Risk Factor For Small Vessel Disease Research Articles

Prevalence and 3-month follow-up of cerebrovascular MRI markers in hospitalized COVID-19 patients: the CORONIS study

PurposeTo investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months.MethodsCORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders.Results125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07–8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%).ConclusionOverall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization.

Social Determinants of Health and Cerebral Small Vessel Disease: Is Epigenetics a Key Mediator?

Cerebral small vessel disease is highly prevalent, particularly in marginalized communities, and its incidence is expected to increase given the aging global population. Cerebral small vessel disease contributes to risk for stroke, vascular cognitive impairment and dementia, late-life depression, and gait disorders. A growing body of evidence suggests that adverse outcomes, including cerebral small vessel disease, caused by traditional cardiovascular risk factors are at least partly mediated by epigenetic changes, some of them already beginning during fetal development. Societal and health care access inequities, summarized under the umbrella term social determinants of health, put a higher burden of cardiovascular risk factors on marginalized populations and expose them to an increased risk for adverse outcomes. Social epigenetics has begun to deliver solid evidence that social determinants of health lead to distinct epigenetic signatures that potentially mediate the biological effect of environmental exposures on cardiovascular risk factors. Here, we provide a review of the most recent advances in the epigenetics of cerebral small vessel disease risk factors and social determinants of health and call for research efforts combining insights from both fields to reach a deeper understanding of the causal pathways, ultimately facilitating discovery of new treatment targets for a disease whose burden is magnified by existing health disparities.

1715-P: Osteopenic Obesity Is Associated with Small Vessel Disease in Old Adults—The Bunkyo Health Study

Obesity is one of the most important causes of metabolic disorders and cardiovascular events. Indeed, while the presence of cerebral small vessel disease (SVD) that includes silent brain infarcts, cerebral white matter lesions, and microhemorrhage increased the risk of stroke > 3-fold, and dementia > 2-fold, respectively, obesity has been identified as a risk factor for SVD. On the other hand, low bone mineral density (BMD), is also recognized as a risk factor for SVD. Whereas obesity is generally associated with high BMD, it has recently been reported that there is a special subtype of osteopenic obesity in which obesity and low BMD coexist. Thus, we hypothesized that this osteopenic obesity is at high risk for SVD. To test this hypothesis, we studied 1531 (641 male and 890 female) old adults aged 65 to 85 years without a history of stroke (Bunkyo Health Study). All subjects underwent dual-energy X-ray absorptiometry, brain MRI, and blood sampling, and they were classified into four groups according to the presence or absence of obesity and osteopenia (men) or osteoporosis (women) diagnosed by the BMD at the hip joint. The mean age of the subjects was 73.0 years. The prevalence of osteopenic obesity was 7.8% and 8.0% for men and women, respectively. While overall prevalence of SVD was 25% in men and 22% in women, the prevalence of SVD in osteopenic obesity was 46% and 42%, respectively. Logistic regression analysis revealed that odds ratio [95% CI] for SVD in control, obesity, osteopenia/osteoporosis and osteopenic obesity were 1.00, 1.203 [0.730-1.982], 0.970 [0.670-1.549] and 3.024 [1.560-5.861] in men and 1.00, 1.452 [0.818-2.575], 1.548 [1.012-2.368], 2.747 [1.489-5.069] in women, respectively. In conclusion, osteopenic obesity was independently associated with the presence of SVD in old adults without a history of stroke. Disclosure N.Ito: None. Y.Yoshizawa: None. H.Watada: Research Support; Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, LifeScan Diabetes Institute, Eli Lilly Japan K.K., Sun Pharmaceutical Industries Ltd., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck Sharp & Dohme Corp., Sanwa Kagaku Kenkyusho, Speaker's Bureau; Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., Novo Nordisk, Abbott Japan Co., Ltd., Astellas Pharma Inc., Merck Sharp & Dohme Corp., Kissei Pharmaceutical Co., Ltd., AstraZeneca, Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Eli Lilly Japan K.K. Y.Tamura: None. H.Kaga: None. Y.Someya: None. H.Tabata: None. S.Kakehi: None. M.Kiya: None. T.Tajima: None. H.Naito: None. Funding Strategic Research Foundation at Private Universities (S1411006); Ministry of Education, Culture, Sports, Science and Technology of Japan (18H03184); Mizuno Sports Promotion Foundation; Mitsui Life Social Welfare Foundation

Methylenetetrahydrofolate reductase polymorphisms and elevated plasma homocysteine levels in small vessel disease.

