Impact Of Small Vessel Disease Research Articles

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.

The Contribution of Small Vessel Disease to Neurodegeneration: Focus on Alzheimer's Disease, Parkinson's Disease and Multiple Sclerosis.

Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology of central nervous system (CNS) neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD), and neuroinflammatory diseases, such as multiple sclerosis (MS). These disorders share different pathophysiological pathways and molecular mechanisms (i.e., protein misfolding, derangement of cellular clearance systems, mitochondrial impairment and immune system activation) having neurodegeneration as biological outcome. In these diseases, the actual contribution of SVD to the clinical picture, and its impact on response to pharmacological treatments, is not known yet. Due to the high frequency of SVD in adult-aged patients, it is important to address this issue. In this review, we report preclinical and clinical data on the impact of SVD in AD, PD and MS, with the main aim of clarifying the predictability of SVD on clinical manifestations and treatment response.

November 2020 Stroke Highlights.

November 2020 Stroke Highlights.

Abstract 140: Vascular Structure in Brain: Lack of Small Vessel Recovery Following Hypertension

Vascular remodeling is a feature of small vessel disease (SVD), predictive of vascular events, brain injury, and cognitive decline. Hypertension alters vascular structure including diameter and cross-sectional area (CSA) of the vessel wall. While effects of hypertension on large arteries have been studied relatively widely, detailed quantification, including recovery from hypertension in microvessels, is rare. Previously, angiotensin II (Ang II)-dependent hypertension produced increased CSA but reduced internal diameter (ID) of cerebral arterioles (inward remodeling) in brain. Because cerebral arterioles are targets of SVD, we examined the hypothesis that brain microvessels can recover from hypertension after return of mean arterial pressure (MAP) to normal levels. MAP was measured using radiotelemetry in adult male C57BL6J mice at baseline, during infusion of vehicle or Ang II (1.4 mg/kg per day using osmotic mini-pumps) for 28 days, and during a 28 day recovery period (n=5 in each group). Prior to treatment, MAP was similar in both groups, with MAP remaining stable in vehicle treated mice. With Ang II treatment, MAP began to rise on day 3, steadily increasing until day 28. On day 30, MAP began to decrease, reaching levels seen with vehicle on days 46-47. In anesthetized mice, we measured pressure, diameter, and CSA of the vessel wall in maximally dilated arterioles (baseline diameter of 62±3 microns) at 1, 3, 7, 14, 28, and 56 days after pump implantation (n=7-9 in each group). At day 1, ID and CSA were similar in both groups. With vehicle, there was no significant change in CSA or ID at any time point. With Ang II, CSA increased at day 7 and was maintained at days 14 and 28 (P=0.023). ID did not change at day 3 or 7, but was reduced (by ~15%, P=0.011) at 14 and 28 days. During recovery (day 56), CSA returned 63% of the way to normal (compared to vehicle), while ID remained at day 14 and 28 values. In conclusion, CSA changed rapidly during hypertension onset and largely recovered with a reduction in MAP. Inward remodeling developed slowly and did not recover after return of MAP to control levels. The lack of recovery after hypertension has implications for the impact of SVD including hypoperfusion, impaired vasodilation, and augmented injury during ischemia.

Small vessel disease is associated with an unfavourable outcome in stroke patients on oral anticoagulation.

