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Background: Older people with subjective memory complaints (SMC) and Instrumental Activities of Daily Living impairments (IADL-I) have an increased risk of developing dementia. Previous reports suggest that the predictive value of SMC and IADL-I may differ between sexes, leaving possible consequences for personalized risk prediction and prognosis. However, none of these studies addressed the competing risk of death, which may substantially differ between sexes. Objective: We investigated sex-differences in the association between IADL-I, SMC, and incident dementia and mortality as competing risk. Methods: 3,409 community-dwelling older people without dementia (mean age 74.3±2.5), were followed for 6.7 years (median). Baseline SMC were assessed using the 15-item Geriatric Depression Scale memory question, and IADL-I using the Academic Medical Center Linear Disability Score. Potential sex-differences in the predictive value of SMC and IADL-I were assessed using Cox regression models with an interaction term for sex. Results: HRs for isolated SMC and SMC + IADL-I and risk of dementia were higher in women (HR: 2.02, 95% CI = 0.91–4.46, p = 0.08; HR:2.85, 95% CI = 1.65–4.91, p

ObjectiveTo assess whether angiotensin II–stimulating antihypertensives (thiazides, dihydropyridine calcium channel blockers, and angiotensin I receptor blockers) convey a lower risk of incident dementia compared to angiotensin II–inhibiting antihypertensives (angiotensin-converting enzyme inhibitors, β-blockers, and nondihydropyridine calcium channel blockers), in accordance with the “angiotensin hypothesis.”MethodsWe performed Cox regression analyses of incident dementia (or mortality as competing risk) during 6–8 years of follow-up in a population sample of 1,909 community-dwelling individuals (54% women) without dementia, aged 70–78 (mean 74.5 ± 2.5) years.ResultsAfter a median of 6.7 years of follow-up, dementia status was available for 1,870 (98%) and mortality for 1,904 (>99%) participants. Dementia incidence was 5.6% (27/480) in angiotensin II–stimulating, 8.2% (59/721) in angiotensin II–inhibiting, and 6.9% (46/669) in both antihypertensive type users. Adjusted for dementia risk factors including blood pressure and medical history, angiotensin II–stimulating antihypertensive users had a 45% lower incident dementia rate (hazard ratio [HR], 0.55; 95% CI, 0.34–0.89) without excess mortality (HR, 0.86; 95% CI, 0.64–1.16), and individuals using both types had a nonsignificant 20% lower dementia rate (HR, 0.80; 95% CI,0.53–1.20) without excess mortality (HR, 0.97; 95% CI, 0.76–1.24), compared to angiotensin II–inhibiting antihypertensive users. Results were consistent for subgroups based on diabetes and stroke history, but may be specific for individuals without a history of cardiovascular disease.ConclusionsUsers of angiotensin II–stimulating antihypertensives had lower dementia rates compared to angiotensin II–inhibiting antihypertensive users, supporting the angiotensin hypothesis. Confounding by indication must be examined further, although subanalyses suggest this did not influence results. If replicated, dementia prevention could become a compelling indication for older individuals receiving antihypertensive treatment.

Background Biomarkers for delirium could increase diagnostic accuracy and may help to identify pathological pathways. Until now study findings concerning cytokine levels have been inconsistent. Aims Systematic review and meta-analysis investigating the association between peripheral levels of Insulin-like Growth Factor-1 (IGF-1), C-Reactive Protein (C-RP) and Interleukin-6 (IL-6) and delirium in surgical patients, and to explore if there are distinct/specific patterns that may potentially explain inconsistent results. Methods PubMed, Scopus, CINAHL, Cochrane, and EMBASE databases were searched. Inclusion criteria were: prospective studies, surgical populations excluding preoperative delirium, available data. The following were collected: type of operation (orthopaedic, abdominal, etc), the timing of operation (acute, elective, both), demographics, number of participants with delirium, time of preoperative blood withdrawal, and preoperative levels of each biomarker. Results Low levels of IGF-1 (n = 7 studies) are significantly associated with post-operative delirium in abdominal surgical samples. High levels of C-RP (n = 9) are associated with delirium in acute orthopaedic and elective abdominal operations. IL-6 (n = 14) is a significant predictor of post-operative delirium in a variety of surgical conditions (elective or acute). Discussion A common pattern exists in the otherwise conflicting reported findings. This similarity may reflect different underling mechanisms and predisposing factors like cachexia and catabolic stages. It seems that delirium in abdominal surgery is triggered by IGF-1 disturbances, while in other surgeries by an inflammatory reaction. Conclusions Despite the contradictory results concerning the association of IGF-1, C-RP and IL-6 with postoperative delirium, the present meta-analysis shows that there are certain patterns. IL-6 seems a consistent predictor for delirium in surgical samples.

IntroductionProfiles of high risk for future dementia are well understood and are likely to concern mostly those in low-income and middle-income countries and people at greater disadvantage in high-income countries. Approximately 30%–40% of dementia cases have been estimated to be attributed to modifiable risk factors, including hypertension, smoking and sedentary lifestyle. Tailored interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile health (mHealth) improves accessibility of such prevention strategies in hard-to-reach populations while at the same time tailoring such approaches. In the current study, we will investigate the effectiveness and implementation of a coach-supported mHealth intervention, targeting dementia risk factors, to reduce dementia risk.Methods and analysisThe prevention of dementia using mobile phone applications (PRODEMOS) randomised controlled trial will follow an effectiveness–implementation hybrid design, taking place in the UK and China. People are eligible if they are 55–75 years old, of low socioeconomic status (UK) or from the general population (China); have ≥2 dementia risk factors; and own a smartphone. 2400 participants will be randomised to either a coach-supported, interactive mHealth platform, facilitating self-management of dementia risk factors, or a static control platform. The intervention and follow-up period will be 18 months. The primary effectiveness outcome is change in the previously validated Cardiovascular Risk Factors, Ageing and Incidence of Dementia dementia risk score. The main secondary outcomes include improvement of individual risk factors and cost-effectiveness. Implementation outcomes include acceptability, adoption, feasibility and sustainability of the intervention.Ethics and disseminationThe PRODEMOS trial is sponsored in the UK by the University of Cambridge and is granted ethical approval by the London—Brighton and Sussex Research Ethics Committee (reference: 20/LO/01440). In China, the trial is approved by the medical ethics committees of Capital Medical University, Beijing Tiantan Hospital, Beijing Geriatric Hospital, Chinese People’s Liberation Army General Hospital, Taishan Medical University and Xuanwu Hospital. Results will be published in a peer-reviewed journal.Trial registration numberISRCTN15986016.

Background:Studies on the association between depression and dementia risk mostly use sum scores on depression questionnaires to model symptomatology severity. Since individual items may contribute differently to this association, this approach has limited validity.Methods:We used network analysis to investigate the functioning of individual Geriatric Depression Scale (GDS-15) items, of which, based on studies that used factor analysis, 3 are generally considered to measure apathy (GDS-3A) and 12 depression (GDS-12D). Functional disability and future dementia were also included in our analysis. Data were extracted from 3229 participants of the Prevention of Dementia by Intensive Vascular care trial (preDIVA), analyzed as a single cohort, yielding 20,542 person-years of observation. We estimated a sparse network by only including connections between variables that could not be accounted for by variance in other variables. For this, we used a repeated L1 regularized regression procedure.Results:This procedure resulted in a selection of 59/136 possible connections. GDS-3A items were strongly connected to each other and with varying strength to several GDS-12D items. Functional disability was connected to all three GDS-3A items and the GDS-12D items “helplessness” and “worthlessness”. Future dementia was only connected to the GDS-12D item “memory problems”, which was in turn connected to the GDS-12D items “unhappiness” and “helplessness” and all three GDS-3A items.Conclusion:Network analysis reveals interesting relationships between GDS items, functional disability and dementia risk. We discuss what implications our results may have for (future) research on the associations between depression and/or apathy with dementia.

Objectives: Important precipitating risk factors for delirium such as infections, vascular disorders, and surgery are accompanied by a systemic inflammatory response. Systemic inflammatory mediators can induce delirium in susceptible individuals. Little is known about the trajectory of systemic inflammatory markers and their role in the development and outcome of delirium. Methods: This is a prospective cohort study of older patients undergoing acute surgery for hip fracture. Baseline characteristics were assessed preoperatively. During hospital admission, presence of delirium was assessed daily according to the Confusion Assessment Method criteria. This study compared the trajectory of serum levels of the C-reactive protein (CRP) between people with and without postoperative delirium. Blood samples were taken at baseline and at postoperative day 1 through postoperative day 5. Results: Forty-one out of 121 patients developed postoperative delirium after hip fracture surgery. Longitudinal analysis of the trajectory of serum CRP levels using the Generalized Estimating Equations (GEE) method identified that higher CRP levels were associated with postoperative delirium. CRP levels were higher from postoperative day 2 through postoperative day 5. No significant differences in serum CRP levels were found when we compared patients with short (1-2 days) and more prolonged delirium (3 days or more). Conclusions: Delirium is associated with an increased systemic inflammatory response, and our results suggest that CRP plays a role in the underlying (inflammatory-vascular) pathological pathway of postoperative delirium.

