Framingham General Cardiovascular Risk Score Research Articles

Longitudinal associations of cardiovascular health and vascular events with incident dementia

IntroductionEvidence supporting cardiovascular diseases could increase the risk of dementia remains fragmented. A comprehensive study to illuminate the distinctive associations across different dementia types is still lacking. This study is...

Machine Learning-Assisted Analysis of Sublingual Microcirculatory Dysfunction for Early Cardiovascular Risk Evaluation and Cardiovascular-Kidney-Metabolic Syndrome Stage in Patients With Type 2 Diabetes Mellitus.

To examine whether sublingual microcirculation can be used as an effective and noninvasive method for assessing cardiovascular, kidney, and metabolic risks in patients with type 2 diabetes mellitus (T2DM). This cross-sectional observational study enrolled 186 patients with T2DM. All patients were evaluated using the Framingham General Cardiovascular Risk Score (FGCRS) and cardiovascular-kidney-metabolic (CKM) syndrome stage. Side-stream dark-field microscopy was used for sublingual microcirculation, including total and perfused vessel density (TVD and PVD). Multiple machine-learning prediction models have been developed for CKM risk and stage assessment in T2DM patients. Receiver operating characteristic (ROC) curves were generated to determine cutoff points. Compared to patients with T2DM, diabetic patients with subclinical atherosclerosis (SA) had a greater CV risk, as measured by the FGCRS, accompanied by markedly decreased microcirculation perfusion. Microcirculatory parameters (TVD and PVD), including carotid intima-media thickness (IMT), brachial-ankle pulse wave velocity (ba-PWV), and FGCRS, were closely associated with SA incidence. Microcirculatory parameters, Index (DMSA screen), and cut-off points were used to screen for SA in patients with T2DM. Furthermore, a new set of four factors identified through machine learning showed optimal sensitivity and specificity for detecting CKM risk in patients with T2DM. Decreased microcirculatory perfusion served as a useful early marker for CKM syndrome risk stratification in patients with T2DM without SA. Sublingual microcirculatory dysfunction is closely correlated with the risk of SA and CKM risk in T2DM patients. Sublingual microcirculation could be a novel tool for assessing the CKM syndrome stage in patients with T2DM.

Distinct Lipidomic Profiles between People Living with HIV Treated with E/C/F/TAF or B/F/TAF: An Open-Label Prospective Cohort Study.

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) has been increasingly replaced by bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in the treatment of human immunodeficiency virus (HIV) owing to its more favorable pharmacokinetics and fewer drug-drug interactions. However, the effect of this switch on plasma lipids and lipidomic profiles remains poorly characterized. HIV infected patients on an E/C/F/TAF regimen were recruited into the study and followed up every 12weeks. Participants were divided into E/C/F/TAF and B/F/TAF groups depending on whether they were switched to B/F/TAF during follow-up. Clinical information and blood samples were collected at 0, 12, and 24weeks, and lipidomic analysis was performed using liquid chromatography mass spectrometry. No significant differences were observed between the groups at baseline. At week 24, patients switched to B/F/TAF had lower triglyceride [mmol/L; 1.23 (0.62) versus 2.03 (0.75), P = 0.001] and very low-density lipoprotein cholesterol [mmol/L; 0.64 (0.26) versus 0.84 (0.32), P = 0.037) compared with patients who continued E/C/F/TAF therapy. Small decrease from baseline in Framingham general cardiovascular risk score (FRS) was observed in the B/F/TAF arm [week (W) 0: 2.59 (1.57) versus W24: 2.18 (1.01), P = 0.043]. Lipidomic analysis indicated that E/C/F/TAF treatment increased the levels of several diglycerides (DGs), triacylglycerols (TAGs), and lyso-phosphatidylcholines (LPCs), whereas switching to B/F/TAF led to increased sphingolipids and glycerophospholipids. After adjusting for demographic and clinical parameters, only DG (16:0/18:2), DG (18:2/22:6), DG (18:3/18:2), DG (20:5/18:2), TAG (18:3/18:2/21:5), TAG (20:5/18:2/22:6), and LPC (22:6) were found to be significantly associated with FRS (regression coefficient of 0.17-6.02, P < 0.05). Most of these FRS associate lipid species were significantly elevated in individuals treated with E/C/F/TAF instead of individuals treated with B/F/TAF. E/C/F/TAF promotes the accumulation of lipid species closely associated with cardiovascular disease (CVD) risk among people living with HIV, whereas B/F/TAF has a decreased impact on CVD-related lipid profile and is associated with lower CVD risk. A graphical abstract is available with this article. ClinicalTrials.gov; identifier, NCT06019273.

