Features Of Small Vessel Disease Research Articles

Recurrent cerebrovascular events after recent small subcortical infarction

BackgroundRecent small subcortical infarcts (RSSI) are the neuroimaging hallmark feature of small vessel disease (SVD)-related acute lacunar stroke. Long-term data on recurrent cerebrovascular events including their aetiology after RSSI are scarce.Patients and methodsThis retrospective study included all consecutive ischaemic stroke patients with an MRI-confirmed RSSI (in the supply area of a small single brain artery) at University Hospital Graz between 2008 and 2013. We investigated associations between clinical and SVD features on MRI (STRIVE criteria) and recurrent cerebrovascular events, using multivariable Cox regression adjusted for age, sex, vascular risk factors and MRI parameters.ResultsWe analysed 332 consecutive patients (mean age 68 years, 36% women; median follow-up time 12 years). A recurrent ischaemic cerebrovascular event occurred in 70 patients (21.1%; 54 ischaemic strokes, 22 transient ischaemic attacks) and was mainly attributed to SVD (68%). 26 patients (7.8%) developed intracranial haemorrhage. In multivariable analysis, diabetes (HR 2.43, 95% CI 1.44–3.88), severe white matter hyperintensities (HR 1.97, 95% CI 1.14–3.41), and cerebral microbleeds (HR 1.89, 95% CI 1.32–3.14) on baseline MRI were related to recurrent ischaemic stroke/TIA, while presence of cerebral microbleeds increased the risk for intracranial haemorrhage (HR 3.25, 95% CI 1.39–7.59). A widely used SVD summary score indicated high risks of recurrent ischaemic (HR 1.22, 95% CI 1.01–1.49) and haemorrhagic cerebrovascular events (HR 1.57, 95% CI 1.11–2.22).ConclusionPatients with RSSI have a substantial risk for recurrent cerebrovascular events—particularly those with coexisting chronic SVD features. Recurrent events are mainly related to SVD again.

Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

The analysis of association between single features of small vessel disease and stroke outcome shows the independent impact of the number of microbleeds and presence of lacunes

The impact of small vessel disease (SVD) on stroke outcome was investigated either separately for its single features in isolation or for SVD sum score measuring a qualitative (binary) assessment of SVD-lesions. We aimed to investigate which SVD feature independently impacts the most on stroke outcome and to compare the continuous versus binary SVD assessment that reflects pronouncement and presence correspondingly. Patients with a first-ever anterior circulation ischemic stroke were retrospectively investigated. We performed an ordered logistic regression analysis to predict stroke outcome (mRS 3 months, 0–6) using age, stroke severity, and pre-stroke disability as baseline input variables and adding SVD-features (lacunes, microbleeds, enlarged perivascular spaces, white matter hyperintensities) assessed either continuously (model 1) or binary (model 2). The data of 873 patients (age 67.9 ± 15.4, NIHSS 24 h 4.1 ± 4.8) was analyzed. In model 1 with continuous SVD-features, the number of microbleeds was the only independent predictor of stroke outcome in addition to clinical parameters (OR 1.21; 95% CI 1.07–1.37). In model 2 with the binary SVD assessment, only the presence of lacunes independently improved the prediction of stroke outcome (OR 1.48, 1.1–1.99). In a post hoc analysis, both the continuous number of microbleeds and the presence of lacunes were independent significant predictors. Thus, the number of microbleeds evaluated continuously and the presence of lacunes are associated with stroke outcome independent from age, stroke severity, pre-stroke disability and other SVD-features. Whereas the presence of lacunes is adequately represented in SVD sum score, the microbleeds assessment might require another cutoff and/or gradual scoring, when prediction of stroke outcome is needed.

Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults – A 4D flow MRI study

White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV’s stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.

