Daniel Bos

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Calcification in Major Vessel Beds Relates to Vascular Brain Disease

Objective—Calcification in atherosclerotic plaques is a novel marker of atherosclerosis and is related to cardiovascular disease. However, its relationship with cerebrovascular disease has not been investigated extensively. We investigated the relationship between calcification in various vessel beds outside the brain and imaging markers of vascular brain disease. Methods and Results—A total of 885 community-dwelling people (mean age, 66.7 years) underwent computed tomography of the coronary arteries, aortic arch, and extracranial and intracranial carotid arteries to assess arterial calcification. Brain magnetic resonance imaging scans were performed to assess cerebral infarcts, microbleeds, and white matter lesions (WMLs). Calcification in each vessel bed was associated with presence of cerebral infarcts and with larger WML volume. The most prominent associations were found between intracranial carotid calcification and WML volume and between extracranial carotid calcification and infarcts. Adjustment for cardiovascular risk factors or ultrasound carotid plaque scores did not change these results. No associations were found between calcification and cerebral microbleeds. Conclusion—Arterial calcification in major vessel beds is associated with vascular brain disease on magnetic resonance imaging. Most notably, larger intracranial carotid calcification load relates to larger WML volumes, and larger extracranial carotid calcification load relates to the presence of cerebral infarcts, independently of ultrasound carotid plaque score. This suggests that calcification of atherosclerotic plaque yields other information in addition to merely the presence of plaques, providing novel insights into the etiology of vascular brain disease.

Intracranial carotid artery atherosclerosis: prevalence and risk factors in the general population.

Background and Purpose— Intracranial atherosclerosis is worldwide one of the leading causes of stroke. However, surprisingly little is known about its prevalence and risk factors in a community-dwelling population of white descent. In this study, we determined the prevalence and investigated risk factors of intracranial internal carotid artery calcification (ICAC) as a marker of intracranial atherosclerosis. Methods— To quantify the volume of ICAC, 2495 participants (mean age, 69.6 years) from the population-based Rotterdam Study underwent a nonenhanced computed tomography of the intracranial internal carotid arteries. We calculated the prevalence of ICAC. Next, we defined sex-specific quartiles and defined the upper quartile as severe ICAC. Risk factors of ICAC were investigated by linear and logistic multivariate modeling and were stratified by sex. Results— The overall prevalence of ICAC was 82.2%. The median volume of ICAC was 44 mm3 and was larger in men. Age was independently associated with ICAC in both men and women. In men, excessive alcohol intake and smoking (OR, 1.74 [95% CI, 1.28–2.37] and 1.72 [95% CI, 1.10–2.70]) were strong risk factors of ICAC, whereas diabetes and hypertension were in women (OR, 2.02 [95% CI, 1.29–3.17] and 1.79 [95% CI, 1.20–2.68]). A low high-density-lipoprotein concentration was not associated with ICAC. Conclusions— ICAC is highly prevalent and occurs in over 80% of older, white persons. Conventional cardiovascular risk factors are associated with ICAC, but risk factor profiles differ between men and women.

Intracranial Carotid Artery Atherosclerosis and the Risk of Stroke in Whites: The Rotterdam Study

IMPORTANCE Intracranial atherosclerosis represents a relatively unexplored, but potentially important, cause of stroke in a white population. OBJECTIVE To investigate the relationship between intracranial carotid artery calcification (ICAC) as a marker of intracranial atherosclerosis and the risk of stroke in whites. DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study in the general community with 6 years of follow-up was conducted (the Rotterdam Study). Between 2003 and 2006, a random sample of 2323 stroke-free persons (mean age, 69.5 years) underwent computed tomography scanning to quantify ICAC volume. All participants were continuously monitored for the occurrence of stroke until January 1, 2012. EXPOSURE Atherosclerotic calcification in the intracranial internal carotid arteries. MAIN OUTCOME AND MEASURE Incident stroke. RESULTS During 14,055 person-years of follow-up, 91 participants had a stroke, of which 74 were ischemic. Larger ICAC volume was related to a higher risk of stroke, independent of cardiovascular risk factors, ultrasound carotid plaque score, and calcification in other vessels (fully adjusted hazard ratio per an increase of 1 SD in ICAC volume, 1.43 [95% CI, 1.04-1.96]). Intracranial carotid artery calcification contributed to 75% of all strokes; for aortic arch and extracranial carotid artery calcification this incidence was only 45% and 25%, respectively. CONCLUSIONS AND RELEVANCE Our findings establish intracranial atherosclerosis as a major risk factor for stroke in the general white population and suggest that its contribution to the proportion of all strokes may be greater than that of large-artery atherosclerosis in more proximally located vessel beds.

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.

