The presence of both physical frailty and cognitive impairment has been recently proposed as a distinctive entity. We investigated the effect of physical frailty and cognitive impairment on survival among elderly. Study participants included 2251 dementia-free people aged 60+ years enrolled in the Swedish National study on Aging and Care in Kungsholmen, Stockholm. Physical frailty was defined according to Fried phenotype (weight loss, weakness, exhaustion, slowness, low physical activity). Cognitive Impairment Non Dementia (CIND) was defined on the basis of an extensive neuropsychological battery. We investigated the impact of CIND and physical frailty alone and the combination of these two conditions on survival in terms of mortality rate at 5 and 10 years of follow-up (Cox models) and differences in median age at death (Laplace regression). The strongest association with short and long survival was found among people with both CIND and physical frailty. Those people, after 5 years, had three times higher mortality rate (HR: 3.1; 95% CI: 1.8- 5.4) and 3.7 years shorter life compared to frailty-free subjects (neither CIND nor physical frail). People with only physical frailty but cognitively intact had an HR of 1.7 (95% CI: 1.1–2.8) as compared with frailty-free ones. Isolated CIND was not associated with mortality. After 10 years, similar results were observed, although attenuated (for CIND+ physical frailty: HR: 2.1; 95% CI: 1.3–3.2). Subjects with both physical frailty and cognitive impairment represent a special frail and complex population that deserves ad hoc assessments and care.

Aims: To examine the relationship between body mass index (BMI) and progression to dementia and Alzheimer's disease (AD) in mild cognitive impairment (MCI). Materials and Methods: Two hundred and twenty-eight MCI subjects (mean age 74.04 ± 6.94 years; 57% female) from a memory clinic were followed for 2.40 ± 1.58 years. Baseline height and weight were used to calculate the BMI. The main outcome was progression to dementia (DSM-IV criteria) and AD (NINCDS-ADRDA criteria). Cox proportional hazard models were used to assess the longitudinal association of BMI with dementia and AD, adjusting for a comprehensive set of covariates, including vascular risk factors/diseases and neuroimaging profiles. Results: Out of 228 subjects with MCI, 117 (51.3%) progressed to dementia. Eighty-nine (76%) of the incident dementia cases had AD. In both unadjusted and multi-adjusted models, a higher BMI was associated with a reduced risk of dementia (multi-adjusted HR 0.9; 95% CI 0.8-0.9) and AD (multi-adjusted HR 0.9; 95% CI 0.8-0.9). Being underweight increased the risk of all types of dementia (multi-adjusted HR 2.5; 95% CI 1.2-5.1) but was not specifically associated with AD (multi-adjusted HR 2.2; 95% CI 0.9-5.3). Conclusions: BMI predicted progression of MCI to dementia and AD. In particular, a higher BMI was associated with a lower risk of dementia and AD, and underweight was associated with a higher risk of dementia. BMI assessment may improve the prognostic accuracy of MCI in clinical practice.

AimsWe investigated whether traffic-related air pollution and noise are associated with incident hypertension in European cohorts.Methods and resultsWe included seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). We modelled concentrations of particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), ≤10 µm (PM10), >2.5, and ≤10 µm (PMcoarse), soot (PM2.5 absorbance), and nitrogen oxides at the addresses of participants with land use regression. Residential exposure to traffic noise was modelled at the facade according to the EU Directive 2002/49/EC. We assessed hypertension as (i) self-reported and (ii) measured (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg or intake of BP lowering medication (BPLM). We used Poisson regression with robust variance estimation to analyse associations of traffic-related exposures with incidence of hypertension, controlling for relevant confounders, and combined the results from individual studies with random-effects meta-analysis. Among 41 072 participants free of self-reported hypertension at baseline, 6207 (15.1%) incident cases occurred within 5-9 years of follow-up. Incidence of self-reported hypertension was positively associated with PM2.5 (relative risk (RR) 1.22 [95%-confidence interval (CI):1.08; 1.37] per 5 µg/m³) and PM2.5 absorbance (RR 1.13 [95% CI:1.02; 1.24] per 10 - 5m - 1). These estimates decreased slightly upon adjustment for road traffic noise. Road traffic noise was weakly positively associated with the incidence of self-reported hypertension. Among 10 896 participants at risk, 3549 new cases of measured hypertension occurred. We found no clear associations with measured hypertension.ConclusionLong-term residential exposures to air pollution and noise are associated with increased incidence of self-reported hypertension.