Abstract WP167: Clinical Characteristics and Outcomes of Mixed Cerebral Small Vessel Disease According to the CLAS-ICH Classification

Objectives: Mixed location intracerebral hemorrhages/ microbleeds (CMBs) (mixed ICH) is referred to as potential hypertensive arteriolosclerosis/cerebral amyloid angiopathy (CAA) combination, reflecting small vessel disease (SVD) burden. We assess the clinical features in patients with mixed ICH. Methods: We utilized data from a prospective registry, which consecutively enrolled patients diagnosed with acute ICH between January 2011 and December 2021. Patients with ICH were classified into subtypes according to the CLAS-ICH classification: hypertensive arteriolosclerosis ([HTN]-ICH), CAA-ICH, mixed ICH, genetic SVD, and secondary causes. The clinical data of patients with mixed ICH were compared to those with HTN-ICH or CAA-ICH. The outcome measure was unfavorable functional outcomes defined as mRS score of 5-6 at 90-day. Results: Of 2127 patients with ICH (mean age 70±13 years, 57% male), 1374 (65%) had HTN-ICH, 141 (6%) had CAA-ICH, 409 (19%) had mixed ICH, none (0%) had genetic SVD, 203 (10%) had secondary causes. Patients with mixed ICH were older (75±11 vs. 69±13 years) and had a high frequency of CMBs (68% vs. 25%), had lower initial SBP (176±32 vs. 184±30 mmHg) and initial NIHSS (12 [4-21] vs. 14 [7-23]) and more hematoma volume (17 [6–52] vs. 11 [4–24] ml), compared to those with HTN-ICH (all P&lt;0.001). There were no significant differences in hypertension, dyslipidemia, and diabetes. When comparing patients with mixed ICH to those with CAA-ICH, they were younger (75±11 vs. 78±8 years) and had a high frequency of male (54% vs 33%), hypertension (95% vs. 36%) and diabetes (14% vs. 5%) and had higher initial SBP (176 ± 32 vs. 160 ± 29 mmHg) and less hematoma volume (17 [6–52] vs. 44 [18–84] ml)(all P&lt;0.001). There was no significant difference in unfavorable outcomes between mixed ICH and HTN-ICH (32% vs. 31%, p&gt;0.1), while the outcomes for mixed ICH were lower than those for CAA-ICH (32% vs. 44%, p=0.004). In multivariate analysis adjusting for covariates, there was no significant difference in unfavorable outcomes between mixed SVD-ICH and CAA-ICH (odds ratio 1.19 [95% CI, 0.66–2.13]). Conclusions: Mixed ICH harbors similar features of hypertensive SVD rather than CAA. The rates of disability and mortality were comparable across the groups.

Occupational and domestic exposure associations with cerebral small vessel disease and vascular dementia: A systematic review and meta-analysis.

The prevalence of cerebral smallvessel disease (SVD) and vascular dementia according to workplace or domestic exposure to hazardous substances is unclear. We included studies assessing occupational and domestic hazards/at-risk occupations and SVD features. We pooled prevalence estimates using random-effects models where possible, or presented a narrative synthesis. We included 85 studies (n = 47,743, mean age = 44·5 years). 52/85 reported poolable estimates. SVD prevalence in populations exposed to carbon monoxide was 81%(95% CI = 60-93%; n = 1373; results unchanged in meta-regression), carbon disulfide73% (95% CI = 54-87%; n = 131), 1,2-dichloroethane 88% (95% CI = 4-100%, n = 40), toluene 82% (95% CI = 3-100%, n = 64), high altitude 49% (95% CI = 38-60%; n = 164),and diving 24% (95% CI = 5-67%, n = 172). We narratively reviewed vascular dementia studies and contact sport, lead, military, pesticide, and solvent exposures as estimates were too few/varied to pool. SVD and vascular dementia may be associated with occupational/domestic exposure to hazardous substances. CRD42021297800.

Differential risk factor profile and neuroimaging markers of small vessel disease between lacunar ischemic stroke and deep intracerebral hemorrhage.