Cardiovascular risk burden and disability: findings from the International Mobility in Aging Study (IMIAS).

The association of cardiovascular risk burden with disability is unclear. We examined the association between trajectories of the Framingham general cardiovascular disease risk score (FGCRS) with the trajectories of limitations of physical function in older adults. A total of 1219 participants with no disabilities from the International Mobility in Aging Study (IMIAS) study who had up to three repeated measures of FGCRS between 2012-2016 and without a history of stroke or coronary heart disease at baseline and follow-up were included. FGCRS at baseline was assessed and categorized into tertiles. Physical function was evaluated with the Short Physical Performance Battery (SPPB). The data were analyzed using linear mixed-effects models. At baseline, FGCRS ranged between 3-94 (mean score: 24 ± 15.8), participants were 32 (2.6%), 502 (41.2%) and 685 (56.2%) in lowest, middle, and highest tertiles, respectively. In the trajectories of limitations of physical function, the lowest FGCRS had no differences, while the middle and highest had a decrease in physical performance between 2012-2014 (P = 0.0001). Age, being female, living in Andes Mountains, having middle and highest FGCRS, higher alcohol consumption, being obese, lack of exercise and cognitive impairment increase the probability of disability (P < 0.05). Alternatively, living in more developed regions and having a higher educational level reduced the probability of disability during the follow-up time (P < 0.05). Higher cardiovascular risk burden is associated with decreased physical performance, especially in gait. Results suggest SPPB may provide a measure of cardiovascular health in older adults.

Cardiovascular risk burden, dementia risk and brain structural imaging markers: a study from UK Biobank

BackgroundCardiovascular risk burden is associated with dementia risk and neurodegeneration-related brain structure, while the role of genetics and incident cardiovascular disease (CVD) remains unclear.AimsTo examine the association of overall cardiovascular...

Validation of the Framingham General Cardiovascular Risk Score and Pooled Cohort Equations in a Community-Based Population: A Prospective Cohort Study Analysis 2006-2017.

The 10-year atherosclerotic cardiovascular disease (ASCVD) risk - as assessed using the Framingham general cardiovascular risk score (FRS-CVD) or pooled cohort equations (PCE) - is commonly used in Western cohorts for the primary prevention of cardiovascular disease (CVD). However, the FRS-CVD and PCE have not been validated in Taiwanese cohorts. We aimed to validate the FRS-CVD and PCE for assessing the 10-year ASCVD risk using a Taiwanese community-based population. We extracted patient data from the Landseed Integrated Outreaching Neighborhood Screening registry, a community-based prospective cohort study established in 2006. Cardiovascular events from 2006 to 2017 were determined from electronic medical records. The discriminative power and calibration of the FRS-CVD and PCE were evaluated. Overall, 5,139 subjects were analyzed; the 10-year follow-up rate was 99.6%. The mean age at baseline was 52.8 ± 13.1 years, and 44.6% of the subjects were male. In total, 430 of 4,631 (9.3%) and 227 of 4,022 (5.6%) of the FRS-CVD- and PCE-like cohorts, respectively, had ASCVD events. The calibration χ2 of the FRS-CVD was 7.0267 (p = 0.6343) in males and 7.8845 (p = 0.5458) in females; the χ2 of PCE was 13.007 (p = 0.1623) in males and 38.785 (p < 0.001) in females. The area under the receiver operating characteristic curve (AUROC) of the FRS-CVD was 0.76 (0.72-0.79) in males and 0.71 (0.67-0.74) in females; the AUROC of PCE was 0.68 (0.62-0.73) in males and 0.61 (0.56-0.67) in females. Except for PCE in females, the FRS-CVD and PCE provided good calibration and modest discrimination in statin-naïve Taiwanese individuals without prior CVD.