Despite its public health importance, the causes of small vessel disease (SVD) are not fully understood. The presence of SVD in monogenic twins indicates the involvement of genetic factors in the pathogenesis of this disease. The purpose of this study was to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with SVD risk. Patients with SVD and matched controls were recruited from Tianjin Union Medical Center and Tianjin Huanhu Hospital. Clinical and laboratory data were collected. Plasma total homocysteine (tHcy) and folate levels were measured, and MTHFR rs1801133 (C677T) and rs1801131 (A1298C) single-nucleotide polymorphisms were genotyped. We analyzed potential associations among SVD and MTHFR polymorphisms, tHcy, and folate levels. Patients with SVD displayed significantly decreased plasma folate levels (Z=-3.537, p<.001) and increased tHcy levels (Z=4.910, p<.001) compared with controls. Significantly different plasma tHcy levels were associated with rs1801133 (χ2 =6.664, p=.036), and post hoc analysis indicated higher plasma tHcy levels in individuals carrying the TT allele compared with levels in those carrying the TC allele (Z=2.478, p=.013). No significant differences in tHcy levels were observed for rs1801131 alleles. The genotype and allele frequencies of rs1801133 were different between SVD and control groups (χ2 =9.378, p=.009). There was no significant difference in distributions of rs1801131 genotypes between the two groups, and multivariable logistic regression analysis showed that rs1801131 and rs1801133 were not significantly associated with the risk of SVD. Our study indicates that an elevated plasma tHcy level is independently associated with the development of SVD. Although MTHFR rs1801133 is linked to increased plasma homocysteine (Hcy) levels, it is not a risk factor for SVD. rs1801131 is not related to Hcy levels or SVD risk.

Central vein sign and diffusion MRI differentiate microstructural features within white matter lesions of multiple sclerosis patients with comorbidities.

The Central Vein Sign (CVS) has been suggested as a potential biomarker to improve diagnostic specificity in multiple sclerosis (MS). Nevertheless, the impact of comorbidities on CVS performance has been poorly investigated so far. Despite the similar features shared by MS, migraine and Small Vessel Disease (SVD) at T2-weighted conventional MRI sequences, ex-vivo studies demonstrated their heterogeneous histopathological substrates. If in MS, inflammation, primitive demyelination and axonal loss coexist, in SVD demyelination is secondary to ischemic microangiopathy, while the contemporary presence of inflammatory and ischemic processes has been suggested in migraine. The aims of this study were to investigate the impact of comorbidities (risk factors for SVD and migraine) on the global and subregional assessment of the CVS in a large cohort of MS patients and to apply the Spherical Mean Technique (SMT) diffusion model to evaluate whether perivenular and non-perivenular lesions show distinctive microstructural features. 120 MS patients stratified into 4 Age Groups performed 3T brain MRI. WM lesions were classified in "perivenular" and "non-perivenular" by visual inspection of FLAIR* images; mean values of SMT metrics, indirect estimators of inflammation, demyelination and fiber disruption (EXTRAMD: extraneurite mean diffusivity, EXTRATRANS: extraneurite transverse diffusivity and INTRA: intraneurite signal fraction, respectively) were extracted. Of the 5303 lesions selected for the CVS assessment, 68.7% were perivenular. Significant differences were found between perivenular and non-perivenular lesion volume in the whole brain (p < 0.001) and between perivenular and non-perivenular lesion volume and number in all the four subregions (p < 0.001 for all). The percentage of perivenular lesions decreased from youngest to oldest patients (79.7%-57.7%), with the deep/subcortical WM of oldest patients as the only subregion where the number of non-perivenular was higher than the number of perivenular lesions. Older age and migraine were independent predictors of a higher percentage of non-perivenular lesions (p < 0.001 and p = 0.013 respectively). Whole brain perivenular lesions showed higher inflammation, demyelination and fiber disruption than non perivenular lesions (p = 0.001, p = 0.001 and p = 0.02 for EXTRAMD, EXTRATRANS and INTRA respectively). Similar findings were found in the deep/subcortical WM (p = 0.001 for all). Compared to non-perivenular lesions, (i) perivenular lesions located in periventricular areas showed a more severe fiber disruption (p = 0.001), (ii) perivenular lesions located in juxtacortical and infratentorial regions exhibited a higher degree of inflammation (p = 0.01 and p = 0.05 respectively) and (iii) perivenular lesions located in infratentorial areas showed a higher degree of demyelination (p = 0.04). Age and migraine have a relevant impact in reducing the percentage of perivenular lesions, particularly in the deep/subcortical WM. SMT may differentiate perivenular lesions, characterized by higher inflammation, demyelination and fiber disruption, from non perivenular lesions, where these pathological processes seemed to be less pronounced. The development of new non-perivenular lesions, especially in the deep/subcortical WM of older patients, should be considered a "red flag" for a different -other than MS- pathophysiology.