Lacunar ischemic stroke (LIS) and deep intracerebral hemorrhage (dICH) are two stroke phenotypes of deep perforator arteriopathy. It is unclear what factors predispose individuals with deep perforator arteriopathy to either ischemic or hemorrhagic events. We aimed to investigate risk factors and neuroimaging features of small vessel disease (SVD) associated with LIS versus dICH in a cross-sectional study. We included patients with clinically presenting, magnetic resonance imaging-confirmed LIS or dICH from two tertiary hospitals between 2010 and 2021. We recorded vascular risk factors and SVD markers, including lacunes, white matter hyperintensities (WMH), perivascular spaces (PVS), and cerebral microbleeds (CMB). Logistic regression modeling was used to determine the association between vascular risk factors, SVD markers, and stroke phenotype. We further created WMH probability maps to compare WMH distribution between LIS and dICH. A total of 834 patients with LIS (mean age 61.7 ± 12.1 years) and 405 with dICH (57.7 ± 13.2 years) were included. Hypertension was equally frequent between LIS and dICH (72.3% versus 74.8%, p = 0.349). Diabetes mellitus, hyperlipidemia, smoking, and prior ischemic stroke were more associated with LIS [odds ratio (OR) (95% confidence interval (CI)), 0.35 (0.25-0.48), 0.32 (0.22-0.44), 0.31 (0.22-0.44), and 0.38 (0.18-0.75)]. Alcohol intake and prior ICH were more associated with dICH [OR (95% CI), 2.34 (1.68-3.28), 2.53 (1.31-4.92)]. Lacunes were more prevalent in LIS [OR (95% CI) 0.23 (0.11-0.43)], while moderate-to-severe basal-ganglia PVS and CMB were more prevalent in dICH [OR (95% CI) 2.63 (1.35-5.27), 4.95 (2.71-9.42)]. WMH burden and spatial distribution did not differ between groups. The microangiopathy underlying LIS and dICH reflects distinct risk profiles and SVD features, hence possibly SVD subtype susceptibility. Prospective studies with careful phenotyping and genetics are needed to clarify the mechanisms underlying this difference.

Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-0.0048 [95% CI, -0.0075 to -0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (BNAWM=0.00065 [95% CI, -0.00007 to 0.00137] %/mm Hg per score point increase). Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

Associations for progression of cerebral small vessel disease burden in healthy adults: the Kashima scan study.

To investigate the association between vascular risk factors and progression of cerebral small vessel disease (SVD), we conducted a longitudinal study with neurologically healthy cohort composed mostly of middle-aged adults (n = 665, mean age, 57.7 years). Subjects, who had both baseline data of brain health examinations including MRI and follow-up MRI at least 1 year after the baseline MRI, were included this study. The presence of features of SVD, including lacunes, cerebral microbleeds, white matter hyperintensity, and basal ganglia perivascular spaces were summed to obtain "total SVD score" (range, 0-4). Progression of SVD was evaluated among subjects with a total SVD score of ≤ 3 and was defined as a ≥ 1 point increase in that score at follow-up relative to baseline. As the primary analysis, multivariate logistic regression analyses were performed to determine the associations of progression of SVD at baseline. The median follow-up period was 7.3 years and progression of SVD was observed in 154 subjects (23.2%). Even after adjustment with confounders multivariate logistic regression analyses showed that progression of SVD was associated with age (per 10-year increase, odds ratio [OR]: 2.08, 95% confidence interval [CI] 1.62-2.67), hypertension (OR 1.55, 95%CI 1.05-2.29), systolic blood pressure (BP) (per standard deviation [SD] increase, OR 1.27, 95%CI 1.04-1.54), diastolic BP (per SD increase, OR 1.23, 95%CI 1.01-1.50), and mean arterial pressure (per SD increase, OR 1.27, 95%CI 1.04-1.55). Age and high blood pressure appear to play key roles in the progression of cerebral small vessel burden after mid-life.

Regional cortical thinning, demyelination and iron loss in cerebral small vessel disease.

