Carotid Intima-Media Thickness and Silent Brain Infarctions in a Biracial Cohort: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Both hypertensive and atherosclerotic processes contribute to common carotid artery intima-media thickness (CCA-IMT). Elevated CCA-IMT may be indicative of subclinical cerebrovascular disease; however, its role in the absence of concomitant carotid artery plaque is uncertain, and few studies have examined associations in Black populations. MATERIALS AND METHODS: At cohort visit 3 (1993-1995) a subset of stroke-free participants (641 Blacks and 702 Whites, mean age 63) from the Atherosclerosis Risk in Communities (ARIC) study was imaged by brain MRI and carotid ultrasound. A CCA-IMT >0.9 mm was considered elevated. Asymptomatic brain lesions ≥3 mm were considered silent brain infarctions (SBI). Subcortical SBI measuring 3 to <20 mm were considered lacunes. Associations between elevated CCA-IMT and SBI were analyzed with Poisson regression. RESULTS: Elevated CCA-IMT was identified in 168 participants (16% of Blacks, 10% of Whites), and SBI were observed in 156 (15% of Blacks, 8% of Whites). Elevated CCA-IMT was strongly related to anterior circulation SBI, posterior circulation SBI, and lacunes. After adjustments, elevated CCA-IMT remained associated with greater number of lacunes in Blacks ([prevalence ratio, PR] = 1.60; 95% confidence interval [CI]: 1.02-2.51), but not Whites (PR = 0.85; 95% CI: 0.35-2.04); P value for interaction = 0.12. Among Black participants without concomitant carotid plaque, elevated CCA-IMT was associated with twice the number of lacunes (PR = 2.00; 95% CI: 1.05-3.82). CONCLUSIONS: In older Black adults, elevated CCA-IMT is independently associated with lipohyalinosis of the cerebral small vessels, irrespective of concomitant carotid plaque and vascular risk factors.

Subclinical Cerebrovascular Disease Increases the Risk of Incident Stroke and Mortality: The Northern Manhattan Study.

BACKGROUND: The effects of white matter hyperintensity volume and subclinical brain infarcts on the risk of incident stroke, its ischemic subtypes, and mortality require further study in diverse samples. METHODS AND RESULTS: Stroke-free participants in the Northern Manhattan Study underwent magnetic resonance imaging (N=1287; mean age 71±9 years, 60% women, 15% non-Hispanic white, 17% non-Hispanic black, 68% Hispanic) and were followed for a median of 8 years (interquartile range: 6-9 years). Cox models estimated proportional hazards of incident stroke of all types, ischemic stroke (and its subtypes), and mortality and stratified by race/ethnicity. In total 72 participants (6%) had incident strokes and 244 died (19%). In fully adjusted models, those with larger white matter hyperintensity volume had greater risk of all stroke types (hazard ratio [HR]: 1.4; 95% CI, 1.1-1.9), ischemic stroke (HR: 1.3; 95% CI, 1.0-1.8), and cryptogenic stroke (HR: 2.2; 95% CI, 1.1-4.4). White and black but not Hispanic participants had increased stroke risk (P<0.05 for heterogeneity for all and ischemic stroke). Those with subclinical brain infarct had greater risk for all stroke types (HR: 1.9; 95% CI, 1.1-3.3), ischemic stroke (HR: 2.2; 95% CI, 1.3-3.8), lacunar (HR: 4.0; 95% CI, 1.3-12.3), and cryptogenic stroke (HR: 3.6; 95% CI, 1.0-12.7), without significant heterogeneity across race/ethnic groups. Greater white matter hyperintensity volume increased both vascular (HR: 1.3; 95% CI, 1.1-1.7) and nonvascular (HR: 1.2; 95% CI, 1.0-1.5) mortality among Hispanic and white but not black participants (P=0.040 for heterogeneity). Subclinical brain infarct was associated with increased vascular mortality among Hispanic participants only (HR: 2.9; 95% CI, 1.4-5.8). CONCLUSIONS: In this urban US sample, subclinical cerebrovascular lesions increased the risk of clinical stroke and vascular mortality and varied by race/ethnicity and lesion type.

