Subclinical Vascular Brain Injury Research Articles

Association of abnormal p-wave parameters with brain MRI morphology: The atherosclerosis risk in communities neurocognitive study (ARIC-NCS).

Recent evidence indicates that abnormal P-wave parameters (PWPs)-ECG markers of atrial myopathy-are associated with incident dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. However, the mechanisms remain unclear and may include subclinical vascular brain injury. Hence, we evaluated the association of abnormal PWPs with brain MRI correlates of vascular brain injury in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). ARIC-NCS participants who underwent 3T brain MRI scans in 2011-2013 were included. PWPs were measured from standard 12-lead ECGs. Brain MRI outcomes included cortical infarcts, lacunar infarcts, cerebral microhemorrhages, brain volumes, and white matter disease (WMD) volume. We used weighted multivariable logistic and linear regression to evaluate the associations of abnormal PWPs with brain MRI outcomes. Among 1715 participants (mean age, 76.1 years; 61% women; 29% Black), 797 (46%) had ≥1 abnormal PWP. After multivariable adjustment, including adjusting for prevalent AF, abnormal P-wave terminal force in lead V1 (aPTFV1) and prolonged P-wave duration (PPWD) were associated with increased odds of both cortical (OR 1.41; 95% CI, 1.14 to 1.74 and OR 1.30; 95% CI, 1.04 to 1.63, respectively) and lacunar infarcts (OR 1.36; 95% CI, 1.15 to 1.63 and OR 1.37; 95% CI, 1.15 to 1.65, respectively). Advanced interatrial block (aIAB) was associated with higher odds of subcortical microhemorrhage (OR 2.04; 95% CI, 1.36 to 3.06). Other than a significant association between aPTFV1 with lower parietal lobe volume, there were no other significant associations with brain or WMD volume. In this exploratory analysis of a US community-based cohort, ECG surrogates of atrial myopathy are associated with a higher prevalence of brain infarcts and microhemorrhage, suggesting subclinical vascular brain injury as a possible mechanism underlying the association of atrial myopathy with dementia.

Abstract MP62: Sex-specific Associations Of Vascular Risk Factors And Brain Mri Measures In The Framingham Offspring

Aim: To examine if the associations between vascular risk factors (VRF) and brain MRI measures of brain aging and cerebral small vessel disease are different in men and women. Background: Men and women differ in their propensity to develop stroke and this is reflected in sex-specific versions of the widely used Framingham Stroke Risk Prediction (FSRP) index, that provides an estimate of 10-year risk of incident clinical stroke. However, sex-specific associations between the individual risk factor components of FSRP and subclinical vascular brain injury have not been previously explored in our data. Methods/Design: We related levels of blood pressure, diabetes, current smoking and prevalent non-stroke cardiovascular disease (CVD) to brain MRI measures of total cerebral brain, hippocampal and white matter hyperintensity volumes (TCBV, HPV, WMHV) and covert brain infarcts (CBI) in 1,579 stroke- and dementia-free Framingham Offspring who attended their 8th quadrennial examination (53% F; age 66±9 years). We examined age-adjusted, sex-stratified linear or logistic regression analyses for all VRF that suggested a sex-interaction at a p<0.1. Results: Higher blood pressure (assessed as systolic blood pressure (SBP) or as JNC7 defined Stage 1 HTN (≥140/90 mm Hg or use of antihypertensive medication), had a greater adverse impact on WMHV in women compared to men (SBP: β±SE: 0.009±0.002, p<0.001 versus 0.004±0.002, p<0.031; HTN: β 0.176±0.066, p=0.008 versus non-significant association, in women and men respectively), although prevalent CVD, reflecting lifetime vascular risk factor exposure and injury, had a larger adverse effect on WMHV in men (β -0.221±0.087, p=0.012, versus a non-significant association in women). In addition, both Stage 1 HTN and diabetes had larger adverse effects on TCBV in men (β -0.309±0.141, p<0.029 and -0.853±0.177, p<0.001 respectively, versus non-significant associations in women). Conclusions: In our cohort of young-old participants, wherein most women were post-menopausal, current levels of VRF at the time of examination, were associated with a greater burden of vascular brain injury in women than in men of the same age, whereas current VRF levels appeared to have a greater global impact on brain volumes in men. Our data suggest that the greater risk of dementia noted in older women compared to men may be substantially attributable to modifiable vascular risk factors; more aggressively controlling these in women may reduce sex disparities.

