N-Terminal Pro-B Type Natriuretic Peptide is Associated with Mild Cognitive Impairment in the General Population

Abstract

Background: N-terminal pro-B type natriuretic peptide (NT-proBNP) is a marker of cardiac stress and is linked with silent cardiac diseases. While associations of cognitive impairment with manifest cardiovascular diseases are established, data on whether subclinical elevation of NT-proBNP levels below clinically established threshold of heart failure is related with cognitive functioning, especially mild cognitive impairment (MCI), is rare.

Objective: Aim of the present study was to investigate the cross-sectional association of NT-proBNP levels and MCI in a population-based study sample without heart failure.

Methods: We used data from the second examination of the population based Heinz-Nixdorf-Recall-Study. Subjects with overt coronary heart disease and subjects with NT-proBNP levels indicating potential heart failure (NT-proBNP≥300 pg/ml) were excluded from this analysis. Participants performed a validated brief cognitive assessment and were classified either as MCI [subtypes: amnestic-MCI (aMCI), non-amnestic-MCI (naMCI)], or cognitively-normal.

Results: We included 419 participants with MCI (63.1±7.4 y; 47% men; aMCI n = 209; naMCI n = 210) and 1,206 cognitively normal participants (62.42±7.1 y; 48% men). NT-proBNP-levels≥125 pg/ml compared to <125 pg/ml were associated with MCI in fully adjusted models (OR 1.65 (1.23;2.23) in the total sample, 1.73 (1.09;2.74) in men and 1.63(1.10;2.41) in women). For aMCI, the fully adjusted OR was 1.53 (1.04;2.25) and for naMCI, the fully adjusted OR was 1.34 (1.09; 166) in the total sample.

Conclusion: Within normal ranges and without manifest heart failure, higher NT-proBNPlevels are associated with MCI and both MCI subtypes independent of traditional cardiovascular risk factors and sociodemographic parameters.

Keywords

Alzheimer’s disease BNP mild cognitive impairment natriuretic peptides NT-proBNP

INTRODUCTION

A decrease in cognitive function is common in aging populations. Because Alzheimer’s disease (AD) and vascular dementia represent the end stage of irreversible pathological changes in the brain, recent studies focus on early stages of cognitive impairment. Mild cognitive impairment (MCI) represents an intermediate stage in the trajectory from normal cognition to dementia [1, 2]. Although persons with MCI have an increased risk of developing dementia or AD, they can remain stable for many years or even revert to a cognitively normal state over time. This modifiable characteristic makes the concept of MCI a promising target in the prevention of dementia [1, 2]. Participants with MCI show subjective and objective impairment in cognitive performance that is not severe enough to interfere with activities of daily living [1, 3].

Recent studies have demonstrated an association of heart failure with MCI, presumably due to a decrease in cerebral perfusion [4 –6].

B-type natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP) are natriuretic peptides, secreted from cardiac myocytes in response to ventricular and atrial wall stress and serve as serum biomarkers for the diagnosis of heart failure [7]. Moreover, natriuretic peptides are increased in subjects with early stages of cardiac diseases such as diastolic dysfunction, left ventricular hypertrophy, and silent myocardial ischemia with plasma-levels markedly below the cut-off value used for the diagnosis of heart failure [8]. Thus, natriuretic peptides seem to reflect pancardiac functional heart disease also in early asymptomatic stages [8, 9]. The association between cardiac disease, especially heart failure and cognitive impairment has been previously described [5]. However, there is a lack of studies investigating the association of subclinical NT-proBNP-levels below the threshold of heart failure with MCI in the general asymptomatic population. Therefore, the aim of this analysis was to determine (1) the association of NT-proBNP with MCI in the population based Heinz Nixdorf Recall study, specifically looking at the range of NT-proBNP within normal values, and (2) whether a potential association is independent of traditional risk factors.

MATERIALS AND METHODS

Study cohort

The Heinz Nixdorf Recall (Risk Factors, Evaluation of Coronary Calcium and Lifestyle) study is a population-based, prospective cohort study, designed to assess the predictive value of novel markers for coronary risk stratification in addition to traditional risk factors. In 2000, simply random samples of residents of the cities of Essen, Mülheim, and Bochum, aged 45–75 years were drawn from mandatory lists of residence.