The link between white matter hyperintensities (WMH) and cortical thinning is thought to be an important pathway by which WMH contributes to cognitive deficits in cerebral small vessel disease (SVD). However, the mechanism behind this association and the underlying tissue composition abnormalities are unclear. The objective of this study is to determine the association between WMH and cortical thickness, and the in vivo tissue composition abnormalities in the WMH-connected cortical regions. In this cross-sectional study, we included 213 participants with SVD who underwent standardized protocol including multimodal neuroimaging scans and cognitive assessment (i.e. processing speed, executive function and memory). We identified the cortex connected to WMH using probabilistic tractography starting from the WMH and defined the WMH-connected regions at three connectivity levels (low, medium and high connectivity level). We calculated the cortical thickness, myelin and iron of the cortex based on T1-weighted, quantitative R1, R2* and susceptibility maps. We used diffusion-weighted imaging to estimate the mean diffusivity of the connecting white matter tracts. We found that cortical thickness, R1, R2* and susceptibility values in the WMH-connected regions were significantly lower than in the WMH-unconnected regions (all Pcorrected < 0.001). Linear regression analyses showed that higher mean diffusivity of the connecting white matter tracts were related to lower thickness (β = -0.30, Pcorrected < 0.001), lower R1 (β = -0.26, Pcorrected = 0.001), lower R2* (β = -0.32, Pcorrected < 0.001) and lower susceptibility values (β = -0.39, Pcorrected < 0.001) of WMH-connected cortical regions at high connectivity level. In addition, lower scores on processing speed were significantly related to lower cortical thickness (β = 0.20, Pcorrected = 0.030), lower R1 values (β = 0.20, Pcorrected = 0.006), lower R2* values (β = 0.29, Pcorrected = 0.006) and lower susceptibility values (β = 0.19, Pcorrected = 0.024) of the WMH-connected regions at high connectivity level, independent of WMH volumes and the cortical measures of WMH-unconnected regions. Together, our study demonstrated that the microstructural integrity of white matter tracts passing through WMH is related to the regional cortical abnormalities as measured by thickness, R1, R2* and susceptibility values in the connected cortical regions. These findings are indicative of cortical thinning, demyelination and iron loss in the cortex, which is most likely through the disruption of the connecting white matter tracts and may contribute to processing speed impairment in SVD, a key clinical feature of SVD. These findings may have implications for finding intervention targets for the treatment of cognitive impairment in SVD by preventing secondary degeneration.

A typology of cerebral small vessel disease based on imaging markers

BackgroundLacunes, microbleeds, enlarged perivascular spaces (EPVS), and white matter hyperintensities (WMH) are brain imaging features of cerebral small vessel disease (SVD). Based on these imaging markers, we aimed to identify subtypes of SVD and to evaluate the validity of these markers as part of clinical ratings and as biomarkers for stroke outcome.MethodsIn a cross-sectional study, we examined 1207 first-ever anterior circulation ischemic stroke patients (mean age 69.1 ± 15.4 years; mean NIHSS 5.3 ± 6.8). On acute stroke MRI, we assessed the numbers of lacunes and microbleeds and rated EPVS and deep and periventricular WMH. We used unsupervised learning to cluster patients based on these variables.ResultsWe identified five clusters, of which the last three appeared to represent distinct late stages of SVD. The two largest clusters had no to only mild or moderate WMH and EPVS, respectively, and favorable stroke outcome. The third cluster was characterized by the largest number of lacunes and a likewise favorable outcome. The fourth cluster had the highest age, most pronounced WMH, and poor outcome. Showing the worst outcome, the fifth cluster presented pronounced microbleeds and the most severe SVD burden.ConclusionThe study confirmed the existence of different SVD types with different relationships to stroke outcome. EPVS and WMH were identified as imaging features of presumably early progression. The number of microbleeds and WMH severity appear to be promising biomarkers for distinguishing clinical subgroups. Further understanding of SVD progression might require consideration of refined SVD features, e.g., for EPVS and type of lacunes.

