Cardiovascular and hemodynamic contribution to brain aging

In summary, chapter 1 of this thesis provides a background on the demographic, biologic and cardiovascular aspects of brain aging. Chapter 2 shows that higher blood pressure is associated with lower cognitive decline in very old age. Findings of Chapter 3 indicate that higher blood pressure is associated with lower risk of stroke in very old subjects with higher degrees of disability. In chapter 4, we showed that visit-to-visit blood pressure variability might put subjects at a higher risk for accelerated brain aging. In Chapters 5 to 7, we observed that a strong association exists between a graded decrease in cardiac function and lower brain volumes and cognitive performance. In a meta-analysis (Chapter 8), we demonstrated that in patients with Alzheimer__s disease and vascular dementia have profound disturbances in their cerebrovascular hemodynamics. Chapter 9 shows that in late life, conventional cardiovascular risk factors loss their predictive value while impaired cognitive function better predicts risk of stroke. In Chapter 10, we showed that increased serum markers of endothelial dysfunction associate with lower cerebral blood flow in older subjects. In Chapter 11, we demonstrated that older subjects with lower cerebral blood flow have a shorter survival. Chapter 12 reviews the key findings of this thesis and discusses them in the context of current knowledge and evidence.Financial support for printing of this thesis was provided by the Leiden University Medical Centre, Leyden Academy on Vitality and Ageing, and Internationale Stichting Alzheimer Onderzoek (ISAO.UBL - phd migration 201

Lower Performance in Orientation to Time and Place Associates with Greater Risk of Cardiovascular Events and Mortality in the Oldest Old: Leiden 85-Plus Study

Background: Impairment in orientation to time and place is commonly observed in community-dwelling older individuals. Nevertheless, the clinical significance of this has been not fully explored. In this study, we investigated the link between performance in orientation domains and future risk of cardiovascular events and mortality in a non-hospital setting of the oldest old adults.Methods: We included 528 subjects free of myocardial infarction (Group A), 477 individuals free of stroke/transient ischemic attack (Group B), and 432 subjects free of both myocardial infarction and stroke/transient ischemic attack (Group C) at baseline from the population-based Leiden 85-plus cohort study. Participants were asked to answer five questions related to orientation to time and five questions related to orientation to place. 5-year risks of first-time fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, as well as cardiovascular and non-cardiovascular mortality, were estimated using the multivariate Cox regression analysis.Results: In the multivariable analyses, adjusted for sociodemographic characteristics and cardiovascular risk factors, each point lower performance in “orientation to time” was significantly associated with higher risk of first-time myocardial infarction (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.09–1.67, P = 0.007), first-time stroke (HR 1.35, 95% CI 1.12–1.64, P = 0.002), cardiovascular mortality (HR 1.28, 95% CI 1.06–1.54, P = 0.009) and non-cardiovascular mortality (HR 1.37, 95% CI 1.20–1.56, P < 0.001). Similarly, each point lower performance in “orientation to place” was significantly associated with higher risk of first-time myocardial infarction (HR 1.67, 95% CI 1.25–2.22, P = 0.001), first-time stroke (HR 1.39, 95% CI 1.05–1.82, P = 0.016), cardiovascular mortality (HR 1.35, 95% CI 1.00–1.82, P = 0.054) and non-cardiovascular mortality (HR 1.45, 95% CI 1.20–1.77, P < 0.001).Conclusions: Lower performance in orientation to time and place in advanced age is independently related to higher risk of myocardial infarction, stroke and mortality. Impaired orientation might be an early sign of covert vascular injuries, putting subjects at greater risk of cardiovascular events and mortality

Ventricular repolarization is associated with cognitive function, but not with cognitive decline and brain Magnetic Resonance Imaging (MRI) measurements in older adults

We aimed to investigate the cross-sectional and longitudinal associations of electrocardiogram (ECG)-based QT, QTc, JT, JTc, and QRS intervals with cognitive function and brain magnetic resonance imaging (MRI) measurements in a cohort of older individuals at increased risk for cardiovascular disease, but free of known arrhythmias. We studied 4627 participants (54% female, mean age 75 years) enrolled in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Ten-second ECGs were conducted at baseline. Cognitive function was tested at baseline and repeated during a mean follow-up time of 3.2 years. Structural MRIs were conducted in a subgroup of 535 participants. Analyses were performed with multivariable (repeated) linear regression models and adjusted for cardiovascular risk-factors, co-morbidities, and cardiovascular drug use. At baseline, longer QT, JT, JTc—but not QTc and QRS intervals—were associated with a worse cognitive performance. Most notably, on the Stroop Test, participants performed 3.02 (95% CI 0.31; 5.73) seconds worse per standard deviation higher QT interval, independent of cardiovascular risk factors and medication use. There was no association between longer ventricular de- or repolarization and structural brain measurements. Therefore, specifically ventricular repolarization was associated with worse cognitive performance in older individuals at baseline but not during follow-up

Cognitive impairment and risk of stroke in the oldest old: the Leiden 85-plus study

Public Health and primary careGeriatrics in primary car

Contributions of cerebral blood flow to associations between blood pressure levels and cognition the age, gene/environment susceptibility-Reykjavik study