Elevated Serum Homocysteine (Hcy) Levels May Contribute to the Pathogenesis of Cerebral Infarction.

The purpose of this meta-analysis was to investigate the correlation between serum homocysteine (Hcy) levels and the pathogenesis of cerebral infarction (CI). Relevant studies involving serum Hcy levels and the pathogenesis of CI were identified using electronic database search supplemented with manual search. The search result studies were screened in accordance with our strict inclusion and exclusion criteria. Statistical analyses were conducted with Comprehensive Meta Analysis 2.0 (CMA 2.0) software. A total of 13 studies were eligible for our meta-analysis and included 1206 patients with CI and 1202 healthy controls. Our meta-analysis revealed that the serum Hcy levels in CI patients were significantly higher than those in healthy controls. Subgroup analysis based on ethnicity showed that Caucasians and Asians had significantly higher serum Hcy levels in CI patients compared to healthy controls and Africans showed no significant differences in serum Hcy levels between CI patients and controls. In conclusion, our meta-analysis reveals a strong correlation between elevated serum Hcy levels and the pathogenesis of CI, suggesting that serum Hcy levels may be an important biomarker for the early diagnosis and treatment assessment of CI.

Association between kinase insert domain-containing receptor gene polymorphisms and silent brain infarction: a Korean study.

BACKGROUND: Kinase insert domain-containing receptor (KDR), vascular endothelial growth factor receptor-2, play a pivotal role in endothelial dysfunction, which may lead to silent brain infarction (SBI). We evaluated whether single nucleotide polymorphisms (SNPs) of KDR genes are associated with increased risk of SBI in a Korean population. METHODS: A total of 383 patients with SBI and 387 controls were genotyped for the KDR -604T>C, 1192G>A, and 1719A>T SNPs. We separately analyzed this association according to the age (age≥65 and age<65) and the gender. We also compared haplotype frequencies between SBI patients and controls. RESULTS: Genotype frequencies for three SNPs did not differ significantly between SBI patients and controls. In addition, haplotype analysis for three SNPs did not show a difference between patients and controls. However, the frequency of genotype of KDR -604T>C was significantly associated with an increased risk of SBI in the age<65 years old group (AOR=1.515, 95% CI, 1.003 to 2.289, p=0.048) and in male group (AOR=1.596, 95% CI, 1.018 to 2.503, p=0.042). CONCLUSIONS: KDR -604T>C SNP may serve as genetic markers for the increased risk of SBI among the younger (<65 years) or male only Korean subpopulations.

High-dose atorvastatin enhances impaired cerebral vasomotor reactivity.

The influence of statin therapy on cerebral vasomotor function has not been fully characterized. We report the effects of high-dose atorvastatin therapy on cerebral vasomotor reactivity (VMR) in patients with controlled hypertension and dyslipidemia. We prospectively enrolled 36 patients with controlled hypertension and a low-density lipoprotein (LDL) cholesterol concentration >100 mg/dL. Atorvastatin 80 mg was given daily for 6 months and then discontinued. VMR was assessed by hypercapnic and hypocapnic transcranial Doppler challenge in both the right and left middle cerebral artery (MCA) at baseline, and after 3 and 6 months of therapy. Forty-five days after statin cessation, a repeat VMR was performed. VMR impairment was defined as ≤70%. Blood pressure, lipid levels, liver function, and creatine kinase level were monitored. Mean patient age was 60 years, 16 were men, and 13 had a previous history of subcortical infarction. Mean LDL cholesterol level before treatment was 154 ± 30 mg/dL. Atorvastatin lowered LDL by 53% at 3 months and by 46% at 6 months. Baseline VMR was 71% ± 21% in the right MCA and 70% ± 19% in the left MCA. No significant effect of atorvastatin on VMR was seen at 3 months and 6 months in the study population as a whole. In the subgroup of patients with baseline VMR impairment, atorvastatin therapy was associated with significantly improved VMR at both 3 and 6 months. This effect persisted for at least 45 days after discontinuation of therapy. Our findings indicate that high-dose atorvastatin therapy can significantly improve impaired cerebral VMR, and that the effects of atorvastatin on VMR persist for 1.5 months after discontinuation of therapy. We found no benefit of atorvastatin therapy in patients with preserved baseline vasoreactivity.