Cerebral small vessel disease is an important cause for both ischaemic stroke and intracranial haemorrhage. To date, knowledge on the impact of small vessel disease on the clinical course in stroke patients treated with oral anticoagulation for atrial fibrillation is limited. Registry-based prospective observational study of 320 patients (aged 78.2 ± 9.2 years) treated with anticoagulation following atrial fibrillation stroke. Patients underwent standardised magnetic-resonance-imaging assessing measures of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Median follow-up was 754 (interquartile range = [708-828]) days. Using adjusted logistic and Cox regression, we assessed the association of imaging measures with clinical outcome including recurrent ischaemic stroke, intracranial haemorrhage and death and assessed disability (modified Rankin Scale). Overall, recurrent ischaemic stroke was more common than intracranial haemorrhage (22 versus 8, respectively). Cerebral microbleeds were related to an increased risk of the composite endpoint (ischaemic stroke, intracranial haemorrhage, death: odds ratio (OR) 2.05, 95% confidence interval (CI) 1.27-3.31; P = 0.003), as were white matter hyperintensities (OR 2.00, 95%CI 1.23-3.27, P = 0.005). This was also true in time-to-event analysis (cerebral microbleeds: HR 2.31, 95%CI 1.39-3.52; P < 0.001; white matter hyperintensities: HR 1.99, 95%CI 1.20-3.17; P = 0.007). Both measures were associated with an increased risk for recurrent ischaemic stroke (cerebral microbleeds: HR 4.42, 95%CI 1.07-18.20; P = 0.04; white matter hyperintensities: HR 5.27, 95%CI 1.08-25.79, P = 0.04) and intracranial haemorrhage (cerebral microbleeds: HR 2.43, 95%CI 1.04-5.69; P = 0.04; white matter hyperintensities: HR 2.57, 95%CI 1.11-5.98, P = 0.03). Furthermore, confluent white matter hyperintensities were associated with increased disability (OR 4.03; 95%CI 2.16-7.52; P < 0.001) and mortality (HR 1.81, 95%CI 1.04-3.14, P = 0.04). In atrial fibrillation stroke patients treated with oral anticoagulation, small vessel disease is associated with an unfavourable outcome. The presence of microbleeds indicated a risk higher for recurrent ischaemic stroke than for intracranial haemorrhage.

Contributions of Aging to Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) is characterized by changes in the pial and parenchymal microcirculations. SVD produces reductions in cerebral blood flow and impaired blood-brain barrier function, which are leading contributors to age-related reductions in brain health. End-organ effects are diverse, resulting in both cognitive and noncognitive deficits. Underlying phenotypes and mechanisms are multifactorial, with no specific treatments at this time. Despite consequences that are already considerable, the impact of SVD is predicted to increase substantially with the growing aging population. In the face of this health challenge, the basic biology, pathogenesis, and determinants of SVD are poorly defined. This review summarizes recent progress and concepts in this area, highlighting key findings and some major unanswered questions. We focus on phenotypes and mechanisms that underlie microvascular aging, the greatest risk factor for cerebrovascular disease and its subsequent effects.

Abstract P3004: Brain Microvascular Structure During Hypertension: Temporal Changes and Recovery Support Distinct Arteriolar Mechanisms

Hypertension alters vascular structure including diameter, cross-sectional area (CSA), and stiffness of the vessel wall. Inward remodeling is a feature of small vessel disease (SVD), predictive of vascular events and cognitive decline. While effects of prevention of hypertension on large arteries have been studied widely, quantification of temporal changes and recovery from hypertension in microvessels is rare. Previously, angiotensin II (Ang II)-dependent hypertension produced increased CSA but reduced internal diameter (ID) of maximally dilated arterioles (inward remodeling) in brain. Because cerebral arterioles are targets of SVD, we examined time course and whether microvessels recover from hypertension. Mean arterial pressure (MAP) was measured using radiotelemetry in adult male C57BL6J mice prior to, during infusion of vehicle or Ang II (1.4 mg/kg per day using osmotic mini-pumps) for 28 days, and a 28 day recovery period. Prior to treatment, MAP was similar in both groups. Throughout recording, MAP was stable in vehicle treated mice. With Ang II, MAP began to rise on day 3, steadily increasing until day 28. On day 30, MAP began to decrease, reaching levels seen with vehicle on days 46-47. In anesthetized mice, we measured pressure, diameter, and CSA of the vessel wall (histologically) in maximally dilated arterioles (baseline diameter of 63±1 microns) at 1, 3, 7, 14, 28, and 56 days after pump implantation (n=7-9 in each group). At day 1, ID and CSA were similar in both groups. With vehicle, there was no significant change in CSA or ID at any time point. With Ang II, CSA increased at day 7 and was maintained at days 14 and 28 (P=0.023). ID did not change at day 3 or 7, but was reduced (by ~15%, P=0.011) at 14 and 28 days. During recovery (day 56). CSA returned 63% of the way to normal (compared to vehicle), while ID remained at day 14 and 28 values. In conclusion, CSA changed rapidly during hypertension onset and largely recovered with a reduction in MAP. Inward remodeling developed slowly and did not return to vehicle levels with MAP. The lack of recovery of ID after a period of hypertension has implications for the impact of SVD including hypoperfusion, impaired vasodilation, and augmented injury during ischemia.