Cerebral hypoperfusion leads to adverse sequalae including dementia. Midlife higher blood pressure (BP) can lead to low cerebral blood flow (CBF), but older persons may need higher BP to maintain cerebral perfusion. We investigated the associations among late-life BP, CBF, and cognition. Data are from 2498 participants with a mean age of 79.8 (SD, 4.7) years of the second exam of the AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study. BP was measured, and phase-contrast (PC) magnetic resonance imaging was acquired to estimate total brain CBFPC. Cognitive outcomes included verbal and working memory, processing speed, mild cognitive impairment, and all-cause dementia. Relationships among late-life BP, CBFPC, and cognition were assessed with regression models, controlling for socio-demographics, BP level at midlife (at a mean age of 49.6 [SD, 5.9] years), cardiovascular factors, and total brain volume. In fully adjusted models, each mm Hg increase in late-life diastolic BP was associated with a -0.082 mL/min per 100 mL (95% CI -0.123 to -0.041) lower CBFPC. In contrast, each mm Hg increase in late-life systolic BP or pulse pressure was associated with a 0.027 mL/min per 100 mL (95% CI, 0.0065-0.048) and 0.061 mL/min per 100 mL (95% CI, 0.038-0.084) higher late-life CBFPC, respectively. Higher CBFPC was significantly related to higher cognitive scores for psychomotor speed, verbal, and working memory and to a lower odd of mild cognitive impairment or dementia, irrespective of late-life BP level. Higher late-life diastolic BP and systolic BP were differentially associated with CBFPC. Our findings suggest CBF is an important correlate of late-life cognition, independent of BP level.Neuro Imaging Researc

Spatial QRS-T angle and cognitive decline in older subjects

Background:An abnormally wide spatial QRS-T angle on an ECG is a marker of heterogeneity in electrical activity of cardiac ventricles and is linked with cardiovascular events. Growing evidence suggests that cardiac dysfunction might signal future cognitive decline. Objective: In this study, we investigated whether spatial QRS-T angle associates with future cognitive decline in older subjects at high cardiovascular risk. Methods:We included 4,172 men and women (mean age 75.2±3.3 years) free of cardiac arrhythmias from the PROSPER cohort. Spatial QRS-T angle was calculated from baseline 12-lead ECGs using a matrix transformation method. Cognitive function was assessed using 4 neuropsychological tests including Stroop test, letter-digit coding test, immediate and delayed picture word learning tests. Cognitive function was assessed at baseline and repeatedly during a mean follow-up time of 3.2 years. Using linear mixed models, we calculated the annual changes of cognitive scores in sex-specific thirds of spatial QRS-T angle. Results:Participants with wider spatial QRS-T angle had a steeper decline in letter-digit coding test (β= –0.0106, p = 0.004), immediate picture-word learning test (β= –0.0049, p = 0.001), and delayed picture-word learning test (β= –0.0055, p = 0.013). All associations were independent of arrhythmias, cardiovascular risk factors, comorbidities, medication use, cardiovascular events, and other ECG abnormalities including QRS duration, QTc interval, T wave abnormalities, and left ventricular hypertrophy. Conclusion:Abnormal cardiac electrical activity characterized by wide spatial QRS-T angle associates with accelerated cognitive decline independent of conventional cardiovascular factors. These findings suggest a link between a non-traditional ECG measure of pre-clinical cardiac pathology and future cognitive decline

Association of visit-to-visit variability in blood pressure with cognitive function in old age: prospective cohort study

<p>Objective To investigate the association between visit-to-visit variability in blood pressure and cognitive function in old age (>70 years).</p> <p>Design Prospective cohort study.</p> <p>etting PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) study, a collaboration between centres in Ireland, Scotland, and the Netherlands.</p> <p>Participants 5461 participants, mean age 75.3 years, who were at risk of cardiovascular disease. Blood pressure was measured every three months during an average of 3.2 years. Visit-to-visit variability in blood pressure was defined as the standard deviation of blood pressure measurements between visits.</p> <p>Main outcome measures Four domains of cognitive function, testing selective attention, processing speed, and immediate and delayed memory. In a magnetic resonance imaging substudy of 553 participants, structural brain volumes, cerebral microbleeds, infarcts, and white matter hyperintensities were measured.</p> <p>Results Participants with higher visit-to-visit variability in systolic blood pressure had worse performance on all cognitive tests: attention (mean difference high versus low thirds) 3.08 seconds (95% confidence interval 0.85 to 5.31), processing speed −1.16 digits coded (95% confidence interval −1.69 to −0.63), immediate memory −0.27 pictures remembered (95% confidence interval −0.41 to −0.13), and delayed memory −0.30 pictures remembered (95% confidence interval −0.49 to −0.11). Furthermore, higher variability in both systolic and diastolic blood pressure was associated with lower hippocampal volume and cortical infarcts, and higher variability in diastolic blood pressure was associated with cerebral microbleeds (all P<0.05). All associations were adjusted for average blood pressure and cardiovascular risk factors.</p> Conclusion Higher visit-to-visit variability in blood pressure independent of average blood pressure was associated with impaired cognitive function in old age

