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      Association of Cardiovascular Risk Factors With MRI Indices of Cerebrovascular Structure and Function and White Matter Hyperintensities in Young Adults

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          Abstract

          <div class="section"> <a class="named-anchor" id="ab-jpc180006-1"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e548">Question</h5> <p id="d2064132e550">Are modifiable cardiovascular risk factors in young adults associated with cerebral blood vessel structure and function and neuroimaging white matter hyperintensities? </p> </div><div class="section"> <a class="named-anchor" id="ab-jpc180006-2"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e553">Results</h5> <p id="d2064132e555">In this cross-sectional study of 125 young adults without clinical evidence of cerebrovascular disease, a higher number of optimal cardiovascular health metrics was correlated with higher cerebral vessel density, higher cerebral blood flow, and lower number of white matter hyperintensity lesions. </p> </div><div class="section"> <a class="named-anchor" id="ab-jpc180006-3"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e558">Meaning</h5> <p id="d2064132e560">These preliminary findings suggest a relationship between modifiable cardiovascular risk factors and biomarkers of cerebrovascular structure and function and white matter hyperintensities in young adults. Further research is needed to verify these findings and determine clinical importance. </p> </div><div class="section"> <a class="named-anchor" id="ab-jpc180006-4"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e564">Importance</h5> <p id="d2064132e566">Risk of stroke and brain atrophy in later life relate to levels of cardiovascular risk in early adulthood. However, it is unknown whether cerebrovascular changes are present in young adults. </p> </div><div class="section"> <a class="named-anchor" id="ab-jpc180006-5"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e569">Objective</h5> <p id="d2064132e571">To examine relationships between modifiable cardiovascular risk factors and cerebrovascular structure, function, and white matter integrity in young adults. </p> </div><div class="section"> <a class="named-anchor" id="ab-jpc180006-6"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e574">Design, Setting, and Participants</h5> <p id="d2064132e576">A cross-sectional observational study of 125 young adults (aged 18-40 years) without clinical evidence of cerebrovascular disease. Data collection was completed between August 2014 and May 2016 at the University of Oxford, United Kingdom. Final data collection was completed on May 31, 2016. </p> </div><div class="section"> <a class="named-anchor" id="ab-jpc180006-7"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e579">Exposures</h5> <p id="d2064132e581">The number of modifiable cardiovascular risk factors at recommended levels, based on the following criteria: body mass index (BMI) &lt;25; highest tertile of cardiovascular fitness and/or physical activity; alcohol consumption &lt;8 drinks/week; nonsmoker for &gt;6 months; blood pressure on awake ambulatory monitoring &lt;130/80 mm Hg; a nonhypertensive diastolic response to exercise (peak diastolic blood pressure &lt;90 mm Hg); total cholesterol &lt;200 mg/dL; and fasting glucose &lt;100mg/dL. Each risk factor at the recommended level was assigned a value of 1, and participants were categorized from 0-8, according to the number of risk factors at recommended levels, with higher numbers indicating healthier risk categories. </p> </div><div class="section"> <a class="named-anchor" id="ab-jpc180006-8"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e584">Main Outcomes and Measures</h5> <p id="d2064132e586">Cerebral vessel density, caliber and tortuosity, brain white matter hyperintensity lesion count. In a subgroup (n = 52), brain blood arrival time and cerebral blood flow assessed by brain magnetic resonance imaging (MRI). </p> </div><div class="section"> <a class="named-anchor" id="ab-jpc180006-9"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e589">Results</h5> <p id="d2064132e591">A total of 125 participants, mean (SD) age 25 (5) years, 49% women, with a mean (SD) score of 6.0 (1.4) modifiable cardiovascular risk factors at recommended levels, completed the cardiovascular risk assessment and brain MRI protocol. Cardiovascular risk factors were correlated with cerebrovascular morphology and white matter hyperintensity count in multivariable models. For each additional modifiable risk factor categorized as healthy, vessel density was greater by 0.3 vessels/cm <sup>3</sup> (95% CI, 0.1-0.5; <i>P</i> = .003), vessel caliber was greater by 8 μm (95% CI, 3-13; <i>P</i> = .01), and white matter hyperintensity lesions were fewer by 1.6 lesions (95% CI, −3.0 to −0.5; <i>P</i> = .006). Among the 52 participants with available data, cerebral blood flow varied with vessel density and was 2.5 mL/100 g/min higher for each healthier category of a modifiable risk factor (95% CI, 0.16-4.89; <i>P</i> = .03). </p> </div><div class="section"> <a class="named-anchor" id="ab-jpc180006-10"> <!-- named anchor --> </a> <h5 class="section-title" id="d2064132e609">Conclusions and Relevance</h5> <p id="d2064132e611">In this preliminary study involving young adults without clinical evidence of cerebrovascular disease, a greater number of modifiable cardiovascular risk factors at recommended levels was associated with higher cerebral vessel density and caliber, higher cerebral blood flow, and fewer white matter hyperintensities. Further research is needed to verify these findings and determine their clinical importance. </p> </div><p class="first" id="d2064132e614">This cross-sectional study examines associations between modifiable cardiovascular risk factors—such as BMI, cholesterol and glucose levels, smoking, and alcohol use—and MRI measures of cerebrovascular structure, function, and white matter integrity in adults aged 18 to 40. </p>