White Matter Lesions May Aid in Differentiating Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease.

Idiopathic normal pressure hydrocephalus (iNPH) is often misdiagnosed as Alzheimer's disease (AD) due to overlapping pathophysiology and similar imaging characteristics, including ventricular enlargement and increased white matter lesions (WMLs). To compare the extent and distribution of WMLs directly between iNPH and AD and examine the association with underlying pathophysiology. Twelve patients with iNPH (mean age: 78.08 years; 5 females), 20 with AD (mean age: 75.40 years; 13 females), and 10 normal cognition (NC) participants (mean age: 76.60 years; 7 females) were recruited. The extent and distribution of WMLs and the lateral ventricular volume (LV-V) were evaluated on MRI using voxel-based morphometry analysis. Concentrations of cerebrospinal fluid biomarkers, such as amyloid-β protein (Aβ)42, Aβ40, Aβ38, and tau species, were also measured. Risk factors for small vessel disease (SVD) were assessed by blood examination and medical records. The periventricular WML volume (PWML-V) and deep WML volume (DWML-V) were significantly larger in iNPH than in AD and NC. The DWML-V was dominant in iNPH, while the PWML-V was dominant in AD and NC. GM-V was significantly smaller in AD than in iNPH and NC. The LV-V positively correlated with WML-V in all participants. There was a significant negative correlation between LV-V and Aβ38 in iNPH. Furthermore, there was no significant difference in SVD risk factors between the groups. The differences in the extent and distribution of WMLs between iNPH and AD, especially predominance of DWML-V over PWML-V in iNPH, may reflect decreased fluid and Aβ clearance.

The effects of age and hypertension on cerebral small‐vessel disease differ between men and women at midlife: The PREVENT Dementia study