Systemic infection is an important risk factor for the development cognitive impairment and neurodegeneration in older people. Animal experiments show that systemic challenges with live bacteria cause a neuro-inflammatory response, but the effect of age on this response in these models is unknown. Young (2 months) and middle-aged mice (13&ndash, 14 months) were intraperitoneally challenged with live Escherichia coli (E. coli) or saline. The mice were sacrificed at 2, 3 and 7 days after inoculation, for all time points, the mice were treated with ceftriaxone (an antimicrobial drug) at 12 and 24 h after inoculation. Microglial response was monitored by immunohistochemical staining with an ionized calcium-binding adaptor molecule 1 (Iba-1) antibody and flow cytometry, and inflammatory response by mRNA expression of pro- and anti-inflammatory mediators. We observed an increased microglial cell number and moderate morphologically activated microglial cells in middle-aged mice, as compared to young mice, after intraperitoneal challenge with live E. coli. Flow cytometry of microglial cells showed higher CD45 and CD11b expressions in middle-aged infected mice compared to young infected mice. The brain expression levels of pro-inflammatory genes were higher in middle-aged than in young infected mice, while middle-aged infected mice had similar expression levels of these genes in the systemic compartment. We conclude that systemic challenge with live bacteria causes an age-dependent neuro-inflammatory and microglial response. Our data show signs of an age-dependent disconnection of the inflammatory transcriptional signature between the brain and the systemic compartment.

Objectives Drugs with anticholinergic properties are associated with an increased prevalence of delirium, especially in older persons. The aim of this study was to evaluate the association between the use of this class of drugs in nursing home (NH) patients and prevalence of delirium, particularly in people with dementia. Design Cross-sectional multicenter study. Setting and participants 3924 nursing home patients of 57 nursing homes in 7 European countries participating in the Services and Health for Elderly in Long TERmcare (SHELTER) project. Methods Descriptive statistics, calculation of percentage, and multivariable logistic analysis were applied to describe the relationship between anticholinergic drug use and prevalence of delirium in NH patients. The Anticholinergic Risk Scale (ARS) and the Anticholinergic Burden Scale (ACB) were used to calculate the anticholinergic load. Results 54% of patients with dementia and 60% without dementia received at least 1 anticholinergic drug according to the ACB. The prevalence of delirium was higher in the dementia group (21%) compared with the nondementia group (11%). Overall, anticholinergic burden according to the ACB and ARS was associated with delirium both in patients with and without dementia, with odds ratios ranging from 1.07 [95% confidence interval (CI) 0.94-1.21] to 1.26 (95% CI 1.11-1.44). These associations reached statistical significance only in the group of patients with dementia. Among patients with dementia, delirium prevalence increased only modestly with increasing anticholinergic burden according to the ACB, from 20% (with none or minimal anticholinergic burden) to 25% (with moderate burden) and 27% delirium (with strong burden scores). Conclusions and Implications The ACB scale is relatively capable to detect anticholinergic side effects, which are positively associated with prevalence of delirium in NH patients. Given the modest nature of this association, strong recommendations are currently not warranted, and more longitudinal studies are needed.

Contains fulltext : 235592.pdf (Publisher’s version ) (Open Access) Numerous clinical trials of anti-amyloid beta (Aβ) immunotherapy in Alzheimer's disease have been performed. None of these have provided convincing evidence for beneficial effects. Using traditional frequentist meta-analysis, the conclusion is that there is absence of evidence for a therapeutic effect, with a point estimate effect size of 0.05 (95% confidence interval -0.00 to 0.10, P = .055). In addition, this non-significant effect equates to 0.4 points per year on the cognitive subscale of the Alzheimer's Disease Assessment Scale. This is well below the minimally clinically important difference. Bayesian meta-analysis of these trial data provides strong evidence of absence of a therapeutic effect, with a Bayes factor of 11.27 in favor of the null hypothesis, opposed to a Bayes factor of 0.09 in favor of a treatment effect. Bayesian analysis is particularly valuable in this context of repeatedly reported small, non-significant effect sizes in individual trials. Mechanisms other than removal of Aβ from the brain may be probed to slow progression of Alzheimer's disease.

Delirium is a common serious complication in dementia that is associated with poor prognosis and a high burden on caregivers and healthcare professionals. Appropriate care is therefore important at an early stage for patients with delirium superimposed on dementia To gain insight into the care of six patients with delirium superimposed on dementia, 19 semi-structured interviews were conducted focused on the experiences of caregivers and professionals. The interviews revealed four themes that appeared to play a role: 1. experiences with and views on behavioral problems of these patients, 2. recognition and diagnosis of delirium in dementia, 3. views on good care and 4. organizational aspects. Knowledge gaps about delirium in dementia, as well as ethical considerations, play an important role in organizing timely and adequate care for patients with delirium superimposed on dementia.

ObjectiveHigh blood pressure is one of the main modifiable risk factors for dementia. However, there is conflicting evidence regarding the best antihypertensive class for optimizing cognition. Our objective was to determine whether any particular antihypertensive class was associated with a reduced risk of cognitive decline or dementia using comprehensive meta-analysis including reanalysis of original participant data.MethodsTo identify suitable studies, MEDLINE, Embase, and PsycINFO and preexisting study consortia were searched from inception to December 2017. Authors of prospective longitudinal human studies or trials of antihypertensives were contacted for data sharing and collaboration. Outcome measures were incident dementia or incident cognitive decline (classified using the reliable change index method). Data were separated into mid and late-life (>65 years) and each antihypertensive class was compared to no treatment and to treatment with other antihypertensives. Meta-analysis was used to synthesize data.ResultsOver 50,000 participants from 27 studies were included. Among those aged >65 years, with the exception of diuretics, we found no relationship by class with incident cognitive decline or dementia. Diuretic use was suggestive of benefit in some analyses but results were not consistent across follow-up time, comparator group, and outcome. Limited data precluded meaningful analyses in those ≤65 years of age.ConclusionOur findings, drawn from the current evidence base, support clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals.Clinical trials registrationThe review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454.

Supplemental Digital Content is available in the text., Background. Several studies have reported improved cognitive outcomes after kidney transplantation, but most studies either did not include controls or lacked extensive neuroimaging. In addition, there is uncertainty whether kidney donation is a safe procedure in terms of cognitive outcomes. Methods. We prospectively studied neurocognitive function in kidney transplant recipients. The primary outcome was change in neurocognitive function after 1 year compared with baseline, which was evaluated using the Amsterdam Neuropsychological Task battery and verbal fluency tests. Secondary outcomes included changes in depression and anxiety (measured by the Hospital Anxiety and Depression scale) and changes in fatigue (measured by the Checklist for Individual Strength). We included kidney donors to control for learning effects, socioeconomic status, and surgery. In addition, kidney transplant recipients were evaluated with MRI scans at baseline and at year 1. The MRI protocol included conventional MRI, automated volumetric measurement, diffusion tensor imaging, magnetic resonance spectroscopy, arterial spin labeling, and a resting state functional MRI. Results. Twenty-seven recipients and 24 donors were included. For both recipients and donors, neuropsychologic testing scores improved 1 year after transplantation (donation). Recipient improvement significantly exceeded donor improvement on tasks measuring attention and working memory. These improvements were associated with increases in white matter volume and N-acetylaspartate/creatine (a marker for neuronal integrity). Conclusions. Attention and working memory improve significantly 1 year after kidney transplantation. Learning effects do not account for these improvements because recipient improvement in these areas exceeds donor improvement and correlates with an improvement in white matter integrity after transplantation. Kidney donation appears to be a safe procedure in terms of cognitive outcomes.

