MRI Markers Of Small Vessel Disease Research Articles

Perivascular Spaces, Diffusivity Along Perivascular Spaces, and Free Water in Cerebral Small Vessel Disease.

Previous studies have linked the MRI measures of perivascular spaces (PVSs), diffusivity along the perivascular spaces (DTI-ALPS), and free water (FW) to cerebral small vessel disease (SVD) and SVD-related cognitive impairments. However, studies on the longitudinal associations between the three MRI measures, SVD progression, and cognitive decline are lacking. This study aimed to explore how PVS, DTI-ALPS, and FW contribute to SVD progression and cognitive decline. This is a cohort study that included participants with SVD who underwent neuroimaging and cognitive assessment, specifically measuring Mini-Mental State Examination (MMSE), cognitive index, and processing speed, at 2 time points. Three MRI measures were quantified: PVS in basal ganglia (BG-PVS) volumes, FW fraction, and DTI-ALPS. We performed a latent change score model to test inter-relations between the 3 MRI measures and linear regression mixed models to test their longitudinal associations with the changes of other SVD MRI markers and cognitive performances. In baseline assessment, we included 289 participants with SVD, characterized by a median age of 67.0 years and 42.9% women. Of which, 220 participants underwent the follow-up assessment, with a median follow-up time of 3.4 years. Baseline DTI-ALPS was associated with changes in BG-PVS volumes (β = -0.09, p = 0.030), but not vice versa (β = -0.08, p = 0.110). Baseline BG-PVS volumes were associated with changes in white matter hyperintensity (WMH) volumes (β = 0.33, p-corrected < 0.001) and lacune numbers (β = 0.28, p-corrected < 0.001); FW fraction was associated with changes in WMH volumes (β = 0.30, p-corrected < 0.001), lacune numbers (β = 0.28, p-corrected < 0.001), and brain volumes (β = -0.45, p-corrected < 0.001); DTI-ALPS was associated with changes in WMH volumes (β = -0.20, p-corrected = 0.002) and brain volumes (β = 0.23, p-corrected < 0.001). Furthermore, baseline FW fraction was associated with decline in MMSE score (β = -0.17, p-corrected = 0.006); baseline FW fraction and DTI-ALPS were associated with changes in cognitive index (FW fraction: β = -0.25, p-corrected < 0.001; DTI-ALPS: β = 0.20, p-corrected = 0.001) and processing speed over time (FW fraction: β = -0.29, p-corrected < 0.001; DTI-ALPS: β = 0.21, p-corrected < 0.001). Our results showed that increased BG-PVS volumes, increased FW fraction, and decreased DTI-ALPS are related to progression of MRI markers of SVD, along with SVD-related cognitive decline over time. These findings may suggest that the glymphatic dysfunction is related to SVD progression, but further studies are needed.

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.

THE EFFECTS OF INDUCED BLOOD PRESSURE INCREASE AND DECREASE ON CEREBRAL SMALL VESSELS: THE HYPERINTENSE STUDY

Objective: Cerebral Small vessel disease (SVD) is a disorder of the cerebral microvessels and is the commonest vascular cause of stroke and dementia. Hypertension is the most established risk factor for SVD, but the pathophysiological mechanisms following hypertension that cause SVD remain poorly understood. We aim to examine the effects of changes in blood pressure on cerebral microvasculature in young- and middle-aged adults with hypertension to detect the earliest microvascular changes associated with SVD. Design and method: The Hyperintense study is an ongoing observational cohort study aiming to include 50 hypertensive adults (18–55 years). These patients temporarily discontinue antihypertensive medication for diagnostic purposes, often leading to a temporary increase in blood pressure. Data are collected before medication withdrawal (T = 0), once antihypertensives are withdrawn (T = 1), when patients have restarted medication and reached target blood pressure (T = 2) and 1 year later (T = 3). At each time-point, high-resolution 3T MRI scans are performed with conventional structural sequences and advanced techniques to assess various aspects of microvascular integrity, including integrity of the blood-brain barrier, microperfusion and microstructural integrity. Clinical data includes motor and cognitive examinations and blood sampling. Results: Between July-December 2021, 7 patients (86% male, mean age 47.4 ± 4.4 years) were enrolled. Baseline characteristics and SVD burden are shown in Table. In 3/4 participants who completed T = 1, systolic blood pressure increased after medication withdrawal (median increase systolic blood pressure: 13.7 [3.3 – 15.3] mmHg), demonstrating proof of principle of our approach. Conclusions: First data show increased blood pressure after medication withdrawal in most participants and demonstrate feasibility of our design. Analysis of the effect of blood pressure increase and decrease on MRI outcomes will improve understanding of the pathological mechanisms following hypertension that may lead to MRI markers of SVD. This knowledge can help identify new targets for treatment of SVD, aimed at preventing or limiting disease progression.