AbstractBackgroundSex differences exist in the prevalence, prognosis, and clinical manifestation of cerebral small vessel disease (SVD) and dementia. Given the role of SVD in cognitive impairment – both directly and through accelerating neurodegenerative pathology – understanding sex differences in SVD risk factors could inform targeted intervention strategies. In this longitudinal study, we examined sex differences in the effects of age and hypertension on SVD at midlife.Method185 cognitively‐healthy midlife adults underwent 3T MRI at baseline and two‐year follow‐up. SVD markers were white matter hyperintensities (WMH) volume, enlarged perivascular spaces, microbleeds, lacunes, and global SVD burden (composite score of all four SVD markers). Piecewise linear regression analysis estimated change‐points in age, beyond which WMH accelerates. To examine sex as a moderator of age and hypertension on SVD cross‐sectionally, interaction analysis was conducted in general linear models, adjusting for age and education. To assess interactions on longitudinal SVD progression, linear mixed effects models were fitted, adjusting for the same covariates and random intercept of subjects.ResultMales were twice as likely to have hypertension compared to females (males:53.8%, females:26.4%, X 2=7.97, p=.005). Interaction analysis demonstrated that the effect of hypertension on SVD was amplified in females, compared to males, both cross‐sectionally (WMH: t=2.42, p=.017) and longitudinally (WMH progression: t=3.37, p&lt;.001; new microbleeds: t=2.57, p=.011) (Fig 1). Findings remained consistent when additionally controlling for antihypertensive medication. In terms of age, piecewise linear regression estimated a WMH change‐point at age 50.2 (SE=3.2) in the whole sample, 50.6 years (SE=3.8) in males, but was undetectable in females (Fig 2). Sex*age interaction demonstrated that the effect of age on global SVD burden was amplified in males compared to females (t=‐2.43, p=.016) (Fig 3). Sex*age*hypertension interaction showed that hypertension intensified the effect of age on global SVD burden in males but not females (t=‐2.67, p=.008), for whom hypertension was a stronger predictor than age.ConclusionOlder men (especially those with hypertension) and women with hypertension (regardless of age) were at greatest risk of SVD. Our findings highlight the importance of hypertension management as early as midlife in relation to SVD, but suggest that this may be especially effective for women.

Cerebrovascular Risk-Factors of Prevalent and Incident Brain Infarcts in the General Population: The AGES-Reykjavik Study.

Studies on the association of cerebrovascular risk factors to magnetic resonance imaging detected brain infarcts have been inconsistent, partly reflecting limits of assessment to infarcts anywhere in the brain, as opposed to specific brain regions. We hypothesized that risk-factors may differ depending on where the infarct is located in subcortical-, cortical-, and cerebellar regions. Participants (n=2662, mean age 74.6±4.8) from the longitudinal population-based AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study underwent brain magnetic resonance imaging at baseline and on average 5.2 years later. We assessed the number and location of brain infarcts (prevalent versus incident). We estimated the risk-ratios of prevalent (PRR) and incident (IRR) infarcts by baseline cerebrovascular risk-factors using Poisson regression. Thirty-one percent of the study participants had prevalent brain infarcts and 21% developed new infarcts over 5 years. Prevalent subcortical infarcts were associated with hypertension (PRR, 2.7 [95% CI, 1.1-6.8]), systolic blood pressure (PRR, 1.2 [95% CI, 1.1-1.4]), and diabetes (PRR, 2.8 [95% CI, 1.9-4.1]); incident subcortical infarcts were associated with systolic (IRR, 1.2 [95% CI, 1.0-1.4]) and diastolic (IRR, 1.3 [95% CI, 1.0-1.6]) blood pressure. Prevalent and incident cortical infarcts were associated with carotid plaques (PRR, 1.8 [95% CI, 1.3-2.5] and IRR, 1.9 [95% CI, 1.3-2.9], respectively), and atrial fibrillation was significantly associated with prevalent cortical infarcts (PRR, 1.8 [95% CI, 1.2-2.7]). Risk-factors for prevalent cerebellar infarcts included hypertension (PRR, 2.45 [95% CI, 1.5-4.0]), carotid plaques (PRR, 1.45 [95% CI, 1.2-1.8]), and migraine with aura (PRR, 1.6 [95% CI, 1.1-2.2]). Incident cerebellar infarcts were only associated with any migraine (IRR, 1.4 [95% CI, 1.0-2.0]). The risk for subcortical infarcts tends to increase with small vessel disease risk-factors such as hypertension and diabetes. Risk for cortical infarcts tends to increase with atherosclerotic/coronary processes and risk for cerebellar infarcts with a more mixed profile of factors. Assessment of risk-factors by location of asymptomatic infarcts found on magnetic resonance imaging may improve the ability to target and optimize preventive therapeutic approaches to prevent stroke.