Abstract 10763: Atrial Fibrillation and Supraventricular Ectopy in Relation to Brain Morphology and Subclinical Vascular Brain Injury: The Multi-Ethnic Study of Atherosclerosis

Introduction: Atrial fibrillation (AF) increases stroke risk and is associated with accelerated cognitive decline. Information is mixed about the relationship of AF and other supraventricular (SV) arrhythmias with brain changes on magnetic resonance imaging (MRI). Hypothesis: Prevalent AF and SV ectopy are associated with reduced gray matter (GM) volume and subclinical vascular brain injury. Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), participants completed Zio Patch monitoring and brain MRI. Prevalent AF was estimated from ambulatory monitoring, hospital surveillance, Medicare claims, and MESA electrocardiogram (ECG). For secondary analyses, AF was categorized into continuous - AF during 100% of monitoring - and intermittent - prevalent AF with <100% AF during monitoring. Brain MRI measures included GM volume, white matter (WM) lesion volume, WM fractional anisotropy, and presence of cerebral microbleeds (CMBs). Linear and Poisson regression analyses were adjusted for cardiovascular risk factors and socioeconomic status. Results: In MESA, 967 participants without a history of stroke or transient ischemic attack (TIA) completed >24 hours of ECG monitoring (median, 14.0 days) and completed brain MRI a median 17 months later. Mean (standard deviation) age was 72 (8) years; 53% were women. A total of 116 participants had prevalent AF, of whom 20 had continuous AF. Compared with no AF, prevalent AF was associated with lower WM FA (-0.22 standard deviations, 95% CI: -0.39, -0.04) and higher prevalence of CMBs (prevalence ratio: 1.46, 95% CI: 1.18, 1.80). In secondary analyses, compared with no AF, continuous but not intermittent AF was associated with lower GM volume (-18.6 mL, 95% CI: -31.4, -5.8). Rates of premature atrial contractions and runs of SV tachycardia were not significantly associated with brain MRI measures. Conclusions: In a multi-ethnic sample free of a history of stroke or TIA, prevalent AF was associated with lower WM FA, a measure of WM injury, and presence of CMBs. These results highlight the importance of AF prevention for brain health. Further analysis of subclinical infarcts is needed in this sample, and study in other settings is needed to confirm whether greater AF burden is associated with reduced GM volume.

Abstract 10334: The Association of Trimethylamine N-oxide (TMAO) with Findings of Vascular Brain Injury on Magnetic Resonance Imaging in the Cardiovascular Health Study (CHS)

Introduction: Findings on MRI of vascular brain injury, such as brain infarcts and white matter hyperintensities, are chronic manifestation of atherosclerosis. A gut-microbiome-generated metabolite, trimethylamine N-oxide (TMAO), is an independent predictor of clinical cardiovascular events. However, no study has examined associations between TMAO and subclinical vascular brain injury in the general population. Hypothesis: TMAO levels are positively associated with evidence of progressive subclinical vascular brain injury on serial MRI scans with incident brain infarcts and white matter worsening. Methods: The Cardiovascular Health Study (CHS) is a community-based prospective cohort study in adults aged >65 years. Plasma TMAO was measured using mass spectrometry from samples collected in 1992-1993 and 1996-1997. Brain MRI was performed at 1991-1994 and again at 1997-1999. White matter was graded on a 10-point scale, higher being worse, and white matter worsening (WMW) was defined by an increase of least one point comparing initial and follow up scans. In these analyses, participants with prior TIA or stroke were excluded. Those with serum TMAO and both MRI scans were included: n=1196 for incident brain infarct and n=1553 for white matter worsening. Logistic regression was used for the association of baseline TMAO levels and incident brain infarcts, and Poisson regression, for the change in TMAO levels and WMW. Models were adjusted for age, sex, race, alcohol use, intake of meat and vegetable, and vascular risk factors. Results: Between the two MRI scans, 191(15.9%) participants had subclinical incident brain infarcts, and 423 (27.2%) participants had WMW. Comparing the highest vs. lowest quartile, the first TMAO were not significantly associated with incident brain infarcts: odds ratio 0.78 (95% CI: 0.49 to 1.25). Again comparing the highest vs. lowest quartile, changes in TMAO were not associated with WMW: 1.08 (0.77 to 1.51). Conclusions: Baseline and changes in plasma TMAO levels were not associated with findings of subclinical vascular brain injury on MRI in older US adults. The associations of TMAO with the adverse clinical events seen in prior clinical samples of patients were not seen at the subclinical level in our population-based study.