Association of baseline level of cardiovascular risk burden and its temporal changes with cognitive decline.

Background and aimPrevious studies on cardiovascular risk burden assessed by the Framingham General Cardiovascular Risk Score (FGCRS) and cognitive trajectories mainly focus on Western populations and most of them have used a single measure of cardiovascular risk. In this study, among middle-aged and older Chinese, we investigated (i) the association of baseline FGCRS with subsequent cognitive decline and (ii) the association of FGCRS change with concomitant cognitive decline.Materials and methodsIn wave 1 to wave 4 (2011–2018) of the China Health and Retirement Longitudinal Study, global cognition was assessed by orientation, memory, and executive function. FGCRS was assessed and categorized into tertiles (low, intermediate, and high) at baseline (2011) and 4 years after (2015). Furthermore, external validation was performed to check its generalizability using the English Longitudinal Study of Ageing (ELSA) 2008–2018.ResultsIn total, 6,402 participants with a mean [standard deviation (SD) age of 57.8 (8.4) years, 49.0% women] with complete baseline data and at least one reassessment of cognitive function were included. A 10% increment in baseline FGCRS was associated with a faster decline in global cognition (−0.010 SD/year, 95% CI −0.013, −0.008). Among 4,336 participants [mean (SD) age of 57.8 (8.2) years, 50.0% women] with data on FGCRS changes, compared to individuals with the consistently low FGCRS (reference group), a faster global cognition decline rate was observed in the low to intermediate group (−0.026 SD/year, 95% CI −0.045, −0.007), the low to high group (−0.052 SD/year, 95% CI −0.102, −0.001), the consistently intermediate group (−0.019 SD/year, 95% CI −0.033, −0.005), the intermediate to high group (−0.040 SD/year, 95% CI −0.058, −0.022), the high to intermediate group (−0.024 SD/year, 95% CI −0.047, −0.002), and the consistently high group (−0.047 SD/year, 95% CI −0.060, −0.034). Similar trends were observed for individual cognitive domains. Results from the external validation using the ELSA remained consistent.ConclusionHigher baseline FGCRS was associated with faster cognitive decline. However, there was no consistent relationship between the direction of changes in FGCRS and cognitive decline.

Influence of cardiovascular risk burden on pulmonary function trajectory: role of physical and social activities.

The impact of cardiovascular risk burden on long-term trajectories of pulmonary function (PF) remains unclear. We examined the association of cardiovascular risk burden assessed by Framingham general cardiovascular risk score (FGCRS) with PF decline and explored whether cardiovascular diseases (CVD), physical and social activities play a role in the association. Within the Rush Memory and Aging Project, 1,442 participants (mean age:79.83) were followed up to 22 years. FGCRS at baseline was calculated and categorized into tertiles. Composite PF was measured annually based on peak expiratory flow, forced expiratory volume in one second, and forced vital capacity. We found that the highest FGCRS was associated with faster PF decline (β: -0.013, 95% CI: -0.023 to -0.003) compared with the lowest FGCRS. There were significant interactions between higher FGCRS and low level of physical/social activity (β: -0.014, 95% CI: -0.026 to -0.003)/(β: -0.020, 95% CI:-0.031 to -0.009) or CVD(β: -0.023, 95% CI:-0.034 to -0.011) compared to the low FGCRS with high level of physical/social activity or without CVD (P-interaction<0.05). Our results suggest that higher cardiovascular risk burden is associated with a faster PF decline, especially among people with CVD. High level of physical activity and social activity appears to mitigate this association.

Healthy Eating Index-2015 and Predicted 10-Year Cardiovascular Disease Risk, as Well as Heart Age.

