The term cerebral small vessel disease (SVD) describes a range of neuroimaging, pathological, and associated clinical features. Clinical features range from none, to discrete focal neurological symptoms (eg, stroke), to insidious global neurological dysfunction and dementia. The burden on public health is substantial. The pathogenesis of SVD is largely unknown. Although the pathological processes leading to the arteriolar disease are associated with vascular risk factors and are believed to result from an intrinsic cerebral arteriolar occlusive disease, little is known about how these processes result in brain disease, how SVD lesions contribute to neurological or cognitive symptoms, and the association with risk factors. Pathology often shows end-stage disease, which makes identification of the earliest stages difficult. Neuroimaging provides considerable insights; although the small vessels are not easily seen themselves, the effects of their malfunction on the brain can be tracked with detailed brain imaging. We discuss potential mechanisms, detectable with neuroimaging, that might better fit the available evidence and provide testable hypotheses for future study.

/pdf/mechanisms-of-sporadic-cerebral-small-vessel-disease-24mg5j0ptv.pdf

Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging

American Heart Association Council on cardiovascular nursing.

Importance Covert vascular brain injury (VBI) is highly prevalent in community-dwelling older persons, but its clinical and therapeutic implications are debated. Objective To better understand the clinical significance of VBI to optimize prevention strategies for the most common age-related neurological diseases, stroke and dementia. Data Source We searched for articles in PubMed between 1966 and December 22, 2017, studying the association of 4 magnetic resonance imaging (MRI) markers of covert VBI (white matter hyperintensities [WMHs] of presumed vascular origin, MRI-defined covert brain infarcts [BIs], cerebral microbleeds [CMBs], and perivascular spaces [PVSs]) with incident stroke, dementia, or death. Study Selection Data were taken from prospective, longitudinal cohort studies including 50 or more adults. Data Extraction and Synthesis We performed inverse variance–weighted meta-analyses with random effects andzscore–based meta-analyses for WMH burden. The significance threshold wasP  Main Outcomes and Measures Stroke (hemorrhagic and ischemic), dementia (all and Alzheimer disease), and death. Results Of 2846 articles identified, 94 studies were eligible, with up to 14 529 participants for WMH, 16 012 participants for BI, 15 693 participants for CMB, and 4587 participants for PVS. Extensive WMH burden was associated with higher risk of incident stroke (hazard ratio [HR], 2.45; 95% CI, 1.93-3.12;P  Conclusions and Relevance We report evidence that MRI markers of VBI have major clinical significance. This research prompts careful evaluation of the benefit–risk ratio for available prevention strategies in individuals with covert VBI.

/pdf/clinical-significance-of-magnetic-resonance-imaging-markers-3r5wegohil.pdf

Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury: A Systematic Review and Meta-analysis.

Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations.

/pdf/diabetic-microvascular-disease-an-endocrine-society-15g2pqnt39.pdf

Diabetic Microvascular Disease: An Endocrine Society Scientific Statement.

Hypertension is a highly prevalent condition which has been established as a risk factor for cardiovascular and cerebrovascular disease. Although the understanding of the relationship between cardiocirculatory dysfunction and brain health has improved significantly over the last several decades, it is still unclear whether hypertension constitutes a potentially treatable risk factor for cognitive decline and dementia. While it is clear that hypertension can affect brain structure and function, recent findings suggest that the associations between blood pressure and brain health are complex and, in many cases, dependent on factors such as age, hypertension chronicity, and antihypertensive medication use. Whereas large epidemiological studies have demonstrated a consistent association between high midlife BP and late-life cognitive decline and incident dementia, associations between late-life blood pressure and cognition have been less consistent. Recent evidence suggests that hypertension may promote alterations in brain structure and function through a process of cerebral vessel remodeling, which can lead to disruptions in cerebral autoregulation, reductions in cerebral perfusion, and limit the brain’s ability to clear potentially harmful proteins such as β-amyloid. The purpose of the current review is to synthesize recent findings from epidemiological, neuroimaging, physiological, genetic, and translational research to provide an overview of what is currently known about the association between blood pressure and cognitive function across the lifespan. In doing so, the current review also discusses the results of recent randomized controlled trials of antihypertensive therapy to reduce cognitive decline, highlights several methodological limitations, and provides recommendations for future clinical trial design.

Defining the Relationship Between Hypertension, Cognitive Decline, and Dementia: a Review.