Details of the rationale, recruitment, and study design have been previously published [10]. Briefly, 4,814 subjects (50.3% women) aged 45 to 75 at recruitment years were recruited with a baseline response of 55.6%. Five years after baseline examination, participants were invited to the first follow-up examination resulting in a response rate of 90.2% (n = 4,157). At first follow-up examination, all participants underwent a standardized cognitive performance assessment. Seventy-one participants were excluded from the analysis because of incomplete or missing data regarding cognitive status and 177 participants because of missing NT-proBNP data. Furthermore, we excluded 472 participants with NT-proBNP values higher than≥300 pg/ml indicating potential heart failure [11 –13] as well as 198 participants with known coronary artery disease. Fourteen participants were excluded due to a physician’s diagnosis of dementia, with intake of cholinesterase inhibitors (ATC, anatomic-therapeutic-chemical classification issued by the World Health Organization (WHO), code: N06DA) or other antidementia drugs (N06DX), or fulfilling the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 1994) dementia diagnosis [14]. Furthermore, 1,614 participants who did not meet the MCI criteria (due to objective impairment without subjective impairment) or did not meet the criteria for ‘cognitively normal’ (due to subjective impairment) were excluded as well (see ‘Cognitive measures’). Thus, the final analysis sample consisted of 1,625 participants (Fig. 1). All participants provided written informed consent, and the study was approved by our institutional ethical committee. The study was performed conform the declaration of Helsinki.

Cognitive measures

The cognitive performance assessment has been previously described in detail [15]. Briefly, the assessment was conceptualized as a multidimensional test using established measures of immediate and delayed verbal memory (eight word list, performance measured as number of words recalled in each trial), problem solving/speed of processing (labyrinth test, time in seconds needed to complete the task), verbal fluency (semantic category “animals”, number of recalled words within one minute), and abstraction (as an executive function)/visual-spatial organization (clock-drawing test, range: 1 (perfect clock) to 6 (poor performance; (maximum value in our sample was 5) [15 –18]. The raw data for each subtest were z-transformed (mean = 0, standard deviation (SD)±1) according to three age groups (50–59 years, 60–69 years, and 70–80 years) and within every age group according to the following education groups (≤10 years, 11–13 years, ≥14 years). Based on the age and education adjusted z scores, the performance was rated as impaired (>1 SD below the mean).

Diagnosis of mild cognitive impairment

MCI was diagnosed according to the International Working Group on MCI criteria [3]. The diagnosis requires a self and/or informant reported cognitive complaint. Participants were asked if their cognitive performance had declined during the past two years. A complaint was considered present, if the participant reported a decline in cognitive performance over time. Furthermore, the diagnosis requires a cognitive impairment that is insufficient to fulfill criteria for dementia (DSM-IV) and reflects generally intact activities of daily living [19]. A cognitive subtest (see ‘Cognitive measures’) was rated as impaired if the performance was more than one SD below the age and education adjusted mean or a score of≥3 in the clock drawing test. We distinguished two subtypes of MCI: Participants presenting an objective impairment in memory (immediate and/or delayed verbal memory subtest) with or without impairment in any other cognitive domain received a diagnosis of amnestic MCI (aMCI, n = 209). If a non-memory domain was impaired, the participants received a diagnosis of non-amnestic MCI (naMCI, n = 210). The MCI diagnosis based on this assessment was validated against a detailed neuropsychological and neurological examination in a previous study [15]. The assessment reached a good accuracy (area under the curve (AUC) = 0.82, 95% confidence interval (CI) = 0.78–0.85) in identifying participants with MCI. Participants who presented neither a subjective cognitive complaint nor objective impairment were defined as ‘cognitively normal’ (n = 1,206). As mentioned above, participants who reported either a subjective cognitive complaint (without objective impairment, n = 440) or showed objective impairment (without subjective cognitive complaint, n = 1,149) were excluded from the regression analyses as well as participants with missing information regarding subjective cognitive complaint (n = 11, see Fig. 1).

Assessment of covariates

Education was classified by the International Standard Classification of Education as total years of formal education, combining school and vocational training [20]. Traditional cardiovascular risk factors were measured with details being previously reported [9]. For blood pressure measurement, the mean of a second and third measure was calculated. Body mass index (BMI) was calculated as body weight divided by square of height. Serum levels of HDL, LDL, and total cholesterol as well as serum glucose levels and creatinine were analyzed utilizing standard enzymatic methods (Siemens HealthCare Diagnostics, Eschborn, Germany). Smoking history was classified in current and former smoking and no history of smoking and was assessed by computer-assisted interview [21]. Diabetes was defined as a history of diabetes, current medical treatment for diabetes, or based on blood glucose levels as previously published [22]. High-sensitivity C-reactive protein (hsCRP) concentration was measured in serum by using the hsCRP reagent and the BN-II automated nephelometer (Dade-Behring/Siemens Healthcare Diagnostics, Eschborn, Germany). The abbreviated Modification of Diet in Renal Disease (MDRD) formula was used to estimate renal function. Depressive symptoms were assessed using the German version of the Center for Epidemiologic Studies Depression scale (CES-D) short form (data not available for n = 15 participants). We used Cardio-Metabochip BeadArrays to differentiate the APOE alleles ɛ2, ɛ3, and ɛ4 by identifying the two single nucleotide polymorphisms (SNPs, rs7412 and rs429358, n = 80 missing).