Do polygenic scores of cerebral small vessel disease MRI markers predict white matter lesions?

AbstractBackgroundEvidence of cerebral small vessel disease (CSVD) is commonly found in those with a diagnosis of Alzheimer’s disease (AD) and is associated with T2‐weighted MRI‐visible white matter hyperintensities (WMHs). Here we investigate whether macrostructural and microstructural polygenic risk scores (PRS) predict WMH volumes.MethodWe used Genome Wide Association Studies (GWAS), based on UK Biobank (UKB) MRI markers of WMH, Fractional Anisotropy (FA) and Mean Diffusivity (MD) from (Persyn et al., 2020, https://doi.org/10.1038/s41467‐020‐15932‐3) to compute PRS for n=730 participants (following strict quality control) from the AD Neuroimaging Initiative (ADNI) using PRSice. We calculated WMH volumes for ADNI subjects using a Bayesian Model Selection method BaMoS (Sudre et al., https://doi.org/10.1109/TMI.2015.2419072). Linear regression models (with confounds for age, gender, education, APOE4 status, total intracranial volume and five principal components of population structure) were used to test for association (including multiple testing correction) between WMH, FA and MD PRS (based on p‐value thresholds at p=1.0e‐05 and p=0.5) and WMH volumes in each of three diagnostic groups: Healthy Controls (HC; n=218), Mild Cognitive Impairment (MCI; n=390) and AD (n=122).ResultWMH and FA PRS did not predict WMH volume in the ADNIGO and ADNI2 cohort (Table 1) despite high correlation between BaMoS‐derived and BIANCA‐derived WMH volumes (r=0.84 on 19,070 UKB subjects). However, MD PRS at the p=0.5 threshold in the MCI group was positively correlated with WMH volume (Table 1) with t=3.4 (FDR‐corrected P=0.0008; Figure 1).ConclusionDespite a high heritability of WMH (h2=0.76; Sachdev et al.. 2016, https://doi.org/10.1161/STROKEAHA.116.012532), unexpectedly, WMH PRS did not predict WMH volume in ADNI in any of the diagnostic groups. The correlation between total WMH estimated with both tools was very high and thus is unlikely the source of this lack of association,however, this may be due to different inclusion criteria for ADNI. The statistically significant relationship in the ADNI MCI group between MD PRS and WMH volume may reflect the early white matter tract damage that is visible before AD manifests and these structural insults become overwhelming. This is reflected in many of the other PRS‐WMH corelations in the MCI group which are borderline statistical significance.

Association of enlarged perivascular spaces (ePVS) and MRI markers of small vessel disease (SVD) and neurodegeneration in the Florida Vascular Imaging Phenotypes (FL‐VIP) Study of AD Risk

