) were summed to a validated scales ranging from 0 to 4 to represent the load of cSVD. The associations between SCH and cSVD were analysed by logistic regression analyses. Subclinical hypothyroidism (SCH) was identified in 43 of 229 (18.8%) patients with minor stroke or TIA. Compared with patients without SCH, those with SCH had higher risks of WMLs, CMBs and total cSVD burden. Adjustment of potential confounders did not change these associations. These findings showed that SCH might be associated with the presence of WMLs, CMBs, as well as cSVD burden in patients with minor stroke or TIA.

Relationship between obstructive sleep apnea and neuroimaging signatures of cerebral small vessel disease in community-dwelling older adults. The Atahualpa Project

Background/ObjectivesEvidence of a relationship between obstructive sleep apnea (OSA) and neuroimaging signatures of cerebral small vessel disease (SVD) is limited. The present study aimed to evaluate this association in older adults living in rural Ecuador, where small vessel disease is a major pathogenetic mechanism underlying stroke. MethodsA representative random sample of Atahualpa residents aged ≥60 years enrolled in the Atahualpa Project neuroimaging substudy underwent a single-night diagnostic polysomnography. We evaluated whether OSA associates with severity of white matter hyperintensities (WMH), silent lacunar infarctions and deep cerebral microbleeds, using multivariate models adjusted for relevant confounders. ResultsOf 351 candidates, 104 (30%) were randomly selected. Of these, 97 individuals (mean age 72.3 ± 7 years, 65% women) had adequate recordings and were included. Mean apnea/hypopnea index was 13.8 ± 14.1 episodes per hour; 27 persons (28%) had ≥15 episodes per hour and were considered to have moderate-to-severe OSA. Moderate-to-severe WMH were noticed in 25 individuals (25.8%), silent lacunar infarctions in 22 (22.7%) and deep cerebral microbleeds in 12 (12.4%). In multivariate models, OSA was associated with moderate-to-severe WMH (OR: 3.94; 95% C.I.: 1.09–14.97; p = 0.037), but not with silent lacunar infarctions (p = 0.195) or deep cerebral microbleeds (p = 0.405). A linear regression model confirmed the independent association between the apnea/hypopnea index and moderate-to-severe WMH (β: −7.14; 95% C.I.: −13.6 to −0.69; p = 0.031). ConclusionsIndividuals with moderate-to-severe OSA are almost four times more likely to have diffuse subcortical damage of vascular origin than those with none-to-mild OSA, independently of demographics and cardiovascular risk factors.

Obstructive sleep apnea and silent cerebral infarction in hypertensive individuals.

Obstructive sleep apnea syndrome is very prevalent in hypertensive subjects. Moreover, obstructive sleep apnea syndrome activates multiple processes that might be associated with silent cerebral infarct independently of established risk factors. Our aim is to estimate the frequency of obstructive sleep apnea syndrome in hypertensive patients with and without silent cerebral infarct, and to determine whether obstructive sleep apnea syndrome is an independent risk factor of silent cerebral infarct and/or lacunar silent cerebral infarct in patients with hypertension. In this matched cross-sectional study performed in hypertensive subjects, each patient with silent cerebral infarct detected by magnetic resonance imaging was matched with two patients without silent cerebral infarct. Polysomnographic studies were performed, and the apnea-hypopnea index was calculated. Severe obstructive sleep apnea syndrome was considered in those with apnea-hypopnea index >30. One-hundred and eighty-three patients, 61 with silent cerebral infarct and 122 without silent cerebral infarct, were evaluated. The mean age was 64.1±4.5years, and 72.1% were men. The frequency of severe obstructive sleep apnea syndrome was 44.3% in patients with silent cerebral infarct and 38.5% in the control group. An adjusted conditional logistic regression model did not show a significant increased risk of silent cerebral infarct in patients with severe obstructive sleep apnea syndrome (odds ratio 1.362; 95% confidence interval: 0.659-2.813; P=0.404). Forty-three patients (70.5%) of the silent cerebral infarct were lacunar. The presence of severe obstructive sleep apnea syndrome was significantly higher in lacunar silent cerebral infarct when compared with patients without lacunar infarcts (55.8% versus 35.7%, P=0.019), being independently associated on an adjusted logistic regression model (odds ratio 2.177; 95% confidence interval: 1.058-4.479; P=0.035). In conclusion, severe obstructive sleep apnea syndrome is highly prevalent among hypertensive subjects, and is independently associated with lacunar silent cerebral infarct.