Background and AimsDietary factor plays an important role in the prevention of cardiovascular disease (CVD). The healthy eating index-2015 (HEI-2015), an indicator of the overall dietary quality, has been introduced to reflect adherence to the 2015–2020 Dietary Guidelines for Americans (DGA). This study aims to explore the associations of the HEI-2015 with predicted 10-year CVD risk and heart age among United States adults aged 30–74 years old using data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014.Methods and ResultsWe conducted a cross-sectional analysis among 6,614 participants aged 30–74 years old. The HEI-2015 scores were calculated from 2-days 24-h dietary recall interviews. The 10-year CVD risk and heart age were derived from the sex-specific Framingham general cardiovascular disease risk score. We defined high cardiovascular disease risk as a predicted 10-year cardiovascular disease risk of > 20%. Multiple linear regression and binary logistic regression models were used to investigate the associations of the HEI-2015 with predicted 10-year CVD risk and heart age. Compared with participants in the lowest HEI-2015 quartile, those in the highest quartile had lower predicted 10-year CVD risk (β = −2.37, 95% CI: −3.09 to –1.65, P < 0.0001), lower heart age (β = −2.63, 95% CI: −3.29 to –1.96, P < 0.0001) and lower odds for high risk of CVD (OR = 0.62, 95% CI: 0.49 to 0.80, P-trend < 0.0001) after adjusting for multiple covariates.ConclusionHigher adherence to the 2015–2020 Dietary Guidelines for Americans is associated with lower predicted 10-year cardiovascular disease risk and lower heart age among United States adults.

Influence of Cardiovascular Risk Burden on Motor Function Among Older Adults: Mediating Role of Cardiovascular Diseases Accumulation and Cognitive Decline.

PurposeThis study aimed to investigate the association of the cardiovascular risk burden assessed by the Framingham General Cardiovascular Risk Score (FGCRS) with the trajectories of motor function over time and to assess the mediating effects of cardiovascular diseases (CVDs) accumulation and cognitive decline in such association.MethodsIn Rush Memory and Aging Project, a total of 1,378 physical health participants (mean age: 79.3 ± 7.3 years) were followed up for up to 22 years. FGCRS at baseline was assessed and categorized into tertiles (lowest, middle, and highest). Global motor function (including dexterity, gait, and hand strength) was assessed annually with 10 motor tests. CVDs (including stroke, congestive heart failure, and other heart diseases) were ascertained at baseline and follow-ups, and the number of CVDs accumulation over time was assessed. Global cognitive function was tested annually by 19 tests. Data were analyzed using the linear mixed-effects models and mediation analysis.ResultsAt baseline, FGCRS ranged from 4 to 28 (mean score: 15.6 ± 3.7). Over the follow-up (median: 5.3 years; interquartile range: 2.9–9.0 years), in multi-adjusted mixed-effects models, the highest FGCRS was associated with faster decline in global motor function (β = −0.0038; 95% confidence interval [CI]: −0.0069 to −0.0008), dexterity (β = −0.0056; 95% CI: −0.0093 to −0.0020), gait (β = −0.0039; 95% CI: −0.0077 to −0.0001), and hand strength (β = −0.0053; 95% CI: −0.0098 to −0.0008) compared with the lowest tertile. In mediation analysis, CVDs accumulation and cognitive decline mediated 8.4% and 42.9% of the association between FGCRS and global motor function over time, respectively.ConclusionHigher cardiovascular risk burden is associated with a faster decline in motor function including dexterity, gait, and hand strength. CVDs accumulation and cognitive decline may partially mediate the association between cardiovascular risk burden and global motor function decline.

Lipoprotein oxidation may underlie the paradoxical association of low cholesterol with coronary atherosclerotic risk in rheumatoid arthritis