AbstractBackgroundPVS are fluid filled compartments surrounding small intracerebral vessels. They are conduits for fluid transport, exchange, and waste clearance. ePVS are observed in AD, but their relation to SVD markers and neurodegeneration is unknown. We tested whether ePVS are correlated with markers of SVD but not cortical atrophy.MethodWe analyzed subjects’ brains from the FL‐VIP (comprised of all 1Florida ADRC participants with high quality 3T MRI). ePVS were defined as parenchymal hypo/hyperintensities of &lt;3 mm seen on a single axial T1,T2, or FLAIR section through the basal ganglia (BG) and centrum semiovale (CSO). ePVS were graded as 0 (none), 1 (&lt;10), 2 (11‐20), 3 (21‐40), and 4 (&gt;40). The side with highest ePVS count was graded. BGBG and CSO scores were summed to yield a 0‐8 ePVS total. Generalized linear models were used to estimate ePVS score associations with White‐Matter Hyperintensity Volume (WMHV), silent brain infarcts (SBIs), cerebral microbleeds (CMBs), and mean total cortical thickness. We adjusted for demographics, vascular risk factors and comorbidities, and ApoE4 status.ResultOf 228 non‐demented participants (mean age 72±8 years; 61% women, 60% Hispanic, mean education 15±4 years, 33% ApoE4 carriers), 59% were hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. 73% of subjects had a total ePVS score &gt;1. Scores ranged from 0‐7 total (mean 2.5±1.4), 0‐4 for BG (mean 1.3±0.7) and CSO (1.2 ±0.9). In unadjusted analyses, total ePVS correlated with WMHV (r=0.46, p&lt;0001), SBI (r=0.17, p=0.009), and CMB (r=0.16, p=0.016). BG ePVS correlated with WMHV, SBI and CMB. CSO ePVS correlated only with WMHV (r=0.32, p=0.002). In multivariable analyses, ePVS correlated with WMHV (β=4.97, p&lt;0.001), SBI (OR=1.36, p=0.027), and CMB (OR=1.43, p=0.019). BG ePVS remained associated with WMHV, SBI and CMB; and CSO ePVS only with WMHV (β=4.70, p=0.039). Total, BG, and CSO ePVS were not associated with cortical thickness.ConclusionBG ePVS are highly related to MRI markers of SVD, but not total cortical thickness, and therefore may be considered hallmark features of small vessel disease. CSO ePVS may not have as a prominent role in SVD.

Prediction of dementia using diffusion tensor MRI measures: the OPTIMAL collaboration

ObjectivesIt has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but...

Differences in cerebral small vessel disease magnetic resonance imaging markers between lacunar stroke and non-Lobar intracerebral hemorrhage.

IntroductionIt is unclear why cerebral small vessel disease (SVD) leads to lacunar stroke in some and to non–lobar intracerebral hemorrhage (ICH) in others. We investigated differences in MRI markers of SVD in patients with lacunar stroke or non–lobar ICH.Patients and methodsWe included patients from two prospective cohort studies with either lacunar stroke (RUN DMC) or non–lobar ICH (FETCH). Differences in SVD markers (white matter hyperintensities [WMH], lacunes, cerebral microbleeds [CMB]) between groups were investigated with univariable tests; multivariable logistic regression analysis, adjusted for age, sex, and vascular risk factors; spatial correlation analysis and voxel–wise lesion symptom mapping.ResultsWe included 82 patients with lacunar stroke (median age 63, IQR 57–72) and 54 with non-lobar ICH (66, 59–75). WMH volumes and distribution were not different between groups. Lacunes were more frequent in patients with a lacunar stroke (44% vs. 17%, adjusted odds ratio [aOR] 5.69, 95% CI [1.66–22.75]) compared to patients with a non–lobar ICH. CMB were more frequent in patients with a non–lobar ICH (71% vs. 23%, aOR for lacunar stroke vs non–lobar ICH 0.08 95% CI [0.02–0.26]), and more often located in non–lobar regions compared to CMB in lacunar stroke.DiscussionAlthough we obserd different types of MRI markers of SVD within the same patient, ischemic markers of SVD were more frequent in the ischemic type of lacunar stroke, and hemorrhagic markers were more prevalent in the hemorrhagic phenotype of non-lobar ICH.ConclusionThere are differences between MRI markers of SVD between patients with a lacunar stroke and those with a non-lobar ICH.