In vivo detection of penetrating arteriole alterations in cerebral white matter in patients with diabetes with 7 T MRI

Cerebral small vessel disease (SVD) is responsible for primary intracerebral hemorrhages, lacunar infarcts and white matter hyperintensity in T2 weighted images. While the brain lesions attributed to small vessel disease can be characterized by conventional MRI, it remains challenging to noninvasively measure the early pathological changes of the small underlying vessels. We evaluated the feasibility of detecting alterations in white matter penetrating arterioles (PA) in patients with diabetes with ultra-high field 7 T MRI.19 participants with diabetes mellitus (DM) and 19 age- and sex-matched healthy controls were scanned with whole brain T2 and susceptibility weighted MRI and a single slice phase contrast MRI 15 mm above the corpus callosum. The PC-MRI scans were repeated three times. PA masks were manually drawn on the first images after anonymization or automatically segmented on all three images. For each PA, lumen diameter, flow velocity and volume flow rate were derived by model-based analyses of complex difference images. Quasi-Poisson regression was performed for PA count using disease condition, age, and sex as independent variables. Linear mixed effect model analyses were performed for the other measurements using disease condition and age as fixed effect and participant pair specific disease condition as random effect.No severe radiological features of SVD were observed in T2 and susceptibility weighted images in any of the participants except for white matter hyperintensities with Fazekas score of 1 or 2 in 68% and 26% of patients and controls, respectively. The minimum diameter of visible PA was 78 μm and the majority had diameters <250 μm. Among the manually segmented PA with tilt angle less than 30o from the slice normal direction, flow velocities were lower in the DM group (1.9 ± 0.6 vs. 2.2 ± 0.6; p = 0.022), while no significant difference was observed in count, diameter, or volume flow rate. Similar results were observed in the automatically segmented PA. We also observed significantly increased diameter or decreased velocity with age in some of the scans. This study suggests that early PA alterations that are discriminative of disease state and age might be detectable in human cerebral white matter with 7 T MRI in vivo.

Mechanisms of Healthy Aging: An Integrated Neurobiological Perspective on Mood and Cognitive Function

Neurobiological approaches to healthy aging can protect against declines in cognitive function and mood disturbances in older adults. This symposium will focus on health-based mechanisms associated with mood and cognition in late life using an integrated micro- and macro-level perspective. Mechanistic pathways and predictors of healthy aging will be discussed across multiple levels of analysis (genetic, molecular, systems-level neurocircuitry, and behavioral). We will discuss these mechanisms of aging and late-life depression cross-sectionally and in the context of non-pharmacological interventions to identify potential pathways for more personalized treatments.This symposium will take a unique approach to classifying the neurobiology of healthy aging. Dr. Swathi Gujral will present a large study of 108 community-dwelling older adults who completed an exercise intervention and discuss differences in stress and emotional health as a function of exercise condition and APOE e4 carrier status. Dr. Julie Dumas will discuss functioning of the nicotinic cholinergic system in older adults and will present effects of nicotinic stimulation and blockade on brain activation and working memory performance in older adults with and without subjective cognitive decline. Dr. Lauren Oberlin will present neuroimaging features of small vessel disease (SVD) in older adults with and without depression and discuss the association between white matter abnormalities and cognitive decline in late life. Dr. Lindsay Victoria will present neural correlates of negative cognitive bias in late-life depression and their impact on treatment response to psychotherapy in depressed older adults.The unifying goal of these presentations is to characterize mechanistic pathways to precisely target cognitive deficits, improve mood, and promote healthy aging. With an emphasis on individual differences, we will examine predictors of change across a range of domains impacted in aging and late-life depression, including stress, working memory, and executive function. This mechanistic approach has important implications for the development of personalized interventions that emphasize health-based approaches to mood and cognitive function in older adults.

Standard clinical and imaging-based small vessel disease parameters associated with mild stroke versus non-mild stroke.