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          Most cited references24

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          Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study.

          Cerebral white matter lesions and lacunar infarcts are small vessel disease-related lesions, which are associated with cognitive decline and dementia. We aimed to assess the relationship between risk factors, effect modifiers, and progression of these lesions. Furthermore, we studied the cognitive consequences of lesion progression. Six hundred sixty-eight people, aged 60 to 90 years, underwent repeated MRI scanning and neuropsychological testing within 3-year follow-up. We rated incident lacunar infarcts and change in periventricular and subcortical white matter lesion severity with a semiquantitative scale. We assessed the relationships between age, sex, baseline lesion load, risk factors, lesion progression, and change in cognitive function by multivariate regression analyses and additional stratified analyses. Baseline lesion load, higher age, high blood pressure, and current smoking were independently associated with progression of white matter lesions. Women had more marked progression of subcortical white matter lesions and incident lacunar infarcts compared with men. Carotid atherosclerosis was associated with incident lacunar infarcts. Higher blood pressure did not contribute to lesion progression in people with already severe lesions at baseline nor in the very old. Lesion progression was associated with a paralleled decline in general cognitive function and in particular with a decreased information processing speed. Higher age, female sex, cigarette smoking, elevated blood pressure, and baseline lesion load were associated with small vessel disease progression. Age and baseline lesion load influenced the risk relations with blood pressure. Progression of small vessel disease was related to a paralleled decline in cognitive function.
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            Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.