Associations between total MRI-visible small vessel disease burden and domain-specific cognitive abilities in a community-dwelling older-age cohort

Cerebral small vessel disease (SVD) is a leading cause of vascular cognitive impairment, however the precise nature of SVD-related cognitive deficits, and their associations with structural brain changes, remain unclear. We combined computational volumes and visually-rated MRI markers of SVD to quantify total SVD burden, using data from the Lothian Birth Cohort 1936 (n = 540; age: 72.6 ± 0.7 years). We found negative associations between total SVD burden and general cognitive ability (standardized β: -0.363; 95%CI: [-0.49, -0.23]; p(FDR) < 0.001), processing speed (-0.371 [-0.50, -0.24]; p(FDR) < 0.001), verbal memory (-0.265; [-0.42, -0.11]; p(FDR) = 0.002), and visuospatial ability (-0.170; [-0.32, -0.02]; p(FDR) = 0.029). Only the association between SVD burden and processing speed remained after accounting for covariance with general cognitive ability (-0.325; [-0.61, -0.04]; p(FDR) = 0.029). This suggests that SVD's association with poorer processing speed is not driven by, but is independent of its association with poorer general cognitive ability. Tests of processing speed may be particularly sensitive to the cognitive impact of SVD, but all major cognitive domains should be tested to determine the full range of SVD-related cognitive characteristics.

Lower cerebral perfusion is associated with tau-PET in the entorhinal cortex across the Alzheimer's continuum

Alzheimer's disease (AD) is associated with reduced temporo-parietal cerebral blood flow (CBF). However, a substantial variability in CBF across the clinical spectrum of AD has been reported, possibly due to differences in primary AD pathologies. Here, we assessed CBF (ASL-MRI), tau (AV1451-PET) and amyloid (AV45/FBB-PET) in 156 subjects across the AD continuum. Using mixed-effect regression analyses, we assessed the local associations between amyloid-PET, tau-PET and CBF in a hypothesis-driven way focusing on each pathology's predilection areas. The contribution of Apolipoprotein E (APOE) genotype, and MRI markers of small vessel disease (SVD) to alterations in CBF were assessed as well. Tau-PET was associated with lower CBF in the entorhinal cortex, independent of Aβ. Amyloid-PET was associated with lower CBF in temporo-parietal regions. No associations between MRI markers of SVD and CBF were observed. These results provide evidence that in addition to Aβ, pathologic tau is a major correlate of CBF in early Braak stages, independent of Aβ, APOE genotype and SVD markers.

Trends and challenges in clinical research on cerebral small vessel disease, with a particular emphasis on type-1 small vessel disease

Cerebral small vessel disease (SVD) is defined as difficulty maintaining efficient microcirculation, metabolism, and neural networks caused by degeneration of small vessels of the brain, as well as cognitive or physical dysfunction caused by this difficulty. The most common SVD (i.e., type 1 SVD), which is driven by hypertensive arteriopathy, appears to be more prevalent in people with East Asian ethnicity than in Whites. Recent attention has been paid to a SVD scoring system using major MRI markers of SVD in an attempt to comprehensively semi-quantify the SVD burden in the brain. This concept raised a new question: "Is there a practical threshold for the comprehensive SVD score?" The development of computational methods to assess SVD imaging markers could answer this question, and may help identify the optimal intervention for patients with type 1 SVD to prevent stroke and dementia.

Underlying Small Vessel Disease Associated With Mixed Cerebral Microbleeds.