BACKGROUND:Weight loss is common in people with Alzheimer's disease (AD) and it could be a marker of impending AD in Mild Cognitive Impairment (MCI) and improve prognostic accuracy, if accelerated progression to AD would be shown. AIMS:To assess weight loss as a predictor of dementia and AD in MCI. METHODS:One hundred twenty-five subjects with MCI (age 73.8 ± 7.1 years) were followed for an average of 4 years. Two weight measurements were carried out at a minimum time interval of one year. Dementia was defined according to DSM-IV criteria and AD according to NINCDS-ADRDA criteria. Weight loss was defined as a ≥4% decrease in baseline weight. RESULTS:Fifty-three (42.4%) MCI progressed to dementia, which was of the AD-type in half of the cases. Weight loss was associated with a 3.4-fold increased risk of dementia (95% CI = 1.5-6.9) and a 3.2-fold increased risk of AD (95% CI = 1.4-8.3). In terms of years lived without disease, weight loss was associated to a 2.3 and 2.5 years earlier onset of dementia and AD. CONCLUSIONS:Accelerated progression towards dementia and AD is expected when weight loss is observed in MCI patients. Weight should be closely monitored in elderly with mild cognitive impairment.

Cognitive decline in elderly people often derives from the interaction between aging-related changes and age-related diseases and covers a large spectrum of clinical manifestations, from intact cognition through mild cognitive impairment and dementia. Epidemiological evidence supports the hypothesis that modifiable lifestyle-related factors are associated with cognitive decline, opening new avenues for prevention. Diet in particular has become the object of intense research in relation to cognitive aging and neurodegenerative disease. We reviewed the most recent findings in this rapidly expanding field. Some nutrients, such as vitamins and fatty acids, have been studied longer than others, but strong scientific evidence of an association is lacking even for these compounds. Specific dietary patterns, like the Mediterranean diet, may be more beneficial than a high consumption of single nutrients or specific food items. A strong link between vascular risk factors and dementia has been shown, and the association of diet with several vascular and metabolic diseases is well known. Other plausible mechanisms underlying the relationship between diet and cognitive decline, such as inflammation and oxidative stress, have been established. In addition to the traditional etiological pathways, new hypotheses, such as the role of the intestinal microbiome in cognitive function, have been suggested and warrant further investigation.

BACKGROUND:Few studies have investigated effects of air pollution on the incidence of cerebrovascular events. OBJECTIVES:We assessed the association between long-term exposure to multiple air pollutants and the incidence of stroke in European cohorts. METHODS:Data from 11 cohorts were collected, and occurrence of a first stroke was evaluated. Individual air pollution exposures were predicted from land-use regression models developed within the European Study of Cohorts for Air Pollution Effects (ESCAPE). The exposures were: PM2.5 [particulate matter (PM) ≤ 2.5 μm in diameter], coarse PM (PM between 2.5 and 10 μm), PM10 (PM ≤ 10 μm), PM2.5 absorbance, nitrogen oxides, and two traffic indicators. Cohort-specific analyses were conducted using Cox proportional hazards models. Random-effects meta-analysis was used for pooled effect estimation. RESULTS:A total of 99,446 study participants were included, 3,086 of whom developed stroke. A 5-μg/m3 increase in annual PM2.5 exposure was associated with 19% increased risk of incident stroke [hazard ratio (HR) = 1.19, 95% CI: 0.88, 1.62]. Similar findings were obtained for PM10. The results were robust to adjustment for an extensive list of cardiovascular risk factors and noise coexposure. The association with PM2.5 was apparent among those ≥ 60 years of age (HR = 1.40, 95% CI: 1.05, 1.87), among never-smokers (HR = 1.74, 95% CI: 1.06, 2.88), and among participants with PM2.5 exposure < 25 μg/m3 (HR = 1.33, 95% CI: 1.01, 1.77). CONCLUSIONS:We found suggestive evidence of an association between fine particles and incidence of cerebrovascular events in Europe, even at lower concentrations than set by the current air quality limit value.