No association of ALOX5AP polymorphisms with risk of MRI-defined brain infarcts.

The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene has been associated with stroke. The majority of the reported ALOX5AP associations have considered non-radiologically confirmed infarcts as the stroke phenotype. We assessed the association of genetic variants in ALOX5AP with stroke defined by the presence of infarcts on brain magnetic resonance imaging (MRI). We studied 202 persons with MRI-defined brain infarcts and 487 healthy individuals of Caribbean Hispanic ancestry. Another sample of European ancestry comprised 1823 persons with MRI-defined brain infarct and 7578 control subjects. Subjects were genotyped for the 4 single nucleotide polymorphisms (SNPs) that define ALOX5AP HapA haplotype. No association was found between SNPs and MRI-defined brain infarcts. Our data do not support the hypothesis that variants in ALOX5AP are associated with risk of MRI-defined brain infarcts.

Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia Aging Study Autopsy Study.

OBJECTIVE: This study was untaken to investigate the association of micro brain infarcts (MBIs) with antemortem global cognitive function (CF), and whether brain weight (BW) and Alzheimer lesions (neurofibrillary tangles [NFTs] or neuritic plaques [NPs]) mediate the association. METHODS: Subjects were 436 well-characterized male decedents from the Honolulu Asia Aging Autopsy Study. Brain pathology was ascertained with standardized methods, CF was measured by the Cognitive Abilities Screening Instrument, and data were analyzed using formal mediation analyses, adjusted for age at death, time between last CF measure and death, education, and head size. Based on antemortem diagnoses, demented and nondemented subjects were examined together and separately. RESULTS: In those with no dementia, MBIs were strongly associated with the last antemortem CF score; this was significantly mediated by BW, and not NFTs or NPs. In contrast, among those with an antemortem diagnosis of dementia, NFTs had the strongest associations with BW and with CF, and MBIs were modestly associated with CF. INTERPRETATION: This suggests that microinfarct pathology is a significant and independent factor contributing to brain atrophy and cognitive impairment, particularly before dementia is clinically evident. The role of vascular damage as initiator, stimulator, or additive contributor to neurodegeneration may differ depending on when in the trajectory toward dementia the lesions develop.

Vascular risk factors and longitudinal changes on brain MRI: the ARIC study.

OBJECTIVE: To evaluate associations between vascular risk factors and changes in burden of infarcts, ventricular size (VS), sulcal widening (SW), and white matter hyperintensities (WMH) in an initially middle-aged, biracial cohort from the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Initial brain magnetic resonance (MR) scans and evaluations for vascular risk factors were performed in 1,812 ARIC participants in 1994-1995. In 2004-2006, 1,130 ARIC participants underwent repeat MR scans. MR scans were rated using a validated 9-point scale for VS, SW, and WMH. Infarcts were recorded. Multiple logistic regression analysis was used to assess associations between vascular risk factors and change between MR scans of one or more grades in VS, SW, WMH, or appearance of new infarcts, controlling for age, sex, and race. RESULTS: At baseline, the 1,112 participants with usable scans (385 black women, 200 black men, 304 white women, 223 white men) had a mean age of 61.7 ± 4.3 years. In adjusted models, diabetes at baseline was associated with incident infarcts (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.29-2.95) and worsening SW (OR 2.10, 95% CI 1.36-3.24). Hypertension at baseline was associated with incident infarcts (OR 1.73, 95% CI 1.23-2.42). In subjects with the highest tertile of fasting blood sugar and systolic blood pressure at baseline, the risk of incident infarcts was 3.68 times higher (95% CI 1.89-7.19) than those in the lowest tertile for both. CONCLUSION: Both atrophic and ischemic imaging changes were driven by altered glycemic and blood pressure control beginning in midlife.