Background and Purpose: Whether patients with both lobar and deep cerebral microbleeds (mixed CMB) have advanced cerebral amyloid angiopathy (CAA), hypertensive angiopathy (HA) or both is uncertain. To get insight into the underlying small vessel disease (SVD) associated with mixed CMB, we explored its association with cortical superficial siderosis (cSS), a key marker of CAA and other MRI markers of SVD in patients with intracerebral hemorrhage (ICH).Methods: Of 425 consecutive patients with acute ICH who had received brain MRIs, 260 had ≥1 CMB and were included in the analysis. They were categorized as strictly lobar CMB (suggesting CAA), strictly deep CMB (suggesting HA) or mixed CMB. Clinical and imaging characteristics were compared (1) between the three CMB groups and (2) within mixed CMB patients according to the symptomatic ICH location.Results: Overall, 111 (26%) patients had mixed CMB. Compared to strictly lobar CMB (n = 111) and strictly deep CMB (n = 38), patients with mixed CMB had a more severe burden of lacune, white matter hyperintensities and CMB. cSS was observed in 24.3% of patients with mixed CMB compared to 44.1% in strictly lobar CMB and 10.5% in strictly deep CMB (p < 0.0001). Among patients with mixed CMB, 44 (39.6%) had a lobar symptomatic ICH and 67 (60.4%) had a non-lobar ICH. Patients with non-lobar ICH were more likely to have hypertension, whereas those with lobar ICH were more likely to have cSS and chronic lobar ICH and had higher ratio lobar CMB count/total CMB count.Conclusions: Mixed CMB is frequently encountered in patients with ICH and appears as a heterogeneous group, suggesting that both CAA and HA may be contributing to mixed CMB. Neuroimaging markers including ICH location, cSS, and CMB distribution may indicate the predominant underlying vasculopathy, with potential prognostic implications.

The role of small diffusion-weighted imaging lesions in cerebral small vessel disease

To investigate the prevalence of asymptomatic diffusion-weighted imaging-positive (DWI+) lesions in individuals with cerebral small vessel disease (SVD) and identify their role in the origin of SVD markers on MRI. We included 503 individuals with SVD from the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) study (mean age 65.6 years [SD 8.8], 56.5% male) with 1.5T MRI in 2006 and, if available, follow-up MRI in 2011 and 2015. We screened DWI scans (n = 1,152) for DWI+ lesions, assessed lesion evolution on follow-up fluid-attenuated inversion recovery, T1 and T2* images, and examined the association between DWI+ lesions and annual SVD progression (white matter hyperintensities [WMH], lacunes, microbleeds). We found 50 DWI+ lesions in 39 individuals on 1,152 DWI (3.4%). Individuals with DWI+ lesions were older (p = 0.025), more frequently had a history of hypertension (p = 0.021), and had a larger burden of preexisting SVD MRI markers (WMH, lacunes, microbleeds: all p < 0.001) compared to individuals without DWI+ lesions. Of the 23 DWI+ lesions with available follow-up MRI, 14 (61%) evolved into a WMH, 8 (35%) resulted in a cavity, and 1 (4%) was no longer visible. Presence of DWI+ lesions was significantly associated with annual WMH volume increase and yearly incidence of lacunes and microbleeds (all p < 0.001). Over 3% of individuals with SVD have DWI+ lesions. Although DWI+ lesions play a role in the progression of SVD, they may not fully explain progression of SVD markers on MRI, suggesting that other factors than acute ischemia are at play.

High dilated perivascular space burden: a new MRI marker for risk of intracerebral hemorrhage

Commonly observed in older community persons, dilated perivascular spaces (dPVSs) are thought to represent an emerging MRI marker of cerebral small vessel disease, but their clinical significance is uncertain. We examined the longitudinal relationship of dPVS burden with risk of incident stroke, ischemic stroke, and intracerebral hemorrhage (ICH) in the 3C-Dijon population-based study (N = 1678 participants, mean age 72.7 ± 4.1 years) using Cox regression. dPVS burden was studied as a global score and according to dPVS location (basal ganglia, white matter, hippocampus, brainstem) at the baseline. During a mean follow-up of 9.1 ± 2.6 years, 66 participants suffered an incident stroke. Increasing global dPVS burden was associated with a higher risk of any incident stroke (hazard ratio [HR], 1.24; 95% CI, [1.06–1.45]) and of incident ICH (HR, 3.12 [1.78–5.47]), adjusting for sex and intracranial volume. Association with ICH remained significant after additionally adjusting for vascular risk factors and for other cerebral small vessel disease MRI markers. High dPVS burden in basal ganglia and hippocampus, but not in white matter or brainstem, were associated with higher risk of any stroke and ICH.

