Manifestations Of Cerebral Small Vessel Disease Research Articles

SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study

BackgroundSodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD.MethodsGenetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations.ResultsA lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively.ConclusionsSGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

Abstract TP16: Dental Caries Associated With Cerebral Small Vessel Disease

Background: Dental caries is a chronic oral infection distinct from periodontal disease in that it is associated with both ischemic stroke and intracerebral hemorrhage (ICH). Few studies have investigated the relationship between dental caries and cerebral small vessel disease (CSVD). White matter hyperintensities (WMH) and cerebral microbleeds (CMB) are manifestations of CSVD. Methods: Using the Atherosclerosis Risk in Communities (ARIC) database, we extracted data from 1112 participants assessed for dental caries and vascular risk factors. Of those, 203 (18.3%) had caries and 909 (81.7%) did not. Brain imaging was performed on 3T scanners. WMH was imaged by T2 fluid-attenuated inversion recovery, with volumes derived by a semiautomated algorithm. Multinomial logistic regression to test the association between caries and WMH volume categorized into quartiles. Quartiles (Q) were defined as Q1: <6.4 cm 3 , Q2: 6.4 - <11.6 cm 3 , Q3: 11.6 - <21.4 cm 3 , Q4: ≥21.4 cm 3 . CMBs were graded using a T2* gradient echo. We used binary logistic regression to test the association between caries and CMB dichotomized as >5 or ≤5. Results: Participants with caries were more likely to be African American than white (54% vs. 46%, p<.001), more likely to have hypertension (41% vs. 26%, p<.001) and diabetes (15% vs. 9%, p=.005). There were no differences detected in age (61 + 5 with caries vs. 62 + 5 without caries, p=0.08), gender (54% female vs. 46% male, p=0.66), and smoking history (48% vs. 52%, p=0.71). Dental caries were associated with WMH volume quartiles: Q1 (reference), Q2 OR 1.43 (95% 0.95 to 2.16), Q3 OR 1.78 (1.16 to 2.72), Q4 OR 1.80 (1.17 to 2.77). These associations remained after adjusting for age, gender, race, hypertension, diabetes, and smoking: Q1 (reference), Q2 Adj. OR 1.52 (95% 0.96 to 2.41), Q3 Adj. OR 1.76 (1.11 to 2.78), Q4 Adj. OR 1.63 (1.03 to 2.60). Caries were also associated with CMB>5 (Crude OR 2.78, 95% CI 1.12-6.44), the association strengthened after adjustment (Adj. OR 3.15, 95% CI 1.33-7.47). Conclusion: We report significant independent associations of caries with higher WMH quartiles and CMB>5. This suggests that ischemic stroke and ICH risk in participants with caries may be mediated by CSVD.

Abstract WMP22: Higher Burden of Cerebral Small Vessel Disease is Associated With Risk of Incident Stroke in Community-Dwelling Individuals

Background: Mild manifestations of individual cerebral small vessel disease (CSVD) markers are common and may not denote increased risk, but high CSVD burden identifies individuals at increased risk of stroke and dementia. Scores incorporating multiple CSVD markers may better identify a person’s risk, but it remains unclear if they offer benefit beyond tools based on clinical factors alone such as the revised Framingham Stroke Risk Profile (FSRP). Therefore, we related a multi-marker CSVD score to risk of incident stroke and compared the findings with the FSRP in community-dwelling individuals. Methods: Framingham Heart Study (FHS) participants aged ≥55 years, free of stroke and dementia and with brain magnetic resonance imaging (MRI) ratings of CSVD markers were included. A multi-marker CSVD score reflecting increasing CSVD burden was used (one point each for presence of cerebral microbleeds, severe perivascular spaces, extensive white matter hyperintensities, covert brain infarcts, and cortical superficial siderosis, ranging 0-5). Multivariable Cox proportional hazards regression analyses were used to relate CSVD score to incident stroke. Results: Among 1,154 participants (46% male, mean age 70.9±8.7), 590 (51%) had score 0, 352 (31%) had score 1, 164 (14%) had score 2, and 48 (4%) had score ≥ 3. Over a median follow-up of 8.2 years (Q1-Q3: 5.1-12.5) from the time of MRI, 92 (8%) developed stroke. In models adjusting for time interval between clinic exam and MRI, FHS cohort, and FSRP score, number of CSVD manifestations was associated with increased risk of stroke in a dose-dependent manner: score 1 (HR: 1.73; 95% CI 1.05-2.84), score 2 (HR 1.83; 95% CI: 1.01-3.30), and score ≥ 3 (HR: 3.31; 95% CI: 1.50-7.28) in relation to participants with no CSVD markers. In comparison, a 5-percent increase in FSRP alone was associated with increased risk of stroke (HR: 1.25; 95% CI 1.15-1.36). Interpretation: Higher CSVD burden is associated with increased risk of stroke, beyond the effect explained by risk factors in the FSRP. These findings support consideration of CSVD burden to identify risk of stroke in community-dwelling individuals.