Measurement of NT-proBNP at baseline

Plasma samples were aliquoted and stored at –80°C until further use. We measured NT-proBNP using the Roche Modular E170 Assay (Roche Diagnostics, Mannheim, Germany). The analytic functional sensitivity of the assay, which represents the lowest NT-proBNP concentration determined, was 2 pg/ml. In our analysis we excluded subjects with NT-proBNP levels≥300 pg/ml due to potential heart failure (rule-out cut-point) [11 –13]. The cut-point of 300 pg/ml has a negative predictive value of 98% to exclude heart failure [11].

Statistical analysis

Continuous variables are presented as mean±standard deviation. Binary variables are depicted as n (frequency). Group comparisons between cognitively normal and MCI participants were calculated using the Mann-Whitney U test for continuous measures and Pearson χ² test for categorical variables. The same methods were used for drop-out analyses (see Supplementary Table 1). To estimate odds ratios and their 95% confidence intervals (CI), we used logistic regression models (overall MCI versus cognitively normal participants; aMCI versus cognitively normal participants; naMCI versus cognitively normal participants). To examine the association between NT-pro BNP levels and MCI, we used NT-proBNP as binary variable (<125 pg/ml as reference). The European Society of Cardiology presumes NT-proBNP level <125 pg/ml as normal [12]. Furthermore, we calculated a model using NT-proBNP as a continuous variable (per 10 units increase). In obese subjects, lower levels of natriuretic peptides have been described [12]. Therefore, we additionally analyzed the associations of NT-proBNP with MCI in subjects with BMI≤30 and BMI≤35. We calculated the following models for the total sample and stratified by gender: unadjusted model, (1) adjusted for age, gender (only for the total sample) and education, (2) additionally adjusted for BMI, systolic blood pressure, use of antihypertensive drugs, diabetes mellitus, history of stroke, APOE ɛ4, depressive symptoms, and hs-CRP. As there is a direct link between NT-proBNP and vascular diseases, we have additionally performed the same analyses in participants with APOE ɛ4 negative genotype showing a lower probability to progress to AD than participants with APOE ɛ4 positive genotype. The variables for adjustment were selected based on the current literature describing their effect on cognition and NT-proBNP levels [4]. For sensitivity analyses, we have included participants with objective impairment but no subjective impairment (n = 1,146) to the MCI group. All performed tests were two-sided. A p value below the significance level of α= 0.05 was considered statistically significant. All analyses were conducted using PASW Statistics 19.0.0 (Chicago, SPSS Inc, 2009).

RESULTS

Sociodemographic and clinical characteristics

A total of 1,625 participants (mean age 63.1±7.4 years, 53% women) were included in this analysis with a median (Q1; Q3) NT-proBNP level of 78 pg/ml (57 pg/ml; 107 pg/ml). Median NT-proBNP values were higher in women compared to men (92 pg/ml (70 pg/ml; 122 pg/ml) versus 63 pg/ml (45 pg/ml; 89 pg/ml), p < 0.001 for women and men, respectively). The sociodemographic and clinical characteristics of cognitively normal [NT-proBNP median: 75 pg/ml (Q1 = 54 pg/ml, Q3 = 101 pg/ml)] and MCI participants [NT-proBNP median: 93 pg/ml (Q1 = 67 pg/ml, Q3 = 133 pg/ml)] are reported in Table 1. MCI participants were significantly older, had lower education levels, more depressive symptoms, and showed higher levels of hsCRP. We performed drop-out analyses after excluding participants with either only subjective impairment without objective impairment or only objective impairment without subjective impairment and demented participants from the regression analyses (see Supplementary Table 1). When comparing included participants with participants excluded from the analysis, we observed no significant difference in sociodemographic or clinical characteristics except for a lower systolic blood pressure, less frequent history of stroke, and lower scores on the CES-D in included participants (Supplementary Table 1A).