Background Research links blood pressure variability ( BPV ) with stroke; however, the association with cerebral small‐vessel disease ( CSVD ) remains unclear. As BPV and mean blood pressure are interrelated, it remains uncertain whether BPV adds additional information to understanding cerebrovascular morphological characteristics. Methods and Results A systematic review was performed from inception until March 3, 2019. Eligibility criteria included population, adults without stroke (BPV quantified by any metric over any duration; comparison, (1) low versus high or mean BPV and (2) people with versus without CSVD ; and outcomes, (1) CSVD as subcortical infarct, lacunae, white matter hyperintensities, cerebral microbleeds, or enlarged perivascular spaces; and (2) standardized mean difference in BPV . A total of 27 articles were meta‐analyzed, comprising 12 309 unique brain scans. A total of 31 odds ratios ( OR s) were pooled, indicating that higher systolic BPV was associated with higher odds for CSVD ( OR, 1.27; 95% CI, 1.14–1.42; I 2 =85%) independent of mean systolic pressure. Likewise, higher diastolic BPV was associated with higher odds for CSVD ( OR, 1.30; 95% CI, 1.14–1.48; I 2 =53%) independent of mean diastolic pressure. There was no evidence of a pairwise interaction between systolic/diastolic and BPV /mean OR s ( P =0.47), nor a difference between BPV versus mean pressure OR s ( P =0.58). Fifty‐four standardized mean differences were pooled and provided similar results for pairwise interaction ( P =0.38) and difference between standardized mean differences ( P =0.70). Conclusions On the basis of the available studies, BPV was associated with CSVD independent of mean blood pressure. However, more high‐quality longitudinal data are required to elucidate whether BPV contributes unique variance to CSVD morphological characteristics.

Contains fulltext : 218833.pdf (Publisher’s version ) (Open Access) Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m(2) ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m(2) ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.

Background High visit-to-visit variability (VVV) in blood pressure (BP) is associated with cerebrovascular lesions on neuroimaging. Objective Our primary objective was to investigate whether VVV is associated with incident all-cause dementia. As a secondary objective, we studied the association of VVV with cognitive decline and cardiovascular disease (CVD). Methods We included community-dwelling people (age 70-78 year) from the 'Prevention of Dementia by Intensive Vascular Care' (preDIVA) trial with three to five 2-yearly BP measurements during 6-8 years follow-up. VVV was defined using coefficient of variation (CV; SD/mean×100). Cognitive decline was assessed using the Mini-Mental State Examination (MMSE). Incident CVD was defined as myocardial infarction or stroke. We used a Cox proportional hazard regression and mixed-effects model adjusted for sociodemographic factors and cardiovascular risk factors. Results In 2,305 participants (aged 74.2±2.5), mean systolic BP over all available visits was 150.1 mmHg (SD 13.6), yielding a CV of 9.0. After 6.4 years (SD 0.8) follow-up, 110 (4.8%) participants developed dementia and 140 (6.1%) CVD. Higher VVV was not associated with increased risk of dementia (hazard ratio [HR] 1.00 per point CV increase; 95% confidence interval [CI] 0.96-1.05), although the highest quartile of VVV was associated with stronger decline in MMSE (β -0.09, 95% CI -0.17 to -0.01). Higher VVV was associated with incident CVD (HR 1.07; 95% CI 1.04-1.11). Conclusion In our study among older people, high VVV is not associated with incident all-cause dementia. It is associated with decline in MMSE and incident CVD.

Contains fulltext : 238505.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To systematically review and synthesize the evidence on differential associations between antihypertensive medication (AHM) classes and the risk of incident dementia. DESIGN: Systematic review and random effects frequentist network meta-analysis. Embase, MEDLINE, and the Cochrane library were searched from origin to December 2019. SETTING AND PARTICIPANTS: Randomized controlled trials (RCTs) and prospective cohort studies that compared associations of different AHM classes with incident all-cause dementia and/or Alzheimer's disease over at least 1 year of follow-up. MEASURES: All cause dementia and/or Alzheimer's disease. RESULTS: Fifteen observational studies and 7 RCTs were included. Data on AHM classes were available for 649,790 participants and dementia occurred in 19,600 (3.02%). Network meta-analysis showed that in observational studies, treatment with either calcium channel blockers (CCBs) or angiotensin II receptor blockers (ARBs) was associated with lower dementia risks than treatment with other antihypertensives: CCBs vs angiotensin converting enzyme inhibitors (ACE inhibitors) (HR=0.84, 95% CI 0.74-0.95), beta blockers (HR=0.83, 95% CI 0.73-0.95) and diuretics (HR=0.89, 95% CI 0.78-1.01) and ARBs vs ACE inhibitors (HR=0.88, 95% CI 0.81-0.97), beta blockers (HR=0.87, 95% CI 0.77-0.99), and diuretics (HR=0.93, 95% CI 0.83-1.05). There were insufficient RCTs to create a robust network based on randomized data alone. CONCLUSIONS AND IMPLICATIONS: Recommending CCBs or ARBs as preferred first-line antihypertensive treatment may significantly reduce the risk of dementia. If corroborated in a randomized setting, these findings reflect a low-cost and scalable opportunity to reduce dementia incidence worldwide.

Item does not contain fulltext OBJECTIVES: To explore and compare sociodemographic, clinical, and neuropsychiatric determinants of dropout and nonadherence in older people participating in an open-label cluster-randomized controlled trial-the Prevention of Dementia by Intensive Vascular care (preDIVA) trial-over 6 years. DESIGN: Secondary analysis. SETTING: One hundred sixteen general practices in the Netherlands. PARTICIPANTS: Community-dwelling individuals aged 70 to 78 (N = 2,994). INTERVENTION: Nurse-led multidomain intervention targeting cardiovascular risk factors to prevent dementia. MEASUREMENTS: The associations between participant baseline sociodemographic (age, sex, education), clinical (medical history, disability, cardiovascular risk), neuropsychiatric (depressive symptoms (Geriatric Depression Scale-15), and cognitive (Mini-Mental State Examination)) characteristics and dropout from the trial and nonadherence to the trial intervention were explored using multilevel logistic regression models. RESULTS: Older age, poorer cognitive function, more symptoms of depression, and greater disability were the most important determinants of dropout of older people. The presence of cardiovascular risk factors was not associated with dropout but was associated with nonadherence. Being overweight was a risk factor for nonadherence, whereas people with high blood pressure or a low level of physical exercise adhered better to the intervention. The association between poorer cognitive function and symptoms of depression and dropout was stronger in the control group than in the intervention group, and vice versa for increased disability. CONCLUSION: In a large dementia prevention trial with 6-year follow-up, dropout was associated with older age, poorer cognitive function, symptoms of depression, and disability at baseline. These findings can help to guide the design of future dementia prevention trials in older adults. The associations found between cardiovascular risk factors and nonadherence need to be confirmed in other older populations receiving cardiovascular prevention interventions.

Background and Purpose— This study aimed to evaluate the effect of a nurse-led multidomain cardiovascular intervention on white matter hyperintensity (WMH) progression and incident lacunar infarcts in community-dwelling elderly with hypertension. Methods— The preDIVA trial (Prevention of Dementia by Intensive Vascular Care) was an open-label, cluster-randomized controlled trial in community-dwelling individuals aged 70 to 78 years. General practices were assigned by computer-generated randomization to 6-year nurse-led, multidomain intensive vascular care or standard care. Of 3526 preDIVA participants, 195 nondemented participants with a systolic blood pressure ≥140 mm Hg were consecutively recruited to undergo magnetic resonance imaging at 2 to 3 and 5 to 6 years after baseline. WMH volumes were measured automatically, lacunar infarcts assessed visually, blinded to treatment allocation. Results— One hundred and twenty-six participants were available for longitudinal analysis (64 intervention and 62 control). Annual WMH volume increase in milliliter was similar for intervention (mean=0.73, SD=0.84) and control (mean=0.70, SD=0.59) participants (adjusted mean difference, −0.08 mL; 95% confidence interval, −0.30 to 0.15; P =0.50). Analyses suggested greater intervention effects with increasing baseline WMH volumes ( P for interaction=0.03). New lacunar infarcts developed in 6 (9%) intervention and 2 (3%) control participants (odds ratio, 2.2; 95% confidence interval, 0.4–12.1; P =0.36). Conclusions— Nurse-led vascular care in hypertensive community-dwelling older persons did not diminish WMH accumulation over 3 years. However, our results do suggest this type of intervention could be effective in persons with high WMH volumes. There was no effect on lacunar infarcts incidence but numbers were low. Clinical Trial Information— URL: http://www.isrctn.com/ISRCTN29711771 . Unique identifier: ISRCTN29711771.