Longitudinal decline in structural networks predicts dementia in cerebral small vessel disease.

ObjectiveTo determine whether longitudinal change in white matter structural network integrity predicts dementia and future cognitive decline in cerebral small vessel disease (SVD). To investigate whether network disruption has a causal role in cognitive decline and mediates the association between conventional MRI markers of SVD with both cognitive decline and dementia.MethodsIn the prospective longitudinal SCANS (St George's Cognition and Neuroimaging in Stroke) Study, 97 dementia-free individuals with symptomatic lacunar stroke were followed with annual MRI for 3 years and annual cognitive assessment for 5 years. Conversion to dementia was recorded. Structural networks were constructed from diffusion tractography using a longitudinal registration pipeline, and network global efficiency was calculated. Linear mixed-effects regression was used to assess change over time.ResultsSeventeen individuals (17.5%) converted to dementia, and significant decline in global cognition occurred (p = 0.0016). Structural network measures declined over the 3-year MRI follow-up, but the degree of change varied markedly between individuals. The degree of reductions in network global efficiency was associated with conversion to dementia (B = −2.35, odds ratio = 0.095, p = 0.00056). Change in network global efficiency mediated much of the association of conventional MRI markers of SVD with cognitive decline and progression to dementia.ConclusionsNetwork disruption has a central role in the pathogenesis of cognitive decline and dementia in SVD. It may be a useful disease marker to identify that subgroup of patients with SVD who progress to dementia.

Abstract 170: Metabolomics Profiling and Risk of Small Vessel Ischemic Stroke

Cerebral small vessel disease (SVD) accounts for 25-30% of strokes and is a leading cause of cognitive decline and disability. Identification of blood-based biomarkers for SVD may aid in the early identification of high-risk patients and in the understanding of stroke etiologies, which will facilitate development of therapeutic options. In 3,904 men and women from the Atherosclerosis Risk In Communities study, we investigated the association of 245 serum metabolites measured at the baseline examination via untargeted metabolomic profiling with incident stroke subtypes. We focused on strokes with a small vessel pathology. First stroke events occurring between the baseline examination and December 31, 2013 were ascertained by annual telephone interview and hospital surveillance, followed case adjudication by a committee of experienced physicians. Cox proportional hazard models were used to estimate the hazard ratio (HR) for small vessel ischemic strokes (SVIS) per standard deviation of the standardized serum level of each metabolites, adjusting for baseline age, sex, race and field center (model 1); and additionally for diabetes, hypertension, current smoking, body mass index, and estimated glomerular filtration rate (model 2). Over a median follow-up of 24 years, 65 incident SVIS were observed. After correcting for multiple testing, we identified 4 serum metabolites associated with incident SVIS. A deamination product of tryptophan, indole-3-propionate (IPA) remained significantly associated in model 2 (HR [95%CI] = 1.13 [1.07-1.18], P&lt;0.0001). Consistently, this metabolite was also significantly associated with incident hemorrhagic stroke (HR [95%CI] = 1.11 [1.03-1.19], P=0.0074) but no other stroke subtype. Additional analyses of MRI markers of SVD with the identified metabolite will also be presented. In summary, we identified a novel circulating metabolite, IPA, associated with incident ISVS independently of known risk factors. This compound is a potent neuroprotective antioxidant endogenously produced by human microbiota. These results are consistent with a role of oxidative stress in cerebral small vessel pathology.

