Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

BACKGROUND: A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. METHODS: Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. RESULTS: We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (ß±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. CONCLUSIONS: Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Higher Dietary Inflammatory Index scores are associated with brain MRI markers of brain aging: Results from the Framingham Heart Study Offspring cohort.

INTRODUCTION: We investigated cross-sectional associations between the Dietary Inflammatory Index (DII) and measures of brain volume and cerebral small vessel disease among participants of the Framingham Heart Study Offspring cohort. METHODS: A total of 1897 participants (mean ± standard deviation, age 62±9) completed Food Frequency Questionnaires and brain magnetic resonance imaging (MRI). RESULTS: Higher (pro-inflammatory) DII scores, averaged across a maximum of three time points, were associated with smaller total brain volume (beta ± standard error: -0.16 ± 0.03; P < .0001) after adjustment for demographic, clinical, and lifestyle covariates. In addition, higher DII scores were associated with smaller total gray matter volume (-0.08 ± 0.03; P = .003) and larger lateral ventricular volume (0.04 ± 0.02; P = .03). No associations were observed with other brain MRI measures. DISCUSSION: Our findings showed associations between higher DII scores and global brain MRI measures. As we are one of the first groups to report on the associations between higher DII scores and brain volume, replication is needed to confirm our findings.

Vascular risk factors as predictors of epilepsy in older age: The Framingham Heart Study.

OBJECTIVE: Stroke is the most common cause of epilepsy in older age. Subclinical cerebrovascular disease is believed to underlie some of the 30%-50% of late-onset epilepsy without a known cause (Li et al. Epilepsia. 1997;38:1216; Cleary et al. Lancet. 2004;363:1184). We studied the role of modifiable vascular risk factors in predicting subsequent epilepsy among participants ages 45 or older in the Framingham Heart Study (FHS), a longitudinal, community-based study. METHODS: Participants of the Offspring Cohort who attended FHS exam 5 (1991-1995) were included who were at least 45-years-old at that time, had available vascular risk factor data, and epilepsy follow-up (n = 2986, mean age 58, 48% male). Adjudication of epilepsy cases included review of medical charts to exclude seizure mimics and acute symptomatic seizures. The vascular risk factors studied included hypertension, diabetes mellitus, smoking, and hyperlipidemia. The role of the Framingham Stroke Risk Profile score was also investigated. Cox proportional hazards regression models were used for the analyses. RESULTS: Fifty-five incident epilepsy cases were identified during a mean of 19 years of follow-up. Hypertension was associated with a near 2-fold risk (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.10-3.37, p = .022) of developing epilepsy, even after adjustment for prevalent and interim stroke. In secondary analysis, excluding patients with normal blood pressure who were receiving anti-HTN (anti-hypertensive) treatment (n = 2613, 50 incident epilepsy cases) the association was (HR: 2.44, 95% CI: 1.36-4.35, p = .003). SIGNIFICANCE: Our results offer further evidence that hypertension, a potentially modifiable and highly prevalent vascular risk factor in the general population, increases 2- to 2.5-fold the risk of developing late-onset epilepsy.

Insomnia symptom severity and cognitive performance: Moderating role of APOE genotype.

INTRODUCTION: We evaluated whether insomnia symptom severity was associated with cognitive function, and whether this relationship was modified by biomarkers associated with Alzheimer's disease risk. METHODS: We examined insomnia symptoms and neuropsychological performance 3.4 years later in 511 dementia-free Framingham Heart Study participants (62.65 ± 8.7 years, 50.9% male). Additionally, we explored insomnia symptoms combined with self-reported short habitual sleep duration and effect modification by apolipoprotein E (APOE) ε4 allele status. RESULTS: More severe insomnia symptoms were associated with lower performance on global cognition, and immediate and delayed Logical Memory recall, especially when insomnia symptoms were combined with short sleep duration. The association between insomnia symptoms and poorer memory recall was more pronounced in APOE ε4 allele carriers. DISCUSSION: Insomnia symptom severity was associated with worse subsequent global cognitive and memory performance, which was especially apparent in APOE ε4 allele carriers, suggesting that poor sleep might be particularly detrimental when the brain is already vulnerable to neurodegeneration.

Associations of the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet with cardiac remodelling in the community: the Framingham Heart Study.