Correlation Between Internal Carotid Artery Tortuosity and Imaging of Cerebral Small Vessel Disease.

Background and Purpose: An association between artery tortuosity and neuroimaging of cerebral small vessel disease (SVD) has been reported, especially in the posterior circulation. However, few studies involved the whole magnetic resonance imaging (MRI) spectrum of SVD in association with anterior circulation arterial tortuosity. This study aimed to investigate the relationship between internal carotid artery (ICA) tortuosity and the neuroimaging of SVD.Methods: Data of 1,264 consecutive patients in whom cerebral vessel diseases were suspected and who underwent both MRI and computed tomography angiography were reviewed from a prospective registry. Internal carotid artery tortuosity was evaluated using the tortuosity index (TI), which was defined as the ratio of the vessel centerline length divided by the straight length. Magnetic resonance imaging was used to assess cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), enlarged perivascular spaces (EPVSs), and lacunes.Results: The TIs of the ICA for patients with and without SVD MRI markers were 1.81 ± 0.42 and 1.72 ± 0.33, respectively (P < 0.001). Univariate analysis showed that the ICA TI were positively correlated with each SVD MRI marker (P < 0.001), and the correlation coefficients (rs) were 0.57, 0.42, 0.30, and 0.26 for EPVSs, WMHs, CMBs, and lacunes, respectively. The adjusted ORs of the ICA TI were 1.52 (95% CI 1.44–1.60, P < 0.001) for EPVS grade 1, 2.05 (95% CI 1.93–2.18, P < 0.001) for EPVS grades 2–4, and 1.09 (95% CI 1.03–1.15, P = 0.004) for WMH grade 3.Conclusions: The TI of ICA was higher in patients with neuroimaging of SVD. Internal carotid arteries tortuosity was associated with MRI-defined markers of SVD, including EPVS and high-grade WMH, and positively correlated with EPVS severity. Arterial tortuosity might be a risk factor for SVD. This finding may have potential clinical significance for identifying patients with suspected SVD.

Abstract WP88: Relationship Between Small Vessel Ischemic White Matter Disease and Collateral Recruitment in Patients With Acute Embolic Ischemic Stroke

Introduction: White matter hyperintensities (WMH) is the most prominent neuroimaging feature of small vessel disease (SVD). SVD is thought to be a result of arteriolosclerosis, chronic hypoperfusion of white matter, selective oligodendrocyte death and degeneration of myelinated fibers. The risk of ischemic stroke is significantly increased with the presence of WMH. The presence of intracranial collaterals is a strong predictor of salvageable neurological function in acute stroke; however, the factors affecting the ability to recruit collaterals are poorly understood. We wanted to study if the presence and severity of small vessel white matter disease had an adverse effect on cerebral collateral flow in acute embolic large vessel stroke. Methods: We identified a consecutive series of adult subjects with acute embolic large vessel strokes confirmed on CT angiography (CTA) from a 10-year institutional database. Patients without a brain MRI within six months of CTA were excluded. Collateral scores of the affected hemisphere were calculated on CTA using the modified Tan scale (0-4) by two independent trained reviewers and confirmed by a neuroradiologist. The WMH was quantified using the Fazekas scale (0-3) incorporating both deep and periventricular components. Areas of restricted diffusion on brain MRI in the peri-stroke period were eliminated from the assessment of Fazekas score. Spearman’s correlation tests were performed for the association between collateral scores and WMH. Results: A total of 234 patients (mean age 70±14 years, 47% [110/234] women) satisfied the inclusion criteria. The prevalence of periventricular and deep WMH was 83% and 87% respectively. Aging had a significant impact on periventricular WMH (r=0.48, p &lt;0.001) and deep WMH (r=0.47, p &lt;0.001). However, collateral scores exhibited no statistically significant relationship with the presence or severity of periventricular scores (r=0.08, p=0.17) or deep WMH scores (r=0.01, p=0.77). Conclusions: Our results indicate that the presence of SVD does not affect cerebral collateral flow. The vascular niche and risk factors of SVD appear to be distinct from that of intracranial vessels responsible for collateral reperfusion of ischemic territory in acute large vessel embolic stroke.