Item does not contain fulltext OBJECTIVE: Use of antihypertensive medication (AHM) is potentially associated with a reduced risk of dementia. Both calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs) are suggested to have a more pronounced protective effect. We aimed to study the association between different classes of AHM and dementia in older people. METHODS: A subgroup of community-dwelling older people using AHM included in the 'Prevention of Dementia by Intensive Vascular Care' randomized controlled trial was studied. Incident dementia rates in participants with different AHM classes (mono and combination therapy) were compared with dementia rates in participants with any other AHM. RESULTS: At baseline, 1951 participants (55.3%) used AHM [mean age, 74.4 year (SD 2.5); mean SBP, 156.4 mmHg (SD 21.5)]. In total, 986 participants (50.5%) used beta-blockers, 798 diuretics (40.9%), 623 angiotensin- converting enzyme inhibitors (31.9%), 522 CCBs (26.8%), and 402 ARBs (20.6%). After 6.7 years (interquartile range 6.0-7.3) of follow-up, 136 participants (7.0%) developed dementia. Both use of CCBs [hazard ratio 0.56, 95% confidence interval (95% CI) 0.36-0.87] and ARBs (hazard ratio 0.60, 95% CI 0.37-0.98) were independently associated with a decreased risk of dementia. The association of CCBs with dementia was most apparent in participants without a history of cardiovascular disease (hazard ratio 0.38, 95% CI 0.18-0.81) and with uncontrolled hypertension (hazard ratio 0.26, 95% CI 0.11-0.61). SBP was not significantly lower in participants using CCBs or ARBs. CONCLUSION: Both use of CCBs and ARBs are independently associated with a decreased risk of dementia in older people.

Contains fulltext : 209022.pdf (Publisher’s version ) (Open Access) Cardiovascular risk prediction is mainly based on traditional risk factors that have been validated in middle-aged populations. However, associations between these risk factors and cardiovascular disease (CVD) attenuate with increasing age. Therefore, for older people the authors developed and internally validated risk prediction models for fatal and non-fatal CVD, (re)evaluated the predictive value of traditional and new factors, and assessed the impact of competing risks of non-cardiovascular death. Post hoc analyses of 1811 persons aged 70-78 year and free from CVD at baseline from the preDIVA study (Prevention of Dementia by Intensive Vascular care, 2006-2015), a primary care-based trial that included persons free from dementia and conditions likely to hinder successful long-term follow-up, were performed. In 2017-2018, Cox-regression analyses were performed for a model including seven traditional risk factors only, and a model to assess incremental predictive ability of the traditional and eleven new factors. Analyses were repeated accounting for competing risk of death, using Fine-Gray models. During an average of 6.2 years of follow-up, 277 CVD events occurred. Age, sex, smoking, and type 2 diabetes mellitus were traditional predictors for CVD, whereas total cholesterol, HDL-cholesterol, and systolic blood pressure (SBP) were not. Of the eleven new factors, polypharmacy and apathy symptoms were predictors. Discrimination was moderate (concordance statistic 0.65). Accounting for competing risks resulted in slightly smaller predicted absolute risks. In conclusion, we found, SBP, HDL, and total cholesterol no longer predict CVD in older adults, whereas polypharmacy and apathy symptoms are two new relevant predictors. Building on the selected risk factors in this study may improve CVD prediction in older adults and facilitate targeting preventive interventions to those at high risk.

Contains fulltext : 215579.pdf (Publisher’s version ) (Closed access) PURPOSE: Family physicians need simple yet comprehensive algorithms to discriminate between community-dwelling older persons who are at increased risk of dementia and those who are not. We aimed to investigate associations between incident dementia and responses to a single question regarding subjective memory complaints (SMC) combined with scores on 2 simple memory tests that are easy to use in the primary care setting. METHODS: Analyses were based on data from 3,454 community-dwelling older persons who participated in the 6- to 8-year Prevention of Dementia by Intensive Vascular Care (preDIVA) trial, yielding 21,341 person-years of observation. Participants were considered a single cohort. We used Cox models to assess separate and combined associations of SMC, an imperfect score on the Mini-Mental State Examination delayed recall item (MMSE-5), and an imperfect score on the Visual Association Test (VAT) with future dementia. RESULTS: Subjective memory complaints alone were associated with future dementia (hazard ratio [HR] = 3.01; 95% CI, 2.31-3.94; P

Background:In old age, both apathy and depression have been associated with an increased cardiovascular disease (CVD) risk. This study evaluated the mediating role of cardiovascular risk factors in the relationship of apathy and mood symptoms with incident CVD.Methods:Prospective cohort study of 1,790 community-dwelling older individuals (70–78 years) without a history of CVD or stroke. At baseline, apathy and mood symptoms were assessed with the 15-item Geriatric Depression Scale (GDS-15), of which three items represent apathy symptoms. The mediational risk factors included were diabetes mellitus (DM), body mass index (BMI), current smoking, physical inactivity, systolic blood pressure, and total cholesterol. Incident CVD was evaluated after two years of follow-up. Data were analyzed using structural equation modeling (SEM).Results:Incident CVD occurred in 59 (3.3%) participants. Apathy symptoms had a significant estimated total effect on incident CVD, with increases of 2.2% for each unit increase in apathy score. Of this total effect, 22.7% was due to the mediational effects of physical inactivity (13.6%), current smoking (4.5%), and DM (4.5%). The remaining 77.3% was due to direct effects reflecting other mediational dynamics. No significant (in)direct effects of mood symptoms on incident CVD were found.Conclusions:Physical inactivity, smoking, and DM account for nearly one-fourth of the variation reflecting the link between apathy symptoms and incident CVD. This illustrates the relevance of unfavorable health behaviors and assessment of DM in older individuals with apathy. The majority of the effect of apathy symptoms on incident CVD is caused by other, yet unknown, factors.

Background Wernicke encephalopathy can have different clinical outcomes. Although infections may precipitate the encephalopathy itself, it is unknown whether infections also modify the long-term outcome in patients developing Korsakoff syndrome. Objective To determine whether markers of infection, such as white blood cell (WBC) counts and absolute neutrophil counts in the Wernicke phase, are associated with cognitive outcomes in the end-stage Korsakoff syndrome. Method Retrospective, descriptive study of patients admitted to Slingedael Korsakoff Center, Rotterdam, The Netherlands. Hospital discharge letters of patients with Wernicke encephalopathy were searched for relevant data on infections present upon hospital admission. Patients were selected for further analysis if data were available on WBC counts in the Wernicke phase and at least 1 of 6 predefined neuropsychological tests on follow-up. Results Infections were reported in 35 of 68 patients during the acute phase of Wernicke-Korsakoff syndrome—meningitis (1), pneumonia (14), urinary tract infections (9), acute abdominal infections (4), sepsis (5) empyema, (1) and infection "of unknown origin" (4). The neuropsychological test results showed significant lower scores on the Cambridge Cognitive Examination nonmemory section with increasing white blood cell counts (Spearman rank correlation, ρ = −0.34; 95% CI: −0.57 to −0.06; 44 patients) and on the "key search test" of the behavioral assessment of the dysexecutive syndrome with increasing absolute neutrophil counts ( ρ = −0.85; 95% CI: −0.97 to −0.42; 9 patients). Conclusions Infections may be the presenting manifestation of thiamine deficiency. Patients with Wernicke-Korsakoff syndrome who suffered from an infection during the acute phase are at risk of worse neuropsychological outcomes on follow-up.

Objectives To examine the association of benzodiazepines and anticholinergic drug usage with the risk of dementia. Design Prospective cohort study. Setting Community-dwelling participants, recruited in family practices in the Netherlands. Participants In total, 3526 individuals aged 70 to 78 years without dementia within 116 participating family practices. Methods Information about drug use was reported at baseline and at 2-year follow-up and was cross-checked with the participants’ electronic health records. Anticholinergic drug exposure was defined by the anticholinergic cognitive burden score. Participants were evaluated for dementia during follow-up assessments every 2 years, supplemented by information from electronic health records and the National Death Registry. Results During a median follow-up of 6.7 years, dementia developed in 233 participants (7%). In participants using benzodiazepines, 6% developed dementia vs 7% in nonusers [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58–1.07]. Persistent usage of benzodiazepines at baseline and after 2-year follow-up did not substantially alter the point-estimate (HR 0.60, 95% CI 0.34–1.10). Use of any anticholinergic drugs was not associated with incident dementia (HR 1.01, 95% CI 0.50–1.10). Dementia risk was significantly increased for participants with persistent drug use with a high anticholinergic cognitive burden score (HR 1.95, 95% CI 1.13–3.38) though this effect was absent when excluding participants taking antidepressants or antipsychotics (HR 0.42, 95% CI 0.06–3.01). Conclusions and Implications In our study population, benzodiazepine usage was not associated with an increased risk of dementia. Persistent high anticholinergic exposure was associated with an increased risk of dementia over 6 years of follow-up, and this association was driven by antidepressant or antipsychotic drug use, suggesting confounding by indication bias contributing to this. Although this observation could ameliorate prescription hesitance, healthcare providers are still advised to carefully weigh the potential benefits of benzodiazepines and anticholinergic drugs against the associated adverse health outcomes.