Normal cardiac function is directly associated with the maintenance of cerebrovascular health. Whether the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet, designed for the maintenance of neurocognitive health, is associated with cardiac remodelling is unknown. We evaluated 2512 Framingham Offspring Cohort participants who attended the eighth examination cycle and had available dietary and echocardiographic data (mean age 66 years; 55 % women). Using multivariable regression, we related the cumulative MIND diet score (independent variable) to left ventricular (LV) ejection fraction, left atrial emptying fraction, LV mass (LVM), E/e' ratio (dependent variables; primary), global longitudinal strain, global circumferential strain (GCS), mitral annular plane systolic excursion, longitudinal segmental synchrony, LV hypertrophy and aortic root diameter (secondary). Adjusting for age, sex and energy intake, higher cumulative MIND diet scores were associated with lower values of indices of LV diastolic (E/e' ratio: logß = -0·03) and systolic function (GCS: ß = -0·04) and with higher values of LVM (logß = 0·02), all P ≤ 0·01. We observed effect modification by age in the association between the cumulative MIND diet score and GCS. When we further adjusted for clinical risk factors, the associations of the cumulative MIND diet score with GCS in participants ≥66 years (ß = -0·06, P = 0·005) and LVM remained significant. In our community-based sample, relations between the cumulative MIND diet score and cardiac remodelling differ among indices of LV structure and function. Our results suggest that favourable associations between a higher cumulative MIND diet score and indices of LV function may be influenced by cardiometabolic and lifestyle risk factors.

Bone Mineral Density Measurements and Association With Brain Structure and Cognitive Function: The Framingham Offspring Cohort.

BACKGROUND: Bone mineral density (BMD) is a potential surrogate marker of lifetime estrogen exposure previously linked to increased risk of Alzheimer dementia among elderly women. We examine the association between BMD in the "young old" with imaging biomarkers of brain aging and cognitive performance. METHODS: Offspring participants (N=1905, mean age 66) of a population-based cohort who had BMD, brain imaging and detailed cognitive assessment were included in the study. Sex-stratified, linear, and logistic regression models were used for analysis. RESULTS: Higher femoral neck BMD was associated with lower white matter hyperintensity burden and better performance on Trails B-A in both sexes, even after adjustment for cerebrovascular risk factors. Among women, the positive association with Trails B-A performance was seen only in APOE4 allele carriers. Higher BMD measurements were linked to better visual reproductions test performance in men. Finally, among women, higher femoral trochanter BMD was associated with better logical memory and Hooper visual organization test performance. CONCLUSION: Among the "young old," higher BMD is associated with less white matter hyperintensity burden and better, domain-specific, cognitive performance. This suggests that lifetime estrogen exposure may modulate the degree of cumulative vascular brain injury independent of cerebrovascular risk factors.

Incidence of Transient Ischemic Attack and Association With Long-term Risk of Stroke.