ObjectiveTo compare coronary plaque burden, proatherogenic cytokines, oxidized low-density lipoprotein (oxLDL), anti-oxLDL antibodies, lipoprotein(a)-cholesterol, and their relationships in patients with rheumatoid arthritis with low-density lipoprotein cholesterol (LDL-C)<1.8 mmol/L versus ≥1.8 mmol/L. Also, to study differences in inflammation and proprotein convertase subtilisin/kexin type-9 (PCSK9), which impacts LDL clearance, in patients with low versus high LDL-C. MethodsComputed tomography angiography evaluated coronary plaque (noncalcified, partially calcified, fully calcified, and high-risk plaque) in 150 patients from a single-center observational cohort. Ox-LDL, anti-oxLDL IgG, lipoprotein(a)-cholesterol, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6, tumor necrosis factor-α (TNF-α) and PCSK9 were measured. Analyses adjusted for Framingham general cardiovascular risk score, statin use, and high-density lipoprotein cholesterol. ResultsPatients with LDL-C<1.8 mmol/L versus ≥1.8 mmol/L demonstrated: 1) higher likelihood of per-segment plaque (adjusted-OR = 1.67 [95%CI = 1.10–2.55], p = 0.017) and high-risk plaque presence (adjusted-OR 2.78 [95%CI = 1.06–7.29], p = 0.038); 2) greater anti-oxLDL titers (p = 0.020), which positively associated with TNF-α and likelihood of noncalcified, partially calcified and high-risk plaque presence only in patients with LDL-C<1.8 mmol/L (all p-for-interaction≤0.046); 3) increased lipoprotein(a)-cholesterol content (10.33% [8.11–12.54] versus 6.68% [6.10–7.25], p < 0.001), which positively associated with oxLDL (p < 0.001) and anti-oxLDL (p = 0.036); 4) higher interleukin-6 and PCSK9. No differences in CRP, ESR, or oxLDL were observed. ConclusionRA patients with LDL-C<1.8 mmol/L had more coronary plaque, higher anti-oxLDL titers and anti-oxLDL associated with plaque only in this group. It is possible the observed paradoxical association of low LDL-C with greater atherosclerosis may be related to higher production of the oxidation-prone lipoprotein(a)-cholesterol and anti-oxLDL antibodies, resulting in increased vascular LDL uptake and plaque formation.

Assessing the cumulative impact of vascular burden on structural changes in the brain during ageing

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia. Yet more recent findings from epidemiological and neuropathological studies have revealed the presence of vascular pathology in AD. There is overwhelming evidence from pathological examinations that indicates the presence of ‘mixed cases’ at autopsy. The study aim was to examine whether overall vascular burden measured by the Framingham General Cardiovascular Risk Score (FGCRS) is associated with brain structural changes.MethodIn the first analysis a Voxel Based Morphometry (VBM) multiple regression model was used with group status (60 controls, 74 Mild Cognitive Impairment and 51 AD) and Framingham vascular risk scores as predictors while accounting for age, total intracranial volume, years of education. In the second model a 2x2x2 factorial design with different group comparisons was used with group, APOE ε4 carrier status and Vascular Burden (low vs high load) to understand the interactions across the factors.ResultThe VBM regression model implicated regions that included the thalamus, subcallosal gyrus, precentral and postcentral gyrus, cerebellum, occipital gyri, inferior frontal gyrus, insula and the cuneus.The factorial analysis revealed two different set of interaction effects. There was a APOE x Vascular Burden interaction effect between controls and MCI. The regions implicated in this analysis included the cerebellum, right inferior occipital gyrus, right thalamus, left brainstem, left fusiform gyrus, left precentral and postcentral gyrus and left Insula. There also was a Group x APOE Status x Vascular Burden interaction effect that involved the left brainstem and left parahippocampal gyrus during the transition from MCI and AD.ConclusionThe voxel‐based regression model and the first factorial analysis implicated areas that comprises both cerebellar and subcortical regions that have been previously implicated in dementia with vascular pathology. The areas implicated by vascular pathology have been shown to affect primarily gait, movement and visuospatial abilities. But given that the brainstem and its nuclei are also involved, future studies should look at examining the role of vascular pathology and how it affects the neuromodulatory systems of the brainstem and whether these projections have any effect on the efficient functioning of large‐scale brain networks.

Abstract 13245: Cardiovascular Risk Burden in Relation to Dementia and Brain Structural Imaging Markers: A Study From UK Biobank