Relation of MRI-Visible Perivascular Spaces and Other MRI Markers of Cerebral Small Vessel Disease.

Perivascular spaces (PVS) visible on brain MRI signal cerebral small vessel disease (CSVD). The coexistence of PVS with other CSVD manifestations likely increases the risk of adverse neurological outcomes. We related PVS to other CSVD manifestations and brain volumes that are markers of vascular brain injury and neurodegeneration. Framingham Heart Study (FHS) participants with CSVD ratings on brain MRI were included. PVS were rated in the basal ganglia (BG) and centrum semiovale (CSO) into grades I-IV and a category reflecting high burden in single or mixed CSO-BG regions. We related PVS to covert brain infarcts (CBI), white matter hyperintensities (WMH), cerebral microbleeds (CMB), total brain, hippocampal, and cortical gray matter volumes using adjusted multivariable regression analyses. In 2454 participants (mean age 54 ± 12 years), we observed that higher PVS burden in both BG and CSO was related to CMB in lobar and deep brain regions and increased WMH. Greater CSO PVS burden was associated with decreased total cortical gray volumes. PVS are associated with ischemic markers of CSVD and neurodegeneration markers. Further studies should elucidate the causality between PVS and other CSVD manifestations.

Essential nutrients and cerebral small vessel diseases: a two-sample Mendelian randomization study.

Previous studies have suggested a potential association between nutrients and cerebral small vessel disease (CSVD), but this association has not been fully addressed. We intended to clarify the causal associations between four categories of essential nutrients (amino acids, polyunsaturated fatty acids, minerals and vitamins) and two acute manifestations of CSVD (intracerebral hemorrhage and small vessel stroke) using two-sample Mendelian randomization (MR) analysis. We obtained European-based large-scale genome-wide association studies (GWASs) related to CSVD (6,255 cases and 233,058 controls) and nutrient concentrations. Causality evaluation mainly included the results of the inverse variance-weighted (IVW) method. The simple median method, the weighted median method and the MR-Egger method were adopted for sensitivity analyses. For ICH or SVS, increased levels of phenylalanine (OR = 1.188, p < 0.001) and dihomo-gamma-linolenic acid (DGLA) (OR = 1.153, p = 0.001) showed risk effects, while docosapentaenoic acid (DPA) (OR = 0.501, p < 0.001), zinc (OR = 0.919, p < 0.001), and arachidonic acid (OR = 0.966, p = 0.007) showed protective effects. For lobar hemorrhage or SVS, AA (OR = 0.978, p < 0.001), zinc (OR = 0.918, p < 0.001), and retinol (OR = 0.753, p < 0.001) showed risk effects; DPA (OR = 0.682, p = 0.022), gamma-linolenic acid (OR = 0.120, p = 0.033) and 25(OH)D (OR = 0.874, p = 0.040) showed protective effects. For nonlobar hemorrhage or SVS, DGLA (OR = 1.088, p < 0.001) and phenylalanine (OR = 1.175, p = 0.001) showed risk effects. Our study analyzed the effect of nutrients on CSVD risk from a genetic perspective, with implications for CSVD prevention through nutrient supplementation.