Importance: Accurate estimation of the association between transient ischemic attack (TIA) and risk of subsequent stroke can help to improve preventive efforts and limit the burden of stroke in the population. Objective: To determine population-based incidence of TIA and the timing and long-term trends of stroke risk after TIA. Design, Setting, and Participants: Retrospective cohort study (Framingham Heart Study) of prospectively collected data of 14 059 participants with no history of TIA or stroke at baseline, followed up from 1948-December 31, 2017. A sample of TIA-free participants was matched to participants with first incident TIA on age and sex (ratio, 5:1). Exposures: Calendar time (TIA incidence calculation, time-trends analyses), TIA (matched longitudinal cohort). Main Outcomes and Measures: The main outcomes were TIA incidence rates; proportion of stroke occurring after TIA in the short term (7, 30, and 90 days) vs the long term (>1-10 years); stroke after TIA vs stroke among matched control participants without TIA; and time trends of stroke risk at 90 days after TIA assessed in 3 epochs: 1954-1985, 1986-1999, and 2000-2017. Results: Among 14 059 participants during 66 years of follow-up (366 209 person-years), 435 experienced TIA (229 women; mean age, 73.47 [SD, 11.48] years and 206 men; mean age, 70.10 [SD, 10.64] years) and were matched to 2175 control participants without TIA. The estimated incidence rate of TIA was 1.19/1000 person-years. Over a median of 8.86 years of follow-up after TIA, 130 participants (29.5%) had a stroke; 28 strokes (21.5%) occurred within 7 days, 40 (30.8%) occurred within 30 days, 51 (39.2%) occurred within 90 days, and 63 (48.5%) occurred more than 1 year after the index TIA; median time to stroke was 1.64 (interquartile range, 0.07-6.6) years. The age- and sex-adjusted cumulative 10-year hazard of incident stroke for patients with TIA (130 strokes among 435 cases) was 0.46 (95% CI, 0.39-0.55) and for matched control participants without TIA (165 strokes among 2175) was 0.09 (95% CI, 0.08-0.11); fully adjusted hazard ratio [HR], 4.37 (95% CI, 3.30-5.71; P < .001). Compared with the 90-day stroke risk after TIA in 1948-1985 (16.7%; 26 strokes among 155 patients with TIA), the risk between 1986-1999 was 11.1% (18 strokes among 162 patients) and between 2000-2017 was 5.9% (7 strokes among 118 patients). Compared with the first epoch, the HR for 90-day risk of stroke in the second epoch was 0.60 (95% CI, 0.33-1.12) and in the third epoch was 0.32 (95% CI, 0.14-0.75) (P = .005 for trend). Conclusions and Relevance: In this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years, the risk of stroke was significantly greater after TIA compared with matched control participants who did not have TIA, and the risk of stroke after TIA was significantly lower in the most recent epoch from 2000-2017 compared with an earlier period from 1948-1985.

Plasma total-tau as a biomarker of stroke risk in the community.

Higher plasma total-tau level is associated with incident dementia, but its relationship with stroke risk is unknown. In this prospective community-based study, we evaluated plasma total-tau level as a biomarker of stroke risk in 2,794 Framingham Heart Study participants. Persons with plasma total-tau levels in the top quintile, versus the bottom 4, had an increased risk of incident stroke over a mean follow-up of 8.3 years (hazard ratio = 2.01; 95% confidence interval = 1.32-3.08) following adjustments for age, sex, and stroke risk factors. Our findings demonstrate that plasma total-tau relates to the risk of stroke in a community sample. ANN NEUROL 2019;86:463-467.

Temporal Trends in Ischemic Stroke Incidence in Younger Adults in the Framingham Study.

Background and Purpose- Stroke at midlife has a disproportionately large impact on disability-adjusted life-years lost. Ischemic stroke incidence may be increasing at this age. We investigated long-term trends in ischemic stroke incidence and changes in stroke risk factors in a community sample stratified by stroke onset at middle and older age. Methods- In the Framingham Study, surveillance for incident stroke is ongoing since 1948. We examined age-adjusted and sex-adjusted 10-year incidence of ischemic stroke using Cox models in persons aged 35 to 54 and ≥55 years at start of follow-up. Tests for linear trend were performed over 4 epochs, controlling for the distance in time between intervals. Further, we calculated the mean 10-year risk of stroke at each epoch and for both age groups, based on vascular risk factors from the Framingham Stroke Risk Profile. Results- There were 153, 197, 176, and 165 incident ischemic strokes within each epoch beginning in 1962 (n=3966), 1971 (n=5779), 1987 (n=5133), and 1998 (n=6964). Most ischemic strokes at midlife (n=71) were because of atherosclerotic brain infarction (n=50) or cardioembolism (n=19). Using the risk in the 1962 epoch as the reference, the risk of ischemic stroke at midlife did not significantly decline (hazard ratio, 0.87; 95% CI, 0.74-1.02; P trend =0.09). Incidence of ischemic stroke declined in the older group (hazard ratio, 0.82; 95% CI, 0.77-0.88; P trend <0.001). Between epochs 1 and 4, the average 10-year risk of stroke, as estimated by the Framingham Stroke Risk Profile, declined by 0.7% at midlife and 1.1% at older age. Conclusions- Long-term rates of ischemic stroke declined in our community sample; the decline was greater in older as compared with younger adults. Early prevention, focused on modification of cardiovascular risk factors, is important to see sustained declines in stroke incidence and mortality at midlife.