Cholesterol Variability and Cranial Magnetic Resonance Imaging Findings in Older Adults

Background and Purpose- Serum cholesterol variability, independent of mean, has been associated with stroke, white matter hyperintensities on cranial magnetic resonance imaging (MRI), and other cardiovascular events. We sought to assess the relationship between total serum cholesterol (TC) variability and cranial MRI findings of subclinical or covert vascular brain injury in a longitudinal, population-based cohort study of older adults. Methods- In the Cardiovascular Health Study, we assessed associations between intraindividual TC mean, trend, and variability over ≈5 years with covert brain infarction (CBI) and white matter grade (WMG) on cranial MRI. Mean TC was calculated for each study participant from 4 annual TC measurements between 2 MRI scans. TC trend was calculated as the slope of the linear regression of the TC measurements, and TC variability was calculated as the SD of the residuals from the linear regression. We evaluated the association of intraindividual TC variability with incident CBI and worsening WMG between 2 MRI scans in primary analyses and with prevalent CBI number and WMG on the follow-up MRI scan in secondary analyses. Results- Among participants who were eligible for the study and free of clinical stroke before the follow-up MRI, 17.9% of 1098 had incident CBI, and 27.8% of 1351 had worsening WMG on the follow-up MRI. Mean, trend, and variability of TC were not associated with these outcomes. TC variability, independent of mean and trend, was significantly associated with the number of CBI (β=0.009 [95% CI, 0.003-0.016] P=0.004; N=1604) and was associated with WMG (β, 0.009 [95% CI, -0.0002 to 0.019] P=0.055; N=1602) on the follow-up MRI. Conclusions- Among older adults, TC variability was not associated with incident CBI or worsening WMG but was associated with the number of prevalent CBI on cranial MRI. More work is needed to validate and to clarify the mechanisms underlying such associations.

Abstract 171: Endothelial Microparticle Levels and Silent Stroke in the Framingham Heart Study

Introduction: Endothelial microparticles (EMP) are membrane vesicles, with a characteristic diameter of 0.1-1.0μ, shed by endothelial cells during cellular activation or apoptosis. EMP are associated with cardiovascular disease and risk factors, but data are lacking on the relations of EMP with subclinical vascular brain injury. Methods: We studied 487 individuals (mean age 66.9±8.8 years, 55% women) from the Framingham Offspring Cohort, who were free from clinical stroke. CD31+/CD41- EMP were identified and quantified using flow cytometry. Silent cerebral infarcts (SCI) were quantified as parenchymal lesions on brain MRI >3mm in size with characteristics of previous infarcts. Logistic regression models were used to investigate cross-sectional associations of EMP levels with prevalent SCI. We tested for interaction between EMP levels and statin use in their relationship with SCI. Results: SCI was observed in 49 (10%) participants. Figure 1 displays results of the logistic regression analysis. Circulating CD31+/CD41- EMP levels were inversely associated with SCI, adjusting for age, sex, and time interval between blood draw and brain MRI (OR 0.90 [0.82-0.98], p=0.016). Similar results were observed when adjusting for additional vascular risk factors. We observed an interaction between statin use and EMP levels in their association with SCI. There was an inverse association (OR 0.76 [0.64-0.89], p=0.001) among statin users and no association among non-statin users. Conclusions: In our analysis of the relationship of CD31+/CD41- EMP with SCI, in a well-defined community cohort, we observed an inverse association of higher EMP levels, primarily in participants on statins. Our data question whether constitutive or induced release of EMP, associated with a pleiotropic effect of statin medication, might mitigate vascular risk factor exposure and reduce risk of SCI. Further studies are needed to determine the associations of EMP with SCI and clinical stroke.