Introduction: Cardiovascular risk burden is associated with higher all-cause dementia risk. However, the roles of cardiovascular disease (CVD) and genetic background, and the associations of cardiovascular risk burden with dementia subtypes and brain structure, need to be examined. Hypothesis: We hypothesized that the Framingham General Cardiovascular Risk Score (FGCRS) would be associated with all-cause and subtypes of dementia and brain structure. Methods: We conducted a prospective study among 354,654 participants free of CVD and dementia at baseline (2006-2010, mean age 56.4 years) within UK Biobank. CVD risk burden was evaluated by baseline FGCRS. Dementia case was identified from hospital inpatient records and death register data. Brain MRI volume markers were available for 15,104 participants since 2014. Logistic and linear regression models were used for dementia risk and brain volumes, respectively. Results: During a median 12.0 years of follow-up, 3,996 all-cause dementia cases were identified. Higher FGCRS was associated with an increased all-cause dementia risk after adjusting for demographic, major lifestyle, clinical factors, and polygenic risk score (PRS) of Alzheimer’s disease (AD). Comparing the high vs. low tertile of FGCRS, the odds ratios (ORs) and 95% CIs were 1.26 (1.12, 1.42) for all-cause dementia, 1.67 (1.33, 2.09) for AD, and 1.53 (1.08, 2.17) for vascular dementia (all P trend &lt; 0.05). Incident stroke and coronary heart disease accounted for 13% (95% CI: 9%, 19%) of the association of FGCRS with all-cause dementia. Interaction was not detected for FGCRS and PRS on risk of all-cause or any subtype of dementia (all P for interaction &gt; 0.05). We observed an 83% (95% CI: 47%, 128%) higher all-cause dementia risk comparing the high-high vs. low-low for FGCRS-PRS category. For standardized brain volumes, higher FGCRS was associated with greater log-transformed white matter hyperintensities, smaller cortical volume, and smaller grey matter volume. Conclusions: Cardiovascular risk burden was associated with higher dementia risk and neurodegeneration-related brain volume markers. The association of cardiovascular risk burden with all-cause dementia was partly explained by CVD onset and independent of dementia genetic risk.

The Association Between Perivascular Spaces and Cerebral Blood Flow, Brain Volume, and Cardiovascular Risk.

Background: Basal ganglia perivascular spaces are associated with cognitive decline and cardiovascular risk factors. There is a lack of studies on the cardiovascular risk burden of basal ganglia perivascular spaces (BG-PVS) and their relationship with gray matter volume (GMV) and GM cerebral blood flow (CBF) in the aging brain. Here, we investigated these two issues in a large sample of cognitively intact older adults.Methods: A total of 734 volunteers were recruited. MRI was performed with 3.0 T using a pseudo-continuous arterial spin labeling (pCASL) sequence and a sagittal isotropic T1-weighted sequence for CBF and GMV analysis. The images obtained from 406 participants were analyzed to investigate the relationship between the severity of BG-PVS and GMV/CBF. False discovery rate-corrected P-values (PFDR) of <0.05 were considered significant. The images obtained from 254 participants were used to study the relationship between the severity of BG-PVS and cardiovascular risk burden. BG-PVS were rated using a 5-grade score. The severity of BG-PVS was classified as mild (grade <3) and severe (grade ≥3). Cardiovascular risk burden was assessed with the Framingham General Cardiovascular Risk Score (FGCRS).Results: Severe basal ganglia perivascular spaces were associated with significantly smaller GMV and CBF in multiple cortical regions (PFDR <0.05), and were associated with significantly larger volume in the bilateral caudate nucleus, pallidum, and putamen (PFDR <0.05). The participants with severe BG-PVS were more likely to have a higher cardiovascular risk burden than the participants with mild BG-PVS (60.71% vs. 42.93%; P =0.02).Conclusion: In cognitively intact older adults, severe BG-PVS are associated with smaller cortical GMV and CBF, larger subcortical GMV, and higher cardiovascular risk burden.

Association of cardiovascular risk burden with risk of dementia and brain pathologies: A population-based cohort study.

The impact of cardiovascular risk burden on brain pathologies remains unclear. We aimed to examine the association of the Framingham General Cardiovascular Risk Score (FGCRS) with dementia risk, and brain pathologies. Within the Rush Memory and Aging Project, 1588 dementia-free participants were assessed on FGCRS at baseline and followed up to 21 years. During the follow-up, 621 participants died and underwent autopsies. The multi-adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of FGCRS were 1.03 (1.00-1.07) for dementia and 1.04 (1.01-1.07) for Alzheimer's disease (AD) dementia. Further, a higher FGCRS was associated with higher gross chronic cerebral infarctions (odds ratio [OR] 1.08, 95% CI 1.02-1.14), cerebral atherosclerosis (OR 1.10, 95% CI 1.03-1.17), and global AD pathology (OR 1.06, 95% CI 1.01-1.12). A higher FGCRS is associated with an increased risk of dementia and AD dementia. Both vascular and AD pathologies in the brain may underlie this association.

