Advanced MRI in cerebral small vessel disease

Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia. This review summarizes recent developments in advanced neuroimaging of cSVD with a focus on clinical and research applications. In the first section, we highlight how advanced structural imaging techniques, including diffusion magnetic resonance imaging (MRI), enable improved detection of tissue damage, including characterization of tissue appearing normal on conventional MRI. These techniques enable progression to be monitored and may be useful as surrogate endpoint in clinical trials. Quantitative MRI, including iron and myelin imaging, provides insights into tissue composition on the molecular level. In the second section, we cover how advanced MRI techniques can demonstrate functional or dynamic abnormalities of the blood vessels, which could be targeted in mechanistic research and early-stage intervention trials. Such techniques include the use of dynamic contrast enhanced MRI to measure blood–brain barrier permeability, and MRI methods to assess cerebrovascular reactivity. In the third section, we discuss how the increased spatial resolution provided by ultrahigh field MRI at 7 T allows imaging of perforating arteries, and flow velocity and pulsatility within them. The advanced MRI techniques we describe are providing novel pathophysiological insights in cSVD and allow improved quantification of disease burden and progression. They have application in clinical trials, both in assessing novel therapeutic mechanisms, and as a sensitive endpoint to assess efficacy of interventions on parenchymal tissue damage. We also discuss challenges of these advanced techniques and suggest future directions for research

Characteristics of patients with minor ischaemic strokes and negative MRI: a cross-sectional study

International audienceAbstract Background: Diffusion weighted (DWI) MRI is recommended in UK guidelines to evaluate minor strokes, yet can produce negative results. Objective: We determined the rate of negative MRI (including DWI) and associated features in patients presenting to hospital with minor strokes. Methods: We performed a prospective observational cross sectional study in a teaching hospital of patients with a clinical diagnosis of ischaemic lacunar or minor cortical stroke. We performed MRI (DWI, T2, FLAIR, T2* and T1) as soon as possible after presentation. We used multivariate analysis to determine predictors of negative DWI and MRI (all sequences). Gold standard for clinical diagnosis of stroke was the opinion of an expert panel. Results: We recruited 246 patients, mean age 68.1 years (SD 11.6 years), 162 were males (66%) and the median NIHSS was 2 (range 0-8). The median time from stroke onset to MR scan was 12 days (IQR 4-27 days). Eighty-one patients (33%) did not show any ischaemia on DWI. Sixty patients (24%) did not show the recent infarct on MRI (DWI/T2/FLAIR). With multivariate analysis, less severe stroke, younger age, female gender and increased time from stroke onset to scan were associated with negative DWI. With multivariate analysis, younger age and female gender were associated with negative MRI (DWI or T2 or FLAIR) scans. Conclusions: There is a high rate of negative MRI and DWI amongst patients with minor stroke (a third) which has important management and research implications. A negative MRI or DWI does not exclude the diagnosis of stroke

Little Association between Intracranial Arterial Stenosis and Lacunar Stroke

Atheromatous middle cerebral artery (MCA) stenosis could cause lacunar stroke by occluding lenticulostriate artery origins, but atheroma is common, and previous studies lacked suitable controls. We aimed to determine if intracranial atheroma was more common in lacunar than in cortical ischaemic stroke. We recruited patients with lacunar stroke and controls with mild cortical stroke, confirmed the stroke subtype with magnetic resonance imaging and used transcranial Doppler ultrasound imaging to record flow velocity and focal stenoses in the basal intracranial arteries 1 month after stroke. We compared ipsi- and contralateral MCA mean flow velocities between stroke subtypes and tested for associations using linear mixed models. Amongst 67 lacunar and 67 mild cortical strokes, mean age 64 and 67 years, respectively, we found no difference in MCA mean flow velocity between cortical and lacunar patients. Increasing age and white matter lesion scores were independently associated with lower MCA flow velocities (0.2 cms−1 fall in velocity per year increase in age, p = 0.045; 3.75 cms−1 fall in flow velocity per point increase in white matter lesion score, p = 0.004). We found no intracranial arterial stenoses. MCA atheromatous stenosis is unlikely to be a common cause of lacunar stroke in white populations. Falling velocities with increasing white matter lesion scores may reflect progressive brain tissue loss leaving less tissue to supply