Risk factors for ischemic stroke and stroke subtypes in patients with chronic kidney disease.

The aim of this study was to compare ischemic stroke subtypes with the effects of risk factors, the relationship between grades of kidney disease and the severity of stroke subtypes. The current study was designed retrospectively and performed with data of patients who were hospitalised due to ischemic stroke. We included 198 subjects who were diagnosed with ischemic stroke of Grade 3 and above with chronic kidney disease. In our study were reported advanced age, coronary artery disease, moderate kidney disease as the most frequent risk factors for cardioembolic etiology. Hypertension, hyperlipidemia, smoking and alcohol consumption were the most frequent risk factors for large-artery disease. Female sex and anaemia were the most frequent risk factors for small-vessel disease. Dialysis and severe kidney disease were the most frequent risk factors in unknown etiologies, while male sex, diabetes mellitus, prior stroke and mild kidney disease were the most frequent risk factors for other etiologies. National Institute of Health Stroke Scale (NIHSS) scores were lower for small-vessel disease compared with other etiologies. This relation was statistically significant (p=0.002). In order to improve the prognosis in ischemic stroke with chronic kidney disease, the risk factors have to be recognised and the treatment options must be modified according to those risk factors.

Imaging features of cerebral small vessel disease in systemic lupus erythematosus patients with impaired renal function and its associated risk factors

Objective To investigate the imaging features of cerebral small vessel disease(SVD) in systemic lupus erythematosus(SLE) patients with impaired renal function and their related risk factors. Methods Seventy-six SLE patients and forty age- and sex-matched healthy controls were recruited, and SLE patients were divided into the impaired renal function group [estimated glomerular filtration rate (eGFR) <90 ml/(min·1.73 m2)] (n=38) and the normal renal function group [eGFR≥90 ml/(min·1.73 m2)] (n=38) according to their eGFR. All subjects underwent brain MRI, cognitive and psychiatric testing. The SVD scores were measured, total white matter hyperintensity (WMH) and SVD scores were calculated, and the risk factors of SVD scores were analyzed by using ordinal logistic regression. Results SLE patients in the impaired renal function group showed higher basal ganglia PVS, centrum semiovale perivascular space (PVS), periventricular WMH, deep WMH and total SVD scores compared with normal controls or patients with normal renal function (H=44.568, 31.380, 31.172, 43.419, 24.317, P<0.001) . The ordinal logistic regression analysis showed that C-reactive protein was a risk factor for SVD in patients with SLE(OR=1.323, P<0.01). Conclusion SLE patients with impaired renal function had a higher SVD burden on MR imaging, particularly PVS in the basal ganglia and deep WMH, which was affected by the C-reactive protein level. Key words: Lupus erythematosus, systemic; Cerebral small vessel disease; Glomerular filtration rate; White matter lesions

Cerebral Small Vessel Disease is Associated with Genetic Variations in CYP2J

Cerebral Small Vessel Disease (SVD) can cause cognitive impairment, disability and dementia. While it is still unclear about the pathogenesis of SVD, several risk factors of SVD have been identified, and studies suggested that hypertension may play a critical role in SVD. Furthermore, studies have demonstrated that CYP2J2 isoform, 50 G>T variant, is associated with increasing the risk of ischemic stroke. Thus, we hypothesized that CYP2J2 50 G>T variant is associated with increased risk of cerebral SVD. Thus, in this case-control study, we evaluated the association of CYP2J2 polymorphisms with the susceptibility to cerebral SVD in a population of Chinese Han adults. We found that CYP2J2 50 G>T genotype was significantly higher in SVD patients compared to healthy control group. Furthermore, 50 G>T genotype of CYP2J2 was associated with a significantly higher risk of SVD. Additionally, this polymorphism was significantly associated with WMH volume and a number of impaired cognitive domains in SVD patients. In conclusion, our study demonstrated that CYP2J2 50 G>T polymorphism is associated with increased risk of cerebral SVD in Han Chinese.