Association of (pro)renin receptor gene polymorphisms with lacunar infarction and left ventricular hypertrophy in Japanese women: the Ohasama study.

Recent studies have revealed that (pro)renin receptor ((P)RR), a newly identified member of the renin-angiotensin system, is associated with organ damage that occurs with cardiovascular disease. We investigated the association of genetic polymorphisms in the (P)RR gene with lacunar infarction, white matter hyperintensity and left ventricular hypertrophy (LVH) in a Japanese general population recruited from the Ohasama study, a Japanese cohort study. A total of 779 subjects (men=250 and women=529) were recruited. For the association study, we selected three polymorphisms: -782A>G (rs2968915), intervening sequence (IVS)5+169C>T (rs5918007) and +1513A>G (rs6609080). In women, the prevalence of lacunar infarction and LVH was significantly higher in subjects with the +1513GG genotype than in those with the AA or AG genotypes (lacunar infarction: P=0.01, LVH: P=0.003). Plasma renin activity (PRA) levels in women with the GG genotype were significantly lower than in women with the AA or AG genotypes (P=0.01). Multiple logistic regression analysis adjusted for confounding factors demonstrated that +1513A>G polymorphism was significantly and independently associated with the risk of lacunar infarction (trend P=0.03) and LVH (trend P=0.003). In men, there were no significant differences in lacunar infarction, LVH or PRA levels among the three genotypes. The polymorphism of the (P)RR gene +1513A>G is associated with lacunar infarction and LVH in Japanese women. These results suggest that (P)RR has a role in organ damage in humans.

IkappaB-alpha expression following transient focal cerebral ischemia is modulated by nitric oxide.

The role of nitric oxide (NO) in cerebral ischemia/reperfusion (IR) has been intensively investigated. In general NO is regarded as a mediator of ischemia-associated neuronal damage, as inhibitors of NO synthesis ameliorate neuronal injury during permanent focal cerebral ischemia, however the exact role of NO in ischemia remains controversial. It has been previously shown that NO-donors can directly inhibit the DNA binding activity of NF-kappaB family proteins and strong evidence supports that activation of NF-κB contributes to ischemia-induced neuronal injury. In this study, we have investigated whether NO production by nNOS, eNOS and iNOS modulates IkB-alpha expression in cerebral ischemia, by using various inhibitors of NOS, in rats subjected to transient (1h) middle cerebral artery occlusion (tMCAo). Male Wistar rats were treated intraperitoneally (i.p.) with 3mg/kg of NG-nitro-l-arginine methyl ester (l-NAME, a non-selective NOS inhibitor), 5mg/kg of l-N6-(1-iminoethyl)-lysine (l-NIL, an inducible NOS inhibitor), 25mg/kg of 7-Nitroindazole (7-NI, a neuronal NOS inhibitor) and 10mg/Kg of l-N-(1-iminoethyl)ornithine (l-NIO, a selective eNOS inhibitor) 15min before the induction of tMCAo. Cortical IkB-alpha expression was evaluated by western blotting and its decrease was considered as an indicator of NF-κB activation. IkB-alpha expression decreased in ischemic cortices when compared with the cortices of the sham group, thus confirming the activation of NF-κB in ischemic conditions. Pre-treatment with l-NAME, l-NIL and 7-NI significantly reduced the infarct volume and prevented ischemia-induced reduction in IkB-alpha expression. Conversely, pretreatment with l-NIO was associated with a significant increase in infarct volume and a reduction in IkB-alpha expression. These findings suggest that NO of neuronal and inducible origin promotes NF-κB activation via IkB-alpha modulation and mediates ischemic-related damage in the brain following ischemia.

Clinical features of a first-ever lacunar infarction in Japanese patients: poor outcome in females.