Non-alcoholic fatty liver disease, liver fibrosis score and cognitive function in middle-aged adults: The Framingham Study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is common and has been recently related to brain health. We aimed to assess the relationships of NAFLD and its severity, using the NAFLD fibrosis score (NFS), with cognitive performance. METHODS: Framingham study Offspring and 3rd generation participants were included if they attended exams 9 (2002-2008) and 2 (2008-2011), respectively, were free of dementia and stroke, and did not have excessive alcohol intake. Between 2008 and 2011, participants underwent Multi-detector computed tomography scans of the abdomen to determine NAFLD diagnosis and the NFS was used to categorize the severity of fibrosis. Cross-sectional relationships of NAFLD and the NFS with cognitive testing of memory, abstract reasoning, visual perception, attention and executive function were assessed, while adjusting for multiple cardiometabolic variables including visceral adipose tissue, diabetes and insulin resistance. RESULTS: Of the 1287 participants (mean age = 61±12 years, 48% men), 378 (29%) had NAFLD. The presence of NAFLD was not associated with cognitive function. However, among those with NAFLD (mean age = 61±12 years; 58% men), high compared to low risk of advanced fibrosis was associated with poorer performance on similarities (ß = -2.22 ± 0.83; P = 0.009) and trail-making B minus A (ß = -0.11 ± 0.05; P = 0.028), independently of potential confounders. CONCLUSIONS: Participants with high risk of advanced fibrosis may have poorer cognitive function compared to those with low risk, particularly in executive function and abstract reasoning. Future findings are necessary to evaluate the value of the NFS as a biomarker that predicts cognitive impairment and dementia and to explore the role of hepatic fibrosis in brain health.

Revised Framingham Stroke Risk Profile to Reflect Temporal Trends.

BACKGROUND: Age-adjusted stroke incidence has decreased over the past 50 years, likely as a result of changes in the prevalence and impact of various stroke risk factors. An updated version of the Framingham Stroke Risk Profile (FSRP) might better predict current risks in the FHS (Framingham Heart Study) and other cohorts. We compared the accuracy of the standard (old) and of a revised (new) version of the FSRP in predicting the risk of all-stroke and ischemic stroke and validated this new FSRP in 2 external cohorts, the 3C (3 Cities) and REGARDS (Reasons for Geographic and Racial Differences in Stroke) studies. METHODS: We computed the old FSRP as originally described and a new model that used the most recent epoch-specific risk factor prevalence and hazard ratios for individuals ≥55 years of age and for the subsample ≥65 years of age (to match the age range in REGARDS and 3C studies, respectively) and compared the efficacy of these models in predicting 5- and 10-year stroke risks. RESULTS: The new FSRP was a better predictor of current stroke risks in all 3 samples than the old FSRP (calibration χ2 of new/old FSRP: in men: 64.0/12.1, 59.4/30.6, and 20.7/12.5; in women: 42.5/4.1, 115.4/90.3, and 9.8/6.5 in FHS, REGARDS, and 3C, respectively). In the REGARDS, the new FSRP was a better predictor among whites compared with blacks. CONCLUSIONS: A more contemporaneous, new FSRP better predicts current risks in 3 large community samples and could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors.

Circulating Vascular Growth Factors and Magnetic Resonance Imaging Markers of Small Vessel Disease and Atrophy in Middle-Aged Adults.

Background and Purpose- Little is known about associations between vascular growth factors and magnetic resonance imaging (MRI) markers in midlife. We investigated the association of serum VEGF (vascular endothelial growth factor), Ang2 (angiopoietin 2), sTie2 (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2), and HGF (hepatocyte growth factor) concentrations with MRI markers of brain aging in middle-aged adults. Methods- We evaluated 1853 participants (mean age, 46±9 years; 46% men) from the Framingham Heart Study. Serum growth factor concentrations were measured using standardized immunoassays. Outcomes included total brain, cortical and subcortical gray matter, white matter, cerebrospinal fluid, and white matter hyperintensity volumes derived from MRI; as well as fractional anisotropy in white matter tracts from diffusion tensor imaging. We related VEGF, Ang2, sTie2, and HGF to MRI measures using multivariable regression models adjusting for vascular risk factors. We tested for interactions with APOE (apolipoprotein E) genotype and CRP (C-reactive protein). Results were corrected for multiple comparisons. Results- Higher sTie2 was associated with smaller total brain (estimate by SD unit±SE=-0.08±0.02, P=0.002) and larger white matter hyperintensity (0.08±0.02, P=0.002) volumes. Furthermore, higher Ang2 (0.06±0.02, P=0.049) and HGF (0.09±0.02, P=0.001) were associated with larger cerebrospinal fluid volumes. Finally, higher Ang2 was associated with decreased fractional anisotropy, in APOE-ε4 carriers only. Conclusions- Vascular growth factors are associated with early MRI markers of small vessel disease and neurodegeneration in middle-aged adults.

