Atherosclerotic Calcification: Determinants and Clinical Neurological Consequences

__Abstract__ Atherosclerosis is a highly frequent vascular disease that exerts huge influence on the health care system. Major clinical conditions caused by atherosclerosis are ischemic heart disease (myocardial infarction) and stroke, both top causes of global morbidity and mortality in middle-aged and elderly persons. Due to the aging of the population, the global burden of atherosclerosis, and thereby of its clinical consequences, will continue to rise in the coming decades. The purpose of my thesis is to expand the knowledge on determinants - or risk factors - and neurological consequences of atherosclerosis, with a specific focus on differences across vessel beds. The research described in my thesis was performed within the framework of the Rotterdam Study;21 a large prospective, population-based cohort study aimed at investigating determinants of various chronic diseases in the elderly. Using CT-imaging in this population-based setting, I studied atherosclerosis in four major vessel beds: the coronary arteries, aortic arch and the extracranial and intracranial part of the internal carotid arteries

Leveraging the coronary calcium scan beyond the coronary calcium score

Abstract: Non-contrast cardiac computed tomography in order to obtain the coronary artery calcium score has become an established diagnostic procedure in the clinical setting, and is commonly employed in clinical and population-based research. This state-of-the-art review paper highlights the potential gain in information that can be obtained from the non-contrast coronary calcium scans without any necessary modifications to the scan protocol. This includes markers of cardio-metabolic health, such as the amount of epicardial fat and liver fat, but also markers of general health including bone density and lung density. Finally, this paper addresses the importance of incidental findings and of radiation exposure accompanying imaging with non-contrast cardiac computed tomography. Despite the fact that coronary calcium scan protocols have been optimized for the visualization of coronary calcification in terms image quality and radiation exposure, it is important for radiologists, cardiologists and medical specialists in the field of preventive medicine to acknowledge that numerous additional markers of cardio-metabolic health and general health can be readily identified on a coronary calcium scan. Key Points: • The coronary artery calcium score substantially increased the use of cardiac CT.• Cardio-metabolic and general health markers may be derived without changes to the scan protocol.• Those include epicardial fat, aortic valve calcifications, liver fat, bone density, and lung density.• Clinicians must be aware of this potential additional yield from non-contrast cardiac CT

Dose reduction for CT coronary calcium scoring with a calcium-aware image reconstruction technique: a phantom study

Objective: To assess the dose reduction potential of a calcium-aware reconstruction technique, which aims at tube voltage-independent computed tomography (CT) numbers for calcium. Methods and materials: A cardiothoracic phantom, mimicking three different patient sizes, was scanned with two calcium inserts (named D100 and CCI), containing calcifications varying in size and density. Tube voltage was varied both manually (range 70–150 and Sn100 kVp) and automatically. Tube current was automatically adapted to maintain reference image quality defined at 120 kVp. Data was reconstructed with the standard reconstruction technique (kernel Qr36) and the calcium-aware reconstruction technique (kernel Sa36). We assessed the radiation dose reduction potential (volumetric CT dose index values (CTDIvol)), noise (standard deviation (SD)), mean CT number (HU) of each calcification, and Agatston scores for varying kVp. Results were compared with the reference acquired at 120 kVp and reconstructed with Qr36. Results: Automatic selection of the optimal tube voltage resulted in a CTDIvol reduction of 22%, 15%, and 12% compared with the reference for the small, medium, and large phantom, respectively. CT numbers differed up to 64% for the standard reconstruction and 11% for the calcium-aware reconstruction. Similarly, Agatston scores deviated up to 40% and 8% for the standard and calcium-aware reconstruction technique, respectively. Conclusion: CT numbers remained consistent with comparable calcium scores when the calcium-aware image reconstruction technique was applied with varying tube voltage. Less consistency was observed in small calcifications with low density. Automatic reduction of tube voltage resulted in a dose reduction of up to 22%. Key Points: •