Differential impact of serum total bilirubin level on cerebral atherosclerosis and cerebral small vessel disease.

BackgroundA low serum total bilirubin (T-bil) level is associated with an increased risk of atherosclerosis. However, the differential impact of the serum T-bil level on cerebral atherosclerosis and cerebral small vessel disease (SVD) is still unclear.MethodsWe evaluated serum T-bil levels from 1,128 neurologically healthy subjects. Indices of cerebral atherosclerosis (extracranial arterial stenosis [ECAS] and intracranial arterial stenosis [ICAS]), and indices of SVD (silent lacunar infarct [SLI], and moderate-to-severe white matter hyperintensities [msWMH]) were evaluated by the use of brain magnetic resonance imaging (MRI) and MR angiography.ResultsIn logistic regression analysis after adjusting for confounding variables, subjects within middle T-bil (odds ratio [OR]: 0.63; 95% CI: 0.41–0.97) and high T-bil tertiles (OR: 0.54; 95% CI: 0.33–0.86) showed a lower prevalence of ECAS than those in a low T-bil tertile. Although subjects with a high T-bil tertile had a lower prevalence of ICAS than those with a low T-bil tertile, the statistical significance was marginal after adjusting for confounding variables. There were no significant differences in the proportions of subjects with SLI and msWMH across serum T-bil tertile groups.ConclusionsThe serum T-bil level is negatively associated with cerebral atherosclerosis, especially extracranial atherosclerosis, but not with SVD.

Total magnetic resonance imaging burden of cerebral small-vessel disease is associated with post-stroke depression in patients with acute lacunar stroke.

Despite extensive studies on post-stroke depression (PSD), the role of the total burden of cerebral small-vessel disease (cSVD) in its pathogenesis remains unclear. We conducted a magnetic resonance imaging (MRI)-based cohort study to investigate the relationship between total MRI burden of cSVD and PSD among patients with first-ever lacunar stroke. From June 2013 to January 2016, 374 patients were consecutively recruited. PSD was identified using the Chinese version of the Structured Clinical Interview for DSM-IV. Brain MRI presence of silent lacunar infarcts, white-matter lesions, cerebral microbleeds and enlarged perivascular spaces was summed to an ordinal score between 0 and 4. Multivariable logistic regression analysis was performed to determine the contribution of total MRI cSVD burden in the prediction of PSD. Ninety patients (24.1%) were diagnosed with PSD at 3months after stroke. Only two MRI markers of cSVD, asymptomatic lacunar infarcts and white-matter lesions, were related to PSD [odds ratio (OR), 3.167; 95% confidence interval (CI), 1.879-5.338; P=0.001 and OR, 2.284; 95% CI, 1.403-3.713; P=0.001, respectively]. Moreover, higher total MRI cSVD burden was an independent predictor for PSD (high tertile OR, 4.577; 95% CI, 2.400-8.728; P=0.001) after adjusting for individual cSVD MRI marker and other potential confounders. This study demonstrated that greater total MRI burden of cSVD may predict the presence of PSD in patients with acute lacunar stroke.