A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls

Background: The aetiology of cerebral small vessel disease is unknown. An association with endothelial dysfunction has been suggested. We systematically assessed all relevant studies of dynamic endothelial function in patients with lacunar stroke, as a marker of small vessel disease. Methods: We searched for studies of cerebral or peripheral vascular reactivity in patients with lacunar or cortical (i.e. large artery atheromatous) ischaemic stroke or non-stroke controls. We calculated standardised mean difference (SMD) in vascular reactivity, +/- 95% confidence intervals (CI) between small vessel disease and control groups. Results: Sixteen publications (974 patients) were included. In lacunar stroke: cerebrovascular reactivity (n=534) was reduced compared with age-matched normal (SMD -0.94, 95%CI -1.17, -0.70), but not age+risk factor-matched controls (SMD 0.08, 95%CI -0.36, 0.53) or cortical strokes (SMD -0.29, 95%CI -0.69, 0.11); forearm flow mediated dilatation (n=401) was reduced compared with age-matched normal controls (SMD -1.04, 95%CI -1.33, -0.75) and age+risk factor-matched controls (SMD -0.94, 95%CI -1.26, -0.61), but not cortical strokes (SMD -0.23, 95%CI -0.55, 0.08). Conclusions: Endothelial dysfunction is present in patients with lacunar stroke but may simply reflect exposure to vascular risk factors and having a stroke, as a similar degree of dysfunction is found in cortical (large artery atheromatous) stroke. Current data do not confirm that endothelial dysfunction is specific to small vessel stroke. Future studies should include controls with non-lacunar stroke

Neuropsychiatric symptoms as a sign of small vessel disease progression in cognitive impairment

BACKGROUND: Neuropsychiatric symptoms associate cross-sectionally with cerebral small vessel disease but it is not clear whether these symptoms could act as early clinical markers of small vessel disease progression. We investigated whether longitudinal change in Neuropsychiatric Inventory (NPI) scores associated with white matter hyperintensity (WMH) progression in a memory clinic population. MATERIAL AND METHODS: We included participants from the prospective Sunnybrook Dementia Study with Alzheimer's disease and vascular subtypes of mild cognitive impairment and dementia with two MRI and ≥ 1 NPI. We conducted linear mixed-effects analyses, adjusting for age, atrophy, vascular risk factors, cognition, function, and interscan interval. RESULTS: At baseline (n=124), greater atrophy, age, vascular risk factors and total NPI score were associated with higher baseline WMH volume, while longitudinally, all but vascular risk factors were associated. Change in total NPI score was associated with change in WMH volume, χ2 = 7.18, p = 0.007, whereby a one-point change in NPI score from baseline to follow-up was associated with a 0.0017 change in normalized WMH volume [expressed as cube root of (WMH volume cm³ as % intracranial volume)], after adjusting for age, atrophy, vascular risk factors and interscan interval. CONCLUSIONS: In memory clinic patients, WMH progression over 1–2 years associated with worsening neuropsychiatric symptoms, while WMH volume remained unchanged in those with stable NPI scores in this population with low background WMH burden

Variation in risk factors for recent small subcortical infarcts with infarct size, shape and location