Association of NT-proBNP with MCI

As reported above, participants with MCI had higher NT-proBNP levels compared to participants with normal cognitive function. Logistic regression analyses for the association of NT-proBNP with MCI are shown in Table 2. Subjects with a NT-proBNP level≥125 pg/ml had a 2-fold increased risk in a crude model for prevalent MCI without any relevant difference in gender specific analyses. These associations were slightly attenuated but remained statistically significant in fully adjusted models for the complete sample and for men and women separately. After including participants with only objective impairment (n = 1,149) to the MCI group for sensitivity analyses, we found similar results: Using MCI as outcome variable, the fully adjusted OR for participants with NT-proBNP levels of 125–299 pg/ml versus <125 pg/ml was 1.36 (1.11–1.66), p = 0.010, for men the OR was 1.51 (1.10–2.08), p = 0.011, and for women the OR was 1.26 (0.97–1.63), p = 0.08.

Of all subjects with MCI (n = 419), 209 participants had aMCI and 210 naMCI. Logistic regression analyses for the association of NT-proBNP with aMCI and naMCI are depicted in Fig. 2. Higher levels of NT-proBNP were significantly associated with both subgroups of MCI with more than a 2-fold increased risk for naMCI in the crude model. Associations were attenuated, but remained statistically significant after further adjustment in model 1 and 2 (Fig. 2). After including participants with only objective impairment (n = 1,149) to the MCI group for sensitivity analyses, we found similar results: For aMCI the OR was 1.30 (1.03–1.65), p = 0.03, and for naMCI the OR was 1.41 (1.12–1.78), p = 0.004.

In gender specific analyses, the association remained unchanged in unadjusted models (OR (95% CI) for aMCI: 1.92 (1.17; 3.17), p = 0.01 in men; 1.89 (1.24; 2.91), p = 0.003 in women, and for naMCI: 2.79 (1.67; 4.66) in men; 1.90 (1.28; 2.82) in women, p < 0.001 for both). For aMCI, the fully adjusted OR was 1.46 (0.82; 2.61), p = 0.20 in men and 1.63 (0.97; 2.75), p = 0.06 in women. Regarding naMCI, the fully adjusted OR was 2.09 (1.16; 3.77), p = 0.015 in men and 1.62 (1.01; 2.61), p = 0.048 in women.

Table 3 shows the association of NT-proBNP with MCI in a subgroup with APOE ɛ4 negative genotype. The associations were significant in crude and adjusted models and comparable to the total cohort with slightly higher odds ratios. NT-proBNP was significantly associated with both amnestic and non-amnestic MCI subtypes (OR (95% CI) for aMCI: 1.81 (1.31; 2.48), p < 0.001, and for naMCI: 2.25 (1.65; 3.07), p < 0.001. For aMCI, the fully adjusted OR was 1.53 (1.04; 2.25), p = 0.029, and for naMCI 1.76 (1.22; 2.56), p = 0.003).

After including participants with only objective impairment and APOE ɛ4 negative genotype (n = 832) to the MCI group for sensitivity analyses, the results did not change considerably. Using MCI as outcome variable, the fully adjusted OR for NT-proBNP levels of 125–299 pg/ml versus <125 pg/ml was 1.54 (1.22; 1.93), p < 0.001, for aMCI the OR was 1.46 (1.11; 1.91), p = 0.006, and for naMCI the OR was 1.61 (1.12; 1.78), p < 0.001. Using NT-proBNP as a continuous variable (per 10 units increase), analyses showed significant associations with MCI in crude models (OR (95% CI): 1.05 (1.03; 1.07), p < 0.001 for the total cohort; 1.06 (1.03; 1.09), p < 0.001 in men; 1.04 (1.02; 1.06) in women, p = 0.001). After full adjustment, the results remained significant for the total cohort and in men, but showed only a non-significant trend in women (1.03 (1.01; 1.05), p = 0.005 for total cohort; 1.04 (1.004; 1.07), p = 0.027 for men; 1.03 (0.999; 1.06), p = 0.059 for women). The results did not differ considerably in our sensitivity analyses showing a fully adjusted OR for MCI of 1.02 (1.002–1.03), p = 0.023 for the total cohort, 1.02 (1.002; 1.05), p = 0.033 for men and 1.01 (0.992; 1.03), p = 0.24 for women.