Vascular risk factor burden and new-onset depression in the community.

Depression is associated with an increased likelihood of cardiac events and stroke. We hypothesized that the vascular risk factor burden might itself predispose to both cardiovascular events and depression. Therefore, we examined whether aggregate scores of vascular risk factor burden were associated with the new-onset of depression in the community. We studied 2023 depression- and dementia-free Framingham Heart Study (Framingham, USA) Offspring participants who attended both examination cycles 7 (1998-2001) and 8 (2005-2008). The American Heart Association Ideal Cardiovascular Health metric and the Framingham stroke risk profile were calculated at exam seven. New-onset depression was adjudicated at examination cycle eight as antidepressant medication use or Centre for Epidemiologic Studies Depression Scale scores ≥16, after a mean follow-up of 6.6years (standard deviation=0.7). Of the 2023 participants, 269 (13%) developed new-onset depression. Following adjustments for age, sex, education, and the time interval between baseline and follow-up, the odds of new-onset depression decreased by 10% for each one-point increase in ideal cardiovascular health scores (Odds Ratio [OR], 0.90; 95% confidence interval [CI] 0.81-0.99) and increased by 4% for each percentage point increase in the Framingham stroke risk profile (OR, 1.04; CI, 1.00-1.07). Results were not explained by interim clinical stroke or cerebral white matter injury. In conclusion, vascular risk factor burden was associated with the new onset of depression. Shared vascular risk factors may contribute to the increased risk of cardiovascular events observed in persons with depression.

Lacunar Infarcts and Intracerebral Hemorrhage Differences: A Nested Case-Control Analysis in the FHS (Framingham Heart Study).

BACKGROUND AND PURPOSE: Lacunar stroke (LS) and intracerebral hemorrhage (ICH) are 2 diverse manifestations of small vessel disease. What predisposes some patients to ischemic stroke and others to hemorrhage is not well understood. METHODS: We performed a nested case-control study within the FHS (Framingham Heart Study) comparing people with incident ICH and lacunar ischemic stroke, to age- and sex-matched controls for baseline prevalence and levels of cardiovascular risk factors. RESULTS: We identified 118 LS (mean age 74 years, 51% male) and 108 ICH (75 years, 46% male) events. Hypertension, diabetes mellitus, smoking, and obesity were strongly associated with LS. Hypertension, but not diabetes mellitus, smoking, or cholesterol levels increased the odds of ICH. Contrary to LS, ICH cases had lower body mass index (BMI) than their controls (26 versus 27); BMI <20 was associated with 4-fold higher odds for ICH. In direct comparison, LS cases had higher BMI (28 versus 26) and obesity prevalence (odds ratio, 3.1); BMI <20 was associated with significantly lower odds of LS (odds ratio, 0.1). CONCLUSIONS: LS and ICH share hypertension, but not diabetes mellitus, as a common risk factor. ICH cases had lower BMI compared with not only LS but their controls as well; this finding is unexplained and merits further exploration.

Cerebral Microbleeds as Predictors of Mortality: The Framingham Heart Study.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMB) represent a common magnetic resonance imaging marker of cerebral small vessel disease, increasingly recognized as a subclinical marker of stroke and dementia risk. CMB detection may reflect the cumulative effect of vascular risk burden and be a marker of higher mortality. We investigated the relation of CMB to risk of death in community dwelling participants free of stroke and dementia. METHODS: We evaluated 1963 Framingham Original and Offspring Cohort participants (mean age 67 years; 54% women) with available brain magnetic resonance imaging and mortality data. Using Cox proportional hazards models, we related CMB to all-cause, cardiovascular, and stroke-related mortality. RESULTS: Participants with CMB (8.9%) had higher prevalence of cardiovascular risk factors and use of preventive medications. During a mean follow-up of 7.2±2.6 years, we observed 296 deaths. In age- and sex-adjusted analysis, CMB were associated with increased all-cause mortality (hazards ratio, 1.39; 95% confidence interval 1.03-1.88), a relation that was no longer significant after adjustment for cardiovascular risk and preventive medication use (hazards ratio, 1.15; 95% confidence interval, 0.82-1.63). CONCLUSIONS: CMBs may represent the deleterious effect of cardiovascular risk factors in the cerebral vasculature. Although their presence was associated with increased all-cause mortality, the effect was no longer present after accounting for vascular risk factors and preventive treatment use. Further studies are required to clarify the role of cardiovascular preventive therapies for prevention of mortality in persons with incidental detection of CMB.