BACKGROUND Slow walking speed has been shown to predict dementia. We investigated the relation of walking speed, processing speed, and their changes over time to dementia among older adults. METHODS This study included 2,938 participants (age 60+ years) in the population-based Swedish National study on Aging and Care in Kungsholmen, Sweden, who were free from dementia and severe walking impairment at baseline. Walking speed was assessed with participants walking at their usual pace and processing speed was defined by a composite measure of standard tests (digit cancellation, trail making test-A, pattern comparison). Dementia at 3- and 6-year follow-ups was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria. RESULTS Of the 2,232 participants who were reassessed at least once, 226 developed dementia. Logistic regression models showed that each standard deviation slower baseline walking speed or decline in walking speed over time increased the likelihood of incident dementia (odds ratios 1.61, 95% confidence interval [CI] 1.31-1.98; and 2.58, 95% CI 2.12-3.14, respectively). Adjustment for processing speed attenuated these associations (odds ratios 1.26, 95% CI 1.01-1.58 and 1.76, 95% CI 1.33-2.34). Mixed-effects models revealed statistical interactions of time with dementia on change in walking and processing speed, such that those who developed dementia showed accelerated decline. At baseline, poorer performance in processing speed, but not in walking speed, was observed for persons who developed dementia during the study period. CONCLUSIONS Processing speed may play an important role for the association between walking speed and dementia. The slowing of walking speed appears to occur secondary to slowing of processing speed in the path leading to dementia.

OBJECTIVES:To study the effect of long term exposure to airborne pollutants on the incidence of acute coronary events in 11 cohorts participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE). DESIGN:Prospective cohort studies and meta-analysis of the results. SETTING:Cohorts in Finland, Sweden, Denmark, Germany, and Italy. PARTICIPANTS:100 166 people were enrolled from 1997 to 2007 and followed for an average of 11.5 years. Participants were free from previous coronary events at baseline. MAIN OUTCOME MEASURES:Modelled concentrations of particulate matter <2.5 μm (PM2.5), 2.5-10 μm (PMcoarse), and <10 μm (PM10) in aerodynamic diameter, soot (PM2.5 absorbance), nitrogen oxides, and traffic exposure at the home address based on measurements of air pollution conducted in 2008-12. Cohort specific hazard ratios for incidence of acute coronary events (myocardial infarction and unstable angina) per fixed increments of the pollutants with adjustment for sociodemographic and lifestyle risk factors, and pooled random effects meta-analytic hazard ratios. RESULTS:5157 participants experienced incident events. A 5 μg/m(3) increase in estimated annual mean PM2.5 was associated with a 13% increased risk of coronary events (hazard ratio 1.13, 95% confidence interval 0.98 to 1.30), and a 10 μg/m(3) increase in estimated annual mean PM10 was associated with a 12% increased risk of coronary events (1.12, 1.01 to 1.25) with no evidence of heterogeneity between cohorts. Positive associations were detected below the current annual European limit value of 25 μg/m(3) for PM2.5 (1.18, 1.01 to 1.39, for 5 μg/m(3) increase in PM2.5) and below 40 μg/m(3) for PM10 (1.12, 1.00 to 1.27, for 10 μg/m(3) increase in PM10). Positive but non-significant associations were found with other pollutants. CONCLUSIONS:Long term exposure to particulate matter is associated with incidence of coronary events, and this association persists at levels of exposure below the current European limit values.

