Chronic hypertension, particularly midlife high blood pressure, has been associated with an increased risk for cognitive decline and dementia. In this context, antihypertensive drugs might have a ...preventive effect, but the association remains poorly understood.
The aim of this systematic review was to examine all published findings that investigated this relationship and discuss the mechanisms underlying the potential benefits of antihypertensive medication use.
A literature search was conducted using MEDLINE, Embase, and the Cochrane Library for publications from 1990 onwards mentioning hypertension, antihypertensive drugs, cognitive decline, and dementia.
A total of 38 relevant publications, corresponding to 18 longitudinal studies, 11 randomized controlled trials, and nine meta-analyses were identified from the 10,251 articles retrieved in the literature search. In total, 1,346,176 subjects were included in these studies; the average age was 74 years. In the seven longitudinal studies assessing the effect of antihypertensive medication on cognitive impairment or cognitive decline, antihypertensive drugs appeared to be beneficial. Of the 11 longitudinal studies that assessed the effect of antihypertensive medication on incidence of dementia, only three did not find a significant protective effect. Antihypertensive medication could decrease the risk of not only vascular dementia but also Alzheimer's disease. Four randomized controlled trials showed a potentially preventive effect of antihypertensive drugs on the incidence of dementia or cognitive decline: SYST-EUR (Systolic Hypertension in Europe Study) I and II, with a 55% reduction in dementia risk (3.3 vs. 7.4 cases per 1,000 patient years; p<0.001); HOPE (Heart Outcomes Prevention Evaluation), with a 41% reduction in cognitive decline associated with stroke (95% confidence interval CI 6-63); and PROGRESS (Perindopril Protection against Recurrent Stroke Study), with a 19% reduction in cognitive decline (95% CI 4-32; p=0.01). Meta-analyses have sometimes produced conflicting results, but this may be due to methodological considerations. The lack of homogeneity across study designs, patient populations, exposition, outcomes, and duration of follow-up are the most important methodological limitations that might explain the discrepancies between some of these studies.
Antihypertensive drugs, particularly calcium channel blockers and renin-angiotensin system blockers, may be beneficial in preventing cognitive decline and dementia. However, further randomized controlled trials with longer periods of follow-up and cognition as the primary outcome are needed to confirm these findings.
Thanks to the growing interest in personalized medicine, joint modeling of longitudinal marker and time‐to‐event data has recently started to be used to derive dynamic individual risk predictions. ...Individual predictions are called dynamic because they are updated when information on the subject's health profile grows with time. We focus in this work on statistical methods for quantifying and comparing dynamic predictive accuracy of this kind of prognostic models, accounting for right censoring and possibly competing events. Dynamic area under the ROC curve (AUC) and Brier Score (BS) are used to quantify predictive accuracy. Nonparametric inverse probability of censoring weighting is used to estimate dynamic curves of AUC and BS as functions of the time at which predictions are made. Asymptotic results are established and both pointwise confidence intervals and simultaneous confidence bands are derived. Tests are also proposed to compare the dynamic prediction accuracy curves of two prognostic models. The finite sample behavior of the inference procedures is assessed via simulations. We apply the proposed methodology to compare various prediction models using repeated measures of two psychometric tests to predict dementia in the elderly, accounting for the competing risk of death. Models are estimated on the French Paquid cohort and predictive accuracies are evaluated and compared on the French Three‐City cohort.
Evidence is limited regarding the relation between cardiovascular health level and dementia risk.
To investigate the association between cardiovascular health level, defined using the 7-item tool ...from the American Heart Association (AHA), and risk of dementia and cognitive decline in older persons.
Population-based cohort study of persons aged 65 years or older from Bordeaux, Dijon, and Montpellier, France, without history of cardiovascular diseases or dementia at baseline who underwent repeated in-person neuropsychological testing (January 1999-July 2016) and systematic detection of incident dementia (date of final follow-up, July 26, 2016).