Aortic Stiffness, Increased White Matter Free Water, and Altered Microstructural Integrity: A Continuum of Injury.

BACKGROUND AND PURPOSE: Previous reports from the Framingham Heart Study have identified cross-sectional associations of arterial stiffness, as reflected by carotid-femoral pulse wave velocity (CFPWV) and systolic blood pressure with vascular brain injury. The purpose of this study is to examine free water (FW), fractional anisotropy (FA), and white matter hyperintensities (WMH) in relation to arterial stiffness among subjects of the Framingham Offspring and Third-Generation cohorts. METHODS: In 2422 participants aged 51.3±11.6 years, FA, FW, and WMH were related to CFPWV using voxel-based linear and generalized linear regressions, adjusting for relevant covariables. Mean FW, mean FA, and WMH burden (log transformed) were computed within white matter (WM) region and related to systolic blood pressure and CFPWV using multiple mediation analyses. RESULTS: CFPWV was found to be associated with higher FW, lower FA, and higher WMH incidence in WM areas covering, respectively, 356.1, 211.8, and 10.9 mL of the WM mask. Mediation analyses revealed that the effect of systolic blood pressure on FW was mediated by CFPWV (direct and indirect effects: a=0.040; P<0.001, and a'=0.020; P>0.05). Moreover, the effect of CFPWV on FA was mediated by FW (direct and indirect effects: b=-0.092; P<0.001, and b'=0.012; P>0.05), whose effect on WMH was, in turn, mediated by FA (direct and indirect effects: c=0.246; P<0.001, and c'=0.116; P>0.05). CONCLUSIONS: From these data, we propose a biomechanical hypothesis designed for future research experiments to explain how hemodynamic alteration may lead to WM injury by impacting cerebral water content and more subtly WM integrity, to finally lead to WMH development.

Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia: A Prospective Cohort Study.

BACKGROUND AND PURPOSE: Sugar- and artificially-sweetened beverage intake have been linked to cardiometabolic risk factors, which increase the risk of cerebrovascular disease and dementia. We examined whether sugar- or artificially sweetened beverage consumption was associated with the prospective risks of incident stroke or dementia in the community-based Framingham Heart Study Offspring cohort. METHODS: We studied 2888 participants aged >45 years for incident stroke (mean age 62 [SD, 9] years; 45% men) and 1484 participants aged >60 years for incident dementia (mean age 69 [SD, 6] years; 46% men). Beverage intake was quantified using a food-frequency questionnaire at cohort examinations 5 (1991-1995), 6 (1995-1998), and 7 (1998-2001). We quantified recent consumption at examination 7 and cumulative consumption by averaging across examinations. Surveillance for incident events commenced at examination 7 and continued for 10 years. We observed 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer's disease). RESULTS: After adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk of ischemic stroke, all-cause dementia, and Alzheimer's disease dementia. When comparing daily cumulative intake to 0 per week (reference), the hazard ratios were 2.96 (95% confidence interval, 1.26-6.97) for ischemic stroke and 2.89 (95% confidence interval, 1.18-7.07) for Alzheimer's disease. Sugar-sweetened beverages were not associated with stroke or dementia. CONCLUSIONS: Artificially sweetened soft drink consumption was associated with a higher risk of stroke and dementia.

Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study.