Multiple Silent Lacunes Are Associated with Recurrent Ischemic Stroke

Background: Silent lacunes are a common finding on brain imaging in ischemic stroke patients, but the prognostic significance of these lesions is uncertain. We aimed at investigating the association of silent lacunes and the risk of ischemic stroke recurrence, death, and cardiovascular events in a cohort of patients with incident ischemic stroke and no atrial fibrillation (AF). Methods: We included 786 patients (mean age 59.5 (SD 14.0); 42.9% females) in a registry-based, observational cohort study on patients with first-ever ischemic stroke. On brain MRI we assessed the number of silent lacunes as none, single, or multiple and we calculated stratified incidence rates of the outcomes. Cox proportional hazard ratios (HRs) adjusted for age, gender, congestive heart failure, hypertension, diabetes, and vascular disease were calculated with no silent lacunes as reference. In additional analyses, we further adjusted for white matter hyperintensities. Patients were followed up until death or recurrence of ischemic stroke. Results: In 81 (10.3%) patients, a single silent lacune was present, and in 87 (11.1%) patients, multiple silent lacunes were present. Patients with at least one silent lacune were older (mean age 66.1 vs. 57.7, p < 0.001) and were more often hypertensive (60.1 vs. 43.4%, p < 0.001) compared to patients with no silent lacunes. During a median follow-up time of 2.9 (interquartile range 3.1) years, we observed 53 recurrent ischemic strokes, 76 deaths, and 96 cardiovascular events. Incidence rates per 100 person-years of ischemic stroke recurrence were 1.6, 2.5, and 5.0 for none, single, and multiple silent lacunes respectively. Corresponding incidence rates were 2.6, 2.4, and 4.4 for death, and 3.4, 4.0, and 6.6 for cardiovascular events respectively. Adjusted HRs of ischemic stroke recurrence were 1.53 (0.67-3.49) and 2.52 (1.25-5.09) for a single and multiple silent lacunes, respectively. Further adjustment for white matter hyperintensities maintained positive association although not significant. Corresponding adjusted HRs were 0.56 (0.25-1.25) and 0.65 (0.33-1.25) for death and 1.16 (0.61-2.22) and 1.51 (0.86-2.66) for cardiovascular events. Conclusions: In this large cohort of patients with incident ischemic stroke and no AF, an increasing number of silent lacunes was associated with increasing incidence rates of ischemic stroke recurrence. In the adjusted Cox proportional hazard analyses, the presence of multiple silent lacunes was significantly associated with an increased risk of ischemic stroke recurrence. The risk of death or cardiovascular events was not significantly influenced by the presence of silent lacunes.

Redox Imbalance and Stroke.