The number of the AHA's Life's Simple 7 metrics at recommended optimal level (nonsmoking, body mass index <25, regular physical activity, eating fish twice a week or more and fruits and vegetables at least 3 times a day, cholesterol <200 mg/dL untreated, fasting glucose <100 mg/dL untreated, and blood pressure <120/80 mm Hg untreated; score range, 0-7) and a global cardiovascular health score (range, 0-14; poor, intermediate, and optimal levels of each metric assigned a value of 0, 1, and 2, respectively).
Incident dementia validated by an expert committee and change in a composite score of global cognition (in standard units, with values indicating distance from population means, 0 equal to the mean, and +1 and -1 equal to 1 SD above and below the mean).
Among 6626 participants (mean age, 73.7 years; 4200 women 63.4%), 2412 (36.5%), 3781 (57.1%), and 433 (6.5%) had 0 to 2, 3 to 4, and 5 to 7 health metrics at optimal levels, respectively, at baseline. Over a mean follow-up duration of 8.5 (range, 0.6-16.6) years, 745 participants had incident adjudicated dementia. Compared with the incidence rate of dementia of 1.76 (95% CI, 1.38-2.15) per 100 person-years among those with 0 or 1 health metrics at optimal levels, the absolute differences in incident dementia rates for 2, 3, 4, 5, and 6 to 7 metrics were, respectively, -0.26 (95% CI, -0.48 to -0.04), -0.59 (95% CI, -0.80 to -0.38), -0.43 (95% CI, -0.65 to -0.21), -0.93 (95% CI, -1.18 to -0.68), and -0.96 (95% CI, -1.37 to -0.56) per 100 person-years. In multivariable models, the hazard ratios for dementia were 0.90 (95% CI, 0.84-0.97) per additional optimal metric and 0.92 (95% CI, 0.89-0.96) per additional point on the global score. Furthermore, the gain in global cognition associated with each additional optimal metric at baseline was 0.031 (95% CI, 0.009-0.053) standard units at inclusion, 0.068 (95% CI, 0.045-0.092) units at year 6, and 0.072 (95% CI, 0.042-0.102) units at year 12.
In this cohort of older adults, increased numbers of optimal cardiovascular health metrics and a higher cardiovascular health score were associated with a lower risk of dementia and lower rates of cognitive decline. These findings may support the promotion of cardiovascular health to prevent risk factors associated with cognitive decline and dementia.
Consuming fruit and vegetables (FVs) may protect against frailty, but to our knowledge no study has yet assessed their prospective dose-response relation.
We sought to examine the dose-response ...association between FV consumption and the risk of frailty in older adults.
Data were taken from 3 independent cohorts of community-dwelling older adults: the Seniors-ENRICA (Study on Nutrition and Cardiovascular Risk Factors in Spain) cohort (n = 1872), Three-City (3C) Bordeaux cohort (n = 581), and integrated multidisciplinary approach cohort (n = 473). Baseline food consumption was assessed with a validated computerized diet history (Seniors-ENRICA) or with a food-frequency questionnaire (3C Bordeaux and AMI). In all cohorts, incident frailty was assessed with the use of the Fried criteria. Results across cohorts were pooled with the use of a random-effects model.
During a mean 2.5-y follow-up, 300 incident frailty cases occurred. Fully adjusted models showed that the pooled ORs (95% CIs) of incident frailty comparing participants who consumed 1, 2, or ≥3 portions of fruit/d to those with no consumption were, respectively, 0.59 (0.27, 0.90), 0.58 (0.29, 0.86), and 0.48 (0.20, 0.75), with a P-trend of 0.04. The corresponding values for vegetables were 0.69 (0.42, 0.97), 0.56 (0.35, 0.77), and 0.52 (0.13, 0.92), with a P-trend < 0.01. When FVs were analyzed together, the pooled ORs (95% CIs) of incident frailty were 0.41 (0.21, 0.60), 0.47 (0.25, 0.68), 0.36 (0.18, 0.53), and 0.31 (0.13, 0.48), with a P-trend < 0.01 for participants who consumed 2, 3, 4, or ≥5 portions/d, respectively, compared with those who consumed ≤1 portion/d. An inverse dose-response relation was also found between the baseline consumption of fruit and risk of exhaustion, low physical activity, and slow walking speed, whereas the consumption of vegetables was associated with a decreased risk of exhaustion and unintentional weight loss.