Abstract TP176: Lipids, Apolipoproteins And CSVD: A Mendelian Randomization Study

Aims: The role of dyslipidemia in cerebral small vessel disease (CSVD) has not been well established. Our primary aim was to apply the Mendelian randomization (MR) design to investigate the associations of lipid and apolipoprotein traits with CSVD manifestations. We also used drug target MR to analyze the effects of lipid-modifying strategies on the outcomes. Methods and Results: We conducted a Two-sample MR analysis using the levels of HDL-C, LDL-C, TG, ApoB and ApoA-I as exposures and CSVD manifestations including lacunar strokes, cerebral microbleeds (CMBs) and white matter integrity as outcomes. In addition, we analyzed the effects of TG lowering and LDL-C lowering genetic variants on CSVD manifestations. In univariable MR, increases in HDL-C reduce the occurrence of lacunar strokes (OR: 0.86; 95% CI: 0.76-0.99; p=0.03), increases in TG (OR: 0.73; 95% CI: 0.54,0.99; p=0.04) and ApoA-I (OR: 0.61; 95% CI: 0.46-0.83; p=0.001) respectively reduce all and deep CMBs, elevated ApoA-I levels were associated with lower FA (β: -0.381; 95% CI: -0.72, -0.04; p=0.028) and higher MD (β: 0.386; 95% CI: 0.02, 0.75; p=0.036). Multivariable MR revealed that HDL-C could help prevent lacunar strokes (OR: 0.86; 95% CI: 0.34-0.91; p=0.019), elevated ApoA-I was related to lower risk of both lobar (OR: 0.37; 95% CI: 0.18, 0.79; p=0.01) and deep (OR: 0.31; 95% CI: 0.10, 0.95; p=0.04) CMBs while HDL-C lead to higher risk of lobar CMBs (OR: 2.70; 95% CI: 1.32, 5.49; p=0.006), ApoA-I (β: -0.23; 95% CI: -0.41, -0.05; p=0.013) and HDL-C (β: 0.19; 95% CI: 0.01, 0.36; p=0.034) were closely related to WMH. Besides, increases in LDL-C (OR: 0.26; 95% CI: 0.07, 0.99; p=0.049) and TG (OR: 0.63; 95% CI: 0.46, 0.88; p=0.007) both lead to lower risk of lobar CMBs. Drug-target MR indicated that both LDL-C lowering and TG lowering therapies might help prevent CSVD manifestations. Conclusions: CSVD manifestations are associated with conventional lipids levels as well as apolipoproteins and certain lipid-modifying strategies could help alleviate CSVD manifestations.

The NLRP3 Inflammasome in Age-Related Cerebral Small Vessel Disease Manifestations: Untying the Innate Immune Response Connection.

In this narrative review, we present the evidence on nucleotide-binding and oligomerization (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome activation for its putative roles in the elusive pathomechanism of aging-related cerebral small vessel disease (CSVD). Although NLRP3 inflammasome-interleukin (IL)-1β has been implicated in the pathophysiology of coronary artery disease, its roles in cerebral arteriothrombotic micro-circulation disease such as CSVD remains unexplored. Here, we elaborate on the current manifestations of CSVD and its' complex pathogenesis and relate the array of activators and aberrant activation involving NLRP3 inflammasome with this condition. These neuroinflammatory insights would expand on our current understanding of CSVD clinical (and subclinical) heterogenous manifestations whilst highlighting plausible NLRP3-linked therapeutic targets.

The Correlation Between Modified Total Cerebral Small Vessel Disease Score and Gait and Balance Disorder in Middle-aged to Older Adults.