In obese subjects, lower levels of natriuretic peptides have been described. Therefore, we additionally analyzed the associations of NT-proBNP (<125 pg/ml as reference) with MCI in subjects with BMI≤30 and BMI≤35. The result did not differ relevantly from the total cohort (BMI≤30: fully adjusted OR for the total cohort: 1.90 (1.21; 2.99, p = 0.006); BMI≤35: fully adjusted OR for the total cohort: 1.66 (1.21; 2.26, p = 0.001)). Similar results were obtained in the sensitivity analysis: BMI≤30: fully adjusted OR for the total cohort: 1.40 (1.11; 1.78), p = 0.005; BMI≤35: fully adjusted OR for the total cohort: 1.26 (1.02; 1.55), p = 0.032.

DISCUSSION

In this cohort study, we examined the association of NT-proBNP levels below the threshold for heart failure with mild cognitive impairment in the general population.

We found that within normal range, higher NT-proBNP levels were associated with MCI, which remained statistically significant after adjustment for traditional cardiovascular risk factors and sociodemographic parameters. These associations were also found for both MCI subtypes (amnestic and non-amnestic MCI) and in a sample including only subjects with APOE ɛ4 negative genotypes. Effect sizes were comparable for both genders, suggesting that the described correlation may equally affect both men and women.

Several studies have investigated the association of heart failure and MCI and found relevant associations [4 –6]. The results of these studies emphasize the hypothesis that reduced cardiac output might be linked to reduced cerebral perfusion and might therefore be associated with cognitive impairment. Furthermore, cardiac diseases, such as coronary heart disease are linked with cognitive decline even in the absence of heart failure [23 –27].

Although the pathophysiology is not fully understand, several mechanisms provide a potential explanation for the association of MCI and cardiac diseases. It has been shown that inflammatory cytokines are elevated in cardiac diseases [27, 28]. In concordance, even in our sample with NT-proBNP values below the threshold for heart failure, participants with NT-proBNP≥ 125 mg/ml showed significantly higher hsCRP in comparison to participants with NT-proBNP <125 mg/ml (data not shown). Peripheral cytokines are able to affect the central nervous system and activate microglia and astrocytes. This might result in altered synaptic plasticity and neurogenesis in the hippocampus leading to memory impairment [28].

Natriuretic peptides are established in the diagnosis of heart failure [7]. In addition to their role in heart failure, natriuretic peptides seem to reflect pancardiac functional heart diseases in early asymptomatic stages and could serve as biomarkers for silent heart diseases [7–9 , 29–32]. Nadir et al. showed that a BNP screening in asymptomatic patients treated for primary prevention is able to identify existing left ventricular hypertrophy, systolic and diastolic dysfunction, left atrial enlargement, and ischemia [8]. Notably, BNP screening levels for detecting cardiac diseases were clearly below the cut-off value for heart failure. Moreover, natriuretic peptides are powerful predictors of future major cardiac events in the general population without known, preexisting cardiac diseases [9 , 30–32].

We investigated the association of silent cardiac diseases by measurement of NT-proBNP with MCI in subjects without heart failure and NT-proBNP values below existing thresholds and found relevant associations, independent of cardiovascular risk factors. There are several mechanisms, which could explain these associations: First, subjects with elevated NT-proBNP levels, but still below the cut-off value for heart failure, may have early and subclinical stages of impaired cardiac function and cerebral perfusion may already be reduced due to reduced cardiac index. Second, NT-proBNP is a marker of silent cardiac disease including coronary heart disease and hypertensive heart disease. There is a link of cardiac diseases with cognitive impairment. Third, cognitive impairment and cardiac diseases share the same risk factors, such as hypertension, obesity, hyperlipidemia, diabetes, and smoking. Therefore, these risk factors result in cardiac and cerebral diseases. However, in our analysis, adjustments for traditional cardiovascular and cerebrovascular risk factors did not change the associations relevantly. A recent study by Sabayan et al. showed higher levels of NT-proBNP to be linked to alternations in brain structure and function. These results are in line with our study. Thus, there is evidence of brain alternations in patients with higher NT-proBNP levels [33]. The results of studies by Hilal et al. and Marksteiner et al. are also in line with our results: The studies showed associations of NT-proBNP with cognitive impairment, however, not excluding subjects with known cardiac diseases and having smaller sample sizes [34, 35].