Abstract T MP35: Frequency, Risk Factors, and Impact of Coexistent Small Vessel Disease in the SAMMPRIS Trial

Background: Intracranial atherosclerotic stenosis (ICAS) and small vessel disease (SVD) may coexist. We investigated the frequency and risk factors for SVD in SAMMPRIS patients and the impact of SVD on stroke recurrence in the medical arm of the trial. Methods: Of 451 patients enrolled in SAMMPRIS, 313 had baseline brain MRIs read centrally for SVD. SVD was defined by any of the following: old lacunar infarction, Fazekas score of 2-3 for white matter hyperintensities, or microbleeds. We compared risk factors in patients with vs. without SVD using Fisher’s exact test (for percentages), independent groups t test (for means) or Wilcoxon rank sum test (for medians), and compared the survival curves of patients with vs. without SVD in the medical arm for ischemic stroke in the territory of the stenotic artery and any ischemic stroke using the logrank test. Results: Of the 313 patients, 161 (51.4%) had SVD on the baseline MRI. Variables that were significantly (p&lt;0.05) higher in patients with SVD were age, diabetes, lipid disorder, baseline SBP, coronary disease, and old infarct in the territory. The Kaplan-Meier curves in the figure show that patients with SVD were at significantly higher risk of any ischemic stroke (p = 0.048) but not stroke in the territory (p = 0.10) compared with patients without SVD. Conclusion: SVD in patients with ICAS is common, especially in patients who are older, diabetic, hyperlipidemic, and have higher SBP. Patients with ICAS and coexistent SVD are at higher risk of any ischemic stroke but may not be at higher risk for stroke in the territory.

Vascular incontinence: incontinence in the elderly due to ischemic white matter changes.

This review article introduces the new concept of vascular incontinence, a disorder of bladder control resulting from cerebral white matter disease (WMD). The concept is based on the original observation in 1999 of a correlation between the severity of leukoareosis or WMD, urinary symptoms, gait disorder and cognitive impairment. Over the last 20 years, the realization that WMD is not a benign incidental finding in the elderly has become generally accepted and several studies have pointed to an association between geriatric syndromes and this type of pathology. The main brunt of WMD is in the frontal regions, a region recognized to be crucial for bladder control. Other disorders should be excluded, both neurological and urological, such as normal-pressure hydrocephalus, progressive supranuclear palsy, etc., and prostatic hyperplasia, physical stress incontinence, nocturnal polyuria, etc. Treatment involves management of small vessel disease risk factors and anticholinergic drugs that do not easily penetrate the blood brain barrier to improve bladder control.

TGF-beta 1 Codon 10 Polymorphism is Associated with Cerebral SVD

To clarify the role of inflammation in the pathogenesis of cerebral small vessel disease (SVD), we investigated whether the gene encoding transforming growth factor-beta 1(TGF-beta 1) is a risk factor for cerebral SVD as a whole, and for two different SVD subtypes. TGF-beta 1 codon10 (T+29C) genotype was determined in 441 Chinese patients (313 male and 128 female) with cerebral SVD and 450 control subjects (326 male and 124 female). Cerebral SVD patients were retrospectively classified into two groups based on neuroimaging findings: lacunar infarction group with 112 patients and ischaemic leukoaraiosis group with 329 patients. Subjects carrying TT homozygote were susceptible to cerebral SVD [adjusted odds ratio (OR) =1.44, 95% confidence interval (CI), 1.05-1.98; P=0.026]. Further analysis of SVD subtypes revealed a moderate association with the ischaemic leukoaraiosis group [OR= 1.60, 95% CI, 1.14-2.25; P=0.007]. Codon 10 of TGF-beta 1 might be a risk factor for SVD, specifically in ischaemic leukoaraiosis phenotype.