Item does not contain fulltext Importance: Fear of dementia is pervasive in older people with cognitive concerns. Much research is devoted to finding prognostic markers for dementia risk. Studies suggest apathy in older people may be prodromal to dementia and could be a relevant, easily measurable predictor of increased dementia risk. However, evidence is fragmented and methods vary greatly between studies. Objective: To systematically review and quantitatively synthesize the evidence for an association between apathy in dementia-free older individuals and incident dementia. Data Sources: Two reviewers conducted a systematic search of Medline, Embase, and PsychINFO databases. Study Selection: Inclusion criteria were (1) prospective cohort studies, (2) in general populations or memory clinic patients without dementia, (3) with clear definitions of apathy and dementia, and (4) reporting on the association between apathy and incident dementia. Data Extraction and Synthesis: PRISMA and MOOSE guidelines were followed. Data were extracted by 1 reviewer and checked by a second. Main Outcomes and Measures: Main outcomes were pooled crude risk ratios, maximally adjusted reported hazard ratios (HR), and odds ratios (OR) using DerSimonian-Laird random effects models. Results: The mean age of the study populations ranged from 69.2 to 81.9 years (median, 71.6 years) and the percentage of women ranged from 35% to 70% (median, 53%). After screening 2031 titles and abstracts, 16 studies comprising 7365 participants were included. Apathy status was available for 7299 participants. Studies included populations with subjective cognitive concerns (n = 2), mild cognitive impairment (n = 11), cognitive impairment no dementia (n = 1), or mixed cognitive and no cognitive impairment (n = 2). Apathy was present in 1470 of 7299 participants (20.1%). Follow-up ranged from 1.2 to 5.4 years. In studies using validated apathy definitions (n = 12), the combined risk ratio of dementia for patients with apathy was 1.81 (95% CI, 1.32-2.50; I2 = 76%; n = 12), the hazard ratio was 2.39 (95% CI, 1.27-4.51; I2 = 90%; n = 7), and the odds ratio was 17.14 (95% CI, 1.91-154.0; I2 = 60%; n = 2). Subgroup analyses, meta-regression, and individual study results suggested the association between apathy and dementia weakened with increasing follow-up time, age, and cognitive impairment. Meta-regression adjusting for apathy definition and follow-up time explained 95% of heterogeneity in mild cognitive impairment. Conclusions and Relevance: Apathy was associated with an approximately 2-fold increased risk of dementia in memory clinic patients. Moderate publication bias may have inflated some of these estimates. Apathy deserves more attention as a relevant, cheap, noninvasive, and easily measureable marker of increased risk of incident dementia with high clinical relevance, particularly because these vulnerable patients may forgo health care.

Background: Selecting high-risk participants for dementia prevention trials based on a modifiable dementia risk score may be advantageous, as it increases the opportunity for intervention. We studied whether a multi-domain intervention can prevent all-cause dementia and cognitive decline in older people across three different levels of a modifiable dementia risk score.Methods: Prevention of Dementia by Intensive Vascular Care (preDIVA) is a randomised controlled trial studying the effect of multi-domain vascular care during 6–8 years on incident all-cause dementia in community-dwelling people aged 70–78 years. For this post hoc analysis, we stratified preDIVA participants in tertiles based on their baseline LIfestyle for BRAin Health (LIBRA) index, a modifiable dementia risk score. With Cox proportional hazards regression, the intervention effect on dementia was assessed. The effect on cognition was measured every 2 years with the Mini-Mental State Examination and Visual Association Test.Results: Dementia developed in 220 of 3274 (6.7%) participants. In participants with a low, intermediate and high LIBRA index, the hazard ratio (HR) of the intervention on incident dementia was respectively 0.71 (95% CI 0.45–1.12), 1.06 (95% CI 0.66–1.69) and 1.02 (95% CI 0.64–1.62). Also, when adding the non-modifiable risk factors age, education and sex to the index, results were comparable (respectively HR 0.88, 95% CI 0.54–1.43; HR 0.91, 95% CI 0.57–1.47; HR 0.92, 95% CI 0.59–1.41). There was no statistically significant intervention effect on cognition during follow-up across the LIBRA groups.Conclusions: In the preDIVA study population aged 70–78 years, the LIBRA modifiable dementia risk score did not identify a (high-)risk group in whom the multi-domain intervention was effective in preventing dementia or cognitive decline.Trial registration: International Standard Randomised Controlled Trial Number registry, ISRCTN29711771. Registered on 14 February 2006.

ObjectiveTo assess whether apathy and depressive symptoms are independently associated with incident dementia during 6-year follow-up in a prospective observational population-based cohort study.MethodsParticipants were community-dwelling older people in the Prevention of Dementia by Intensive Vascular Care trial, aged 70–78 years, without dementia at baseline. Apathy and depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Dementia during follow-up was established by clinical diagnosis confirmed by an independent outcome adjudication committee. Hazard ratios (HRs) were calculated using Cox regression analyses. Given its potentially strong relation with incipient dementia, the GDS item referring to memory complaints was assessed separately.ResultsDementia occurred in 232/3,427 (6.8%) participants. Apathy symptoms were associated with dementia (HR 1.28, 95% confidence interval [CI] 1.12–1.45; p < 0.001), also after adjustment for age, sex, Mini-Mental State Examination score, disability, and history of stroke or cardiovascular disease (HR 1.21, 95% CI 1.06–1.40; p = 0.007), and in participants without depressive symptoms (HR 1.26, 95% CI 1.06–1.49; p = 0.01). Depressive symptoms were associated with dementia (HR 1.12, 95% CI 1.05–1.19), also without apathy symptoms (HR 1.16, 95% CI 1.03–1.31; p = 0.015), but not after full adjustment or after removing the GDS item on memory complaints.ConclusionsApathy and depressive symptoms are independently associated with incident dementia in community-dwelling older people. Subjective memory complaints may play an important role in the association between depressive symptoms and dementia. Our findings suggest apathy symptoms may be prodromal to dementia and might be used in general practice to identify individuals without cognitive impairment at increased risk of dementia.

Our objective was to study the preventive effect of lowering blood pressure (BP) by medication and/or lifestyle changes on incident all-cause dementia, Alzheimer's disease and vascular dementia. In this systematic review, we included randomized controlled trials with a BP-lowering intervention. Of the nine included trials, seven assessed the effect of antihypertensive medication and two of a lifestyle or combined intervention. In the intervention arm, 1041 out of 29 029 (3.6%) participants were diagnosed with dementia compared with 1090 out of 28 653 (3.8%) controls during a median follow-up of 3.9 years [range 2-10], resulting in a pooled risk ratio of 0.93 (95% confidence interval 0.84-1.02; I 16%). Three trials specified dementia subtypes, with no significant effect on Alzheimer's disease or vascular dementia. To conclude, lowering BP by medication and/or lifestyle changes did not lead to a significantly reduced risk of dementia. This appeared independent of dementia subtype.

Computerized Adaptive Testing (CAT) of cognitive function, selects for every individual patient, only items of appropriate difficulty to estimate his or her level of cognitive impairment. Therefore, CAT has the potential to combine brevity with precision. We retrospectively examined the evaluation of treatment effects of cholinesterase inhibitors by CAT using longitudinal data from 643 patients from a Dutch teaching hospital who were diagnosed with Alzheimer disease or Lewy Body disease. The Cambridge Cognitive Examination (CAMCOG) was administered before treatment initiation and after intervals of six months of treatment. A previously validated CAT was simulated using 47 CAMCOG items. Results demonstrated that the CAT required a median number of 17 items (inter-quartile range 16-20), or a corresponding 64% test reduction, to estimate patients' global cognitive impairment levels. At the same time, intraclass correlations between global cognitive impairment levels as estimated by CAT or based on all 47 CAMCOG items, ranged from 0.93 at baseline to 0.91-0.94 at follow-up measurements. Slightly more people had substantial decline on the original CAMCOG (N = 31/285, 11%) than on the CAT (N = 17/285, 6%). We conclude that CAT saves time, does not lose much precision, and therefore deserves a role in the evaluation of treatment effects in dementia. Copyright © 2015 John Wiley & Sons, Ltd.