Impact of small vessel disease on severity of motor and cognitive impairment in Parkinson’s disease

BackgroundSubcortical small vessel disease and vascular risk factors are associated with motor and cognitive impairment. In this study we examined the relationship between these factors and the severity of motor impairment and dementia in pathologically-confirmed Parkinson’s disease (PD). MethodsThe extent and severity of small vessel disease (SVD) was assessed pathologically in 77 patients with PD. The severity of motor impairment was determined using a cumulative index derived from longitudinal measures of Hoehn and Yahr score. The presence of dementia was scored using the Clinical Dementia Rating. The presence or absence of vascular risk factors and stroke were also recorded. Interactions were assessed using stepwise multiple regression analyses. ResultsSignificant correlations were demonstrated between perivascular pallor in the globus pallidus interna and the Hoehn and Yahr stage and between increasing Braak PD stage, the number of vascular risk factors and dementia. Among the vascular risk factors, hypertension was the only variable to independently correlate with dementia. SVD pathology did not correlate with dementia in our cohort. ConclusionsThis study demonstrates an association between SVD and motor impairment, and between vascular risk factors, particularly hypertension, and dementia in PD and highlights the need to manage vascular co-morbidities in PD patients.

Lesion location and cognitive impact of cerebral small vessel disease.

Cerebral small vessel disease (SVD) is an important cause of cognitive impairment. Important MRI manifestations of SVD include white matter hyperintensities (WMH) and lacunes. This narrative review addresses the role of anatomical lesion location in the impact of SVD on cognition, integrating findings from early autopsy studies with emerging findings from recent studies with advanced image analysis techniques. Early autopsy and imaging studies of small case series indicate that single lacunar infarcts in, for example the thalamus, caudate nucleus or internal capsule can cause marked cognitive impairment. However, the findings of such case studies may not be generalizable. Emerging location-based image analysis approaches are now being applied to large cohorts. Recent studies show that WMH burden in strategic white matter tracts, such as the forceps minor or anterior thalamic radiation (ATR), is more relevant in explaining variance in cognitive functioning than global WMH volume. These findings suggest that the future diagnostic work-up of memory clinic patients could potentially be improved by shifting from a global assessment of WMH and lacune burden towards a quantitative assessment of lesion volumes within strategic brain regions. In this review, a summary of currently known strategic regions for SVD-related cognitive impairment is provided, highlighting recent technical developments in SVD research. The potential and challenges of location-based approaches for diagnostic purposes in clinical practice are discussed, along with their potential prognostic and therapeutic applications.

Impact of small vessel disease in the brain on gait and balance

Gait and balance impairment is highly prevalent in older people. We aimed to assess whether and how single markers of small vessel disease (SVD) or a combination thereof explain gait and balance function in the elderly. We analysed 678 community-dwelling healthy subjects from the Lothian Birth Cohort 1936 at the age of 71–74 years who had undergone comprehensive risk factor assessment, gait and balance assessment as well as brain MRI. We investigated the impact of individual SVD markers (white matter hyperintensity – WMH, microbleeds, lacunes, enlarged perivascular spaces, brain atrophy) as seen on structural brain MRI and of a global SVD score on the patients’ performance. A regression model revealed that age, sex, and hypertension significantly explained gait speed. Among SVD markers white matter hyperintensity (WMH) score or volume were additional significant and independent predictors of gait speed in the regression model. A similar association was seen with the global SVD score. Our study confirms a negative impact of SVD-related morphologic brain changes on gait speed in addition to age, sex and hypertension independent from brain atrophy. The presence of WMH seems to be the major driving force for SVD on gait impairment in healthy elderly subjects.

Impact of Strategically Located White Matter Hyperintensities on Cognition in Memory Clinic Patients with Small Vessel Disease.