The aim of this study is to investigate the relationships between the original and modified total cerebral Small Vessel Disease (CSVD) score and gait and balance impairment using quantitative and semi-quantitative tests. In our study, patients aged 45 to 85 consecutively recruited. CSVD manifestations were identified with brain Magnetic Resonance Imaging (MRI), and the original and modified CSVD scores were calculated based on the results. Gait and balance function were assessed using both gait parameters and clinical rating scales. The correlation between the original and modified total scores of the CSVD and gait and balance dysfunction was demonstrated. 224 patients were enrolled in the study. Gait and balance disorders were associated with both the original and modified CSVD scores. A significant association remained after adjusting for gender, height, age, hypertension, and other relevant risk factors. The binary logistic regression and chi-squared trend tests revealed that impairment of movement function significantly correlated with the modified CSVD score and that the dysfunction was significantly higher for patients with modified CSVD scores of 5-6 than those with scores of 1-2. In Receiver Operating Characteristic (ROC) analysis, modified CSVD scores were more accurate in predicting gait impairment than original CSVD scores. We found both original and modified total CSVD scores to be related to gait and balance disorder, and the modified CSVD score was more accurate in identifying movement impairment and should be used as an effective tool in investigating CSVD and motor dysfunction.

A Novel Rodent Model of Hypertensive Cerebral Small Vessel Disease with White Matter Hyperintensities and Peripheral Oxidative Stress.

Cerebral small vessel disease (CSVD) is the second most common cause of stroke and a major contributor to dementia. Manifestations of CSVD include cerebral microbleeds, intracerebral hemorrhages (ICH), lacunar infarcts, white matter hyperintensities (WMH) and enlarged perivascular spaces. Chronic hypertensive models have been found to reproduce most key features of the disease. Nevertheless, no animal models have been identified to reflect all different aspects of the human disease. Here, we described a novel model for CSVD using salt-sensitive ‘Sabra’ hypertension-prone rats (SBH/y), which display chronic hypertension and enhanced peripheral oxidative stress. SBH/y rats were either administered deoxycorticosteroid acetate (DOCA) (referred to as SBH/y-DOCA rats) or sham-operated and provided with 1% NaCl in drinking water. Rats underwent neurological assessment and behavioral testing, followed by ex vivo MRI and biochemical and histological analyses. SBH/y-DOCA rats show a neurological decline and cognitive impairment and present multiple cerebrovascular pathologies associated with CSVD, such as ICH, lacunes, enlarged perivascular spaces, blood vessel stenosis, BBB permeability and inflammation. Remarkably, SBH/y-DOCA rats show severe white matter pathology as well as WMH, which are rarely reported in commonly used models. Our model may serve as a novel platform for further understanding the mechanisms underlying CSVD and for testing novel therapeutics.

Presence of enlarged perivascular spaces is associated with reduced processing speed in asymptomatic, working-aged adults.

Enlarged perivascular spaces (ePVS) and white matter hyperintensities (WMHs) are recognised neuroimaging lesions for symptomatic and/or occult cerebral small vessel disease (CSVD) that are linked with the predisposition to cardiocerebrovascular risk and neurocognitive impairment. This study aimed to determine the interrelation between the WMHs and ePVS, neurocognition, and cardiocerebrovascular risk profiles in asymptomatic working-aged adults at a single-center population-based cohort. Fifty-four asymptomatic subjects (mean age: 39.6 ± 11.6 years) with low-to-moderate cardiocerebrovascular risk measured by QRISK3 prediction score were recruited and underwent neurocognitive evaluation and 3T MRI brain scan. Contour plot with multiple logistic and linear regression were utilized to study the interrelation between the variables. The presence of WMHs and ePVS was associated with hypertension, systolic blood pressure, QRISK3 score, and age, whereby asymptomatic older subjects had higher prevalence for WHMs and ePVS (mean age: WMHs [46.6 ± 12.2 years]; ePVS [43.12 ± 12.2 years]). Higher ePVS load and reduced hippocampal volume among ePVS subjects was associated with reduced processing speed (odd ratio, 1.06; 95% confidence interval: 1.00 to 1.13) and reduced working memory performance (standardized β coefficients, -0.46 [95% CI: 0.46 to 12.1], p < 0.05), respectively. Albeit from a single center in the suburban east coast peninsular Malaysia, this study is to first from the region to highlight the subtle impacts of occult CSVD manifestations (WMHs and ePVS) on some aspects of neurocognition in an otherwise asymptomatic, relatively young working-aged adults with low-to-moderate cardiocerebrovascular risk scores.