Effects of Arterial Stiffness on Brain Integrity in Young Adults From the Framingham Heart Study.

Previous work from the Framingham Heart Study suggests that brain changes because of arterial aging may begin in young adulthood and that such changes precede cognitive deficits. The objective of this study was to determine the association of arterial stiffness with measures of white matter and gray matter (GM) integrity in young adults. One thousand nine hundred three participants from the Framingham Heart Study Third Generation (mean age, 46±8.7 years) had complete tonometry measurements and brain magnetic resonance imaging (T1-weighted and diffusion tensor imaging). Tonometry measures included carotid-femoral pulse wave velocity, augmentation index, carotid-brachial pressure amplification, and central pulse pressure. Fractional anisotropy and GM density images were computed from diffusion tensor imaging and T1 images. Registration to a common anatomic template enabled voxel-based linear regressions relating measures of fractional anisotropy and GM to tonometry measures, adjusting for relevant covariables. Higher carotid-femoral pulse wave velocity was associated with lower regional fractional anisotropy, including the corpus callosum and the corona radiata (8.7 and 8.6 cc, respectively, P<0.001), as well as lower GM density in the thalamus region (0.9 cc, P<0.001). Analyses did not reveal significant associations between other tonometry measures and fractional anisotropy or GM. Among young healthy adults, higher aortic stiffness was associated with measures of reduced white matter and GM integrity in areas implicated in cognitive decline and Alzheimer's disease. Greater aortic stiffness may result in subclinical vascular brain injury at ages much younger than previously described.

Association of arterial stiffness with progression of subclinical brain and cognitive disease.

We tested whether abnormal arterial stiffness and blood pressure would be associated with progression of brain aging measured by brain MRI and neurocognitive testing. Framingham Offspring Cohort participants (n = 1,223, 61 ± 9 years, 56% women) without previous stroke or dementia underwent applanation tonometry, brain MRI, and neurocognitive testing at examination 7 (1998-2001). Follow-up brain MRI and neurocognitive testing was performed at examination 8 (2005-2008, mean interval 6.4 ± 1.3 years). We related examination 7 inverse-transformed carotid-femoral pulse wave velocity (iCFPWV), central pulse pressure (CPP), and mean arterial pressure to changes in the following variables between examinations 7 and 8: total cerebral brain volume, white matter hyperintensity volume, and performance on executive function and abstraction tasks, the Trail Making Test, Parts B and A (ΔTrails B-A), and Similarities tests. Higher baseline iCFPWV and CPP were associated with greater progression of neurocognitive decline (iCFPWV and ΔTrails B-A association: SD unit change in outcome variable per SD change in tonometry variable [β] ± SE = 0.10 ± 0.04, p = 0.019; CPP and ΔSimilarities association: -0.08 ± 0.03, p = 0.013). Higher mean arterial pressure, but not iCFPWV or CPP, was associated with increase in white matter hyperintensity volume ([β ± SE] 0.07 ± 0.03, p = 0.017). No tonometry measures were associated with change in cerebral brain volume. In middle-aged and older adults without evidence of clinical stroke or dementia, elevated arterial stiffness and pressure pulsatility are associated with longitudinal progression of subclinical vascular brain injury and greater neurocognitive decline. Treatments to reduce arterial stiffness may potentially reduce the progression of neurovascular disease and cognitive decline.

Association of Exhaled Carbon Monoxide With Stroke Incidence and Subclinical Vascular Brain Injury: Framingham Heart Study.