Atherosclerotic calcification relates to cognitive function and to brain changes on magnetic resonance imaging

Increasing evidence suggests a role of atherosclerosis in the pathogenesis of cognitive impairment and dementia. Calcification volume measured with computed tomography (CT) is a valid marker of atherosclerosis. This study investigates associations of atherosclerosis (measured using CT) at four locations with cognition and brain changes on magnetic resonance imaging (MRI).

Risk Scores of Common Genetic Variants for Lipid Levels Influence Atherosclerosis and Incident Coronary Heart Disease

Objective—Circulating levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides are recognized risk factors for cardiovascular disease. We tested the hypothesis that the cumulative effects of common genetic variants for lipids are collectively associated with subclinical atherosclerosis and incident coronary heart disease. Approach and Results—Participants were drawn from the Erasmus Rucphen Family Study (n=2269) and the Rotterdam Study (n=8130). Linear regression and Cox proportional hazards models were applied to assess the influence of 4 risk scores derived from common genetic variants for lipids (total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglycerides) on carotid plaque, intima-media thickness, incident myocardial infarction, and coronary heart disease. Adjusted for age and sex, all 4 risk scores were associated with carotid plaque. This relationship was the strongest for the LDL-C score, which increased plaque score by 0.102 per SD increase in genetic risk score (P=3.2×10−8). The LDL-C score was also nominally associated with intima-media thickness, which increased 0.006 mm per SD increase in score (P=0.05). Both the total cholesterol and LDL-C scores were associated with incident myocardial infarction and coronary heart disease with hazard ratios between 1.10 and 1.13 per SD increase in score. Inclusion of additional risk factors as covariates minimally affected these results. Conclusions—Common genetic variants with small effects on lipid levels are, in combination, significantly associated with subclinical and clinical cardiovascular outcomes. As knowledge of genetic variation increases, preclinical genetic screening tools might enhance the prediction and prevention of clinical events.

Atherosclerotic calcification is related to a higher risk of dementia and cognitive decline

Longitudinal data on the role of atherosclerosis in different vessel beds in the etiology of cognitive impairment and dementia are scarce and inconsistent.

Rating Method for Dilated Virchow–Robin Spaces on Magnetic Resonance Imaging

Background and Purpose— Dilated Virchow–Robin spaces are an emerging neuroimaging biomarker, but their assessment on MRI needs standardization. Methods— We developed a rating method for dilated Virchow–Robin spaces in 4 brain regions (centrum semiovale, basal ganglia, hippocampus, and mesencephalon) and tested its reliability in a total of 125 MRI scans from 2 population-based studies. Six investigators with varying levels of experience performed the ratings. Intraclass correlation coefficients were calculated to determine intra- and interrater reliability. Results— Intrarater reliability was excellent for all 4 regions (intraclass correlation coefficient, >0.8). Interrater reliability was excellent for the centrum semiovale and hippocampus (intraclass correlation coefficient, >0.8) and good for the basal ganglia and mesencephalon (intraclass correlation coefficient, 0.6–0.8). This did not differ between the cohorts or experience levels. Conclusions— We describe a reliable rating method that can facilitate pathogenic and prognostic research on dilated Virchow–Robin spaces using MRI.

Comparison of Atherosclerotic Calcification in Major Vessel Beds on the Risk of All-Cause and Cause-Specific Mortality: The Rotterdam Study.

Background—Atherosclerosis is a major contributor to global morbidity and mortality. Although atherosclerosis is a systemic disease, its burden varies considerably across vessel beds, which may translate into differences in mortality risk. Methods and Results—From 2003 to 2006, a sample of 2408 elderly participants (mean age, 69.6±6.7 years; 52.4% female) from the population-based Rotterdam Study underwent computed tomography to quantify atherosclerotic calcification in the coronary arteries, aortic arch, extracranial, and intracranial internal carotid arteries. Mortality follow-up was complete until January 1, 2012. We investigated associations of calcification in each vessel bed with mortality using Cox regression, adjusting for age, sex, and cardiovascular risk factors. Next, all vessel beds were included into 1 model to investigate independency of associations. Finally, we investigated the predictive value of calcification beyond the predictors included in the Pooled Cohort equations. During 15 775 person-years of follow-up, 283 participants died. Larger calcification volumes in all vessels were related to higher risks of all-cause mortality, cardiovascular, and noncardiovascular mortality, independent of cardiovascular risk factors. Most prominent associations were found for aortic arch calcification and cardiovascular mortality (age- and sex-adjusted hazard ratio per 1-SD increase 2.72 [95% confidence interval, 1.85–4.02]), independent of calcification elsewhere (hazard ratio, 1.75 (95% confidence interval, 1.13–2.72]). Calcification in any vessel improved prediction for all 3 outcomes. Conclusions—Atherosclerotic load in major vessel beds is associated with an increased risk of death. In particular, aortic arch calcification volume yields unique information with regard to mortality in addition to atherosclerosis in other vessel beds.