Welcome to the ESOC 2021 Virtual Conference Calendar

Group Name

The Edinburgh SVD Research Group

Background And Aims

Increased pulsatility due to blood vessel stiffening is associated with cerebral small vessel disease (SVD). While arterial pulsatility is often the focus in regards to downstream microvascular damage, recent findings appear to suggest a role of venous sinus pulsatility in SVD. We aimed to assess these relationships longitudinally.

Methods

We prospectively recruited patients with minor stroke and SVD. We assessed SVD neuroimaging lesion volumes and used phase-contrast magnetic resonance imaging at 3T to examine the venous sinuses, internal carotids, and vertebral arteries. We extracted flow data using in-house code, and calculated pulsatility (Gosling’s Pulsatility Index equation PI=(flow_max–flow_min)/flow_mean). WMH volumes were calculated as % of intracranial volume (ICV) for each visit. We tested for associations between baseline pulsatility, WMH volume, and WMH volume change (baseline to 1-year) with univariate regression analysis.

Results

We recruited 104 patients, mean age 67.63±9.9, 66% male. Patients with higher superior sagittal sinus (SSS) PI had higher baseline WMH volume (+0.98% of ICV per unit increase in PI, p=0.043, CI:0.03-1.94). Baseline-to-1-year WMH volume growth increased more in patients with higher PI in each venous sinus (e.g. +0.18% of ICV per unit increase in SSS PI, p=0.024, CI:0.02-0.34). No significant associations were found with arterial PI.

Conclusions

Longitudinal WMH growth is linked to intracranial venous sinus pulsatility, rather than major arterial pulsatility. The increased venous PI may reflect transmission of pulsatile waveforms to venous sinuses through the brain via loss of elasticity and damping in the cerebral vasculature. This study is ongoing; future analysis will help elucidate pulsatility’s role in SVD.

Trial Registration Number

Not applicable

Group Name

On behalf of the SVDs@target group

Background And Aims

Cerebral small vessel diseases (SVDs) are a major cause of stroke and dementia. To better understand underlying disease mechanisms, we need to study SVDs at their core, the small vessels. Here we use 7T MRI to investigate cerebral small vessel function in patients with genetically defined SVD and controls.

Methods

23 patients with CADASIL and 13 age-matched controls underwent clinical assessment, 3T brain MRI (for SVD lesions) and 7T brain MRI (for small vessel function). Small vessel function measures included blood flow velocity and pulsatility in perforating arteries in the semioval centre and basal ganglia, vascular reactivity in the visual cortex after visual stimulation and whole brain vascular reactivity to a hypercapnic stimulus.

Results

Compared with controls, patients with CADASIL had decreased blood flow velocity in perforating arteries in the semioval centre (mean difference -0.09 cm/s, p=.03) and basal ganglia (mean difference -0.98 cm/s, p=.003), and pulsatility index was increased (mean difference 0.19, p=.009 and 0.17, p=.05, respectively). Small vessel reactivity to a visual stimulus in the visual cortex was decreased (BOLD mean difference -0.21%, p=.04). Small vessel reactivity to a hypercapnic stimulus was increased in the cortex (BOLD mean difference 0.42%, p=.05) and decreased in white matter hyperintensities (BOLD mean difference -0.13%, p=.04). Semioval centre perforating artery flow velocity and cortical reactivity to hypercapnia correlated with white matter hyperintensity volume in patients.

Conclusions

We show that cerebral small vessel function was abnormal in patients with CADASIL versus controls and that small vessel dysfunction is partly related with disease severity.

Trial Registration Number

Not applicable

Group Name

Edinburgh SVD research group

Background And Aims

Cerebral small vessel disease (SVD) is characterised by cerebrovascular dysfunction but its specific relationships to tissue damage are unclear. We analysed cross-sectional and longitudinal relationships between baseline cerebrovascular reactivity (CVR) and white matter hyperintensities (WMH) burden in patients with sporadic SVD from the Mild Stroke Study 3.

Methods

We acquired 3T brain MRI in patients with minor stroke stratified for SVD burden, measuring WMH volumes at baseline and 12 months, and BOLD CVR following a 6% CO₂ gas challenge at baseline. We computed CVR (%signal/mmHg) in deep grey (GM) and normal-appearing white matter (NAWM) using linear modelling of end-tidal CO₂. We analysed baseline WMH volume (fraction of intracranial volume %ICV) and change in WMH volume (ΔWMH, %ICV/year) relative to baseline CVR using multiple linear regression models, adjusting for vascular risk factors.