Cardiovascular Risk Burden in Relation to Dementia and Brain Structural and Metabolic Imaging Markers

Background: The roles of cardiovascular disease (CVD) and dementia genetic predisposition in the association of cardiovascular risk burden with dementia need to be elucidated. Relevant evidence regarding the brain structural and metabolic pathways underlying this association is scarce. Methods: We conducted a prospective cohort study among 354,654 participants free of baseline CVD and dementia (2006-2010, mean age 56.4 years) within UK Biobank (UKB); brain MRI measurement was available for 15,104 participants since 2014. Cardiovascular risk burden was evaluated by baseline Framingham General Cardiovascular Risk Score (FGCRS); polygenic risk score (PRS) was constructed from common Alzheimer’s disease (AD) variants. Incident dementia was identified from hospital inpatient and death register data. The associations of cardiovascular risk burden with brain glucose uptake indices were evaluated cross-sectionally among 304 individuals free of CVD and cancer with 18F-FDG PET/CT scan measurement in a hospital-based study in China. Findings: During a median 12.0-year follow-up, 3,998 all-cause dementia cases were identified in UKB. Higher FGCRS was associated with increased all-cause dementia risk after controlling for demographic, major lifestyle, clinical factors, and PRS. The corresponding ORs (95% CIs) across increasing FGCRS tertiles were1.00 (ref), 1.10 (0.98, 1.23), and 1.26 (1.12, 1.41) (Ptrend 0.05). Regarding the joint association of FGCRS and PRS with all-cause dementia, we observed an 83% (95% CI: 47%, 128%) higher risk comparing the high-high vs. low-low category. For standardized brain volumes, higher FGCRS was associated with greater white matter hyperintensities (log-transformed), and smaller grey matter volume and cortical volume. FGCRS was inversely associated with the glucose uptake level in all brain lobes and total grey matter. Interpretation: Higher cardiovascular risk burden was associated with higher dementia risk and neurodegeneration-related brain volumes and lower glucose uptake in brain. The association of cardiovascular risk burden with all-cause dementia was partially mediated by CVD onset and independent of dementia genetic risk. Funding: National Key Research and Development Plan of China, Zhejiang University Education Foundation Global Partnership Fund, National Science Fund for Excellent Young Scholars, and Talent Introduction Programme of Chinese Academy of Sciences. Declaration of Interest: None to declare. Ethical Approval: This study received ethical approval from the North West Multi-center Research Ethics Committee (REC reference: 16/NW/0274).

Tau Pathologies Mediate the Associations of Vascular Risk Burden with Cognitive Impairments in Non-demented Elders: The CABLE Study.

Studies suggested that vascular dysfunction might increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms still remain obscure. To evaluate the associations of vascular risk burden with AD core pathologies and investigate the effects of AD core pathologies on relationships between vascular risk burden and cognitive impairments. The Chinese Alzheimer's Biomarker and LifestyLE (CABLE) study was principally focusing on aging, as well as the risk factors and biomarkers of AD initiated in 2017. The CABLE study was a large cohort study established in Qingdao, China. A total of 618 non-demented elders were obtained from CABLE study. The general vascular risk burden was assessed by the Framingham General Cardiovascular Risk Score (FGCRS). Multivariate linear regression analyses were performed to evaluate the associations of FGCRS with cerebrospinal fluid (CSF) AD biomarkers and cognition. Casual mediation analyses were performed to investigate the mediating effects of AD biomarkers on cognition. Increased FGCRS was related to higher levels of CSF total tau (t-tau, p < 0.001), phosphorylated tau (p-tau, p < 0.001) as well as the ratio of t-tau and amyloid-β 42 (t-tau/Aβ42, p = 0.010), and lower Chinese-Modified Mini-Mental State Examination (CM-MMSE, p = 0.010) score. Stratified analysis indicated that age modified the associations, with FGCRS being significantly associated with tau pathology (p < 0.001 for t-tau and p-tau) in middle-aged group (<65 years old), instead of older group. The influences of FGCRS on cognitive impairments were partially mediated by tau pathologies (a maximum proportion of 20.9%). Tau pathology might be a pivotal mediator for effects of vascular risk on cognitive decline. Early and comprehensive intervention for vascular risk factors might be a potential approach to delaying or preventing cognitive impairment and AD.