Long-Term Factors Associated With Falls and Fractures Poststroke

Background: Risk factors for poststroke falls and fractures remain poorly understood. This study aimed to evaluate which factors increased risk of these events after stroke. Methods: Data from 7,267 hospitalized stroke patients were acquired from the Norfolk and Norwich University Hospital Stroke Register from 2003–2015. The impacts of multiple patient level and stroke characteristics and comorbidities on post-discharge falls and fractures were assessed. Univariate and multivariable models were constructed, adjusting for multiple confounders, using binary logistic regression for short-term analysis (up to 1-year post-discharge) and Cox-proportional hazard models for longer term analysis (1–3, 3–5, and 0–10 years follow-up). Results: The mean age (SD) was 76.3 ± 12.1 years at baseline. 1,138 (15.7%) participants had an incident fall; and 666 (9.2%) an incident fracture during the 10-year follow-up (total person years = 64,447.99 for falls and 67,726.70 for fractures). Half of the sample population were females (50.6%) and the majority had an ischemic stroke (89.8%). After adjusting for confounders: age, sex, previous history of falls, and atrial fibrillation were associated with an increased risk of both falls and fractures during follow-up. Furthermore, chronic kidney disease and hyperlipidemia were associated with an increased risk of falls, while previous stroke/transient ischemic attack increased fracture risk. Total anterior circulation stroke and a prestroke modified Rankin Scale score of 3–5 were associated with decreased risk of both events, with hypertension and cancer decreasing risk of falls only. Conclusion: We identified demographic, stroke-related, and comorbid factors associated with poststroke falls and fracture incidence. Further studies are required to examine and establish the relationship between reversible factors and further explore the role of preventative measures to prevent poststroke falls and fractures

Cognitive function in dementia-free subjects and survival in old Age: The PROSPER study

Impairment in domain-specific cognitive function is associated with the increased risk of mortality. We prospectively evaluated the association of executive function and memory with the risk of long-term mortality in dementia-free older subjects. Moreover, we investigated the role of structural brain abnormalities in this association. We included 547 dementia-free participants (mean age 78years, 56.5% male) from the nested magnetic resonance imaging sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cox proportional hazard models were used to model 10-year risk of all-cause, cardiovascular and non-cardiovascular mortality in relation to performance in executive function and memory. Moreover, we evaluated the role of total brain parenchymal volume, cerebral blood flow, white matter hyperintensity and the presence of microbleeds and infarcts in the link between cognitive function and mortality. In the multivariable model, lower performance in executive function was associated with greater risk of all-cause (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.31-1.70), cardiovascular (HR 1.69, 95%CI 1.36-2.11) and non-cardiovascular (HR 1.36, 95%CI 1.15-1.62) mortality. Similarly, poorer performance in memory tests associated with higher risk of all-cause (HR 1.47, 95%CI 1.29-1.68), cardiovascular (HR 1.45, 95%CI 1.15-1.83) and non-cardiovascular (HR 1.49, 95%CI 1.27-1.76) mortality. The associations were similar in subjects with various levels of brain structural abnormalities and cerebral blood flow (all p for interaction >0.05). Poorer performance in both executive function and memory tests associates with all-cause, cardiovascular and non-cardiovascular mortality in elderly individuals. This association is independent of cardiovascular risk factors and diseases, brain structural abnormalities and cerebral blood flow

Interplay of circulating leptin and obesity in cognition and cerebral volumes in older adults

We aimed to investigate whether circulating leptin and body mass index (BMI) associate independently with cognitive function (decline) and brain volumes using magnetic resonance imaging (MRI) in older individuals at risk of cardiovascular disease. We studied the cross-sectional and longitudinal associations in participants enrolled in the PROSPER study (Prospective Study of Pravastatin in the Elderly at Risk). Cognitive function was tested at baseline and repeated during a mean follow-up time of 3.2 years. Analyses were performed with multivariable (repeated) linear regression models and adjusted for demographics, cardiovascular risk-factors, and stratified by sex. We included 5623 dementia-free participants (52 % female, mean age 75 years) with a mean BMI of 26.9 (SD = 4.1). In a sub-study, 527 participants underwent brain MRI. At baseline, individuals with a BMI > 30 had a worse performance on the Stroop test (beta 5.0 s, 95 %CI 2.6;7.5) and larger volumes of the amygdala (beta 234 mm(3), 95 %CI 3;464) and hippocampus (beta 590 mm(3), 95 %CI 181;999), independent of intracranial volume and serum leptin levels, compared with individuals with the reference BMI (BMI 18-25 kg/m(2)). Per log ng/mL higher serum leptin, independent of BMI, a 135 mm(3) (95 %CI 2;268) higher volume of the amygdala was found, but no association was observed with cognitive tests nor with other brain volumes. Stratification for sex did not materially change the results. Whereas higher BMI associated with worse cognitive function independent of leptin levels, our study provided evidence that leptin and BMI independently associate with amygdala volume suggesting potential distinct biological associations.Neuro Imaging Researc