Results

Processable CVR data were obtained in 94/105 SVD patients with median [min, max] age 69.0 [40.2,85.5] years, 67% male and median baseline CVR_GM=0.20 [0.06,0.36] %/mmHg and CVR_NAWM=0.05 [0.02,0.10] %/mmHg. Median baseline WMH volume was 7.48ml (0.47 [0.06,6.06] %ICV) with median increase of 0.32ml (0.02 [-0.26,0.71] %ICV) at one year. At baseline, patients with lower CVR had more WMH (B_CVR(GM)=-4.85, 95%CI=[-7.97,-1.72], and B_CVR(NAWM)=-20.80 [-31.81,-9.79] %ICV per %signal/mmHg). ΔWMH was greater in patients with lower baseline CVR ( B_CVR(GM)=-0.59 [-1.10,-0.09] and B_CVR(NAWM)=-2.44 [-4.23,-0.65] %ICV/year per %signal/mmHg).

Conclusions

We confirm that CVR impairment is associated with higher SVD burden cross-sectionally and showed that lower baseline CVR, particularly in NAWM, predicts increased WMH progression over one year.

Trial Registration Number

ISRCTN12113543

Background And Aims

Cerebral small vessel disease (SVD) is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of underlying pathophysiology. Metabolomics can be used to identify novel risk factors in order to better understand pathogenesis and predict disease progression and severity.

Methods

618 patients with symptomatic cerebral SVD from two prospective cohort studies provided baseline serum samples and underwent regular MRI scans and cognitive testing with up to 15 years follow-up. Using ultra-performance liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy, we obtained metabolic and lipidomic profiles and examined their association with MRI SVD markers, cognition, and future risk of dementia.

Results

Lower levels of multiple glycerophospholipids, sphingolipids, and sterol lipids were associated with higher white matter hyperintensities (WMH) volume, lower white matter mean diffusivity, greater brain atrophy, and impaired cognition in baseline cross-sectional analyses. Higher levels of several amino acids and nucleotides were associated with higher WMH volume, greater atrophy, and lower diffusivity. Several metabolites, including lower levels of valine, caffeine, and VLDL analytes, and higher levels of urocanate and HDL and LDL analytes, were associated with future dementia incidence.

Conclusions

We found multiple distinct metabolic signatures associated with SVD imaging markers, cognition, and conversion to dementia. Further research should assess causality and the use of metabolomic screening to improve the ability to predict future disease severity and dementia risk in SVD. The metabolomic profiles may also provide novel insights into disease pathogenesis and help develop novel treatment approaches.

Trial Registration Number

Not applicable

Group Name

On behalf of the SVDS@targert Investigators and Collaborators

Background And Aims

Blood-brain barrier impairment in small vessel disease (SVD) may be measured by subtle changes in permeability-surface area product (PS) in dynamic-contrast enhanced MRI (DCE-MRI). We noted areas of high PS spots (hPSS) on PS maps in subcortical tissues and assessed their relationship to SVD lesions.

Methods

Prospective multicentre observational study of 77 patients, 45 sporadic SVD, 32 CADASIL, (INVESTIGATE@SVD). All patients had structural 3T MRI sequences, DCE-MRI and cerebrovascular reactivity MRI with 6%CO2 (CVR-MRI). After excluding 19 artifactual PS maps, we identified subcortical white matter regions with highest 10% PS values, and their relation to lacunes, microbleeds or white matter hyperintensities (WMH). We assessed factors associated with hPSS and SVD lesions in univariable and multivariable logistic regression adjusted for age, SVD type, WMH volume, number of lacunes and microbleeds.

Results

Amongst 58 selected patients, median (IQR) number of hPSS was 62 (51-83). hPSS corresponded with lacune and microbleed edges in 22/36 (61%) and 4/10 (40%) patients presenting lacunes and microbleeds in the white matter, respectively. hPSS appeared within or bounding WMH in 11/50 (21%) and 14/50 (27%) patients with focal WMH. In adjusted analysis, CVR in WMH was inversely related to lacune-hPSS (OR=0.48; 95%CI, 0.27-0.86), and CMB to WMH-bounding-hPSS (OR=1.1; 1.01-1.21), while SVD type and other relevant factors in the univariable analysis were no longer significant.

Conclusions

Highest PS values frequently occur around lacunes and microbleeds, and in or at the edge of WMH in a fifth of patients. The relationships between different vascular function measures and focal SVD should be further investigated.

Trial Registration Number

ISRCTN10514229

Group Name

Framingham Heart Study

Background And Aims

Background: Hypertension (HTN), the most potent stroke risk factor, is also related to cerebral small vessel disease including white matter injury.

Aims: To relate mid to late-life HTN trends to white matter injury on brain magnetic resonance imaging (MRI) in community-dwelling Framingham Heart Study (FHS) participants.

Methods

Design/Methods: We studied FHS Offspring Cohort participants with midlife and late-life blood pressure measurements. In late-life, 1018 had diffusion tensor imaging (DTI), and 2323 had T2/FLAIR brain MRIs. We used multiple linear regression to relate mid-to-late-life HTN trends (normotension - normotension (N-N), normotension - hypertension (N-H), hypertension-hypertension (H-H)) to white matter injury. We log-transformed and then standardized (zero mean and unit variance) all continuous white matter injury measures for the regression analysis.