Exhaled carbon monoxide (CO) is associated with cardiometabolic traits, subclinical atherosclerosis, and cardiovascular disease, but its specific relations with stroke are unexplored. We related exhaled CO to magnetic resonance imaging measures of subclinical cerebrovascular disease cross-sectionally and to incident stroke/transient ischemic attack prospectively in the Framingham Offspring study. We measured exhaled CO in 3313 participants (age 59±10 years; 53% women), and brain magnetic resonance imaging was available in 1982 individuals (age 58±10 years; 54% women). Participants were analyzed according to tertiles of exhaled CO concentration. In age- and sex-adjusted models, the highest tertile of exhaled CO was associated with lower total cerebral brain volumes, higher white-matter hyperintensity volumes, and greater prevalence of silent cerebral infarcts (P<0.05 for all). The results for total cerebral brain volume and white-matter hyperintensity volume were consistent after removing smokers from the sample, and the association with white-matter hyperintensity volume persisted after multivariable adjustment (P=0.04). In prospective analyses (mean follow-up 12.9 years), higher exhaled CO was associated with 67% (second tertile) and 97% (top tertile) increased incidence of stroke/transient ischemic attack relative to the first tertile that served as referent (P<0.01 for both). These results were consistent in nonsmokers and were partially attenuated upon adjustment for vascular risk factors. In this large, community-based sample of individuals without clinical stroke/transient ischemic attack at baseline, higher exhaled CO was associated with a greater burden of subclinical cerebrovascular disease cross-sectionally and with increased risk of stroke/transient ischemic attack prospectively. Further investigation is necessary to explore the biological mechanisms linking elevated CO with stroke.

Abstract 16816: Association of Exhaled Carbon Monoxide With Stroke Incidence and Subclinical Vascular Brain Injury: The Framingham Study

Introduction: Exhaled carbon monoxide (CO) is associated with cardiometabolic traits, subclinical atherosclerosis, and cardiovascular disease, but its specific relations with stroke have not been explored. Hypothesis: We hypothesized that exhaled CO is related to MRI measures of subclinical cerebrovascular disease cross-sectionally, and to incident stroke/ transient ischemic attack (TIA) prospectively in the Framingham Offspring Study. Methods: We measured exhaled CO in 3313 participants (age 59±10 years, 53% women) and Brain MRI imaging was available in 1982 individuals (age 58±10, 54% women). Participants were analyzed according to tertiles of exhaled CO concentration. Results: In age- and sex-adjusted models, the highest tertile of exhaled CO was associated with lower total cerebral brain volumes (TCBV), higher white matter hyperintensity volumes (WMHV), and greater prevalence of silent cerebral infarcts (p &lt;0.05 for all). The results for TCBV and WMHV were consistent after removing smokers from the sample, and the association with WMHV persisted after multivariable adjustment (p=0.04). In prospective analyses (mean follow-up 12.9 years), higher exhaled CO was associated with 67% (second tertile) and 97% (top tertile) increased incidence of stroke/TIA relative to the first tertile that served as referent (p &lt;0.01 for both), Table. These results were consistent in nonsmokers, and were partially attenuated upon adjustment for vascular risk factors, but were maintained after adjusting for circulating biomarkers B-type natriuretic peptide and C-reactive protein, Table. Conclusion: In this large, community-based sample of individuals free of clinical stroke/TIA at baseline, higher exhaled CO was associated with a greater burden of subclinical cerebrovascular disease cross-sectionally, and with increased risk of stroke/TIA prospectively. Further investigation is necessary to explore the biological mechanisms linking CO with stroke.

Associations of Circulating Growth Differentiation Factor-15 and ST2 Concentrations With Subclinical Vascular Brain Injury and Incident Stroke.