BACKGROUND AND PURPOSE: Low insulin-like growth factor 1 (IGF-1) has been associated with increased risk of atherosclerosis and atrial fibrillation in cross-sectional studies. Yet, prospective data linking IGF-1 levels to the development of ischemic stroke remain inconclusive. We examined prospectively the association between serum IGF-1 levels and incident ischemic stroke. METHODS: We measured serum IGF-1 levels in 757 elderly individuals (mean age 79±5, 62% women), free of prevalent stroke, from the Framingham original cohort participants at the 22nd examination cycle (1990-1994) and were followed up for the development of ischemic stroke. Cox models were used to relate IGF-1 levels to the risk for incident ischemic stroke, adjusted for potential confounders. RESULTS: During a mean follow-up of 10.2 years, 99 individuals developed ischemic stroke. After adjustment for age, sex, and potential confounders, higher IGF-1 levels were associated with a lower risk of incident ischemic stroke, with subjects in the lowest quintile of IGF-1 levels having a 2.3-fold higher risk of incident ischemic stroke (95% confidence interval, 1.09-5.06; P=0.03) as compared with those in the top quintile. We observed an effect modification by diabetes mellitus and waist-hip ratio for the association between IGF-1 and ischemic stroke (P<0.1). In subgroup analyses, the effects were restricted to subjects with diabetics and those in top waist-hip ratio quartile, in whom each standard deviation increase in IGF-1 was associated with a 61% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P=0.007) and 41% (hazard ratio, 0.59; 95% confidence interval, 0.37-0.95; P=0.031) lower risk of incident ischemic stroke, respectively. CONCLUSIONS: IGF-1 levels were inversely associated with ischemic stroke, especially among persons with insulin resistance.

Serum brain-derived neurotrophic factor and risk of atrial fibrillation.

Brain-derived neurotrophic factor (BDNF) is expressed by endothelial cells and can affect cardiovascular function. We examined if serum BDNF was associated with risk of incident atrial fibrillation (AF) in the Framingham Heart Study. METHODS: We studied individuals without an AF diagnosis at baseline from the Framingham original and offspring cohorts. We used age- and sex-adjusted, and multivariable-adjusted Cox proportional hazards regression models to examine the association of serum BDNF concentrations with 10-year risk of incident AF. RESULTS: We studied 3,457 participants (mean age 65±11years, 58% women). During follow-up, 395 participants developed AF. In unadjusted analysis, higher mean serum BDNF concentration was associated with lower incidence of AF (hazard ratio 0.89 per SD, 95% CI 0.80-0.99). In multivariable-adjusted analyses, serum BDNF concentration was not significantly associated with incident AF (hazard ratio 0.98 per SD, 95% CI 0.88-1.09). Compared with the lowest quartile, BDNF levels in the other quartiles were not associated with risk of AF in multivariable-adjusted analyses. No interactions between sex or age with serum BDNF concentrations and risk of AF were found. CONCLUSIONS: In our prospective, community-based sample, we did not find a statistically significant association of serum BDNF levels with risk of incident AF.

Effects of white matter integrity and brain volumes on late life depression in the Framingham Heart Study.

BACKGROUND: It is unclear whether brain white matter hyperintensities (WMHI) causes or is a result of late life depression. We used the Framingham Heart Study offspring to examine whether indices of brain aging are related to incident depression in the elderly. METHODS: The Center for Epidemiologic Studies Depression Scale (CES-D) was administered along with a brain MRI scan at baseline and was re-administered (n = 1212) at an average 6.6 + 0.6 year follow-up. The outcomes (i) change in CES-D scores from baseline; (ii) depression defined as CES-D ≥16; (iii) severe depression defined as CES-D ≥21; and (iv) CES-D cutoff scores and/or on antidepressant were used. RESULTS: Among those who did not have depression at baseline, 9.1% (n = 110) developed depression, 4.0% (n = 48) developed severe depressive symptoms, and 11.1% (n = 135) were put on antidepressants. When depressive symptoms only was the outcome, we found that baseline WMHI was positively associated with change in CES-D scores and that those with an extensive WMHI at baseline had a high risk of developing severe depressive symptoms; the relationship was strengthened in the absence of cardiovascular diseases. In contrast, when depressive symptoms or taking antidepressant was the outcome, larger total cerebral brain volume and temporal lobe brain volume, but not WMHI, were negatively associated with the development of depression. CONCLUSIONS: Brain WMHI is a probable risk factor for vascular depression in the elderly. The depression outcomes with and without antidepressant were related to different brain pathologies. Copyright © 2016 John Wiley & Sons, Ltd.