Abstract
The association of aortic valve calcification (AVC) with dementia remains unknown. In 2,428 non-demented participants from the population-based Rotterdam Study, we investigated the association of CT-assessed AVC with risk of dementia and cognitive decline. AVC was present in 33.1% of the population. During a median follow-up of 9.3 years, 160 participants developed dementia. We found no association between presence of AVC and risk of all-cause dementia [hazard ratio (HR): 0.89 (95% confidence interval (CI):0.63;1.26)]. Presence of AVC was not associated with cognitive decline on any of the cognitive tests, nor with a measure of global cognition.
INTRODUCTION
Aortic valve calcification (AVC) is a strong risk factor for cardiac disease and mortality [1, 2]. Moreover, AVC has recently been associated with covert brain infarcts [3], which may reflect direct thromboembolic and hemodynamic consequences of AVC on the brain. Both thromboembolism and hemodynamic impairment of brain perfusion are also implicated in the pathophysiology of dementia, including Alzheimer’s disease [4, 5], but whether AVC is associated with cognition and dementia remains unknown. We investigated the association of AVC with cognitive decline and risk of dementia in a population-based setting.
MATERIALS AND METHODS
Study population
This study was embedded in the ongoing Rotterdam Study [6], a prospective population-based cohort study in middle-aged and elderly persons. Every 4-5 years, all participants are re-invited to undergo follow-up examinations at the Rotterdam Study research center. Between 2003 and 2006, all participants visiting the research center were invited to undergo a computed tomography examination for the visualization of vascular calcifications in major arteries, including the aortic root, where the aortic valves are located. In total, 2,524 people participated [7]. The Rotterdam Study has been approved by the medical ethics committee according to the Population Screening Act: Rotterdam Study, executed by the Ministry of Health, Welfare and Sports of the Netherlands. All participants provided written informed consent.
Assessment of AVC and arterial calcification
We acquired a non-contrast cardiac, and extra-cardiac CT-examination with a multidetector computed tomography (MDCT) scanner (Somatom Sensation 16/64, Siemens, Forchheim, Germany) [7]. Using an ECG-gated cardiac imaging protocol, we visualized the heart including the coronary arteries and the aortic root with the aortic valve. Using an extra-cardiac imaging protocol, we visualized the aortic arch, and carotid arteries. We quantified AVC (mm3), located on the aortic valve leaflets, the base of the cusps, and the annulus [3, 8], using dedicated commercially available software (Syngo.ViaCalciumScoring, Siemens, Germany). The same software was used for the quantification of coronary artery calcification, aortic arch calcification, and extracranial carotid artery calcification. Intracranial carotid artery calcification was quantified using custom-made software, which has been described in detail before [9].
Ascertainment of cognition and dementia
Participants underwent extensive neuropsychological assessment at time of CT and at one subsequent follow-up visit (on average 6 years after the CT-examination). This cognitive examination included a verbal fluency task, a letter-digit substitution task, a word-learning test, the Stroop task, and the Purdue pegboard test [10]. Participants were screened for dementia at baseline and subsequent follow-up examinations using a three-step protocol [11]. Screening was done using the Mini-Mental State Examination (MMSE) and the Geriatric Mental Schedule (GMS) organic level. Those with MMSE < 26 or GMS > 0 subsequently underwent examination and informant interview using the Cambridge Examination for Mental Disorders in the Elderly (CAMDEX). Additionally, the total cohort was continuously monitored for dementia through computerized linkage between the study database and medical records from general practitioners and the Regional Institute for Outpatient Mental Health Care. For all suspected cases of dementia, a consensus panel led by a consultant neurologist decided on the final diagnosis in accordance with standard criteria for dementia (DSM-III-R), and Alzheimer’s disease (NINCDS-ADRDA). Follow-up was near complete (96.5% of potential person-years) until 2015.
Other measurements in the Rotterdam Study
Information on relevant covariates was obtained by interview, physical examination, blood sampling, and medical records [6]. Body mass index (BMI) was calculated as weight (kg)/height2 (m). Systolic and diastolic blood pressure was assessed at the right arm and the mean of two measurements was used in the analyses. We used blood samples to determine serum total cholesterol and high-density lipoprotein (HDL) cholesterol, and glucose. Diabetes mellitus was defined as fasting serum glucose levels ≥7.0 mmol/L and/or the use of anti-diabetic therapy. Smoking status was categorized into “current”, “former”, or “never”. We assessed the use of blood pressure-lowering medication and lipid-lowering medication by interview. We assessed history of coronary heart disease (previous myocardial infarction or revascularization procedure) and heart failure at time of the CT using interviews, and medical records.
Statistical analysis
Given the right-skewed distribution of AVC-volume, a natural-log transformation was performed after we added 1.0 mm3 to the original volumes in order to deal with participants with a zero calcium score [LN(AVC+1.0 mm3)]. Missing data on covariates (maximum 5.7%), except APOE-genotype, were handled using 5-fold multiple imputation.