Apathy is a frequently reported neuropsychiatric symptom in Parkinson's disease (PD), but its prevalence and clinical correlates are debated. We aimed to address these issues by conducting a systematic review and meta-analysis. Embase, Medline/PubMed, and PsychINFO databases were searched for relevant studies. Data were extracted by two independent observers, using predefined extraction forms tailored specifically to the research question. From 1,702 titles and abstracts, 23 studies were selected. Meta-analysis showed a prevalence of apathy in PD of 39.8% (n = 5,388, 905% CI 34.6-45.0%). Apathy was associated with higher age (3.3 years, 95% CI = 1.7-4.9), lower mean Mini-Mental State Evaluation (MMSE) score (-1.4 points, 95% CI = -2.1 to -0.8), an increased risk of co-morbid depression (relative risk [RR] = 2.3, 95% CI = 1.9-2.8), higher Unified Parkinson's Disease Rating Scale (UPDRS) motor score (6.5 points, 95% CI = 2.6-10.3), and more severe disability (Hedges-G = 0.5, 95% CI = 0.3-0.6). Half of the patients with apathy had concomitant depression (57.2%, 95% CI = 49.4-64.9%), and this estimate was similar after exclusion of patients with cognitive impairment (52.5%, 95% CI = 42.2%-62.8%). In conclusion, we found that apathy affects almost 40% of patients with PD. Several factors influence reported prevalence rates, contributing to the considerable heterogeneity in study results. Half of patients with apathy do not suffer from concomitant depression or cognitive impairment, confirming its status as a separate clinical syndrome in PD. The pervasiveness of apathy in PD warrants research into its treatment, although different underlying pathophysiological mechanisms may require different treatment strategies. Treatment of apathy could improve patient quality of life, reduce caregiver burden, alleviate disability by increasing motivation for self-care, and reduce cognitive impairment by improving executive functioning. (c) 2015 International Parkinson and Movement Disorder Society.

Background A neuroinflammatory response is suggested to play an important role in delirium, a common complication in older hospitalized patients. We examined whether hip fracture patients who develop postoperative delirium have a different proteome in cerebrospinal fluid (CSF) prior to surgery. Methods Patients (≥ 75 years) were admitted for hip fracture surgery. CSF was collected during spinal anaesthesia; proteins were separated using gel electrophoresis and identified with mass spectrometry. We compared the proteome of patients with and without postoperative delirium. Findings were validated in an independent, comparable cohort using immuno-assays. Results In the derivation cohort 53 patients were included, 35.8% developed postoperative delirium. We identified differences in levels of eight CSF proteins between patients with and without subsequent delirium: complement factor C3, contactin-1, fibulin-1 and I-beta-1,3-N-acetylglucosaminyltransferase were significantly lower in patients with postoperative delirium, while neural cell adhesion molecule-2, fibrinogen, zinc-α-2-glycoprotein and haptoglobin levels were significantly higher. In the validation cohort 21.2% of 52 patients developed postoperative delirium. Immuno-assays confirmed contactin-1 results although not statistically significant. Complement factor C3 was significantly higher in patients with postoperative delirium. Conclusion Our results show the complexity of pathophysiological mechanisms involved in delirium and emphasizes the need of independent validation of findings. General significance This study highlights the challenges and inconsistent findings in studies of delirium, a serious complication in older patients. We analysed proteins in CSF, the most proximal fluid to the brain. All patients were free from delirium at the time of sampling., Highlights • Patients prone to delirium have different CSF protein levels. • Pathophysiological mechanisms involved in delirium are complex. • There is a need of independent validation of findings in research on delirium. • This study highlights the challenges and inconsistent findings in delirium studies.

Background:Systemic low-grade inflammation has repeatedly been associated with depression in old age, but the relationship with apathy is less clear. The present study assessed whether C-reactive protein (CRP) is differentially associated with symptoms of apathy and depression.Methods:A population-based cohort study was carried-out. At baseline and after two and four years of follow-up, CRP levels were assessed and symptoms of apathy and depression were measured using the 15-item Geriatric Depression Scale. Logistic regression analysis was used to investigate the cross-sectional and longitudinal associations of CRP with symptoms of apathy and depression.Results:Two thousand forty-seven community-dwelling participants (70–78 years) without a history of cardiovascular disease or stroke were studied. A cross-sectional association was found between CRP and apathy symptoms at three time points (odds ratio (OR) per natural log unit increase in CRP: baseline visit = 1.40, 95% CI = 1.12–1.75; two-year follow-up visit = 1.62, 95% CI = 1.17–2.25; four-year follow-up visit = 1.51, 95% CI = 1.03–2.21). This did not change after adjustment for demographics and depressive symptoms, and was slightly attenuated after adjustment for cardiovascular risk factors. No cross-sectional association was found with depressive symptoms. Baseline CRP did not predict incident apathy or depressive symptoms during four years of follow-up.Conclusions:Increased CRP levels are associated with apathy symptoms but not with depressive symptoms. This suggests a differential effect of inflammation on apathy and depression. In older persons, symptoms of apathy may be a behavioral manifestation of concurrent low-grade inflammation.

Objective:Use of antihypertensive medication (AHM) is potentially associated with a reduced risk of dementia. Both calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs) are suggested to have a more pronounced protective effect. We aimed to study the association between different c

Background High visit-to-visit variability (VVV) in blood pressure (BP) is associated with cerebrovascular lesions on neuroimaging. Objective Our primary objective was to investigate whether VVV is associated with incident all-cause dementia. As a secondary objective, we studied the association of VVV with cognitive decline and cardiovascular disease (CVD). Methods We included community-dwelling people (age 70-78 year) from the 'Prevention of Dementia by Intensive Vascular Care' (preDIVA) trial with three to five 2-yearly BP measurements during 6-8 years follow-up. VVV was defined using coefficient of variation (CV; SD/mean×100). Cognitive decline was assessed using the Mini-Mental State Examination (MMSE). Incident CVD was defined as myocardial infarction or stroke. We used a Cox proportional hazard regression and mixed-effects model adjusted for sociodemographic factors and cardiovascular risk factors. Results In 2,305 participants (aged 74.2±2.5), mean systolic BP over all available visits was 150.1 mmHg (SD 13.6), yielding a CV of 9.0. After 6.4 years (SD 0.8) follow-up, 110 (4.8%) participants developed dementia and 140 (6.1%) CVD. Higher VVV was not associated with increased risk of dementia (hazard ratio [HR] 1.00 per point CV increase; 95% confidence interval [CI] 0.96-1.05), although the highest quartile of VVV was associated with stronger decline in MMSE (β -0.09, 95% CI -0.17 to -0.01). Higher VVV was associated with incident CVD (HR 1.07; 95% CI 1.04-1.11). Conclusion In our study among older people, high VVV is not associated with incident all-cause dementia. It is associated with decline in MMSE and incident CVD.

This study aims to evaluate the relation between a cluster of neuropsychiatric symptoms related to cholinergic deficiency and degradation of the cortical cholinergic projections which project from the nucleus basalis of Meynert to the cerebral cortex. An atlas of the pathway from the nucleus basalis to the cortex (NbM cortical pathway) was constructed using diffusion tensor imaging and tractography in 87 memory clinic patients. Structural degradation was considered to be represented by lower fractional anisotropy (FA) and higher mean diffusivity (MD). Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. A predefined cluster including agitation, anxiety, apathy, delusions, hallucinations, and irritability was labeled as the cholinergic deficiency syndrome (CDS). In regression analyses, lower FA and higher MD in the NbM cortical pathway were associated with CDS symptoms but not with other neuropsychiatric symptoms. These associations were independent of cerebral atrophy and overall FA or MD. There was no association between interruption of the NbM cortical pathway by white matter hyperintensities and CDS symptoms. Cox regression suggested a trend for higher mortality with lower FA in the NbM cortical pathway may exist. These findings provide anatomical support for the hypothesis that degradation of the cholinergic projections from the nucleus basalis of Meynert may lead to a distinct clinical syndrome. Future studies could use our results to test the utility of assessing NbM projection integrity to identify patients who may benefit from cholinergic treatment or with a worse prognosis. Electronic supplementary material The online version of this article (doi:10.1007/s11682-016-9631-5) contains supplementary material, which is available to authorized users.