After stratifying for amnestic and non-amnestic MCI, we found similar associations of NT-proBNP and both MCI subtypes. Amnestic MCI is most likely reflecting the prodromal stage of AD and non-amnestic MCI is most likely reflecting the prodromal stage of vascular dementia (but also dementia with Lewy bodies or frontotemporal dementia) [3]. The association of NT-proBNP as a marker of cardiac stress with both MCI subtypes seems surprising given that NT-proBNP is considered a stronger marker of vascular burden with a lower influence on AD pathophysiology. However, a substantial body of evidence supports the hypothesis of a vascular component in the pathogenesis of AD, especially when focusing on inflammatory processes and the association of hypoperfusion and amyloid-beta accumulation, a hallmark of AD [36 –38]. Thus, the association of NT-proBNP with both MCI subtypes seems plausible. The OR for naMCI was slightly higher than for aMCI and the results of the regression models with APOE ɛ4 negative participants (lower probability to develop sporadic AD in comparison to participants with APOE ɛ4 genotype) showed stronger associations. Thus, these results emphasis the importance of elevated NT-proBNP levels under the cut-off value as a marker of cardiovascular alternations.

Strength and limitations

Strengths of our study are the population-based design in middle-aged and elderly participants and the detailed clinical, laboratory, and medication data available for study participants. Regarding the cognitive outcomes, we used an assessment that has previously been validated and showed a good accuracy in identifying participants with MCI and MCI subtypes [25]. Furthermore, we excluded all participants with either only objective impairment or only subjective cognitive complaint in our regression analyses to reduce misclassification resulting in a reference group of cognitively healthy participants. The excluded participants did not differ relevantly regarding sociodemographic or cardiovascular risk factors or APOE genotype from the participants included in our analyses. Furthermore, our sensitivity analyses in which we had included participants with only objective cognitive impairment, but no subjective complaint (n = 1,149) to the MCI group, did not change the results considerably.

There are also some limitations. Because the cross-sectional design of this analysis we only describe associations and it is not possible to draw conclusions regarding causality. Additionally, we did not assess cerebral blood flow and cerebrovascular reactivity. Although, heart failure was excluded using NT-proBNP, which is a strong marker for heart failure, echocardiographic parameters would have given additional information. A further limitation of our study is that the participants are mainly urban citizens and predominantly Caucasians, hence, generalization to other ethnic groups or more rural populations might be limited. The longitudinal follow-up of our participants will allow us to further elucidate whether increased NT-proBNP levels are an independent risk factor for cognitive decline.

CONCLUSION

Within normal ranges and without manifest heart failure, higher NT-proBNP levels are associated with MCI and both MCI subtypes independent of traditional cardiovascular risk factors and sociodemographic parameters.

ADVISORY BOARD

Meinertz T., Hamburg, Germany (Chair); Bode C., Freiburg, Germany; de Feyter P.J., Rotterdam, Netherlands; Güntert B., Hall LT, Austria; Gutzwiller F., Bern, Switzerland; Heinen H., Bonn, Germany; Hess O., Bern, Switzerland; Klein B., Essen, Germany; Löwel H., Neuherberg, Germany; Reiser M., Munich, Germany; Schmidt G. (†), Essen, Germany; Schwaiger M., Munich, Germany; Steinmüller C., Bonn, Germany; Theorell T., Stockholm, Sweden; Willich S.N., Berlin, Germany.

CRITERIA AND ENDPOINT COMMITTEE

C. Bode, Freiburg, Germany (Chair); K. Berger, Münster, Germany; H.R. Figulla, Jena, Germany; C. Hamm, Bad Nauheim, Germany; P. Hanrath, Aachen, Germany; W. Köpcke, Münster, Germany; Ringelstein, Münster, Germany; C. Weimar, Essen, Germany; A. Zeiher, Frankfurt, Germany.

Footnotes

ACKNOWLEDGMENTS

We thank the Heinz Nixdorf Foundation [Chairman: Martin Nixdorf; Past Chairman: Dr. Jur Gerhard Schmidt (deceased)], for their generous support of this study. This study is also supported by the German Ministry of Education and Science (BMBF), and the German Aero-space Center [Deutsches Zentrum für Luft- und Raumfahrt (DLR)], Bonn, Germany. The German Research Council Assessment supported the study (DFG project: ER 155/6-2) and funded the study of psychosocial factors and neighbourhood level information (DFG project SI 236/8-1 and SI 236/9-1) and the cognitive screening (DFG project SI 236/10-1). The sponsor of the study transferred the monitoring of the study to the German Ministry of Education and Science, Bonn using an international advisory board and quality control as well as event committee, but had no role concerning the study design, data collection, analysis, interpretation, or writing the report. The corresponding authors had full access to all data in the study and final responsibility for the submission of the manuscript for publication.

Authors’ disclosures available online ().

Appendix

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