Redox status is correlated with mitochondrial function, lipid raft turnover, and cellular cross talk in the neurovascular coupling. Redox imbalance is a hallmark event in the pathophysiology and prognosis of stroke. Excessive reactive oxygen species (ROS) can cause oxidative damage to various biological macromolecules including DNA, lipids, and proteins, thereby altering several signaling pathways that ultimately promote cellular damage and death. It is critical to address the relationship between redox status and stroke and to translate the accumulated mechanistic knowledge from animal models to clinical settings. This special issue is devoted to highlighting novel findings on the role of redox imbalance in stroke and possibilities of the antioxidant supplementation for stroke treatment. In this issue there are two investigations focused on the contribution of systemic inflammatory status to pathophysiology and prognosis of ischemic stroke patients. In a cross-sectional study, lower serum level of caveolin-1, which has been reported to maintain blood-brain barrier integrity and counteract oxidative stress, was found to be significantly related to cerebral microbleeds in patients with acute ischemic stroke. However, no relationship was observed between caveolin-1 and the presence of silent lacunar infarcts and white matter hyperintensities, two other types of cerebral small vessel disease. Though the relatively small sample size (~156 patients) may cripple the power of the evaluation, this study strongly supports caveolin-1 as a biomarker for predicting cerebral microbleeds in acute ischemic stroke. Maintaining caveolin-1 level appeared to be a potential strategy in treating cerebral small vessel diseases. X. Zhang et al. carried out a prospective study on the predictive effects of the presence of metabolic syndrome (MetS) on early neurological deterioration following acute ischemic stroke. Interestingly, systemic markers of inflammation, fibrinogen and high-sensitivity C-reactive protein, were not the mediators of the relation between MetS and early neurological deterioration. The authors addressed that local oxidative or inflammatory response markers may be more appropriate when involved in studies of stroke and other potential correlated factors. Two investigations focused on how comorbidity affects stroke outcome and therapeutic approaches. Stroke patients with diabetes mellitus have worsened mortality and neurological recovery. Bradykinin receptors have been demonstrated to play important roles in cerebral ischemia/reperfusion injury in the context of diabetes. R. Shi et al. carried out a study to elucidate the differential roles of bradykinin B1 receptor and B2 receptor underlying the effect of tissue kallikrein on the stroke outcome in diabetic rats. The results revealed that tissue kallikrein protects against inflammatory reactions by suppression of microglial activation and neutrophil infiltration through bradykinin B2 receptor, rather than B1 receptor. The bradykinin B2 receptor-dependent protection requires the activation of ERK/CREB/Bcl-2 signaling pathway to counteract apoptosis and neuroinflammation. Another potent antioxidant agent, minocycline, was investigated by E. A. Fontes-Junior et al. in cortical ischemic injury combined with chronic alcohol intoxication. The results showed that chronic alcohol intoxication increased nitrite and lipid peroxidation levels and neuronal loss caused by ischemia. Minocycline was effective in preventing histological and neurological damage caused by stroke alone. Nevertheless, the protection of minocycline was abolished when stroke was preceded by chronic alcohol intoxication. This study suggests that ischemic stroke combined with chronic alcohol intoxication is more severe and may require different therapeutic strategies. J. Qu et al. provided a comprehensive review to summarize the role of ROS in the intracerebral hemorrhage. ROS is mainly released from neurons exposed to hemoglobin metabolic products after intracerebral hemorrhage, which is strikingly different from the pathophysiology in ischemic stroke. This ROS is harmful to the central nervous system through cell death and structural damage, especially the disruption of the blood-brain barrier. The review continues to discuss how endogenous antioxidant system interacts with the oxidant agents and why previous antioxidant therapy failed to confer practical neuroprotection in clinical trials. The authors suggest more attention be paid to the local and systemic influences of ROS in intracerebral hemorrhage and the longitudinal profile of ROS burst after intracerebral hemorrhage. In another review article, J. Bu et al. discussed the effects of a natural product, omega-3 polyunsaturated fatty acids (n-3 PUFAs), the major component of fish oil, on the redox imbalance after stroke. Due to their antioxidation, anti-inflammation, and interaction with pathways such as Nrf2/HO-1 signaling, n-3 PUFAs are neuroprotective in reducing infarction volume and improving neurogenesis and revascularization. The authors also expressed that further studies were warranted to establish the specific treatment strategy of n-3 PUFAs in stroke. In conclusion, the goal of this special issue is to drive a better understanding of how redox imbalance modulates pathophysiology and prognosis of stroke and how this can be harnessed as a therapeutic target in the stroke treatment. The original and review articles in this issue contributed by the experts in the fields of redox and stroke will nurture and expand knowledge of the mechanisms behind oxidative damage. Ruidong Ye Ming Shi Qian Liu Jieli Chen

Lower Serum Caveolin-1 Is Associated with Cerebral Microbleeds in Patients with Acute Ischemic Stroke.

Caveolin-1 (Cav-1) plays pivotal roles in the endothelial damage following stroke. The present study aimed to investigate whether serum Cav-1 level is associated with the presence of cerebral small vessel disease (cSVD) in patients with acute ischemic stroke. To this end, 156 patients were consecutively enrolled. Cranial magnetic resonance imaging was analyzed to determine the surrogates of cSVD, including cerebral microbleeds (CMBs), silent lacunar infarcts (SLIs), and white matter hyperintensities (WMHs). After adjusting for potential confounders, patients with low Cav-1 level had a higher risk of CMBs than patients with high Cav-1 level (OR: 4.05, 95% CI: 1.77–9.30). However, there was no relationship between Cav-1 and the presence of SLIs or WMHs. When CMBs were stratified by location and number, a similar association was found in patients with deep or infratentorial CMBs (OR: 4.04, 95% CI: 1.59–10.25) and with multiple CMBs (OR: 3.18, 95% CI: 1.16–8.72). These results suggest lower serum Cav-1 levels may be associated with CMBs, especially those that are multiple and located in deep brain or infratentorial structures, in patients with acute ischemic stroke. Cav-1 may be involved in the pathophysiology of CMBs, and may act as a potential target for treating cSVD.