Mild stroke has variable outcomes, and there is an ongoing debate regarding whether the administration of thrombolytics improves outcomes in this subgroup of stroke patients. Having a better understanding of the features of mild stroke may help identify patients who are at risk of poor outcomes. The objective of this study is to evaluate the association of clinical and imaging-based small vessel disease features (white matter hyperintensities and cerebral microbleeds) with stroke severity and clinical outcomes in patients with mild stroke. In this retrospective study, mild stroke was defined as a National Institute of Health stroke scale (NIHSS) score <5. Clinical, laboratory and imaging data were compared between patients with mild stroke versus non-mild stroke (NIHSS≥5). Multivariate logistic regression analysis was performed to identify predictors of mild stroke and poor discharge outcome. Among 296 patients included in the study, 131 patients (44%) had mild stroke. On multivariate analysis, patients with mild stroke were three times more likely to have sensory symptoms [odds ratio (OR) = 2.9; 95% confidence interval (CI) = (1.2-6.8)] and four times more likely to have stroke due to small vessel disease (OR = 3.7; 95%CI = 1.4-9.9). Among patients with mild stroke, higher age (OR = 1.1; 95%CI = 1.02-1.1), presence of cerebral microbleed (OR = 4.5; 95%CI = 1.5-13.8), vertigo (OR = 7.3; 95%CI = 1.2-45.1) and weakness (OR = 5.0; 95%CI = 1.2-20.3) as presenting symptoms were more likely to have poor discharge outcome. Sensory symptoms and stroke due to small vessel disease are more common in mild stroke than non-mild stroke. Among patients with mild stroke, presence of cerebral microbleeds on imaging and symptoms of muscle weakness are associated with poor discharge outcome. Larger studies are needed to assess the impact of cerebral microbleed on mild stroke outcomes and risk stratify the benefit of thrombolytics in this group.

Predicting incident dementia in cerebral small vessel disease: comparison of machine learning and traditional statistical models

BackgroundCerebral small vessel disease (SVD) contributes to 45% of dementia cases worldwide, yet we lack a reliable model for predicting dementia in SVD. Past attempts largely relied on traditional statistical approaches. Here, we investigated whether machine learning (ML) methods improved prediction of incident dementia in SVD from baseline SVD-related features over traditional statistical methods. MethodsWe included three cohorts with varying SVD severity (RUN DMC, n = 503; SCANS, n = 121; HARMONISATION, n = 265). Baseline demographics, vascular risk factors, cognitive scores, and magnetic resonance imaging (MRI) features of SVD were used for prediction. We conducted both survival analysis and classification analysis predicting 3-year dementia risk. For each analysis, several ML methods were evaluated against standard Cox or logistic regression. Finally, we compared the feature importance ranked by different models. ResultsWe included 789 participants without missing data in the survival analysis, amongst whom 108 (13.7%) developed dementia during a median follow-up of 5.4 years. Excluding those censored before three years, we included 750 participants in the classification analysis, amongst whom 48 (6.4%) developed dementia by year 3. Comparing statistical and ML models, only regularised Cox/logistic regression outperformed their statistical counterparts overall, but not significantly so in survival analysis. Baseline cognition was highly predictive, and global cognition was the most important feature. ConclusionsWhen using baseline SVD-related features to predict dementia in SVD, the ML survival or classification models we evaluated brought little improvement over traditional statistical approaches. The benefits of ML should be evaluated with caution, especially given limited sample size and features.