Background and PurposeStudies on the impact of small vessel disease (SVD) on cognition generally focus on white matter hyperintensity (WMH) volume. The extent to which WMH location relates to cognitive performance has received less attention, but is likely to be functionally important. We examined the relation between WMH location and cognition in a memory clinic cohort of patients with sporadic SVD.MethodsA total of 167 patients with SVD were recruited from memory clinics. Assumption-free region of interest-based analyses based on major white matter tracts and voxel-wise analyses were used to determine the association between WMH location and executive functioning, visuomotor speed and memory.ResultsRegion of interest-based analyses showed that WMHs located particularly within the anterior thalamic radiation and forceps minor were inversely associated with both executive functioning and visuomotor speed, independent of total WMH volume. Memory was significantly associated with WMH volume in the forceps minor, independent of total WMH volume. An independent assumption-free voxel-wise analysis identified strategic voxels in these same tracts. Region of interest-based analyses showed that WMH volume within the anterior thalamic radiation explained 6.8% of variance in executive functioning, compared to 3.9% for total WMH volume; WMH volume within the forceps minor explained 4.6% of variance in visuomotor speed and 4.2% of variance in memory, compared to 1.8% and 1.3% respectively for total WMH volume.ConclusionsOur findings identify the anterior thalamic radiation and forceps minor as strategic white matter tracts in which WMHs are most strongly associated with cognitive impairment in memory clinic patients with SVD. WMH volumes in individual tracts explained more variance in cognition than total WMH burden, emphasizing the importance of lesion location when addressing the functional consequences of WMHs.

Abstract T MP35: Frequency, Risk Factors, and Impact of Coexistent Small Vessel Disease in the SAMMPRIS Trial

Background: Intracranial atherosclerotic stenosis (ICAS) and small vessel disease (SVD) may coexist. We investigated the frequency and risk factors for SVD in SAMMPRIS patients and the impact of SVD on stroke recurrence in the medical arm of the trial. Methods: Of 451 patients enrolled in SAMMPRIS, 313 had baseline brain MRIs read centrally for SVD. SVD was defined by any of the following: old lacunar infarction, Fazekas score of 2-3 for white matter hyperintensities, or microbleeds. We compared risk factors in patients with vs. without SVD using Fisher’s exact test (for percentages), independent groups t test (for means) or Wilcoxon rank sum test (for medians), and compared the survival curves of patients with vs. without SVD in the medical arm for ischemic stroke in the territory of the stenotic artery and any ischemic stroke using the logrank test. Results: Of the 313 patients, 161 (51.4%) had SVD on the baseline MRI. Variables that were significantly (p&lt;0.05) higher in patients with SVD were age, diabetes, lipid disorder, baseline SBP, coronary disease, and old infarct in the territory. The Kaplan-Meier curves in the figure show that patients with SVD were at significantly higher risk of any ischemic stroke (p = 0.048) but not stroke in the territory (p = 0.10) compared with patients without SVD. Conclusion: SVD in patients with ICAS is common, especially in patients who are older, diabetic, hyperlipidemic, and have higher SBP. Patients with ICAS and coexistent SVD are at higher risk of any ischemic stroke but may not be at higher risk for stroke in the territory.

Association between carotid stenosis or lacunar infarction and incident dementia in patients with vascular risk factors.

The association between vascular risk factors and dementia is of interest. Several studies have shown that cerebral small vessel disease (SVD) is associated with dementia. However, the association between cerebral large vessel disease (LVD) and dementia has not been thoroughly examined. The Osaka Follow-up Study for Carotid Atherosclerosis, Part 2, was a prospective cohort study of cardiovascular events and dementia in which patients (n = 1106) with vascular risk factors underwent carotid ultrasound. Of these patients, 600 who had normal cognitive function were included and underwent brain magnetic resonance imaging. The presence of lacunar infarction and carotid stenosis served as markers for SVD and LVD, respectively. Amongst 600 patients (mean 68 years, 57% men), 261 (44%) showed lacunar infarction and 94 (16%) showed carotid stenosis. During the follow-up period (median 8.0 years), 57 patients had incident dementia. Patients with carotid stenosis and lacunar infarction were significantly more likely to be diagnosed with dementia (log-rank test, P = 0.037 and P < 0.001, respectively). The association between lacunar infarction and dementia remained significant after adjusting for risk factors including stroke history, apolipoprotein E genotype and years of education (hazard ratio 2.64, 95% confidence interval 1.22-6.09). However, the presence of carotid stenosis was not associated with incident dementia after adjusting for age and sex (P = 0.477). This study demonstrated that carotid stenosis had little association with dementia, but lacunar infarction had a significant association. The impact of SVD on dementia could be much greater than that of LVD.