Aberrant Neurogliovascular Unit Dynamics in Cerebral Small Vessel Disease: A Rheological Clue to Vascular Parkinsonism.

The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood–brain barrier permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, metabolic waste, and clearance through the venous circulation. As a physiologically integrated neurogliovascular unit (NGVU) serving a particularly vulnerable cerebral white matter (from hypoxia, metabolic insults, infection, and inflammation), a likely insidious process over a lifetime could inflict microenvironment damages that may lead to pathological conditions. Two such conditions, cerebral small vessel disease (CSVD) and vascular parkinsonism (VaP), with poorly understood pathomechanisms, are frequently linked to this brain-wide NGVU. VaP is widely regarded as an atypical parkinsonism, described by cardinal motor manifestations and the presence of cerebrovascular disease, particularly white matter hyperintensities (WMHs) in the basal ganglia and subcortical region. WMHs, in turn, are a recognised imaging spectrum of CSVD manifestations, and in relation to disrupted NGVU, also include enlarged perivascular spaces. Here, in this narrative review, we present and discuss on recent findings that argue for plausible clues between CSVD and VaP by focusing on aberrant multicellular dynamics of a unique integrated NGVU—a crossroad of the immune–vascular–nervous system—which may also extend fresher insights into the elusive interplay between cerebral microvasculature and neurodegeneration, and the potential therapeutic targets.

P-OT008. Non-invasive 3-D image analysis of microcirculation vascular integrity in asymptomatic cerebral small vessel disease

Introduction. Today, people worldwide are living longer than before. The pace of population aging is also increasing dramatically in the world. Cerebral small vessel disease (CSVD) is a neurological disease resulted from pathological aetiologies affecting small vessel (microcirculation) in the brain parenchyma and often diagnosed in the old generation. Alarmingly, CSVD causes dementia, risk of incident stroke, Alzheimer’s disease (AD), and depression. Image analysis plays a pivotal role, which gives a clue in identifying the different manifestation of CSVD. This study intended to explore the microcirculation vascular integrity of individuals with and without CSVD. Methods. A neural tracing software neuTube was used to accurately reconstruct the blood vessel network of brains from noninvasive 3D-time-of-flight Magnetic Resonance Angiography (MRA) images. The quantitative analysis of the reconstructed blood vessel network provides potentially valuable information for the diagnostic and monitoring of CSVD. Results. neuTube provides a set of functions that enable us to delineate and reconstruct the fine details of the blood vessel network. With ten human MRA images, the microcirculation vascular integrity of individuals with and without CSVD was explored. Further quantitative analysis will aid future clinical studies using this method for patients with CSVD. Conclusion. This study opens a window to provide a non-invasive technique assessing the integrity of small vessel in the brain.

Diets and Cellular-Derived Microparticles: Weighing a Plausible Link With Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) represents a spectrum of pathological processes of various etiologies affecting the brain microcirculation that can trigger neuroinflammation and the subsequent neurodegenerative cascade. Prevalent with aging, CSVD is a recognized risk factor for stroke, vascular dementia, Alzheimer disease, and Parkinson disease. Despite being the most common neurodegenerative condition with cerebrocardiovascular axis, understanding about it remains poor. Interestingly, modifiable risk factors such as unhealthy diet including high intake of processed food, high-fat foods, and animal by-products are known to influence the non-neural peripheral events, such as in the gastrointestinal tract and cardiovascular stress through cellular inflammation and oxidation. One key outcome from such events, among others, includes the cellular activations that lead to elevated levels of endogenous cellular-derived circulating microparticles (MPs). MPs can be produced from various cellular origins including leukocytes, platelets, endothelial cells, microbiota, and microglia. MPs could act as microthrombogenic procoagulant that served as a plausible culprit for the vulnerable end-artery microcirculation in the brain as the end-organ leading to CSVD manifestations. However, little attention has been paid on the potential role of MPs in the onset and progression of CSVD spectrum. Corroboratively, the formation of MPs is known to be influenced by diet-induced cellular stress. Thus, this review aims to appraise the body of evidence on the dietary-related impacts on circulating MPs from non-neural peripheral origins that could serve as a plausible microthrombosis in CSVD manifestation as a precursor of neurodegeneration. Here, we elaborate on the pathomechanical features of MPs in health and disease states; relevance of dietary patterns on MP release; preclinical studies pertaining to diet-based MPs contribution to disease; MP level as putative surrogates for early disease biomarkers; and lastly, the potential of MPs manipulation with diet-based approach as a novel preventive measure for CSVD in an aging society worldwide.