Total small vessel disease burden and brain network efficiency in cerebral amyloid angiopathy

BackgroundCerebral amyloid angiopathy (CAA) is associated with hemorrhagic and nonhemorrhagic markers small vessel disease (SVD). A composite score to quantify the total burden of SVD on MRI specifically for CAA patients was recently developed. Brain network alterations related to individual MRI markers of SVD in CAA were demonstrated. ObjectivesConsidering diffusion based network measures sensitive to detect different relevant SVD-related brain injury, we investigated if increased overall SVD injury on MRI corresponds to worse global brain connectivity in CAA. MethodsSeventy-three patients (79.5% male, mean age 70.58±8.22years) with a diagnosis CAA were considered. SVD markers in total MRI SVD score included: lobar cerebral microbleeds, cortical superficial siderosis (cSS), white matter hyperintensities (WMH) and centrum semiovale-enlarged perivascular spaces. Diffusion imaging based network reconstruction was made. The associations between total MRI SVD score and global network efficiency (GNE) were analyzed. ResultsA modest significant inverse correlation between total MRI SVD score and GNE existed (p=0.013; R2=0.07). GNE was related with the presence of cSS and moderate-severe WMHs. ConclusionsAn increased burden of SVD neuroimaging markers corresponds to more reductions in global brain connectivity, implying a possible cumulative effect of overall SVD markers on disrupted physiology. GNE was related with some components of the score, specifically cSS and moderate-severe WMHs.

Cortical superficial siderosis and first-ever cerebral hemorrhage in cerebral amyloid angiopathy.

To investigate whether cortical superficial siderosis (cSS) is associated with increased risk of future first-ever symptomatic lobar intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA) presenting with neurologic symptoms and without ICH. Consecutive patients meeting modified Boston criteria for probable CAA in the absence of ICH from a single-center cohort were analyzed. cSS and other small vessel disease MRI markers were assessed according to recent consensus recommendations. Patients were followed prospectively for future incident symptomatic lobar ICH. Prespecified Cox proportional hazard models were used to investigate cSS and first-ever lobar ICH risk adjusting for potential confounders. The cohort included 236 patients with probable CAA without lobar ICH at baseline. cSS prevalence was 34%. During a median follow-up of 3.26 years (interquartile range 1.42-5.50 years), 27 of 236 patients (11.4%) experienced a first-ever symptomatic lobar ICH. cSS was a predictor of time until first ICH (p = 0.0007, log-rank test). The risk of symptomatic ICH at 5 years of follow-up was 19% (95% confidence interval [CI] 11%-32%) for patients with cSS at baseline vs 6% (95% CI 3%-12%) for patients without cSS. In multivariable Cox regression models, cSS presence was the only independent predictor of increased symptomatic ICH risk during follow-up (HR 4.04; 95% CI 1.73-9.44, p = 0.001), after adjusting for age, lobar cerebral microbleeds burden, and white matter hyperintensities. cSS is consistently associated with an increased risk of future lobar ICH in CAA with potentially important clinical implications for patient care decisions such as antithrombotic use.

MRI-visible perivascular spaces in cerebral amyloid angiopathy and hypertensive arteriopathy

To assess MRI-visible enlarged perivascular spaces (EPVS) burden and different topographical patterns (in the centrum semiovale [CSO] and basal ganglia [BG]) in 2 common microangiopathies: cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). Consecutive patients with spontaneous intracerebral hemorrhage (ICH) from a prospective MRI cohort were included. Small vessel disease MRI markers, including cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), and white matter hyperintensities (WMH), were rated. CSO-EPVS/BG-EPVS were assessed on a validated 4-point visual rating scale (0 = no EPVS, 1 = <10, 2 = 11-20, 3 = 21-40, and 4 = >40 EPVS). We tested associations of predefined high-degree (score >2) CSO-EPVS and BG-EPVS with other MRI markers in multivariable logistic regression. We subsequently evaluated associations with CSO-EPVS predominance (i.e., CSO-EPVS > BG-EPVS) and BG-EPVS predominance pattern (i.e., BG-EPVS > CSO-EPVS) in adjusted multinomial logistic regression (reference group, BG-EPVS = CSO-EPVS). We included 315 patients with CAA-ICH and 137 with HA-ICH. High-degree CSO-EPVS prevalence was greater in CAA-related ICH vs HA-related ICH (43.8% vs 17.5%, p < 0.001). In multivariable logistic regression, high-degree CSO-EPVS was associated with lobar CMB (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.10-1.61, p = 0.003) and cSS (OR 2.08, 95% CI 1.30-3.32, p = 0.002). Deep CMBs (OR 2.85, 95% CI 1.75-4.64, p < 0.0001) and higher WMH volume (OR 1.02, 95% CI 1.01-1.04, p = 0.010) were predictors of high-degree BG-EPVS. A CSO-EPVS-predominant pattern was more common in CAA-ICH than in HA-ICH (75.9% vs 39.4%, respectively, p < 0.0001). CSO-PVS predominance was associated with lobar CMB burden and cSS, while BG-EPVS predominance was associated with HA-ICH and WMH volumes. Different patterns of MRI-visible EPVS provide insights into the dominant underlying microangiopathy type in patients with spontaneous ICH.