Among community-dwelling older adults, FV consumption was associated with a lower short-term risk of frailty in a dose-response manner, and the strongest association was obtained with 3 portions of fruit/d and 2 portions of vegetables/d.
OBJECTIVES: To determine whether adding cognitive impairment to frailty improves its predictive validity for adverse health outcomes.
DESIGN: Four‐year longitudinal study.
SETTING: The French ...Three‐City Study.
PARTICIPANTS: Six thousand thirty community‐dwelling persons aged 65 to 95.
MEASUREMENTS: Frailty was defined as having at least three of the following criteria: weight loss, weakness, exhaustion, slowness, and low physical activity. Subjects meeting one or two criteria were prefrail and those meeting none as nonfrail. The lowest quartile in the Mini‐Mental State Examination (MMSE) and the Isaacs Set Test (IST) was used to identify subjects with cognitive impairment. The predictive validity of frailty for incident disability, hospitalization, dementia, and death was calculated first for frailty subgroups and then rerun after stratification according to the presence or absence of cognitive impairment.
RESULTS: Four hundred twenty‐one individuals (7%) met frailty criteria. Cognitive impairment was present in 10%, 12%, and 22% of the nonfrail, prefrail, and frail subjects, respectively. Those classified as frail scored lower on the MMSE and IST than those classified as prefrail and nonfrail. After adjustment, frail persons with cognitive impairment were significantly more likely to develop disability in activities of daily living (ADLs) and instrumental ADLs over the following 4 years. The risk of incident mobility disability and hospitalization was marginally greater. Incident dementia was greater in the groups with cognitive impairment irrespective of their frailty status. Conversely, frailty was not a significant predictor of mortality.
CONCLUSION: Cognitive impairment improves the predictive validity of the operational definition of frailty, because it increases the risk of adverse health outcomes in this particular subgroup of the elderly population.
Abstract Motivation Diseases that progress slowly are often studied by observing cohorts at different stages of disease for short periods of time. The Alzheimer's Disease Neuroimaging Initiative ...(ADNI) follows elders with various degrees of cognitive impairment, from normal to impaired. The study includes a rich panel of novel cognitive tests, biomarkers, and brain images collected every 6 months for as long as 6 years. The relative timing of the observations with respect to disease pathology is unknown. We propose a general semiparametric model and iterative estimation procedure to estimate simultaneously the pathological timing and long-term growth curves. The resulting estimates of long-term progression are fine-tuned using cognitive trajectories derived from the long-term “Personnes Agées Quid” study. Results We demonstrate with simulations that the method can recover long-term disease trends from short-term observations. The method also estimates temporal ordering of individuals with respect to disease pathology, providing subject-specific prognostic estimates of the time until onset of symptoms. When the method is applied to ADNI data, the estimated growth curves are in general agreement with prevailing theories of the Alzheimer's disease cascade. Other data sets with common outcome measures can be combined using the proposed algorithm. Availability Software to fit the model and reproduce results with the statistical software R is available as the grace package. ADNI data can be downloaded from the Laboratory of NeuroImaging.