Objective: Lacunar infarctions are mainly due to 2 microvascular pathologies: lipohyalinosis and microatheroma. Little is known about risk factor differences for these subtypes. We hypothesized that diabetes and glycated hemoglobin (HbA1c) would be related preferentially to the lipohyalinotic subtype. Methods: We performed a cross-section analysis of the brain MRI data from 1,827 participants in the Atherosclerosis Risk in Communities study. We divided subcortical lesions 20 mm in diameter into those 7 mm (of probable lipohyalinotic etiology) and 8–20 mm (probably due to microatheroma) and used Poisson regression to investigate associations with the number of each type of lesion. Unlike previous studies, we also fitted a model involving lesions 3 mm. Results: Age (prevalence ratio [PR] 1.11 per year; 95% confidence interval [CI] 1.08–1.14), black ethnicity (vs white, PR 1.66; 95% CI 1.27–2.16), hypertension (PR 2.12; 95% CI 1.61–2.79), diabetes (PR 1.42; 95% CI 1.08–1.87), and ever-smoking (PR 1.34; 95% CI 1.04–1.74) were significantly associated with lesions 7 mm. Findings were similar for lesions 3 mm. HbA1c, substituted for diabetes, was also associated with smaller lesions. Significantly associated with 8–20 mm lesions were age (PR 1.14; 95% CI 1.09–1.20), hypertension (PR 1.79; 95% CI 1.14– 2.83), ever-smoking (PR 2.66; 95% CI 1.63–4.34), and low-density lipoprotein (LDL) cholesterol (PR 1.27 per SD; 95% CI 1.06–1.52). When we analyzed only participants with lesions, history of smoking (PR 1.99; 95% CI 1.23–3.20) and LDL (PR 1.33 per SD; 95% CI 1.08–1.65) were associated with lesions 8–20 mm. Conclusions: Smaller lacunes (even those 3 mm) were associated with diabetes and HbA1c, and larger lacunes associated with LDL cholesterol, differences which support long-held theories relating to their underlying pathology. The findings may contribute to broader understanding of cerebral microvascular disease. Neurology ® 2012;78:102–108

/pdf/risk-factors-for-lacune-subtypes-in-the-atherosclerosis-risk-2iekz8345r.pdf

Risk factors for lacune subtypes in the Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— The term metabolic syndrome describes the clustering of risk factors found in many individuals with obesity. Because of their pathophysiology, we hypothesized that 2 features of metabolic syndrome, central obesity and insulin resistance (IR), would be associated with cerebrovascular changes on magnetic resonance imaging, and specifically with incident lacunar disease and not white matter hyperintensity (WMH) progression.

Methods— Risk factors were defined at study baseline in 934 participants in the Atherosclerosis Risk in Communities (ARIC) study, who completed 2 brain magnetic resonance imagings ≈10 years apart. WMH progression and incident lacunes between the 2 magnetic resonance imagings were determined. An IR score for each participant was created using principal component analysis of 11 risk factors, including (among others): insulin, homeostatic model assessment-IR, body mass index, and waist circumference. Metabolic syndrome (presence/absence), using standard clinical definitions, and IR score at the first magnetic resonance imaging, were independent variables, evaluated in multivariate logistic regression to determine odds of WMH progression (Q5 versus Q1–Q4) and incident lacunes.

Results— Metabolic syndrome (adjusted odds ratio, 1.98; 95% confidence interval, 1.28–3.05) and IR score (adjusted odds ratio per 1-SD increase, 1.33; 95% confidence interval, 1.05–1.68) were associated with incident lacunes but not with WMH progression. Insulin, homeostatic model assessment-IR, and body mass index were not associated with incident lacunes or WMH progression in separate models.

Conclusions— The IR score and central obesity are associated with incident lacunar disease but not WMH progression in individuals. Central obesity and IR may be important risk factors to target to prevent lacunar disease.

Obesity, Insulin Resistance, and Incident Small Vessel Disease on Magnetic Resonance Imaging: Atherosclerosis Risk in Communities Study.

BACKGROUND Although cerebral lesions 3 mm or larger on imaging are associated with incident stroke, lesions smaller than 3 mm are typically ignored. OBJECTIVE To examine stroke risks associated with subclinical brain lesions (<3 mm only, ≥3 mm only, and both sizes) and white matter hyperintensities (WMHs). DESIGN Community cohort from the ARIC (Atherosclerosis Risk in Communities) Study. SETTING Two ARIC sites with magnetic resonance imaging (MRI) data from 1993 to 1995. PARTICIPANTS 1884 adults aged 50 to 73 years with MRI, no prior stroke, and average follow-up of 14.5 years. MEASUREMENTS Lesions on MRI (by size), WMH score (scale of 0 to 9), incident stroke, all-cause mortality, and stroke-related mortality. Hazard ratios (HRs) were estimated with proportional hazards models. RESULTS Compared with no lesions, stroke risk tripled with lesions smaller than 3 mm only (HR, 3.47 [95% CI, 1.86 to 6.49]), doubled with lesions 3 mm or larger only (HR, 1.94 [CI, 1.22 to 3.07]), was 8-fold higher with lesions of both sizes (HR, 8.59 [CI, 4.69 to 15.73]), and doubled with a WMH score of at least 3 (HR, 2.14 [CI, 1.45 to 3.16]). Risk for stroke-related death tripled with lesions smaller than 3 mm only (HR, 3.05 [CI, 1.04 to 8.94]) and was 7 times higher with lesions of both sizes (HR, 6.97 [CI, 2.03 to 23.93]). LIMITATION Few strokes (especially hemorrhagic) and few participants with lesions smaller than 3 mm only or lesions of both sizes. CONCLUSION Very small cerebrovascular lesions may be associated with increased risks for stroke and death; presence of lesions smaller than 3 mm and 3 mm or larger may result in a particularly striking risk increase. Larger studies are needed to confirm findings and provide more precise estimates. PRIMARY FUNDING SOURCE National Heart, Lung, and Blood Institute.

Small Brain Lesions and Incident Stroke and Mortality: A Cohort Study

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Risk factors for lacune subtypes in the Atherosclerosis Risk in Communities (ARIC) Study

Obesity, Insulin Resistance, and Incident Small Vessel Disease on Magnetic Resonance Imaging: Atherosclerosis Risk in Communities Study.

Small Brain Lesions and Incident Stroke and Mortality: A Cohort Study