Lacunar infarction (LI) remains an important stroke subtype in Japan. The aim of this study was to investigate the characteristics of outcome determinants in LI. This study was a single center observational study and included 163 consecutive patients (108 male, 55 female; mean age 69 years). The National Institutes of Health Stroke Scale (NIHSS) score on admission and the modified Rankin scale (mRS) score at discharge were used to evaluate stroke severity. We determined the location of the infarct, the grade of white matter hyperintensity (WMH), and the prevalence of silent brain infarcts, hypertension, hypercholesterolemia, diabetes mellitus, ischemic heart disease, and smoking. We compared 2 groups, good outcome (mRS score 0-2) and poor outcome (mRS score 3-5), using multiple logistic regression analysis. We found significant differences between the 2 groups according to female sex (P = .04), WMH (P = .04), and NIHSS score (P < .001). After multivariate analysis, female sex (odds ratio [OR] = 3.4, 95% confidence interval [CI] = 1.1-11.4; P = .03), and NIHSS score (OR = 2.3, 95% CI = 1.7-3.3; P < .001) were independently associated with poor outcome. Elderly onset, poor outcome, and hypercholesterolemia were more common in female patients, whereas smoking was more prevalent in males. Our data indicate that sex differences exist in Japanese LI patients with regard to risk factors and outcome. The treatment of risk factors based on sex differences is important to the management of LI.

Association between tumor necrosis factor-alpha (-308G→A and -238G→A) polymorphisms and homocysteine levels in patients with ischemic strokes and silent brain infarctions.

BACKGROUND AND PURPOSE: The aims of this study were to evaluate the role of tumor necrosis factor-α (TNF-α) polymorphisms in patients susceptible to ischemic stroke and silent brain infarction (SBI), and to determine the relationship between TNF-α polymorphisms and plasma total homocysteine (tHcy) levels. METHODS: We studied 237 patients with ischemic stroke, 257 patients with SBIs, and 216 control subjects. For control subjects, we selected healthy individuals matched for gender and age from those individuals who came to our hospital for health examinations. The TNF-α-308G→A and -238G→A genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The frequency of the TNF-α-308G→A polymorphism was significantly different between the patients with ischemic stroke and the control group (GG vs. GA+AA; adjusted odds ratio, AOR, 0.50; 95% CI 0.255-0.989). By subgroup analysis, when tHcy levels were stratified into high (>10.80 µmol/l), moderate (8.21-10.80 µmol/l), and low levels (<8.21 µmol/l), the frequency of the TNF-α-308GA+AA genotype in the highest tertile group was higher than in the lowest tertile group (AOR 2.46; 95% CI 1.063-5.699). However, the relationship between SBI susceptibility and polymorphisms of TNF-α was not established. The tHcy levels were significantly and inversely correlated with folate levels in the TNF-α-308GG and TNF-α-238GG genotypes in the ischemic stroke, SBI, and control groups (p< 0.05). CONCLUSIONS: Our results suggest that the TNF-α-308G→A polymorphism is responsible for susceptibility to ischemic stroke and is associated with high tHcy levels in Koreans.

Association of kidney dysfunction with silent lacunar infarcts and white matter hyperintensity in the general population: the Ohasama study.

BACKGROUND: No previous study has investigated the association of kidney dysfunction with silent lacunar infarcts and white-matter hyperintensity (WMH) independent of ambulatory blood pressure (BP). METHODS: A cross-sectional study involving 1,008 participants (mean age 66 years) from a general population of Ohasama, Japan, was conducted. Calculated creatinine clearance (CCr) was estimated using the Cockcroft-Gault equation. In continuous and categorical analyses, the association between CCr and the prevalence of silent lacunar infarcts and WMH was investigated. Silent lacunar infarcts and WMH were detected on MRI. Multiple logistic regression analysis adjusted for 24-hour ambulatory BP, sex, age, body mass index, smoking and drinking status, antihypertensive medication, and histories of hypercholesterolemia, diabetes mellitus and heart disease was performed. RESULTS: On univariate analysis, decreased CCr (continuous variable) and CCr <60 ml/min/1.73 m(2) (categorical variable) were significantly associated with lacunar infarcts and WMH. After adjustment, each 1-standard-deviation decrease in CCr (odds ratio = 1.22; p = 0.036) and CCr <60 ml/min/1.73 m(2) (odds ratio = 1.68; p = 0.007) was significantly associated with a high prevalence of lacunar infarcts. Even when 24-hour ambulatory BP was within the normal range (<130/80 mm Hg), CCr <60 ml/min/1.73 m(2) was associated with a high prevalence of lacunar infarcts (odds ratio = 1.62; p = 0.047). CCr <60 ml/min/1.73 m(2) and 24-hour ambulatory BP had additive effects on lacunar infarcts. After the same adjustment, the association between CCr and WMH was not significant. CONCLUSIONS: CCr is closely associated with lacunar infarcts, suggesting that kidney dysfunction in the elderly is an independent risk factor or predictor for silent lacunar infarcts.