Calcifications in the carotid siphon correlate with silent cerebral small vessel disease in community-dwelling older adults: A population-based study in rural Ecuador.

Using a population-based, cross-sectional design, we aimed to assess whether the presence of calcifications in the carotid siphon (as seen on computed tomography) is associated with silent markers of cerebral small vessel disease (on magnetic resonance imaging) in apparently healthy older adults living in Atahualpa, a rural Ecuadorian village. Stroke-free Atahualpa residents aged ≥60 years identified during a door-to-door survey underwent head computed tomography for assessment of carotid siphon calcifications, and brain magnetic resonance imaging for identification of white matter hyperintensities and silent lacunar infarcts. We evaluated the association between calcifications and markers of small vessel disease using logistic regression models adjusted for demographics and cardiovascular risk factors. The mean age of the 236 participants was 71 ± 8 years, and 139 (59%) were women. Computed tomography readings showed high calcium content in the carotid siphon in 64 individuals (27%), and magnetic resonance imaging showed moderate-to-severe white matter hyperintensities in 51 (30%) and lacunar infarcts in 28 (12%). In the univariate analysis, individuals with high calcium content were older and were more likely to have high fasting glucose levels than those with low calcium content. After adjusting for confounding variables, we found an independent association between high calcium content in the carotid siphon and moderate-to-severe white matter hyperintensities (OR 2.3, 95% CI 1.1-4.9, P = 0.035) as well as lacunar infarcts (OR 3.1, 95% CI 1.3-7.6, P = 0.013). The present study shows a direct relationship between calcium content in the carotid siphon and silent small vessel disease in an indigenous Latin American population. Geriatr Gerontol Int 2016; 16: 1063-1067.

Deep Cerebral Microbleeds and Renal Dysfunction in Patients with Acute Lacunar Infarcts

Cerebral small-vessel disease (SVD) is associated with renal dysfunction such as chronic kidney disease. Although cerebral microbleeds (CMBs) are common in patients with acute lacunar infarcts (ALI), the association between renal dysfunction and CMBs in such patients remains unclear. Between April 2007 and March 2013, we evaluated consecutive first-ever ALI patients, who were admitted to our hospital within 24 hours of stroke onset. CMBs were defined as focal areas of signal loss in brain parenchyma less than 5 mm on T2(∗)-weighted gradient-echo imaging. Renal dysfunction was defined as an estimated glomerular filtration rate less than 60 mL/minute/1.73 m(2) on admission. Correlations between renal dysfunction and the presence (model 1) and location of CMBs (model 2; any deep or infratentorial CMBs) were determined by multivariable logistic regression analyses. Among 152 patients (33.6% men; mean age, 67.6 years), 53 had CMBs. Patients with CMBs were older (69.9 versus 66.3 years, P = .03) and had a higher frequency of white matter hyperintensity (WMH; 62.3% versus 25.3%, P < .001), silent lacunar infarcts (SLI; 75.5% versus 43.3%, P < .001), and renal dysfunction (41.5% versus 22.2%, P = .015) than those without CMBs. On multivariable analyses, renal dysfunction (odds ratio, 95% confidence interval; model 1: 2.38, 1.02-5.66; model 2: 2.78, 1.16-6.81), WMH (3.87, 1.76-8.80; 3.72, 1.64-8.71), SLI (3.85, 1.71-9.14; 4.20, 1.77-10.8), and diabetes mellitus (.26, .09-.63; .24, .08-.63) were independently associated with CMBs. In patients with ALI, renal dysfunction was positively associated with CMBs independent of cerebral SVD.