Abstract T MP115: Association Between Cerebral Large/Small Vessel Disease and Incident Dementia in Patients with Vascular Risk Factors - Sub-analysis of OSACA2 follow-up study

Background and Purpose: Involvement of vascular risk factors on dementia has attracted much attention. Several prospective studies have shown that the presence of cerebral small vessel disease (SVD) is associated with incident dementia. However, the significance of cerebral large vessel disease (LVD) on dementia development has not been examined thoroughly. Methods: OSACA2 is a prospective cohort study for cardiovascular events and dementia in which patients with vascular risk factors undergo carotid ultrasound and blood sampling. Between 2001 and 2009, 1106 outpatients were enrolled. Among them, 600 patients who underwent brain MRI and had normal cognitive function were included in this study. Follow-up data for dementia occurrence were collected in June 2011. Baseline MRI was used to determine lacunar infarction as a sign of SVD. The presence of carotid stenosis as a sign of cerebral LVD was defined with 50% or more stenosis in carotid ultrasound. Results: Among 600 subjects (mean: 68 years, male: 57%), 264 patients (44%) had lacunar infarction, and 94 patients (16%) showed carotid stenosis. During the follow-up period of median 7.5 years, 50 patients had incident dementia (24 AD, 18 vascular dementia, 5 mixed type, 3 others). The presence of lacunar infarction had close association with dementia in Kaplan-Meier plots analysis ( p &lt;0.001). The association remained significant after adjustment with modifiable factors including history of stroke, APOE genotype and education year (HR:2.20, 95% CI [1.11-4.53]). However, the presence of carotid stenosis was not associated with incident dementia ( p value=0.07). Conclusion: This study suggested that carotid stenosis have little association with future dementia while lacunar infarction had significant association. The impact of SVD on dementia could be much greater than that of cerebral LVD.

Neuropathology of Vascular Cognitive Impairment and Vascular Dementia

Understanding of vascular substrates of cognitive decline in the elderly is evolving to include a major emphasis on the impact of small vessel disease (SVD). While existing concepts of multi-infarct dementia and strategic infarct dementia remain valid, they present difficulty in generalizing clinicopathological correlations from patient to patient. The range and significance of lesions that should be included as manifestations of SVD are unresolved, as is their impact on, and association with, neurodegenerative changes. This mini-review summarizes the authors' views on SVD substrates leading to cognitive decline and proposes priorities for pathological investigations of human cerebrovascular mechanisms leading to cognitive decline.

Multiarterial coronary artery bypass grafting with special reference to small vessel disease and results in women

From 1985 to 1991 a total of 220 patients underwent coronary artery bypass grafting (CABG) with at least two native pedicled artery grafts. Bilateral internal mammary artery (IMA) grafting was performed in 201 patients, IMA combined with gastro-epiploic artery (GEA) grafting in five, and double IMA plus GEA grafting in 14; in addition 156 patients received 1-3 vein grafts. The primary indication for elective multi-arterial CABG was coronary arteries of small calibre (small vessel disease) in 77 patients, repeat CABG in 17 (without small vessel disease), varicose/stripped saphenous veins in 57 (without small vessel disease), while the remaining 69 were routine cases; the distribution differed between women (42, 0, 47, and 11%, respectively) and men (33, 10, 19, and 38%, respectively; P < 0.0001). The women also were older (62 +/- 7 vs 56 +/- 9 years; P < 0.001), and had higher prevalences of systemic hypertension, diabetes mellitus, and hypercholesterolaemia. The number of artery grafts and total number of grafts were, however, similar for women and men. Early mortality (< or = 30 days) was 5.6% in women and 2.4% in men (ns). Early mortalities in relation to primary indications were: 7.8% for small vessel disease, 5.9% for repeat CABG, and 0% for both varicose/stripped saphenous veins and routine cases (P < 0.05). Logistic regression analysis identified small vessel disease, insufficient grafting, age of > = 60 years, a history of smoking, a family history of ischaemic heart disease, and female gender as independent risk factors for early mortality.(ABSTRACT TRUNCATED AT 250 WORDS)