The association of magnetic resonance imaging measures with cognitive function in a biracial population sample.

BACKGROUND: White matter hyperintensity volume (WMHV), cerebral infarcts, and total brain volume (TBV) are associated with cognitive function, but few studies have examined these associations in the general population or whether they differ by race. OBJECTIVE: To examine the association of WMHV, cerebral infarcts, and TBV with global cognition and cognition in 5 separate domains in a biracial population sample. SETTING: A biracial community population of Chicago, Illinois. DESIGN: Cross-sectional population study. PARTICIPANTS: The study population comprised 575 participants from the Chicago Health and Aging Project (CHAP). MAIN OUTCOME MEASURES: Volumetric magnetic resonance imaging (MRI) measures of WMHV, TBV, and cerebral infarcts and detailed neuropsychological testing assessments of global cognition and 5 cognitive domains. RESULTS: Overall and among those without dementia, cognition was inversely associated with WMHV and number of infarcts but was positively associated with TBV. When all 3 measures were simultaneously added to the model, the association of global cognition with WMHV and TBV remained significant and unchanged but was no longer significant with infarcts. Among subjects without dementia, all 3 MRI measures were associated with performance in multiple cognitive domains, specifically perceptual speed. However, among subjects with dementia, only TBV was associated with cognition and performance in multiple cognitive systems. Race did not significantly modify any of these associations. CONCLUSIONS: In this biracial general population sample, the associations of MRI measures with cognition differed according to clinical status of subjects (stronger among subjects without dementia) and were not modified by race. These associations did not affect all cognitive domains equally but were more consistent with impairments in perceptual speed.

Association of PRKCH gene with lacunar infarction in a local Chinese Han population.

Recent evidence indicated that the PRKCH gene was a susceptibility gene for lacunar infarction in a Japanese population. The aim of the present study was to explore the association of the gene with lacunar infarction in a population of Chinese Han ancestry. A total of 280 consecutive lacunar infarction patients and 306 unrelated population-based controls that had been matched for age and sex were examined using a case-control design. Two single nucleotide polymorphisms (SNPs) of PRKCH gene (rs3783799 and rs2230500) were genotyped with ligase detection reaction (LDR) and multiplex polymerase chain reaction (PCR). Linkage disequilibrium (LD) and haplotype analysis were also investigated between these two groups. Overall alleles and genotype frequencies were similar between cases and controls. No significant association was detected with the gene polymorphisms mentioned above and lacunar infarction; no significant difference was found with haplotype analysis between these two groups. None of the two SNPs showed significant association with lacunar infarction in the whole subjects before and after adjustment for conventional stroke risk factors (hypertension, diabetes mellitus, and hypercholesterolemia). The frequencies of PRKCH differed largely from those in the Japanese population. The present study suggests that variants in the PRKCH gene are not the risk factors for lacunar infarction in individuals from a small population of Chinese Han ancestry. Population differences in alleles and haplotype frequencies as well as LD structure may contribute to the observed differences between populations.

Ethnicity a risk factor? The relation between ethnicity and large- and small-vessel disease in White people, Black people, and Asians within a hospital-based population.