Time Trends in Survival Following First Hemorrhagic or Ischemic Stroke Between 1991 and 2015 in the Rotterdam Study

Background and Purpose- The introduction of stroke units and the implementation of evidence-based interventions have been a breakthrough in the management

Determinants of the Presence and Size of Intracranial Aneurysms in the General Population The Rotterdam Study

BACKGROUND AND PURPOSE: The prevalence of unruptured intracranial aneurysms (UIAs) in the adult population is ≈3%. Rupture of an intracranial aneurysm can have devastating consequences, which emphasizes the importance of identification of potentially modifiable determinants for the presence and size of UIAs. Our aim was to study the association of a broad spectrum of potential determinants with the presence and size of UIAs in a general adult population. METHODS: Between 2005 and 2015, 5841 participants from the population-based Rotterdam Study (mean age, 64.4 years, 45.0% male) underwent brain magnetic resonance imaging (1.5T). These scans were evaluated for the presence of incidental UIAs. We determined number and volume of the UIAs. Using logistic and linear regression models, we assessed the association of cardiovascular, lifestyle and emerging inflammatory and hormonal determinants with the presence and volume of UIAs. RESULTS: In 134 (2.3%) participants, ≥1 UIAs were detected (149 UIAs in total), with a median volume of 61.1 mm3 (interquartile range, 33.2–134.0). In multivariable models, female sex (odds ratio, 1.92 [95% CI, 1.33–2.84]), hypertension (odds ratio, 1.73 [95% CI, 1.13–2.68]), and current smoking (odds ratio, 3.75 [95% CI, 2.27–6.33]) were associated with the presence of UIAs. We found no association of alcohol use, physical activity, or diet quality with UIA presence. Finally, we found white blood cell count to relate to larger aneurysm volume (difference in volume of 33.6 mm3 per 109/L increase in white blood cell [95% CI, 3.92–63.5]). CONCLUSIONS: In this population-based study, female sex, hypertension, and smoking, but no other lifestyle determinants, were associated with the presence of UIAs. White blood cell count is associated with size of UIAs. Preventive strategies should focus on treating hypertension and promoting cessation of smoking

The Rotterdam Scan Study: design update 2016 and main findings

Imaging plays an essential role in research on neurological diseases in the elderly. The Rotterdam Scan Study was initiated as part of the ongoing Rotterdam Study with the aim to elucidate the causes of neurological disease by performing imaging of the brain in a prospective population-based setting. Initially, in 1995 and 1999, random subsamples of participants from the Rotterdam Study underwent neuroimaging, whereas from 2005 onwards MRI has been implemented into the core protocol of the Rotterdam Study. In this paper, we discuss the background and rationale of the Rotterdam Scan Study. Moreover, we describe the imaging protocol, image post-processing techniques, and the main findings to date. Finally, we provide recommendations for future research, which will also be topics of investigation in the Rotterdam Scan Study

Serum insulin levels are associated with vulnerable plaque components in the carotid artery: the Rotterdam Study

Background: To investigate the association between fasting serum insulin and glucose levels with atherosclerotic plaque composition in the carotid artery. Impaired insulin and glucose levels are implicated in the etiology of cardiovascular disease; however, their influence on the formation and composition of atherosclerotic plaqu

Corrigendum: Hearing impairment is associated with smaller brain volume in aging

In the original article, Roshchupkin et al. (2016) was not cited in the article. The citation has now been inserted in Materials and Methods, subsection Brain MRI Acquisition and Processing, second paragraph and should read: Voxel based morphometry (VBM) was performed according to an optimized VBM protocol (Good et al., 2001) and was previously described (Roshchupkin et al., 2016). FSL software (Smith et al., 2004) was used for VBM data processing, all GM and WM density maps were non-linearly registered to the standard ICBM MNI152 GM and WM template (Montreal Neurological Institute) with a 1 mm × 1 mm × 1 mm voxel resolution. Subsequently, a spatial modulation and smoothing procedure with 3 mm (FWHM 8 mm) isotropic Gaussian kernel were applied to all images. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