Growth differentiation factor-15 (GDF-15) and soluble (s)ST2 are markers of cardiac and vascular stress. We investigated the associations between circulating concentrations of these biomarkers and incident stroke and subclinical vascular brain injury in a sample from the Framingham Offspring cohort. We followed 3374 stroke- and dementia-free individuals (mean age, 59.0±9.7 years; 53% women) attending the Framingham Offspring sixth examination cycle 11.8±3.0 years for incident stroke. A subsample of 2463 individuals underwent brain magnetic resonance imaging and neuropsychological testing ≈4.0±1.7 years after the sixth examination. After adjustment for traditional cardiovascular risk factors, B-type natriuretic peptide, high-sensitivity C-reactive protein, and urine albumin levels, higher stress biomarker levels were associated cross-sectionally with lower brain volumes (β coefficients for intracranial volume comparing fourth [Q4] versus first biomarker [Q1] quartiles: -0.71% for GDF-15; P=0.002 and 0.47% for sST2; P=0.02) and worse performance on the visual reproduction test (β coefficients for Q4 versus Q1: -0.62 for GDF-15; P=0.009 and -0.40 for sST2; P=0.04). Higher GDF-15 concentrations were also associated with greater log-transformed white-matter hyperintensity volumes (β for Q4 versus Q1=0.19; P=0.01). Prospectively, a total of 203 (6%) individuals developed incident stroke/transient ischemic attack during follow-up. After multivariable adjustment, sST2 remained significantly associated with stroke/transient ischemic attack, hazard ratio for Q4 versus Q1 of 1.76, 95% confidence interval of 1.06 to 2.92, and P=0.03. Circulating GDF-15 and sST2 are associated with subclinical brain injury and cognitive impairment. Higher sST2 concentrations are also associated with incident stroke, suggesting potential links between cardiac stress biomarkers and brain injury.

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Serum Brain–Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Levels Are Associated With Risk of Stroke and Vascular Brain Injury

Background and Purpose— Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) have a documented role in neurogenesis, angiogenesis, and neuronal survival. In animal experiments, they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample. Methods— In 3440 Framingham Study participants (mean age, 65±11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61±9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume on brain MRI, and to visuospatial memory and executive function tests. Results— During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age, sex, and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (hazard ratio comparing BDNF Q1 versus Q2–Q4, 1.47; 95% confidence interval, 1.09–2.00; P =0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04–1.40; P =0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (β±SE=−0.05±0.02; P =0.025), and better visual memory (β±SE=0.18±0.07; P =0.005). Conclusions— Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.

Vascular Cognitive Impairment

Vascular cognitive impairment (VCI) is a term used to capture the entire spectrum of cognitive impairment from mild to more severe forms and includes all forms of stroke (e.g., ischemic and hemorrhagic forms) associated and underlying cognitive impairment related with subclinical vascular brain injury. Vascular contributions to cognitive impairment are common, especially as one ages. Therefore, both stroke and Alzheimer's disease may be important causes of cognitive impairment in later life, and the concomitant occurrence of these disorders may synergize to increase the risk of poor cognition in later life. In this review we discuss the definition and clinical presentation, mechanisms, cardiovascular risk factors and possible prevention and treatment of VCI. VCI is a potentially treatable and preventable cause of cognitive impairment in later life, and familiarity with this condition will help the practitioner provide better care to patients.

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Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain Injury

Background— Several biomarkers have been individually associated with vascular brain injury, but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/transient ischemic attack and the prevalence of subclinical brain injury. Methods and Results— In 3127 stroke-free Framingham offspring (age, 59±10 years; 54% female), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function ( homocysteine and urinary albumin/creatinine ratio) measured at the sixth examination (1995–1998) to risk of incident stroke/transient ischemic attack. In a subset of 1901 participants with available brain magnetic resonance imaging (1999–2005), we further related these biomarkers to total cerebral brain volume, covert brain infarcts, and large white-matter hyperintensity volume. During a median follow-up of 9.2 years, 130 participants experienced incident stroke/transient ischemic attack. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/transient ischemic attack and with total cerebral brain volume ( P &lt;0.05 for both) but not with covert brain infarcts or white-matter hyperintensity volume ( P &gt;0.05). In backward elimination analyses, higher log–B-type natriuretic peptide (hazard ratio, 1.39 per 1-SD increment; P =0.002) and log–urinary albumin/creatinine ratio (hazard ratio, 1.31 per 1-SD increment; P =0.004) were associated with increased risk of stroke/transient ischemic attack and improved risk prediction compared with the Framingham Stroke Risk Profile alone; when the &lt;5%, 5% to 15%, or &gt;15% 10-year risk category was used, the net reclassification index was 0.109 ( P =0.037). Higher C-reactive protein (β=−0.21 per 1-SD increment; P =0.008), D-dimer (β=−0.18 per 1-SD increment; P =0.041), total homocysteine (β=−0.21 per 1-SD increment; P =0.005), and urinary albumin/creatinine ratio (β=−0.15 per 1-SD increment; P =0.042) were associated with lower total cerebral brain volume. Conclusion— In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.