Background Recent reports have suggested declining age-specific incidence rates of dementia in high-income countries over time. Improved education and cardiovascular health in early age have been suggested to be bringing about this effect. The aim of this study was to estimate the age-specific dementia incidence trend in primary care records from a large population in the Netherlands. Methods and findings A dynamic cohort representative of the Dutch population was composed using primary care records from general practice registration networks (GPRNs) across the country. Data regarding dementia incidence were obtained using general-practitioner-recorded diagnosis of dementia within the electronic health records. Age-specific dementia incidence rates were calculated for all persons aged 60 y and over; negative binomial regression analysis was used to estimate the time trend. Nine out of eleven GPRNs provided data on more than 800,000 older people for the years 1992 to 2014, corresponding to over 4 million person-years and 23,186 incident dementia cases. The annual growth in dementia incidence rate was estimated to be 2.1% (95% CI 0.5% to 3.8%), and incidence rates were 1.08 (95% CI 1.04 to 1.13) times higher for women compared to men. Despite their relatively low numbers of person-years, the highest age groups contributed most to the increasing trend. There was no significant overall change in incidence rates since the start of a national dementia program in 2003 (−0.025; 95% CI −0.062 to 0.011). Increased awareness of dementia by patients and doctors in more recent years may have influenced dementia diagnosis by general practitioners in electronic health records, and needs to be taken into account when interpreting the data. Conclusions Within the clinical records of a large, representative sample of the Dutch population, we found no evidence for a declining incidence trend of dementia in the Netherlands. This could indicate true stability in incidence rates, or a balance between increased detection and a true reduction. Irrespective of the exact rates and mechanisms underlying these findings, they illustrate that the burden of work for physicians and nurses in general practice associated with newly diagnosed dementia has not been subject to substantial change in the past two decades. Hence, with the ageing of Western societies, we still need to anticipate a dramatic absolute increase in dementia occurrence over the years to come., Using primary care data, Emma van Bussel and colleagues examine trends in dementia incidence trend over 1992-2014 in the Netherlands., Author summary Why was this study done? The absolute number of persons with dementia is rising due to a growing and ageing population. Recent studies showed a decline in dementia incidence rates that might be attributed to improved vascular care and better education in more recent years. Available studies were based on relatively small samples collected in specific years. Large-scale data with yearly incidence rates were so far lacking. What did the researchers do and find? In the Netherlands, all data on dementia diagnoses from general practitioner networks between 1992 and 2014 were collected, yielding over 23,000 incident dementia cases in 4 million person-years. We found that the incidence of registered dementia cases has slightly increased during this 23-year period. What do these findings mean? Based on these registry data, the age-specific incidence of dementia has not declined over the last two decades. Increased awareness of the disease may have led to earlier diagnosis, which could have influenced the number of registered dementia cases.

OBJECTIVE: Although depression is considered to be associated with cardiovascular disease (CVD), specifically symptoms of apathy have been strongly associated with a history of CVD in recent studies. In this study, we prospectively assess whether symptoms of apathy and depression are independent risk factors for incident CVD and stroke. METHODS: We carried out a prospective cohort study of 1810 community-dwelling older individuals (70-78 years) without a history of CVD or stroke. Symptoms of apathy and depression were assessed with the 15-item Geriatric Depression Scale. Incident CVD and stroke were assessed after 2 years follow-up. The associations of symptoms of apathy and depression with incident CVD and stroke were analyzed separately using logistic regression analysis. RESULTS: Symptoms of apathy and depression were present in 281 (15.5%) and 266 (14.7%) participants, respectively. Incident CVD occurred in 62 (3.5%) participants and stroke in 55 (3.1%) participants. Apathy was associated with incident CVD after adjustment for demographics and cardiovascular risk factors (odds ratio (OR) = 2.60, 95% CI = 1.46-4.65). Exclusion of subjects with depressive symptoms yielded a similar OR (2.94, 95% CI = 1.45-5.96, n = 1544). No association was found between depressive symptoms and incident CVD. Neither apathy symptoms nor depressive symptoms were associated with incident stroke. CONCLUSIONS: Apathy, but not depression, is a strong, independent risk factor for incident CVD. It may be a marker of underlying vascular disease. By its nature, apathy may cause non-adherence to a healthy lifestyle, diminished activities, and possibly even withdrawal from clinical care aimed at improving vascular risk profiles.

Background: Delirium is a risk factor for long-term cognitive impairment and dementia. Yet, the nature of these cognitive deficits is unknown as is the extent to which the persistence of delirium symptoms and presence of depression at follow-up may account for the association between delirium and cognitive impairment at follow-up. We hypothesized that inattention, as an important sign of persistent delirium and/or depression, is an important feature of the cognitive profile three months after hospital discharge of patients who experienced in-hosptial delirium.Methods: This was a prospective cohort study. Fifty-three patients aged 75 years and older were admitted for surgical repair of acute hip fracture. Before the surgery, baseline characteristics, depressive symptomatology, and global cognitive performance were documented. The presence of delirium was assessed daily during hospital admission and three months after hospital discharge when patients underwent neuropsychological assessment.Results: Of 27 patients with in-hospital delirium, 5 were still delirious after three months. Patients with in-hospital delirium (but free of delirium at follow-up) showed poorer performance than patients without in-hospital delirium on tests of global cognition and episodic memory, even after adjustment for age, gender, and baseline cognitive impairment. In contrast, no differences were found on tests of attention. Patients with in-hospital delirium showed an increase of depressive symptoms after three months. However, delirium remained associated with poor performance on a range of neuropsychological tests among patients with few or no signs of depression at follow-up.Conclusion: Elderly hip fracture patients with in-hospital delirium experience impairments in global cognition and episodic memory three months after hospital discharge. Our results suggest that inattention, as a cardinal sign of persistent delirium or depressive symptomatology at follow-up, cannot fully account for the poor cognitive outcome associated with delirium.

Patients with mild cognitive impairment (MCI) do not always convert to dementia. In such cases, abnormal neuropsychological test results may not validly reflect cognitive symptoms due to brain disease, and the usual brain-behavior relationships may be absent. This study examined symptom validity in a memory clinic sample and its effect on the associations between hippocampal volume and memory performance. Eleven of 170 consecutive patients (6.5%; 13% of patients younger than 65 years) referred to memory clinics showed noncredible performance on symptom validity tests (SVTs, viz. Word Memory Test and Test of Memory Malingering). They were compared to a demographically matched group (n = 57) selected from the remaining patients. Hippocampal volume, measured by an automated volumetric method (Freesurfer), was correlated with scores on six verbal memory tests. The median correlation was r = .49 in the matched group. However, the relation was absent (median r = -.11) in patients who failed SVTs. Memory clinic samples may include patients who show noncredible performance, which invalidates their MCI diagnosis. This underscores the importance of applying SVTs in evaluating patients with cognitive complaints that may signify a predementia stage, especially when these patients are relatively young.

Background: Delirium in elderly patients is associated with various long-term sequelae that include cognitive impairment and affective disturbances, although the latter is understudied.Methods: For a prospective cohort study of elderly patients undergoing hip fracture surgery, baseline characteristics and affective and cognitive functioning were assessed preoperatively. During hospital admission, presence of delirium was assessed daily. Three months after hospital discharge, affective and global cognitive functioning was evaluated again in patients free from delirium at the time of this follow-up. This study compared baseline characteristics and affective functioning between patients with and without in-hospital delirium. We investigated whether in-hospital delirium is associated with increased anxiety and depressive levels, and post-traumatic stress disorder (PTSD) symptoms three months after discharge.Results: Among 53 eligible patients, 23 (43.4%) patients experienced in-hospital delirium after hip fracture repair. Patients who had experienced in-hospital delirium showed more depressive symptoms at follow-up after three months compared to the 30 patients without in-hospital delirium. This association persisted in a multivariate model controlling for age, baseline cognition, baseline depressive symptoms, and living situation. The level of anxiety and symptoms of PTSD at follow-up did not differ between both groups.Conclusion: This study suggests that in-hospital delirium is associated with an increased burden of depressive symptoms three months after discharge in elderly patients who were admitted to the hospital for surgical repair of hip fracture. Symptoms of depression in patients with previous in-hospital delirium cannot be fully explained by persistent (sub)syndromal delirium or baseline cognitive impairment.Trial name: The Effect of Taurine on Morbidity and Mortality in the Elderly Hip Fracture Patient. URL: http://clinicaltrials.gov/ct2/show/NCT00497978?term=taurine+hip+fracture&rank=1. Registration number: NCT00497978.

Contains fulltext : 167841.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Cardiovascular disease and dementia share a number of risk factors including hypertension, hypercholesterolaemia, smoking, obesity, diabetes and physical inactivity. The rise of eHealth has led to increasing opportunities for large-scale delivery of prevention programmes encouraging self-management. The aim of this study is to investigate whether a multidomain intervention to optimise self-management of cardiovascular risk factors in older individuals, delivered through an coach-supported interactive internet platform, can improve the cardiovascular risk profile and reduce the risk of cardiovascular disease and cognitive decline. METHODS AND ANALYSIS: HATICE is a multinational, multicentre, prospective, randomised, open-label blinded end point (PROBE) trial with 18 months intervention. Recruitment of 2600 older people (>/=65 years) at increased risk of cardiovascular disease will take place in the Netherlands, Finland and France. Participants randomised to the intervention condition will have access to an interactive internet platform, stimulating self-management of vascular risk factors, with remote support by a coach. Participants in the control group will have access to a static internet platform with basic health information.The primary outcome is a composite score based on the average z-score of the difference between baseline and 18 months follow-up values of systolic blood pressure, low-density-lipoprotein and body mass index. Main secondary outcomes include the effect on the individual components of the primary outcome, the effect on lifestyle-related risk factors, incident cardiovascular disease, mortality, cognitive functioning, mood and cost-effectiveness. ETHICS AND DISSEMINATION: The study was approved by the medical ethics committee of the Academic Medical Center in Amsterdam, the Comite de Protection des Personnes Sud Ouest et Outre Mer in France and the Northern Savo Hospital District Research Ethics Committee in Finland.We expect that data from this study will result in a manuscript published in a peer-reviewed clinical open access journal. TRIAL REGISTRATION NUMBER: ISRCTN48151589.