Imaging features of small vessel disease in cerebral amyloid angiopathy among patients with Alzheimer’s disease

Background and purposeCerebral small vessel disease biomarkers including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (ePVS) are under investigation to identify those specific to cerebral amyloid angiopathy (CAA). In subjects with Alzheimer’s disease (AD), we assessed characteristic features and amounts of WMH, lacunes, and ePVS in four CAA categories (no, mild, moderate and severe CAA) and correlated these with Clinical Dementia Rating sum of boxes (CDRsb) score, ApoE genotype, and neuropathological changes at autopsy. MethodsThe study included patients with a clinical diagnosis of dementia due to AD and neuropathological confirmation of AD and CAA in the National Alzheimer’s Coordinating Center (NACC) database. The WMH, lacunes, and ePVS were evaluated using semi-quantitative scales. Statistical analyses compared the WMH, lacunes, and ePVS values in the four CAA groups with vascular risk factors and AD severity treated as covariates, and to correlate the imaging features with CDRsb score, ApoE genotype, and neuropathological findings. ResultsThe study consisted of 232 patients, of which 222 patients had FLAIR data available and 105 patients had T2-MRI. Occipital predominant WMH were significantly associated with the presence of CAA (p = 0.007). Among the CAA groups, occipital predominant WMH was associated with severe CAA (β = 1.22, p = 0.0001) compared with no CAA. Occipital predominant WMH were not associated with the CDRsb score performed at baseline (p = 0.68) or at follow-up 2–4 years after the MRI (p = 0.92). There was no significant difference in high grade ePVS in the basal ganglia (p = 0.63) and centrum semiovale (p = 0.95) among the four CAA groups. The WMH and ePVS on imaging did not correlate with the number of ApoE ε4 alleles but the WMH (periventricular and deep) correlated with the presence of infarcts, lacunes and microinfarcts on neuropathology. ConclusionAmong patients with AD, occipital predominant WMH is more likely to be found in patients with severe CAA than in those without CAA. The high-grade ePVS in centrum semiovale were common in all AD patients regardless of CAA severity.

Longitudinal Changes of White Matter Hyperintensities in Sporadic Small Vessel Disease: A Systematic Review and Meta-analysis.

White matter hyperintensities (WMHs) are frequent imaging features of small vessel disease (SVD) and related to poor clinical outcomes. WMH progression over time is well described, but regression was also noted recently, although the frequency and associated factors are unknown. This systematic review and meta-analysis aims to assess longitudinal intraindividual WMH volume changes in sporadic SVD. We searched EMBASE and MEDLINE for articles up to 28 January 2022 on WMH volume changes using MRI on ≥2 time points in adults with sporadic SVD. We classified populations (healthy/community-dwelling, stroke, cognitive, other vascular risk factors, and depression) based on study characteristics. We performed random-effects meta-analyses with Knapp-Hartung adjustment to determine mean WMH volume change (change in milliliters, percentage of intracranial volume [%ICV], or milliliters per year), 95% CI, and prediction intervals (PIs, limits of increase and decrease) using unadjusted data. Risk of bias assessment tool for nonrandomized studies was used to assess risk of bias. We followed Preferred Reporting in Systematic Review and Meta-Analysis guidelines. Forty-one articles, 12,284 participants, met the inclusion criteria. Thirteen articles had low risk of bias across all domains. Mean WMH volume increased over time by 1.74 mL (95% CI 1.23-2.26; PI -1.24 to 4.73 mL; 27 articles, N = 7,411, mean time interval 2.7 years, SD = 1.65); 0.25 %ICV (95% CI 0.14-0.36; PI -0.06 to 0.56; 6 articles, N = 1,071, mean time interval 3.5 years, SD = 1.54); or 0.58 mL/y (95% CI 0.35-0.81; PI -0.26 to 1.41; 8 articles, N = 3,802). In addition, 13 articles specifically mentioned and/or provided data on WMH regression, which occurred in asymptomatic, stroke, and cognitive disorders related to SVD. Net mean WMH volume increases over time mask wide-ranging change (e.g., mean increase of 1.75 mL ranging from 1.25 mL decrease to 4.75 mL increase), with regression documented explicitly in up to one-third of participants. More knowledge on underlying mechanisms, associated factors, and clinical correlates is needed, as WMH regression could be an important intervention target.