BACKGROUND: Previous studies suggest that in patients with ischaemic stroke, White people often present with large-vessel and Black people with small-vessel strokes. This study investigates the relation between large- and small-vessel disease, and ethnicity in White, Black, and Asian patients in Amsterdam, The Netherlands. METHODS: In a hospital-based population of 668 patients ethnicity was determined by self-identification. The relation between ethnicity and carotid stenosis, as an indicator of large-vessel disease, was determined using univariate analysis, and adjusted for age, gender, hypertension and smoking. Subsequently the relation between ethnicity and lacunar infarcts, as a manifestation of small-vessel disease, was investigated. RESULTS: The odds ratio for having carotid stenosis, compared to White patients, was 0.55 (0.23-1.33) for Blacks, 0.53 (0.18-1.52) for Asians, and 0.64 (0.14-2.85) for other ethnicities. The adjusted odds ratio for a non-White patient compared to a White patient was 0.44 (0.19-1.02) (P = 0.05). The non-White patients more often presented with lacunar infarcts compared to Whites. CONCLUSION: We found an association between White patients and the presence of carotid artery stenosis. Not only in Black but also in Asian patients the association with carotid artery stenosis was substantially lower. In the non-White population there was an association with lacunar infarcts compared to Whites.

A case-controlled study of cognitive progression in Chinese lacunar stroke patients.

OBJECTIVE: (1) To determine and compare the rates of cognitive change using global and executive psychometric measures between lacunar stroke patients and matched controls and; (2) to identify features associated with cognitive changes in patients. METHODS: Sixty-one lacunar stroke patients and 35 demographically-matched controls were followed-up for 28.6 months (range 19.4-45.9 months) with psychometric assessments performed at baseline and follow-up. RESULTS: Lacunar stroke patients were more impaired than controls in general and executive functions at both time points. Both groups had similar stability in all psychometric tests. Patients, but not controls, exhibited a trend for improvement in general cognitive functions overtime (interaction term, p=0.084). No patient who was non-demented at baseline became demented during the study period. Two (5.7%) and five (8.2%) incident cerebrovascular events occurred among the controls and patients, respectively. Linear regression analyses performed upon patients failed to identify any predictor for the cognitive change. CONCLUSION: Similar to controls, cognition in lacunar stroke patients is stable during the first 2-3 years after the stroke. There maybe a spontaneous improvement in general cognition overtime, but this awaits confirmation by future studies.

Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study.

BACKGROUND AND PURPOSE: To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the C-reactive protein (CRP) and interleukin (IL)-6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study. METHODS: Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (n=532) and Whites (n=2905). RESULTS: Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the -174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95% CI: [1.02; 1.28]). The common haplotype tagged by the -572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95% CI: [1.15; 2.14]). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race. CONCLUSIONS: This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.

ACE I/D polymorphism in Korean patients with ischemic stroke and silent brain infarction.

OBJECTIVES: Angiotensin-converting enzyme (ACE) polymorphism may play a role in stroke and silent brain infarction (SBI) susceptibility, but the results among the populations studied to date have not been consistent. Thus, we investigated the association between ACE genotypes and ischemic stroke and SBI in Korean patients. SUBJECTS AND METHODS: DNA samples from 237 stroke patients, 264 SBI patients and 234 age-matched controls were amplified using polymerase chain reaction to detect the ACE ins/del (I/D) polymorphism. Genotype was determined by the presence of a 490-bp band (I allele) or a 190-bp band (D allele) in agarose gel electrophoresis. RESULTS: Odds ratios of the I/D and D/D genotypes and the overall (I/D + D/D) for the I/I genotype were significantly different between stroke patients and normal controls. However, there was no significant difference between patients with SBI and controls. CONCLUSIONS: This study is the first report of a significant association between ACE polymorphism and ischemic stroke in the Asian population. Although no consistent associations have been found between ACE polymorphism and stroke in the populations studied to date, the ACE polymorphism may be a genetic determinant of ischemic stroke, at least in Korean patients.