Abstract 36: Association of Parental Stroke with Cognitive and Brain MRI Measures in Offspring - The Framingham Heart Study

Objectives- Parental stroke is related to an increased risk of stroke among the offspring. Vascular related brain changes, however, often occur before clinical stroke and the association of parental history of stroke and structural brain measures and cognition has not been fully explored. We hypothesized that prospectively verified parental stroke will be associated with increased vascular brain injury and poorer cognitive performance. Methods- A total of 1,297 Framingham offspring (mean age: 61 ± 9 years, 54% women) were studied. Of these, 9.9% had prospectively identified stroke in one or both parents before age 65. Volumetric brain MRI measures of total cerebral brain volume (TCBV), regional brain volumes, white matter hyperintensity volume (WMHV), and covert brain infarcts (CBI) and performance on tests of verbal memory, abstract reasoning, verbal learning and visuospatial memory (VRd) were compared for offspring with and without parental history of stroke. All measures were assessed cross-sectionally and longitudinally (mean duration of follow-up was 6.1±1.2 years). We used models adjusted only for age, sex, education and also additionally adjusted for vascular risk factors and for WMHV as an index of subclinical vascular brain injury. GEE models were used to adjust for sibling relationships among offspring. Results- Higher WMHV (β±SE=0.17±0.08;p=0.027) and lower VRd scores (β±SE=-0.80±0.34; p=0.017) at baseline were found in offspring with parental history of stroke. In addition, participants with parental stroke by age 65 years were more likely to be in the highest quintile of increase in WMHV (OR=1.87;p=0.04) as well as worsening executive function (Trails B-A) (OR:1.81;p=0.03). Parental stroke was not associated with total and regional brain volumes or with memory, abstract reasoning and verbal learning. Conclusions- In our community-based sample of middle-aged asymptomatic subjects, the occurrence of parental stroke by age 65 years is associated with higher baseline WMHV and with a more rapid increase in WMHV. Further, parental stroke is also associated with poorer performance on VRd and a decline in executive function. The effects on baseline WMH and VRd were substantial equivalent to 2.8 and 7 years of brain aging, respectively.

Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review

Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.

Association of Plasma ADMA Levels With MRI Markers of Vascular Brain Injury

Asymmetrical dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, is a marker of endothelial dysfunction. Elevated circulating ADMA concentrations have been associated with systemic and carotid atherosclerosis, an elevated risk of developing stroke, and magnetic resonance imaging white-matter hyperintensities (WMHs). The relation of plasma ADMA to subclinical vascular brain injury has not been previously studied in a middle-aged, community-based sample. In 2013 stroke-free Framingham offspring (mean+/-SD age, 58+/-9.5 years; 53% women), we related baseline plasma ADMA levels (1995-1998) to subsequent brain magnetic resonance imaging measures (1999-2004) of subclinical vascular injury: presence of silent brain infarcts (SBIs) and large white-matter hyperintensity volumes (LWMHs; defined as >1 SD above the age-specific mean). Prevalences of SBIs and LWMHs were 10.7% and 12.6%, respectively. In multivariable analyses adjusting for age, sex and traditional stroke risk factors, higher ADMA levels were associated with an increased risk of prevalent SBIs (odds ratio [OR] per 1-SD increase in ADMA=1.16; 95% CI, 1.01 to 1.33; P=0.04). We observed that participants in the upper 3 age-specific quartiles (Qs) of plasma ADMA values had an increased prevalence of SBIs (OR for Q2-Q4 vs Q1=1.43; 95% CI, 1.00 to 2.04; P<0.05). The prevalence of SBIs in Q1and Q2-Q4 was 8.3% and 11.6%, respectively. The prevalence of LWMHs did not differ according to ADMA concentrations. Higher plasma ADMA values were associated with an increased prevalence of SBIs, after adjustment for traditional stroke risk factors. Thus, ADMA may be a potentially useful new biomarker of subclinical vascular brain injury, which is an important correlate of vascular cognitive impairment and risk of stroke.