Elevated Circulating Microparticle Subpopulations in Incidental Cerebral White Matter Hyperintensities: A Multimodal Study.

Asymptomatic (or “silent”) manifestations of cerebral small vessel disease (CSVD) are widely recognized through incidental findings of white matter hyperintensities (WMHs) as a result of magnetic resonance imaging (MRI). This study aims to examine the potential associations of surrogate markers for the evaluation of white matter integrity in CSVD among asymptomatic individuals through a battery of profiling involving QRISK2 cardiocerebrovascular risk prediction, neuroimaging, neurocognitive evaluation, and microparticles (MPs) titers. Sixty asymptomatic subjects (mean age: 39.83 ± 11.50 years) with low to moderate QRISK2 scores were recruited and underwent neurocognitive evaluation for memory and cognitive performance, peripheral venous blood collection for enumeration of selected MPs subpopulations, and 3T MRI brain scan with specific diffusion MRI (dMRI) sequences inclusive of diffusion tensor imaging (DTI). WMHs were detected in 20 subjects (33%). Older subjects (mean age: 46.00 ± 12.00 years) had higher WMHs prevalence, associated with higher QRISK2 score and reduced processing speed. They also had significantly higher mean percentage of platelet (CD62P)- and leukocyte (CD62L)-derived MPs. No association was found between reduced white matter integrity—especially at the left superior longitudinal fasciculus (LSLF)—with age and neurocognitive function; however, LSLF was associated with higher QRISK2 score, total MPs, and CD62L- and endothelial cell-derived MPs (CD146). Therefore, this study establishes these multimodal associations as potential surrogate markers for “silent” CSVD manifestations in the well-characterized cardiocerebrovascular demographic of relatively young, neurologically asymptomatic adults. Furthermore, to the best of our knowledge, this study is the first to exhibit elevated MP counts in asymptomatic CSVD (i.e., CD62P and CD62L), which warrants further delineation.

Cerebral small vessel disease: classification, clinical manifestations, diagnosis, and features of treatment

The paper considers the relevance of the problem of cerebral small vessel disease (CSVD) that is an important cause of ischemic and hemorrhagic stroke, associated with the development of cognitive impairment and complications of antithrombotic therapy. It presents briefly the current issues of etiology and pathogenesis of the disease. Sporadic non-amyloid microangiopathy, cerebral amyloid angiopathy, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are discussed in detail from the point of view of their clinical presentation, neuroimaging, and features of therapeutic tactics. An algorithm for diagnosing CSVD in patients admitted to hospital for stroke and a differentiated approach to their treatment are proposed. Consideration of the neuroimaging manifestations of CSVD is noted to be necessary for the safe and more effective treatment of patients with cerebrovascular diseases.

Are risk factors of cerebral small vessel disease differ from those in patients with high atherothrombotic risk without cerebrovascular disease?