Abstract WP166: Prediction of Recurrent Stroke in Lacunar Stroke Patients: Performance of the Small Vessel Disease (SVD) Score in the SPS3 Trial

Introduction: The previously published cerebral SVD Score is a four-point rating scale based on the four cardinal MRI markers of SVD: moderate-severe white matter hyperintensities, , lacune(s), moderate-severe enlarged perivascular spaces (PVS), and microbleed(s). We evaluated the score’s ability to predict recurrent stroke in the Secondary Prevention of Small Subcortical Strokes (SPS3) Trial. Methods: One point each was awarded for these 4 MRI findings: max periventricular Fazekas score = 3 and/or max subcortical Fazekas score &gt; 2; &gt;1 cerebral microbleed 2 (i.e. &gt; 11 PVS unilaterally); &gt; 1 old lacune (3-15 mm) on FLAIR/T1. Annualized rates of recurrent stroke were computed assuming a Poisson model, and c-statistics were calculated for the SVD score model and for two other previously published SPS3 derived models. Results: Of 3020 participants, 1137 had complete data available for SVD scoring. Prevalence of SVD scores 0, 1, 2, 3, and 4 were 19% (n=219), 29% (n=325), 24% (n=277), 18% (n=200), and 10% (n=116). PVS (55%) were most common, followed by moderate-severe white matter hyperintensities (45), lacunes (41), and microbleeds (30). Recurrent stroke rates did not strictly increase with increasing SVD score, i.e. rates were 2.4%/pt-yr (95% CI 1.5, 3.9), 1.4 (0.8, 2.3), 2.0 (1.3, 3.2), 3.8 (2.5, 5.7), and 3.2 (1.8, 5.6) respectively. When SVD scores of 0-2 vs. 3-4 were grouped and compared with two other models for predicting recurrent stroke in this cohort, the SVD score model did not outperform. (Table) Conclusions: SVD score features were very common in the SPS3 cohort. Higher (3-4) vs. lower (0-2) SVD scores predicted recurrent stroke with similar predictive ability to models including clinical risk factors only +/- fewer MRI features. Further testing of the SVD score is warranted.

Plasma β-amyloid and MRI markers of cerebral small vessel disease: Three-City Dijon study.

We investigated the relation of circulating plasma β-amyloid (Aβ) with MRI markers of small vessel disease (SVD) in dementia-free community persons. Participants were 1,690 individuals aged 65 to 80 years from the Three-City Dijon Study. Plasma Aβ measurement and MRI examination were performed at baseline and after a 4-year follow-up. MRI markers of SVD included white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces. We examined the relation of plasma Aβ levels with MRI markers of SVD at baseline and with progression of WMH over follow-up (n = 1,057). We also assessed whether these relations were modified by vascular risk factors, notably blood pressure. Low plasma Aβ1-40 levels were associated with increased progression of WMH, and low Aβ1-42 with higher odds of extensive WMH progression over the follow-up (odds ratio = 1.66, 95% confidence interval = 1.16-2.38). Consistently low Aβ1-40 and Aβ1-42 levels on both measurements were associated with accelerated progression of WMH. These associations were modified by blood pressure levels but not the APOE ε4 genotype. Progression of WMH volume in dementia-free older persons is associated with levels of circulating plasma Aβ. These results reinforce the notion of an interrelation of vascular and neurodegenerative mechanisms in cerebral aging.