            Based on observational and interventional data for middle-aged cohorts (aged 40-64 years), serum cholesterol level is known to be an established major risk factor for coronary heart disease (CHD). However, findings for younger people are limited, and the value of detecting and treating hypercholesterolemia in younger adults is debated. To evaluate the long-term impact of unfavorable serum cholesterol levels on risk of death from CHD, cardiovascular disease (CVD), and all causes. Three prospective studies, from which were selected 3 cohorts of younger men with baseline serum cholesterol level measurements and no history of diabetes mellitus or myocardial infarction. A total of 11,017 men aged 18 through 39 years screened in 1967-1973 for the Chicago Heart Association Detection Project in Industry (CHA); 1266 men aged 25 through 39 years examined in 1959-1963 in the Peoples Gas Company Study (PG); and 69,205 men aged 35 through 39 years screened in 1973-1975 for the Multiple Risk Factor Intervention Trial (MRFIT). Cause-specific mortality during 25 (CHA), 34 (PG), and 16 (MRFIT) years of follow-up; mortality risks; and estimated life expectancy in relation to baseline serum cholesterol levels. Death due to CHD accounted for 26%, 34%, and 28% of all deaths in the CHA, PG, and MRFIT cohorts, respectively; and CVD death for 34%, 42%, and 39% of deaths in the same cohorts, respectively. Men in all 3 cohorts with unfavorable serum cholesterol levels (200-239 mg/dL [5.17-6.18 mmol/L] and >/=240 mg/dL [>/=6.21 mmol/L]) had strong gradients of relative mortality risk. For men with serum cholesterol levels of 240 mg/dL or greater (>/=6.21 mmol/L) vs favorable levels (<200 mg/dL [<5.17 mmol/L]), CHD mortality risk was 2.15 to 3.63 times greater; CVD disease mortality risk was 2.10 to 2.87 times greater; and all-cause mortality was 1.31 to 1.49 times greater. Hypercholesterolemic men had age-adjusted absolute risk of CHD death of 59 per 1000 men in 25 years (CHA cohort), 90 per 1000 men in 34 years (PG cohort), and 15 per 1000 men in 16 years (MRFIT cohort). Absolute excess risk was 43.6 per 1000 men (CHA), 81.4 per 1000 men (PG), and 12.1 per 1000 men (MRFIT). Men with favorable baseline serum cholesterol levels had an estimated greater life expectancy of 3.8 to 8.7 years. These results demonstrate a continuous, graded relationship of serum cholesterol level to long-term risk of CHD, CVD, and all-cause mortality, substantial absolute risk and absolute excess risk of CHD and CVD death for younger men with elevated serum cholesterol levels, and longer estimated life expectancy for younger men with favorable serum cholesterol levels. JAMA. 2000;284:311-318
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              Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review.

              Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. Pathologically, three lesions are seen: small vessel arteriopathy, lacunar infarction, and diffuse white matter injury (leukoaraiosis). Appropriate experimental models would aid in understanding these pathologic states and also in preclinical testing of therapies. The objective was to perform a systematic review of animal models of SVD and determine whether these resemble four key clinicopathologic features: (1) small, discrete infarcts; (2) small vessel arteriopathy; (3) diffuse white matter damage; (4) cognitive impairment. Fifteen different models were included, under four categories: (1) embolic injuries (injected blood clot, photochemical, detergent-evoked); (2) hypoperfusion/ischaemic injury (bilateral common carotid occlusion/stenosis, striatal endothelin-1 injection, striatal mitotoxin 3-NPA); (3) hypertension-based injuries (surgical narrowing of the aorta, or genetic mutations, usually in the renin-angiotensin system); (4) blood vessel damage (injected proteases, endothelium-targeting viral infection, or genetic mutations affecting vessel walls). Chronic hypertensive models resembled most key features of SVD, and shared the major risk factors of hypertension and age with human SVD. The most-used model was the stroke-prone spontaneously hypertensive rat (SHR-SP). No model described all features of the human disease. The optimal choice of model depends on the aspect of pathophysiology being studied.
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                Author and article information

                Journal
                JAMA
                JAMA
                American Medical Association (AMA)
                0098-7484
                August 21 2018
                August 21 2018
                : 320
                : 7
                : 665
                Affiliations
                [1 ]Oxford Cardiovascular Clinical Research Facility, University of Oxford, Oxford, United Kingdom
                [2 ]Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
                [3 ]Department of Radiology and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
                [4 ]Wellcome Centre for Integrative Neuroimaging, FMRIB Division, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
                [5 ]Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
                [6 ]Department of Radiology, Stoke Mandeville Hospital, Buckinghamshire NHS Trust, Buckinghamshire, England, United Kingdom
                [7 ]Nuffield Department of Population Health, BHF Centre of Research Excellence and Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom
                [8 ]Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, Oxford, United Kingdom
                [9 ]Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
                [10 ]School of Biomedical Engineering and Imaging Sciences, King's College London, United Kingdom
                [11 ]Department of Family Care and Mental Health, University of Greenwich, London, United Kingdom
                [12 ]School of Policy Studies, University of Bristol, Bristol, United Kingdom
                Article
                10.1001/jama.2018.11498
                6142949
                30140877
                e4961a5b-2a7b-4d8f-91fe-b874b9395d7b
                © 2018
                History

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