Knowledge of risk factors for cerebral small vessel disease (CSVD) may generate hypothesis regarding possible targets for prevention. Our aim was to evaluate if atherothrombotic risk factors differ between patients with CSVD and with subjects without cerebrovascular disease but with high cardiovascular (CVD) risk. A single-center, cohort study was performed in consecutive patients with different CSVD manifestations. The study group consisted of 205 patients: 52 with lacunar stroke (LS), 20 with subcortical hemorrhagic stroke (HS), 50 with vascular dementia (VaD), 28 with vascular parkinsonism (VaP) and 55 controls (CG) with high CVD risk (35 with atherosclerotic CVD, 20 with 10-year risk of CVD with SCORE?5). Logistic regression was used to analyze the influence of clinical and laboratory data on the occurrence of CSVD. Mean age, sex distribution, prevalence of smoking, hyperlipidemia, peripheral artery disease and obesity were similar in CSVD and CG. The factors significantly associated with CSVD compared to controls were diabetes mellitus, polymetabolic syndrome, elevated systolic blood pressure, low levels of eGFR, HDL, albumin and high uric acid, fibrinogen, fasting glucose, HbA1c and intima medic thickness (p&lt;0.05). Hypertension, chronic kidney disease and elevated fasting blood glucose were related to LS and HS (p&lt;0.1). Diabetes was significantly associated with LS and VaD while smoking and low total cholesterol were related to HS (p&lt;0.1). The study confirms that risk factors profile for CSVD differs from subjects with proatherogenic profile without history of cerebrovascular disease. Our results also support that unique risk factors profiles exist for different manifestations of the CSVD.

A relationship between the integrated assessment of magnetic resonance imaging markers for cerebral small vessel disease and the clinical and functional status in the acute period of ischemic stroke

Cerebral small vessel disease (CSVD) is the most common neurological pathological process and contributes to the process of aging and to the development of dementia and stroke. At the same time, the role of CSVD as a factor influencing the course of acute ischemic stroke (IS) has been little studied. There is no generally accepted magnetic resonance imaging (MRI) scale for the integrated assessment of CSVD markers. Objective : to carry out an integrated assessment of the MRI manifestations of CSVD in acute ischemic stroke and to analyze a correlation of both individual markers and the final indicator with the clinical and functional status of patients. Patients and methods. 100 patients with acute IS were examined. All patients underwent standard clinical, laboratory and instrumental examinations, as well as brain MRI estimating the number of lacunae, visible perivascular spaces (PVSs) and leukoaraiosis. The number of cerebral microbleeds (CMBs) was additionally calculated in 57 patients. Integral scale scores were calculated by gradation and summation of four MRI markers of CSVD. Results . The patients with acute IS showed the high representativeness of individual markers for CSVD. The values of MRI markers for CSVD correlated with age, education level, and cardiovascular parameters in patients. An integrated CSVD severity assessment scale was developed. The overall manifestations of CSVD, which were assessed using this scale, were associated with the severity of a stenotic process in the brachycephalic arteries, with BP levels at admission, ejection fraction, hyperglycemia, and atherogenic index of blood lipids. The high CSVD score was also correlated with low mobility and more severe disability in patients being discharged from hospital. The high severity of CSVD was associated with lower neurological deficit regression during inpatient treatment. Subgroup analysis showed the greatest negative impact of CSVD on the severity of stroke in female patients, young and middle-aged ones, diabetics, as well as in patients with noncardioembolic stroke, a smallsized focus, and intima-media thickening. Conclusion . The overall manifestations of CSVD calculated using the original scale based on the analysis of the degree of lacunae, PVSs, leukoaraiosis, and CMBs are associated with premorbid cardiovascular parameters in a patient and are important indicators for the neurological, cognitive, and functional outcomes of acute IS.

Risk of vascular events in different manifestations of cerebral small vessel disease: A 2-year follow-up study with a control group

Background and purposeNatural course of cerebral small vessel disease (CSVD) has not yet been thoroughly studied. The aim of the single center study was to establish risk of vascular events or death in different manifestations of CSVD. Methods150 consecutive, functionally independent patients with marked MRI features of CSVD and with recent lacunar stroke (n = 52, LS), deep hemorrhagic stroke (n = 20, HS), vascular parkinsonism (n = 28, VaP), vascular dementia (n = 50, VaD) and 55 controls (CG) with high atherothrombotic risk free of cerebrovascular events were prospectively recruited and followed for 24 months. ResultsMean age and sex distribution were similar in CSVD and CG but patients with CSVD were less likely to have CAD (19% vs 40%, p = 0.02) and tended to have higher prevalence of diabetes (54% vs 37%, p = 0.11). The risk of vascular events or death was increased in any patients with moderate to severe white matter lesions at baseline MRI (HR 2.0; 95% CI 0.85–7.2), in CSVD (4.56; 95% CI 1.3–14.9) vs CG, regardless of its clinical manifestation: LS or HS (HR 4.70; 95% CI 1.3–16.2) and VaD or VaP (HR 4.59; 95% CI 1.3–15.7). Adjustment for confounders did not change the results substantially. ConclusionsPatients with symptomatic CSVD regardless of the clinical (acute or chronic) manifestation had more than fourfold the risk of vascular events or death in 24 months of observation compared with controls with high atherothrombotic risk free of cerebrovascular events.