This is the author accepted manuscript. The final version is available from Elsevier via https://doi.org/10.1016/ S0140-6736(16)30950-3, BACKGROUND: Cardiovascular risk factors are associated with an increased risk of dementia. We assessed whether a multidomain intervention targeting these factors can prevent dementia in a population of community-dwelling older people. METHODS: In this open-label, cluster-randomised controlled trial, we recruited individuals aged 70-78 years through participating general practices in the Netherlands. General practices within each health-care centre were randomly assigned (1:1), via a computer-generated randomisation sequence, to either a 6-year nurse-led, multidomain cardiovascular intervention or control (usual care). The primary outcomes were cumulative incidence of dementia and disability score (Academic Medical Center Linear Disability Score [ALDS]) at 6 years of follow-up. The main secondary outcomes were incident cardiovascular disease and mortality. Outcome assessors were masked to group assignment. Analyses included all participants with available outcome data. This trial is registered with ISRCTN, number ISRCTN29711771. FINDINGS: Between June 7, 2006, and March 12, 2009, 116 general practices (3526 participants) within 26 health-care centres were recruited and randomly assigned: 63 (1890 participants) were assigned to the intervention group and 53 (1636 participants) to the control group. Primary outcome data were obtained for 3454 (98%) participants; median follow-up was 6·7 years (21 341 person-years). Dementia developed in 121 (7%) of 1853 participants in the intervention group and in 112 (7%) of 1601 participants in the control group (hazard ratio [HR] 0·92, 95% CI 0·71-1·19; p=0·54). Mean ALDS scores measured during follow-up did not differ between groups (85·7 [SD 6·8] in the intervention group and 85·7 [7·1] in the control group; adjusted mean difference -0·02, 95% CI -0·38 to 0·42; p=0·93). 309 (16%) of 1885 participants died in the intervention group, compared with 269 (16%) of 1634 participants in the control group (HR 0·98, 95% CI 0·80-1·18; p=0·81). Incident cardiovascular disease did not differ between groups (273 [19%] of 1469 participants in the intervention group and 228 [17%] of 1307 participants in the control group; HR 1·06, 95% CI 0·86-1·31; p=0·57). INTERPRETATION: A nurse-led, multidomain intervention did not result in a reduced incidence of all-cause dementia in an unselected population of older people. This absence of effect might have been caused by modest baseline cardiovascular risks and high standards of usual care. Future studies should assess the efficacy of such interventions in selected populations. FUNDING: Dutch Ministry of Health, Welfare and Sport; Dutch Innovation Fund of Collaborative Health Insurances; and Netherlands Organisation for Health Research and Development.

Epidemiological studies have consistently shown that vascular risk factors including hypertension, diabetes, obesity, hypercholesterolemia, smoking, and lack of physical exercise are associated with an increased risk of cognitive decline and dementia. Neuroradiological and neuropathological studies have confirmed the importance of cerebrovascular lesions in the etiology of late onset dementia. We have reviewed the literature and conclude that up until now randomized controlled clinical trials targeting individual risk factors and assessing cognitive decline or dementia as an outcome have not convincingly shown that treatment of vascular risk factors can actually prevent or postpone cognitive decline and dementia. New studies targeting several vascular risk factors at the same time and using cognitive decline or dementia as primary outcome might answer the question whether cognitive decline can really be postponed or even prevented. The design of such studies is not straightforward and long follow-up is required. In this review we discuss several pertinent methodological issues that need to be addressed to achieve an optimal design of new randomized controlled trials.

Context: Apathy in community-dwelling elderly individuals has been associated with a history of stroke and other cardiovascular disease. Objective: To assess the relationship between symptoms of apathy and cardiovascular risk factors or disease (stroke or other) in a large sample of elderly people aged 70 to 78 years without depression or dementia. Design: Cross-sectional data analysis within an ongoing cluster-randomized, open, multicenter trial. Setting: The Netherlands, general community. Participants: We studied 3534 elderly individuals without dementia who were included in the Prevention of Dementia by Intensive Vascular Care trial. Main Outcome Measures: Symptoms of apathy, assessed with 3 items from the 15-item Geriatric Depression Scale, in participants with few or no depressive symptoms. Results: The median age of participants was 74.3 years. Principal components analysis of the Geriatric Depression Scale confirmed a separate factor for the apathy items (Geriatric Depression Scale-3A). Two or more symptoms of apathy were present in 699 participants (19.9%), of whom 372 (53.2%) were without depressive symptoms (Geriatric Depression Scale-12D score

The focus of most of the research on Alzheimer's disease in the last decades has been on senile plaques and neurofibrillary tangles. The vast majority of patients with Alzheimer's disease are over 75 years of age, whereas most of the research focuses on younger subjects. To consider old-age dementia as a homogenous well-defined condition ignores the complexity of this condition and limits the development of new diagnostic methods, preventive strategies, or treatment strategies that could be widely applicable in daily practice in the majority of the older patients. The current research on biomarkers focuses on correlates of plaques and tangles, which are poor markers in older dementia subjects. Acknowledging that dementia in old age is an essentially different condition from dementia at relatively younger age is needed and should lead to new approaches in dementia research.

Background: There is little information on the prevalence of hypertension and other modifiable cardiovascular risk factors in community-dwelling elderly in the Netherlands and the potential impact of improving antihypertensive treatment on major cardiovascular events. Design: Cross-sectional analysis of Dutch community-dwelling subjects aged 70-78 years without dementia who were included in the cluster randomized preDIVA trial (Prevention of Dementia by Intensive Vascular care). Methods: The prevalence of hypertension and other cardiovascular risk factors are described for participants with and without a history of cardiovascular disease (CVD). Projected benefits of blood pressure decrease are calculated using data from a meta-analysis and a large national registry. Results: Of 3534 subjects, more than one-third (n = 1230, 35.2%) have a history of cardiovascular disease. Overall, 63% of subjects have two or more cardiovascular risk factors amenable to treatment. Systolic blood pressure (SBP) is >= 160mmHg in 37% of patients with CVD, of which 28% is untreated. In subjects without a history of CVD, 41% have a SBP >= 160mmHg of which 52% is untreated. A 5-15mmHg decrease in SBP is projected to prevent 12-32% of coronary heart disease and 16-41% of strokes, respectively. This corresponds with 14-38 prevented cases within 2 years in our intervention group (n = 1895). Conclusions: Hypertension and other cardiovascular risk factors are very common in elderly subjects. Current (primary and secondary) prevention programmes appear insufficient. Improved antihypertensive treatment has the potential to prevent a substantial proportion of strokes and coronary heart disease in this population

OBJECTIVES: To examine the association between cerebrospinal fluid (CSF) B-amyloid (AB1�42), tau, and hyperphosphorylated tau (Ptau) and risk of delirium in older adults with hip fracture. DESIGN: Prospective cohort study. SETTING: University-affiliated general hospital in Alkmaar, the Netherlands. PARTICIPANTS: Seventy-six participants aged 75 and older admitted for surgical repair of acute hip fracture. MEASUREMENTS: Presurgical baseline screening and assessment included the Informant Questionnaire on Cognitive Decline�short form (IQCODE-N), Mini-Mental State Examination, standardized Snellen test for visual impairment, Geriatric Depression Scale, Barthel Index (BI), and Lawton Instrumental Activity of Daily Living (IADL) scale. The number of medical comorbidities and medications at home, American Society of Anesthesiologists score, and Acute Physiology and Chronic Health Evaluation II score were determined according to chart review. Delirium was diagnosed using the Confusion Assessment Method. CSF was collected at the onset of spinal anesthesia. RESULTS: Postoperative delirium occurred in 30 (39.5%) participants. Participants with delirium were older, showed more signs of cognitive decline, were more dependent at home in activity of daily living and IADL functioning, and used more medications before admission. Preoperative CSF AB1-42, tau, and Ptau levels were not significantly different in participants who did and did not develop delirium during subsequent hospitalization. In contrast, prefracture cognitive decline (IQCODE-N) was significantly related to delirium (odds ratio=9.43, 95% confidence interval=2.45�36.31). CONCLUSION: Cognitive impairment predisposes to delirium, but in this study, postoperative delirium was not associated with baseline CSF AB1-42, tau, and Ptau levels. These findings suggest that CSF markers for plaque and tangle formation are not strongly associated with delirium risk in older adults with hip fracture.