Circulating N-Acetylaspartate does not track brain NAA concentrations, cognitive function or features of small vessel disease in humans

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain; although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel disease (SVD). Two datasets were analyzed. In dataset 1, structural MRI was acquired in 533 subjects to assess four features of cerebral SVD. Cognitive function was evaluated with standardized test scores (N = 824). In dataset 2, brain 1H-MRS from the occipital region was acquired (N = 49). In all subjects, fasting circulating NAA was measured with mass spectrometry. Dataset 1: in univariate and adjusted for confounders models, we found no correlation between circulating NAA and the examined features of cerebral SVD. In univariate analysis, circulating NAA levels were associated inversely with the speed in information processing and the executive function score, however these associations were lost after accounting for confounders. In line with the negative findings of dataset 1, in dataset 2 there was no correlation between circulating and central NAA or total NAA levels. This study indicates that circulating NAA levels do not reflect central (occipital) NAA levels, cognitive function, or cerebral small vessel disease in man.

Diffusion-Weighted Lesions After Intracerebral Hemorrhage: Associated MRI Findings.

The current study aimed to investigate whether diffusion-weighted imaging-positive (DWI+) lesions after acute intracerebral hemorrhage (ICH) are associated with underlying small vessel disease (SVD) or linked to the acute ICH. We included patients ≥18 years with spontaneous ICH confirmed on neuroimaging and performed 3T MRIs after a median of 11 days (interquartile range [IQR] 6–43). DWI+ lesions were assessed in relation to the hematoma (perihematomal vs. distant and ipsilateral vs. contralateral). Differences in clinical characteristics, ICH characteristics, and MRI markers of SVD between participants with or without DWI+ lesions were investigated using non-parametric tests. We observed 54 DWI+ lesions in 30 (22%) of the 138 patients (median age [IQR] 65 [55–73] years; 71% men, 59 lobar ICH) with available DWI images. We found DWI+ lesions ipsilateral (54%) and contralateral (46%) to the ICH, and 5 (9%) DWI+ lesions were located in the immediate perihematomal region. DWI+ lesion presence was associated with probable CAA diagnosis (38 vs. 15%, p = 0.01) and larger ICH volumes (37 [8–47] vs. 12 [6–24] ml, p = 0.01), but not with imaging features of SVD. Our findings suggest that DWI+ lesions after ICH are a feature of both the underlying SVD and ICH-related mechanisms.

Effect of Cerebral Small Vessel Disease Burden on Outcomes in Patients With Acute Ischemic Stroke Receiving Endovascular Treatment.

BackgroundCerebral small vessel disease (SVD) is common in the aging population. The study aimed to evaluate the effect of SVD on functional outcomes in patients with acute ischemic stroke (AIS) receiving endovascular treatment (EVT).MethodsFrom a prospective registry, we selected patients with AIS receiving EVT. SVD features, including white matter hyperintensities (WMH), lacunes and brain atrophy, were assessed on MRI and a validated SVD score was calculated to reflect the total SVD burden.ResultsAmong 137 patients included, 106 had none-mild SVD burden and 31 had moderate-severe SVD burden. The moderate-severe SVD burden group showed a significantly higher modified Rankin Scale score at 90 d (median, 4 versus 1 points, adjusted common odds ratio 0.32 [95% CI, 0.14–0.69], P < 0.01) and a significantly smaller improvement of NIHSS at 24 h (median, –3 versus –3 points, adjusted β coefficient 4.02 [95% CI, 0.57–7.48], P = 0.02) and 7 days (median, –4 versus –6 points, adjusted β coefficient 4.71 [95% CI, 1.06–8.36], P = 0.01) than the none-mild group. There was no significant difference in successful recanalization, death within 90 days, symptomatic intracranial hemorrhage within 24 h between two groups (all P > 0.05). Additionally, for each single SVD feature, brain atrophy and WMH, but not lacunes, were associated with the functional outcome.ConclusionModerate-severe SVD burden was associated with poor early and late functional outcomes in patients with AIS receiving EVT. Our results suggest that SVD score may act as a good predictor of outcomes in these patients.