First, we determined the correlation between AVC and arterial calcification in the coronary arteries, aortic arch, and carotid arteries. Second, we investigated the association between presence of AVC and dementia, using Cox proportional hazards models adjusting for age and sex, and additionally in a second model for various cardiovascular risk factors (body-mass index, systolic and diastolic blood pressure, use of blood-pressure lowering medication, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, use of lipid-lowering medication, smoking, history of coronary heart disease, history of heart failure, and apolipoprotein-ɛ4 genotype). In this model, participants were censored within the follow-up period at date of dementia diagnosis, date of death, date of loss to follow-up, or 1 January 2015, whichever came first. We verified that the proportional hazard assumption was met. Third, we calculated tertiles of AVC burden in those with AVC, and determined risk of dementia in each tertile compared to risk in those without AVC. Finally, we determined decline in scores on a cognitive assessment battery (each test and a compound measure of global cognition) [10] in relation to AVC, using linear regression, with adjustments for confounders as described above. For this, Z-scores were computed for each participant by dividing the difference between the individual cognitive test score and the population mean by the population standard deviation.
Analyses were performed with IBM SPSS Statistics version 23 (IBM Corporation, Armonk,New York).
RESULTS
Of 2,480 non-demented participants who underwent CT, we were unable to measure AVC in 52 (2.1%) due to aortic valve replacement, image artifact due to presence of pacemakers or coronary stent implantations, or bad image acquisition. The remaining 2,428 participants were included in the analyses.
Table 1 shows the baseline characteristics of the study population.
The mean age at time of CT was 69.5 years, and 51.7% of participants were female. The prevalence of AVC was 32.9%, and strongly increased with age, from 23.0% at age 60–69 to 70.6% in those ≥90 years. AVC-volume was correlated with volumes of arterial calcification in the coronary arteries, the aortic arch, and the carotid arteries (Spearman’s correlation coefficients ranging from 0.29 to 0.32, p < 0.01).
During a median follow-up of 9.3 years (IQR 7.9–9.8), 160 participants were diagnosed with dementia, of whom 126 had Alzheimer’s disease. Presence of AVC was not associated with the risk of dementia [hazard ratio (HR): 0.89 (95% confidence interval (CI): 0.63;1.26)], or Alzheimer’s disease (Table 2).
Of the 2,418 participants who underwent cognitive testing at time of CT, 1,816 (85.0% of surviving, non-demented participants) had repeated cognitive assessment at follow-up (mean interval 6.0 years, SD 0.5). Presence of AVC was not associated with change in cognitive test performance on any of the tests, nor with global cognition [β (95% CI) for presence of AVC: 0.038 (–0.051;0.127)] (Supplementary Table 1). Again, this was similar per tertile of increasing burden of AVC.
DISCUSSION
In this large population-based study, we found no association of CT-quantified AVC with cognitive decline or risk of dementia during 10 years of follow-up. Although we are not aware of any other studies investigating AVC in relation to dementia, our findings are thought-provoking in view of the abundance of evidence linking vascular risk factors and atherosclerosis to dementia and Alzheimer’s disease [12]. We found lower correlations of AVC with aortic, coronary, and cerebral artery calcification, compared to previously described correlations of calcification among these other vessel beds [13]. As arterial calcification in these vessel beds has been associated with dementia previously [13], our findings suggest that AVC might be a more localized process with, in part, different underlying pathophysiology. Shared risk factors between atherosclerosis and dementia might thus contribute less to the development of AVC. In addition, direct thromboembolic complications of AVC may be too limited in duration or severity to result in significant neuronal injury. Nevertheless, with most severe calcification (i.e., stenosis) the brain may still suffer from hemodynamic impairment. Overall, our study sample was relatively healthy and the number of people with stenosis in our sample was limited, and associations with valve stenosis may therefore be further explored in future observational studies. We were sufficiently powered to detect a moderate effect size of 1.5 for all-cause dementia (α= 0.05, β= 0.80), but observed insufficient cases of vascular dementia to detect presumably stronger associations of AVC with pure vascular dementia.
Footnotes
ACKNOWLEDGMENTS
The dedication, commitment, and contribution of inhabitants, general practitioners, and pharmacists of the Ommoord district to the Rotterdam Study are gratefully acknowledged. The Heart Brain Connection collaborative research group includes Mark A. van Buchem, Geert Jan Biessels, Hans-Peter Brunner la Rocca, Anton J.de Craen†, Wiesje M. van der Flier, M. Arfan Ikram, L. Jaap Kappelle, Peter J. Koudstaal, Simon P. Mooijaart, Wiro Niessen, Robert van Oostenbrugge, Albert de Roos, Albert C. van Rossum, and Mat J. Daemen.
The Heart Brain Connection collaborative research group is supported by the Netherlands Cardiovascular Research Initiative (CVON2012-06). The Rotterdam Study is supported by the Erasmus MC; Erasmus University Rotterdam; Netherlands Organisation for Scientific Research (NWO); Netherlands Organisation for Health Research and Development (ZonMW); Research Institute for Diseases in the Elderly (RIDE); Netherlands Genomics Initiative; Ministry of Education, Culture and Science; Ministry of Health, Welfare and Sports; European Commission (DG XII); and Municipality of Rotterdam.