Association of Low Systolic Blood Pressure with Postmortem Amyloid-β and Tau.

Vascular mechanisms may contribute to the accumulation of AD pathology. We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association. We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau levels and examined if the FRS modified the association of the amyloid-β with tau. On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r = -0.00, p = 0.918) or tau (r = 0.01, p = 0.701). However, the FRS as a whole (estimate = -0.022, SE = 0.008, p = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = -0.033, SE = 0.012, p = 0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP. Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.

Association of Cardiovascular Risk Burden With Risk and Progression of Disability: Mediating Role of Cardiovascular Disease and Cognitive Decline.

BackgroundCardiovascular risk burden has been linked to cardiovascular disease (CVD) and cognitive decline, but its association with disability is unclear. We aimed to examined the association of cardiovascular risk burden assessed by the Framingham general cardiovascular risk score (FGCRS) with the risk and progression of disability and estimated the extent to which CVD and cognitive decline mediate this association.Methods and ResultsA total of 1480 older adults with no disabilities (mean age=79.32±7.38 years) from the Rush Memory and Aging Project were followed for up to 21 years. FGCRS at baseline was calculated and categorized into tertiles. Disability was assessed annually with activities of daily living. The number of CVDs was calculated by summing up the CVD events. Global cognitive function was assessed annually with a battery of 19 tests. Data were analyzed using the Cox model, linear mixed effects model, and mediation analysis. At the end of the follow‐up, 713 (48.2%) participants developed disability. Compared with the lowest tertile of the FGCRS, the multiadjusted hazards ratios of disability were 1.34 (95% CI, 1.11–1.62) for the highest tertile. In addition, the highest FGCRS was associated with a change in activities of daily living score over time (β=0.057; 95% CI, 0.021–0.093). The association between FGCRS and change in activities of daily living was 13.8% mediated by the accumulation of CVDs and 25.1% by cognitive decline, respectively.ConclusionsHigher cardiovascular risk burden increased the risk of disability and accelerated its progression over time. CVD accumulation and cognitive decline may partially mediate the association.

Associations Between Cardiovascular Risk, Structural Brain Changes, and Cognitive Decline

BackgroundThe impact of cardiovascular risk burden on cognitive trajectories and brain structure changes remains unclear. ObjectivesThis study aimed to examine whether cardiovascular risk burden assessed by the Framingham General Cardiovascular Risk Score (FGCRS) is associated with cognitive decline and structural brain differences. MethodsWithin the Rush Memory and Aging Project, 1,588 dementia-free participants (mean age: 79.5 years) were followed for up to 21 years. FGCRS was assessed at baseline and categorized into tertiles (lowest, middle, and highest). Episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with a battery of 19 tests, from which composite scores were derived. A subsample (n = 378) of participants underwent magnetic resonance imaging. Structural total and regional brain volumes were estimated. Data were analyzed using linear mixed-effects models and linear regression models. ResultsIn all participants, FGCRS ranged from 4 to 28 (mean score: 15.6 ± 3.7). Compared with the lowest tertile of FGCRS, the highest tertile was associated with faster decline in global cognition (β = −0.019; 95% confidence interval [CI]: −0.035 to −0.003), episodic memory (β = −0.023; 95% CI: −0.041 to −0.004), working memory (β = −0.021; 95% CI: −0.035 to −0.007), and perceptual speed (β = −0.027; 95% CI: −0.042 to −0.011) over the follow-up. In magnetic resonance imaging data analyses, higher FGCRS was related to smaller volumes of the hippocampus (β = −0.021; 95% CI: −0.042 to −0.000), gray matter (β = −1.569; 95% CI: −2.757 to −0.382), and total brain (β = −1.588; 95% CI: −2.832 to −0.344), and greater volume of white matter hyperintensities (β = 0.035; 95% CI: 0.001 to 0.069). ConclusionsHigher cardiovascular risk burden may predict decline in episodic memory, working memory, and perceptual speed and is associated with neurodegeneration and vascular lesions in the brain.