Summary Background Prevention strategies are urgently needed to tackle the growing burden of Alzheimer's disease. We aimed to assess efficacy of long-term use of standardised ginkgo biloba extract ...for the reduction of incidence of Alzheimer's disease in elderly adults with memory complaints. Methods In the randomised, parallel-group, double-blind, placebo-controlled GuidAge clinical trial, we enrolled adults aged 70 years or older who spontaneously reported memory complaints to their primary-care physician in France. We randomly allocated participants in a 1:1 ratio according to a computer-generated sequence to a twice per day dose of 120 mg standardised ginkgo biloba extract (EGb761) or matched placebo. Participants and study investigators and personnel were masked to study group assignment. Participants were followed-up for 5 years by primary-care physicians and in expert memory centres. The primary outcome was conversion to probable Alzheimer's disease in participants who received at least one dose of study drug or placebo, compared by use of the log-rank test. This study is registered with ClinicalTrials.gov , number NCT00276510. Findings Between March, 2002, and November, 2004, we enrolled and randomly allocated 2854 participants, of whom 1406 received at least one dose of ginkgo biloba extract and 1414 received at least one dose of placebo. By 5 years, 61 participants in the ginkgo group had been diagnosed with probable Alzheimer's disease (1·2 cases per 100 person-years) compared with 73 participants in the placebo group (1·4 cases per 100 person-years; hazard ratio HR 0·84, 95% CI 0·60–1·18; p=0·306), but the risk was not proportional over time. Incidence of adverse events was much the same between groups. 76 participants in the ginkgo group died compared with 82 participants in the placebo group (0·94, 0·69–1·28; p=0·68). 65 participants in the ginkgo group had a stroke compared with 60 participants in the placebo group (risk ratio 1·12, 95% CI 0·77–1·63; p=0·57). Incidence of other haemorrhagic or cardiovascular events also did not differ between groups. Interpretation Long-term use of standardised ginkgo biloba extract in this trial did not reduce the risk of progression to Alzheimer's disease compared with placebo. Funding Ipsen.
Vascular risk factors have been proposed as important targets for the prevention of dementia. As lipid fractions represent easily modifiable targets, we examined the longitudinal relationship of ...baseline lipid fractions with 13-y incident dementia and its subtypes (Alzheimer disease AD and mixed or vascular dementia) in older community-dwelling persons.
Non-institutionalized persons aged 65+ y (n = 9,294) were recruited for the Three-City Study (3C Study), a population-based cohort study from the electoral rolls of the cities of Dijon, Bordeaux, and Montpellier, France, between March 1999 and March 2001. Follow-up examinations were performed every 2 y after the baseline assessment. The final study sample comprised 7,470 participants from the 3C Study (mean age ± standard deviation SD 73.8 ± 5.3 y, 61.0% women) who were prospectively followed up for up to 13 y. Fasting lipid fractions (triglycerides TGs, high-density lipoprotein cholesterol HDL-C, low-density lipoprotein cholesterol LDL-C, total cholesterol TC) were studied as continuous variables, and results are reported per SD increase of each lipid fraction. Incident dementia and its subtypes were studied as censored variables using Cox models with age as time scale. Analyses were adjusted for sex, study center, and educational level, as well as vascular risk factors and apolipoprotein E (APOE) ε4 genotype. We corrected for multiple testing, yielding a significance threshold of 0.0169. p-Values above the significance threshold but less than 0.05 were considered nominally significant. During a mean (± SD) follow-up period of 7.9 ± 3.6 y, 779 participants developed incident dementia (n = 532 AD and n = 154 mixed or vascular dementia). Higher LDL-C and TC concentrations at baseline were associated with an increased risk of AD (hazard ratio HR per SD increase = 1.13 95% CI 1.04-1.22, p = 0.0045, and HR = 1.12 1.03-1.22, p = 0.0072, respectively). These associations were largely unchanged after adjustment for vascular risk factors and were attenuated after adjustment for APOEε4 (HR per SD increase = 1.12 1.03-1.23, p = 0.0110, and HR = 1.12 1.02-1.23, p = 0.0171, respectively). Higher TG concentrations at baseline were associated with an increased risk of all dementia (HR per SD increase = 1.11 1.03-1.19, p = 0.0044) and mixed or vascular dementia (HR = 1.21 1.04-1.41, p = 0.0163). However, these associations disappeared after adjusting for vascular risk factors (HR = 1.07 0.98-1.17, p = 0.1374, and HR = 1.17 0.96-1.42, p = 0.1206, respectively). Main limitations of the study include interval censoring of incident dementia cases, potential selective survival bias, and the fact that variation in lipid concentrations during follow-up could not be accounted for in the analyses.