We investigated the risk of stroke related to long-term ambient air pollution exposure, in particular the role of various exposure time windows, using four cohorts from Stockholm County, Sweden. In total, 22,587 individuals were recruited from 1992 to 2004 and followed until 2011. Yearly air pollution levels resulting from local road traffic emissions were assessed at participant residences using dispersion models for particulate matter (PM 10 ) and nitrogen oxides (NO X ). Cohort-specific hazard ratios were estimated for time-weighted air pollution exposure during different time windows and the incidence of stroke, adjusted for common risk factors, and then meta-analysed. Overall, 868 subjects suffered a non-fatal or fatal stroke during 238,731 person-years of follow-up. An increment of 20 μ g/m 3 in estimated annual mean of road-traffic related NO X exposure at recruitment was associated with a hazard ratio of 1.16 (95% CI 0.83–1.61), with evidence of heterogeneity between the cohorts. For PM 10 , an increment of 10 μ g/m 3 corresponded to a hazard ratio of 1.14 (95% CI 0.68–1.90). Time-window analyses did not reveal any clear induction-latency pattern. In conclusion, we found suggestive evidence of an association between long-term exposure to NO X and PM 10 from local traffic and stroke at comparatively low levels of air pollution.

BACKGROUND:Long-term exposure to air pollution has been hypothesized to elevate arterial blood pressure (BP). The existing evidence is scarce and country specific. OBJECTIVES:We investigated the cross-sectional association of long-term traffic-related air pollution with BP and prevalent hypertension in European populations. METHODS:We analyzed 15 population-based cohorts, participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE). We modeled residential exposure to particulate matter and nitrogen oxides with land use regression using a uniform protocol. We assessed traffic exposure with traffic indicator variables. We analyzed systolic and diastolic BP in participants medicated and nonmedicated with BP-lowering medication (BPLM) separately, adjusting for personal and area-level risk factors and environmental noise. Prevalent hypertension was defined as ≥ 140 mmHg systolic BP, or ≥ 90 mmHg diastolic BP, or intake of BPLM. We combined cohort-specific results using random-effects meta-analysis. RESULTS:In the main meta-analysis of 113,926 participants, traffic load on major roads within 100 m of the residence was associated with increased systolic and diastolic BP in nonmedicated participants [0.35 mmHg (95% CI: 0.02, 0.68) and 0.22 mmHg (95% CI: 0.04, 0.40) per 4,000,000 vehicles × m/day, respectively]. The estimated odds ratio (OR) for prevalent hypertension was 1.05 (95% CI: 0.99, 1.11) per 4,000,000 vehicles × m/day. Modeled air pollutants and BP were not clearly associated. CONCLUSIONS:In this first comprehensive meta-analysis of European population-based cohorts, we observed a weak positive association of high residential traffic exposure with BP in nonmedicated participants, and an elevated OR for prevalent hypertension. The relationship of modeled air pollutants with BP was inconsistent.

The construct of mild cognitive impairment (MCI) has evolved over the past 10years since the publication of the new MCI definition at the Key Symposium in 2003, but the core criteria have remained unchanged. The construct has been extensively used worldwide, both in clinical and in research settings, to define the grey area between intact cognitive functioning and clinical dementia. A rich set of data regarding occurrence, risk factors and progression of MCI has been generated. Discrepancies between studies can be mostly explained by differences in the operationalization of the criteria, differences in the setting where the criteria have been applied, selection of subjects and length of follow-up in longitudinal studies. Major controversial issues that remain to be further explored are algorithmic versus clinical classification, reliability of clinical judgment, temporal changes in cognitive performances and predictivity of putative biomarkers. Some suggestions to further develop the MCI construct include the tailoring of the clinical criteria to specific populations and to specific contexts. The addition of biomarkers to the clinical phenotypes is promising but requires deeper investigation. Translation of findings from the specialty clinic to the population setting, although challenging, will enhance uniformity of outcomes. More longitudinal population-based studies on cognitive ageing and MCI need to be performed to clarify all these issues.