OS 34-04 SAFETY OF EARLY INTENSIVE BLOOD PRESSURE LOWERING IN CEREBRAL SMALL VESSEL DISEASE AND CHRONIC KIDNEY DISEASE IN ACUTE INTRACEREBRAL HEMORRHAGE

Objective: The INTERACT2 trial demonstrated beneficial effects of early intensive blood pressure (BP) lowering in intracerebral hemorrhage (ICH). However, concerns persist over harms associated with the treatment, particularly in patients with cerebral small vessel disease (CSVD) (ie white matter lesions [WML], lacunes and atrophy) and renal failure. We determined associations of CSVD, and renal failure, on outcomes in INTERACT2 participants. Design and Method: There were 2069/2839 patients with baseline brain CT ( 90 mL/min/1.73 m2), mild (60–90 mL/min/1.73 m2), and moderate-severe ( Results: WML and brain atrophy were associated with death/disability (mRS score 3–6) at 90 days: adjusted ORs for WML (grade 3 and 4 vs. 1), FR and TSD (most vs. least severe atrophy quartile) were 1.42 (95%CI 1.02–0.98), 1.47 (1.08–1.99) and 1.64 (1.21–2.22), respectively (P trend Conclusions: Patients with CSVD manifestations of WML and brain atrophy, and renal failure, have significantly worse outcome in acute ICH. However, intensive BP lowering provides similar treatment effects irrespective of degree of CSVD or renal failure.

Abstract TMP113: Long-term Cognitive Decline After Intracerebral Hemorrhage

Introduction: Cerebral small vessel disease (CSVD) is the leading cause of Vascular Cognitive Impairment (VCI). Although Intracerebral Hemorrhage (ICH) is the most severe manifestation of CSVD, VCI among ICH survivors has been the subject of limited investigations. Hypothesis: We sought to test these hypotheses: 1) long-term cognitive decline rates are substantial even among initially non-demented ICH survivors; 2) underlying CSVD plays a substantial role in determining post-ICH long-term cognitive decline. Methods: We enrolled survivors of primary ICH, with no evidence of dementia 6 months post-hemorrhage, in a single-center longitudinal observational study. Presence and severity of CSVD was assessed at enrollment using two established markers of CSVD on CT (CT-defined white hatter hypodensity [CT-WMH]) and MRI (cerebral microbleeds [CMBs]). We captured blood pressure measurements during follow-up via review of medical records. Cognitive performance was assessed using the Modified Telephone Interview for Cognitive Status (TICS-m), a standardized validated telephone-based cognitive battery. We constructed multivariate models of cognitive decline rate, defined as slope of TICS-m scores over time. Results: A total of 275 ICH survivors qualified for inclusion in our analyses; of these 83 (30%) developed incident dementia and 33 (12%) developed incident Mild Cognitive Impairment (MCI) at 5 years (Figure). CSVD imaging markers were associated with cognitive decline rate (CT-WMH: p=0.001, CMBs: p=0.003), as were pulse pressure (p=0.003) and systolic blood pressure variation coefficient (p=0.034). Conclusions: Long-term cognitive decline is frequent and substantial among ICH survivors not demented at time of ICH, and strongly associates with severity of underlying CSVD. Our findings suggest that it is the extent of CSVD and not particular ICH characteristics that are most associated with long-term cognitive decline in survivors of ICH.