In a large population-based sample of older community-dwelling persons with up to 13 y of follow-up, we observed that higher LDL-C and TC concentrations were associated with an increased risk of AD. This result was independent of vascular risk factors and was attenuated after adjustment for APOEε4 carrier status. TG and HDL-C concentrations were not associated with risk of incident dementia or its subtypes after accounting for vascular risk factors.
Summary Background & aims Mediterranean diet (MeDi) is considered as a key component for healthy aging, including prevention of age-related disability, while its association with frailty, independent ...of disability has never been assessed. Our objective was to investigate the relation between MeDi adherence and frailty incidence among persons aged ≥75 years participating at the prospective population-based French Three-City Study. Methods The study sample consisted of 560 initially non-frail participants of the Three-City-Bordeaux center, seen at the 2009–2010 follow-up, and re-examined two years later. Adherence to MeDi was computed from a food frequency questionnaire (scored as 0–9). Frailty was defined as having at least three out of the following five slightly modified Fried frailty criteria: involuntary weight loss, exhaustion, slowness, weakness and low physical activity. Logistic regression models adjusted for sociodemographic and clinical covariates, including cognitive performance and depressive symptomatology, were used to assess the association between MeDi score and subsequent frailty risk. Results Over the 2-year follow-up, 79 participants (14%) became frail. Older adults with the highest MeDi adherence (score 6–9) had a significantly 68% frailty risk reduction (95% CI: 28–86%, p = 0.006) compared to those in the lowest MeDi category (score 0–3). Regarding the frailty criterion separately, the highest MeDi adherence was associated with a significantly reduced risk of incident slowness (OR = 0.45; 95% CI: 0.20–0.99, p = 0.04), poor muscle strength (OR = 0.44; 95% CI: 0.20–0.98, p = 0.04) and low physical activity (OR = 0.39; 95% CI: 0.18–0.82, p = 0.01), compared to the lowest MeDi adherence. Conclusion In addition to its well-documented beneficial effects on health, adherence to MeDi might contribute to prevent the onset of frailty, even at late stages of life.
Abstract Background The relationship between blood pressure and dementia is incompletely understood in elderly individuals. Blood pressure variability may have a role in the risk of dementia. Methods ...This investigation was a cohort study of 6506 elderly individuals followed-up for 8 years (1999–2001 through 2008) with assessments at years 2, 4, and 7–8. Blood pressure was measured by electronic devices at baseline and at 2- and 4-year follow-up examinations. Cox proportional hazard models adjusted for potential confounders were used to estimate the risk of incident dementia according to blood pressure (means and coefficients of variation of the three measures). Results During the 40,151 person-years of follow-up 474 participants developed dementia. We observed no association between mean blood pressure and risk of dementia. In contrast, an increase of 1 standard deviation in the coefficient of variation of blood pressure was associated with a 10% increased risk of dementia. Analysis by deciles of the coefficient of variation showed that the higher the variability, the higher the risk of dementia ( P < .02 for trend). In the fully adjusted Cox model, the risk of dementia for those in the highest decile of the coefficient of variation of systolic blood pressure was 1.77 (1.17–2.69) compared with the lowest decile. Conclusions In this cohort study, variability of blood pressure during follow-up was associated with an increased risk of incident dementia, whereas mean blood pressure was not. Limitation of blood pressure fluctuation may be an important target to preserve cognitive function in the elderly.
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