The impact of APOE ε4 on mild cognitive impairment (MCI) and its progression to dementia remain controversial. We aimed to examine the association of APOE ε4 with MCI, and to verify the hypothesis that ε4 accelerates progression from MCI to dementia. In the Kungsholmen project, 756 cognitively healthy participants and 212 people with MCI aged ≥75 years were identified at baseline. Amnestic MCI (aMCI) and other cognitive impairment no dementia (oCIND) as two subtypes of MCI were assessed based on standard definitions. The two cohorts were followed for 9 years to detect incident cases of MCI and dementia following international criteria. APOE genotypes were assessed at baseline. Data were analyzed using Cox models. During the follow-up, in the cognitively healthy cohort, 165 people developed MCI (40 aMCI and 125 oCIND) and 176 developed dementia; in the MCI cohort, 118 persons progressed to dementia. Compared with APOE ε3ε3, the hazard ratios (HRs) (95% CIs) of ε2ε4/ε3ε4 were 2.24 (1.10-4.57) for aMCI and 1.78 (1.15-2.75) for oCIND, while the ε4ε4 was related to dementia with a HR of 4.35 (1.97-9.63) in the cognitively healthy cohort. In the MCI cohort, the ε4ε4 genotype led to a multi-adjusted HR of 2.89 (1.12-7.48) for dementia and accelerated the progression to dementia by 3.36 years. The APOE ε4 heterozygotes are associated with an increased risk of aMCI and oCIND. The ε4 homozygote substantially accelerates progression from MCI to dementia, and anticipate dementia occurrence by more than 3 years in people with MCI.

BACKGROUND:Empirical models of the natural history of Alzheimer's disease (AD) may help to evaluate new interventions for AD.OBJECTIVE:We aimed to estimate AD-free survival time in people with mild cognitive impairment (MCI) and decline of cognitive and physical function in AD cases.METHODS:Within the Kungsholmen project, 153 incident MCI and 323 incident AD cases (international criteria) were identified during 9 years of follow-up in a cognitively healthy cohort of elderly people aged ≥75 at baseline (n = 1,082). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE), and daily life function was evaluated with the Katz index of activities of daily living (ADL) at each follow-up examination. Data were analyzed using parametric survival analysis and mixed effect models.RESULTS:Median AD-free survival time of 153 participants with incident MCI was 3.5 years. Among 323 incident AD cases, the cognitive decline was 1.84 MMSE points per year, which was significantly associated with age. Physical functioning declined by 0.38 ADL points per year and was significantly associated with age, education, and MMSE, but not with gender.CONCLUSION:Elderly people with MCI may develop AD in approximately 3.5 years. Both cognitive and physical function may decline gradually after AD onset. The empirical models can be used to evaluate long-term disease progression of new interventions for AD.

We investigated the relation of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND) to common chronic diseases of the elderly and multimorbidity, and assessed the contribution of genetic background and shared familial environment to these associations. Subjects were 11,379 dementia-free twin individuals aged ≥ 65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. In unmatched, fully-adjusted regression models, mental, musculoskeletal, respiratory, and urological diseases were all significantly associated with increased odds ratios (ORs) of SCI and CIND. Circulatory and gastrointestinal diseases were related to SCI only, while endocrine diseases were associated with CIND. The adjusted ORs of multimorbidity were 2.1 [95% confidence intervals (95% CI): 1.8-2.3] for SCI and 1.5 for CIND (95% CI: 1.3-1.8). A dose-dependent relationship was observed between number of chronic diseases and ORs for SCI but not for CIND. In co-twin control analyses, the chronic diseases-SCI association was largely unchanged. On the other hand, the chronic diseases-CIND association was no longer statistically significant, except for cancer, where an increased OR was observed. In conclusion, chronic morbidity is associated with both SCI and CIND but disease profiles do not always overlap between the two cognitive syndromes. The association is stronger when diseases co-occur, especially for SCI. Genetic and early-life environmental factors may partially explain the association of CIND but not that of SCI with chronic diseases.