Comparison of CT and CMR for detection and quantification of carotid artery calcification: the Rotterdam Study

Background: Carotid artery atherosclerosis is an important risk factor for stroke. As such, quantitative imaging of carotid artery calcification, as a proxy of atherosclerosis, has become a cornerstone of current stroke research. Yet, population-based data comparing the computed tomography (CT) and cardiovascular magnetic resonance (CMR) for the detection and quantification of calcification remain scarce. Methods: A total of 684 participants from the population-based Rotterdam Study underwent both a CT and CMR of the carotid artery bifurcation to quantify the amount of carotid artery calcification (mean interscan interval: 4.9 ± 1.2 years). We investigated the correlation between the amount of calcification measured on CT and CMR using Spearman's correlation coefficient, Bland-Altman plots, and linear regression. In addition, using logistic regression modeling, we assessed the association of CT and CMR based calcification volumes with a history of stroke. Results: We found a strong correlation between CT and CMR based calcification volumes (Spearman's correlation coefficient:0.86, p-value ≤0.01). Bland-Altman analyses showed a good agreement, though CT based calcification volumes were systematically larger. Finally, calcification volume assessed with either imaging modality was associated with a history of stroke with similar effect estimates (odds ratio (OR) per 1-SD increase in calcification volume: 1.52 (95% CI:1.00;2.30) for CT, and 1.47 (95% CI:1.01;2.14) for CMR. Conclusion: CT based and CMR based volumes of carotid artery calcificatio

The association of innate and adaptive immunity, subclinical atherosclerosis, and cardiovascular disease in the Rotterdam Study: A prospective cohort study

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is driven by multifaceted contributions of the immune system. However, the dysregulation of immune cells that leads to ASCVD is poorly understood. We determined the association of components of innate and adaptive immunity longitudinally with ASCVD, and assessed whether arterial calcifications play a role in this association. METHODS AND FINDINGS: Granulocyte (innate immunity) and lymphocyte (adaptive immunity) counts were determined 3 times (2002-2008, mean age 65.2 years; 2009-2013, mean age 69.0 years; and 2014-2015, mean age 78.5 years) in participants of the population-based Rotterdam Study without ASCVD at baseline. Participants were followed-up for ASCVD or death until 1 January 2015. A random sample of 2,366 underwent computed tomography at baseline to quantify arterial calcification volume in 4 vessel beds. We studied the association between immunity components with risk of ASCVD and assessed whether immunity components were related to arterial calcifications at baseline. Of 7,730 participants (59.4% women), 801 developed ASCVD during a median follow-up of 8.1 years. Having an increased granulocyte count increased ASCVD risk (adjusted hazard ratio for doubled granulocyte count [95% CI] = 1.78 [1.34-2.37], P < 0.001). Higher granulocyte counts were related to larger calcification volumes in all vessels, most prominently in the coronary arteries (mean difference in calcium volume [mm3] per SD increase in granulocyte count [95% CI] = 32.3 [9.9-54.7], P < 0.001). Respectively, the association between granulocyte count and incident coronary heart disease and stroke was partly mediated by coronary artery calcification (overall proportion mediated [95% CI] = 19.0% [-10% to 32.3%], P = 0.08) and intracranial artery calcification (14.9% [-10.9% to 19.1%], P = 0.05). A limitation of our study is that studying the etiology of ASCVD remains difficult within an epidemiological setting due to the limited availability of surrogates for innate and especially adaptive immunity. CONCLUSIONS: In this study, we found that an increased granulocyte count was associated with a higher risk of ASCVD in the general population. Moreover, higher levels of granulocytes were associated with larger volumes of arterial calcification. Arterial calcifications may explain a proportion of the link between granulocytes and ASCVD