Results

Results: Compared to N-N, after adjustment for age and sex, H-H subjects had significantly higher free water (FW), (beta(β)±Standard-Error(SE): 0.17±0.07, p=0.012), the peak of skeletonized mean diffusivity (0.19±0.07, p=0.007) and white matter hyperintensities volumes (WMHV) (0.12±0.06, p=0.026), and N-H subjects had higher FW (0.12±0.06, p=0.055) than N-N. For H-H, results remained consistent after additionally adjusting for late-life vascular risk factors. The stratified analysis revealed a stronger association in age 65+ subjects and those without the APOE-

Conclusions

Conclusions: Mid to late-life HTN trend is significantly associated with brain integrity destruction markers and increased but not extensive WMHV in FHS community-dwelling individuals.

Trial Registration Number

Not applicable

Background And Aims

In early stages of cerebral small vessel disease (CSVD), associations between white matter injury and cognitive deficits remain poorly understood. We performed fixel-based analysis (FBA), a framework for assessment of white matter micro- and macrostructure based on diffusion weighted imaging, to investigate the relationship between salient white matter alterations and cognition in a population-based dataset.

Methods

MRI data of 921 participants from the Hamburg City Health Study at increased risk for cerebrovascular diseases were analysed. We quantified FBA metrics capturing structural alterations of the cerebral white matter: fibre density (FD), fibre-bundle cross-section (FC) and fibre-density and cross-section (FDC) and white matter hyperintensities (WMH) as an imaging hallmark of CSVD. General linear models were applied comparing FBA metrics between the highest (WMH-Q4) and the lowest (WMH-Q1) WMH load (WMH volume/intracranial volume) quartile. Additionally, we investigated the association of processing speed operationalized by the trail making test (TMT) and fixel metrics.

Results

Overall extent of WMH was moderate (WMHL=0.044%). Group comparison showed significantly (FWE-corrected p-value<0.05) lower FD and FDC in fixels corresponding with the corpus callosum and bilateral superior longitudinal fasciculi (SLF) in WMH-Q4 (Figure 1a,c). WMH-Q4 showed lower FC in both corticospinal tracts and SLF (Figure 1b). FD was negatively correlated with performance in the TMT involving sections of the SLF (Figure 1d).

Conclusions

Findings from FBA indicate altered axonal microstructure and tract macrostructure of the corpus callosum, SLF and CST in individuals with minor burden of CSVD. Predominant involvement of long-range white matter tracts supports the notion of CSVD as a whole-brain disease.

Trial Registration Number

Not applicable

Background And Aims

Small vessel disease (SVD) lesions are thought mainly not to cause focal symptoms. SVD lesions worsen over time leading to cognitive and functional dependence. We aimed to determine whether recurrent ‘incident’ infarcts and progression of white matter hyperintensities (WMH) are actually ‘silent’.

Methods

We prospectively recruited patients with non-disabling ischaemic stroke, performed diagnostic MRI, and questioned participants and informants about symptoms. We repeated MRI and subjective symptom assessments at 3-6 monthly intervals for 12 months, assessing all incident infarcts and WMH change on DWI/FLAIR. We used linear mixed-effects models, for gait symptoms adjusting for age, gait speed, mRS, and time; for cognitive symptoms - age, anxiety, MoCA, stroke subtype, and time.

Results

We recruited 179 participants (mean 67 years;range 32-86;32% female); median baseline WMH volumes=8.1mL (IQR 3.7-18.6). Incident infarcts were common (32/179 [18%] participants; total 46 infarcts; 36/46 subcortical) at median 2 [IQR 2-8] months post-stroke, with no active embolic sources. Most (20/32) had non-focal symptoms, 4/32 attended stroke services, 8/32 were truly asymptomatic. Incident infarcts were associated with subjective unsteadiness (OR=3.9 [95%CI 1.3-11.9]), falls (trend; OR=2.23 [0.68-7.33]), ’brain fog’ (OR=2.17 [1.04-4.49]), confusion (OR=8.09 [1.65-39.75]), and informant-reported cognitive/functional decline (IQCODE) (β=0.43, p=0.019), but not dizziness, or memory concerns, adjusted. WMH progression was associated with falls (OR=1.85 [1.14–3.00]), ‘brain fog’ (OR=2.04 [1.37–3.03]), and unsteadiness (trend), but not dizziness, memory concerns, or confusion.

Conclusions

In SVD following minor stroke, incident infarcts occur in almost 20% of patients, are mostly subcortical, and co-associate with non-focal symptoms. Non-focal symptoms may herald SVD progression.

Trial Registration Number

ISRCTN12113543