Aims: To investigate the contribution of vascular risk factors (VRFs), vascular diseases (VDs) and white matter lesions (WMLs) to the progression of mild cognitive impairment (MCI) to dementia and Alzheimer's disease (AD). Methods: Two hundred forty-five consecutive subjects with MCI (age 74.09 +/- 6.92 years) were followed for an average of 2.4 years. The Hachinski Ischemic Score and the Framingham Stroke Risk Profile were used to summarize VRFs and VDs. WMLs were graded using the Age-Related White Matter Changes Scale. Results: One hundred twenty-nine (52.6%) out of 245 subjects at risk converted to dementia, including 87 cases of AD. When hypertension occurred in MCI with deep WMLs, a 1.8-fold increased risk of dementia was observed (95% CI = 1.0-3.4). When deep WMLs occurred in MCI with high scores (>= 4) on the Hachinski scale, a 3.5-fold (95% CI = 1.6-7.4) and 3.8-fold (95% CI = 1.2-11.5) risk of progression to dementia and AD was observed, respectively. Analogously, the joint effect of WMLs and high scores (>= 14) on the Framingham scale nearly doubled the risk of dementia ( hazard ratio = 1.9, 95% CI = 1.1-3.3). Conclusions: Accelerated progression of MCI to dementia and AD is to be expected when VRFs and VDs occur together with WMLs. Copyright (c) 2012 S. Karger AG, Basel

We report the prevalence of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND), their socio-demographic profile, and the contribution of genetic background and shared familial environment to SCI and CIND. Subjects were 11,926 dementia-free twin individuals aged ≥65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. Overall prevalence rates of SCI and CIND were 39% (95% CI 38-39%) and 25% (95% CI 24-25%). In multivariate GEE models, both SCI and CIND were older compared with people without any cognitive impairment. CIND were also less educated, more likely to be unmarried and to have lower socioeconomic status (SES). SCI individuals differed from persons with CIND as they were older, more educated, more likely to be married, and to have higher SES. Co-twin control analysis, which corrects for common genetic and shared environmental background, confirmed the association of low education with CIND. Probandwise concordance for SCI and CIND was 63% and 52% in monozygotic twins, 63% and 50% in dizygotic same-sex twins, and 42% and 29% in dizygotic unlike-sex twins. Tetrachoric correlations showed no significant differences between monozygotic and dizygotic same-sex twins. We conclude that subjective and objective cognitive impairment are both highly prevalent among nondemented elderly yet have distinct sociodemographic profiles. Shared environmental influences rather than genetic background play a role in the occurrence of SCI and CIND.

Objective— To examine the association of common chronic disease and multimorbidity with subjective cognitive impairment (SCI) and cognitive impairment no-dementia (CIND), and to explore the contribution of genetic background and shared familial environment to these associations. Design— Population-based twin study. Swedish twins. Subjects— 11,379 dementia-free individuals aged ≥ 65 from the Swedish Twin Registry. Main Outcome Measures— SCI was defined as subjective complaint of cognitive change without objective cognitive impairment, and CIND was ascertained according to the standard definition. Chronic diseases were classified based on international criteria, and multimorbidity was assessed as the co-occurrence of at least two chronic diseases in the same individual. Results— In unmatched, fully-adjusted regression models, musculoskeletal, respiratory, and urological diseases were significantly associated with increased odds ratios (ORs) of both SCI and CIND. Circulatory and gastrointestinal disorders were related to SCI, while endocrine diseases were associated with CIND. The adjusted ORs of multimorbidity were 2.1 [95% Confidence Intervals (95% CI): 1.8–2.3] for SCI and 1.5 for CIND (95% CI: 1.3–1.8). There was a significant dose-dependent relationship between number of chronic diseases and ORs for SCI but not for CIND. In co-twin control analyses, the Conclusion— Chronic diseases are associated with both SCI and CIND and the association is stronger when there is multimorbidity. Genetic and shared environmental factors may partially explain the association of CIND but not that of SCI with chronic diseases. investigation, conducted in the framework of the large, population-based, Swedish twin-study on aging and dementia (HARMONY), we aimed to: 1) examine the association of individual chronic disease and multimorbidity with SCI and CIND; and 2) explore the contribution of genetic background and early-life environments to these associations.