BACKGROUND AND PURPOSE: Lacunar infarction is due to a perforating arteriolar abnormality. Possible causes include embolism, atheromatosis or intrinsic disease. We examined whether the size, shape or location of the lacunar infarct varied with embolic sources, systemic atheroma or vascular risk factors. METHODS: We examined data from three prospective studies of patients with clinical and diffusion-weighted imaging (DWI) positive symptomatic lacunar infarction who underwent full clinical assessment and investigation for stroke risk factors. Lacunar infarct size (maximum diameter; shape, oval/tubular; location, basal ganglia/centrum semiovale/brainstem) were coded blind to clinical details. RESULTS: Amongst 195 patients, 48 infarcts were tubular, 50 were 15-20mm diameter, 97 were in the basal ganglia and 74 in the centrum semiovale. There was no association between infarct size or shape and any risk factors. Centrum semiovale infarcts were less likely to have a potential relevant embolic source (4% v 11%, OR 0.16 95% confidence interval (CI) 0.03-0.83) and caused a lower National Institute of Health Stroke Scale (NIHSS) (2 v 3, OR 0.78 95% CI 0.62-0.98) than basal ganglia infarcts. There were no other differences by infarct location. CONCLUSIONS: Lacunar infarcts in the basal ganglia caused marginally more severe strokes and were three times as likely to have a potential embolic source than those in the centrum semiovale but the overall rate of carotid or known cardiac embolic sources (11%) was low. We found no evidence that other risk factors differed with location, size or shape suggesting that most lacunar infarcts share a common intrinsic arteriolar pathology

Potential recruitment into a clinical trial of vascular secondary prevention medications in cerebral small vessel disease, based on concomitant medication use

This research has been conducted using the UK Biobank resource. The authors are grateful to UK Biobank participants. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation.Peer reviewedPublisher PD

Sex Differences in Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis

Background: Cerebral small vessel disease (SVD) is a common cause of stroke, mild cognitive impairment, dementia and physical impairments. Differences in SVD incidence or severity between males and females are unknown. We assessed sex differences in SVD by assessing the male-to-female ratio (M:F) of recruited participants and incidence of SVD, risk factor presence, distribution, and severity of SVD features. Methods: We assessed four recent systematic reviews on SVD and performed a supplementary search of MEDLINE to identify studies reporting M:F ratio in covert, stroke, or cognitive SVD presentations (registered protocol: CRD42020193995). We meta-analyzed differences in sex ratios across time, countries, SVD severity and presentations, age and risk factors for SVD. Results: Amongst 123 relevant studies (n = 36,910 participants) including 53 community-based, 67 hospital-based and three mixed studies published between 1989 and 2020, more males were recruited in hospital-based than in community-based studies [M:F = 1.16 (0.70) vs. M:F = 0.79 (0.35), respectively; p < 0.001]. More males had moderate to severe SVD [M:F = 1.08 (0.81) vs. M:F = 0.82 (0.47) in healthy to mild SVD; p < 0.001], and stroke presentations where M:F was 1.67 (0.53). M:F did not differ for recent (2015–2020) vs. pre-2015 publications, by geographical region, or age. There were insufficient sex-stratified data to explore M:F and risk factors for SVD. Conclusions: Our results highlight differences in male-to-female ratios in SVD severity and amongst those presenting with stroke that have important clinical and translational implications. Future SVD research should report participant demographics, risk factors and outcomes separately for males and females. Systematic Review Registration: [PROSPERO], identifier [CRD42020193995]

The application of retinal fundus camera imaging in dementia:A systematic review

INTRODUCTION: The ease of imaging the retinal vasculature, and the evolving evidence suggesting this microvascular bed might reflect the cerebral microvasculature, presents an opportunity to investigate cerebrovascular disease and the contribution of microvascular disease to dementia with fundus camera imaging. METHODS: A systematic review and meta-analysis was carried out to assess the measurement of retinal properties in dementia using fundus imaging. RESULTS: Ten studies assessing retinal properties in dementia were included. Quantitative measurement revealed significant yet inconsistent pathologic changes in vessel caliber, tortuosity, and fractal dimension. Retinopathy was more prevalent in dementia. No association of age-related macular degeneration with dementia was reported. DISCUSSION: Inconsistent findings across studies provide tentative support for the application of fundus camera imaging as a means of identifying changes associated with dementia. The potential of fundus image analysis in differentiating between dementia subtypes should be investigated using larger well-characterized samples. Future work should focus on refining and standardizing methods and measurements