Asymmetric Dimethylarginine in Cerebral Small Vessel Disease

Endothelial dysfunction may play a causal role in cerebral small vessel disease (SVD). Asymmetric dimethylarginine (ADMA), a circulating endogenous inhibitor of nitric oxide, has been implicated in endothelial dysfunction, particularly in hyperhomocystinemia, a known risk factor for SVD. We determined if ADMA was elevated in SVD, correlated with disease severity, and interacted with homocysteine. ADMA and homocysteine levels were determined in 47 consecutive symptomatic SVD patients and 38 controls. SVD was graded by leukoariosis severity and number of lacunar infarcts. Mean (and SD) ADMA was higher in SVD patients compared with controls (0.814 [0.145] versus 0.747 [0.184] micromol/L; P=0.014) after controlling for age, gender, vascular risk factors, and creatinine clearance. Additionally controlling for homocysteine had only a small effect on this relationship (P=0.055). Mean homocysteine was higher in SVD cases compared with controls (15.14 [5.59] versus 12.49 [4.15] micromol/L; P=0.035). Leukoariosis grade correlated positively with ADMA (P=0.026) and homocysteine (P=0.003). Lacunar grade correlated with homocysteine (P=0.017), but not ADMA. ADMA is independently associated with SVD and correlates with leukoariosis severity.

Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease.

Genetic influences are important in multifactorial cerebral small-vessel disease (SVD) and may act via endothelial dysfunction. Nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) is a key mediator of endothelial function. We determined the role of 3 potentially functional eNOS polymorphisms (T-786C, intron 4ab, G894T) located toward the 5' flanking end of the gene as risk factors for SVD and different SVD subtypes: isolated lacunar infarction (n=137) and ischemic leukoaraiosis (n=160). Three hundred patients with SVD and 600 community controls were studied. Genotypes were determined through polymerase chain reaction with or without restriction fragment digestion. Nitrate (NO(x)) levels were determined in a subgroup by use of a Griess method. Polymorphisms were tested individually and in combination with haplotype analysis. The intron 4a variant was protective against SVD. This effect was confined to isolated lacunar infarction (odds ratio, 0.55; 95% confidence interval, 0.35 to 0.86; P=0.01). Haplotypes encountered were significantly different in this subtype compared with controls (P=0.001), with the -786C promoter/intron 4a combination particularly underrepresented. NO(x) levels were associated with the T-786C locus (P=0.03) but only in the presence of the intron 4a allele (P=0.07 for interaction). The intron 4ab insertion/deletion genotype was associated with isolated lacunar infarction. Haplotype and functional studies suggested that the protective effect of the 4a variant could be mediated through changes in eNOS promoter activity and increased NO levels. The specific association with isolated symptomatic lacunar infarction and not ischemic leukoaraiosis may reflect different etiopathogeneses of the 2 subtypes. Lack of NO could predispose to localized microatheroma in proximal arterioles rather than diffuse arteriosclerosis affecting distal perforating vessels.

Blood Pressure Variability in Binswanger’s Disease and Isolated Lacunar Infarction

To determine whether blood pressure (BP) variability is increased in hypertensive patients with Binswanger’s disease (BD), we studied two samples of consecutive treated hypertensive patients: (1) 11 with BD (mean age 71.3 ± 5.2 years); (2) 16 with lacunar infarction (mean age 65.2 ± 8.3 years) without cognitive impairment. An averaged baseline office BP was obtained for 3 consecutive weeks. Ambulatory BP monitoring was then carried out to obtain the averaged mean systolic (SBP) and diastolic BP, and BP variability was defined as the standard deviation of consecutive BP values. Results: Diurnal SBP variability was significantly increased in the BD group (p = 0.04). However, with the analysis of covariance for age and baseline office BP, the difference was no longer significant (p = 0.17 and p = 0.09, respectively). We conclude that increased BP variability in BD patients is probably due to older age and increased baseline office BP. Increased BP variability may be a risk factor for small-vessel disease, but not for cognitive impairment.