Sexual dimorphisms in serum calcium and phosphate concentrations in the Rotterdam Study.

Sex differences in serum phosphate and calcium have been reported but the exact nature and underlying regulatory mechanisms remain unclear. We aimed to compare calcium and phosphate concentrations between sexes, and explore potential covariates to elucidate underlying mechanisms of sex differences in a prospective, population-based cohort study. Pooled data of subjects > 45 years from three independent cohorts of the Rotterdam Study (RS) were used: RS-I-3 (n = 3623), RS-II-1 (n = 2394), RS-III-1 (n = 3241), with separate analyses from an additional time point of the first cohort RS-I-1 (n = 2688). Compared to men, women had significantly higher total serum calcium and phosphate concentrations which was not explained by BMI, kidney function nor smoking. Adjustment for serum estradiol diminished sex differences in serum calcium while adjustment for serum testosterone diminished sex differences in serum phosphate. Adjustment for vitamin D and alkaline phosphatase did not change the association between sex and calcium or phosphate in RS-I-1. In the sex-combined group, both serum calcium and phosphate decreased with age with a significant interaction for sex differences for serum calcium but not phosphate. In sex-stratified analyses, serum estradiol but not testosterone was inversely associated with serum calcium in both sexes. Serum estradiol was inversely associated with serum phosphate in both sexes to a similar degree, while serum testosterone was inversely associated with serum phosphate in both sexes with an apparent stronger effect in men than in women. Premenopausal women had lower serum phosphate compared to postmenopausal women. Serum testosterone was inversely associated with serum phosphate in postmenopausal women only. In conclusion, women > 45 years have higher serum calcium and phosphate concentrations compared to men of similar age, not explained by vitamin D or alkaline phosphatase concentrations. Serum estradiol but not testosterone was inversely associated with serum calcium while serum testosterone was inversely associated with serum phosphate in both sexes. Serum testosterone may in part explain sex differences in serum phosphate while estradiol could partly explain sex differences in serum calcium.

Biological Aging for Risk Prediction of First-Ever Intracerebral Hemorrhage and Cerebral Infarction in Advanced Age.

BACKGROUND AND OBJECTIVES: successful interventions to prevent cerebrovascular disease and stroke require early identification of persons at risk before clinical manifestation of disease. The literature remains to be sparse on accessible plasma-based biomarkers for monitoring brain health and cerebrovascular disease in advanced age. We assessed the predictive value of biological age (BA) as an early indicator for cerebrovascular disease and risk of first-ever intracerebral hemorrhage (ICH) and cerebral infarction (CI) in advanced age and compared these relationships with chronological age (CA) and commonly used biomarkers including tau and Aß40 and Aß42. METHODS: The study included Individuals who consented for blood draw and follow-up. We computed biological age using structural equation modelling. The criteria for the biomarkers included their representability of the various body systems; their availability in the Rotterdam study and their pre-hypothesized reflection of aging in other populations. The algorithm integrates biomarkers that represent six body systems involved in overall cerebrovascular health including metabolic function, cardiac function, lung function, kidney function, liver function, immunity, and inflammation. Time to event analysis was conducted using Cox-regression models. Prediction analysis was conducted using Harrel's C and Area under the receiver operating characteristic curve. RESULTS: The sample included a total of 1699 individuals at baseline followed up over a median of 11 years. During a period of 15, 780 and 16, 172 person-years, a total of 17 first-ever intracerebral hemorrhage and 83 cerebral infarction cases occurred. In time-to-event analysis, BA showed higher magnitude of associations with ICH compared to CA (HRBA-ICH: 2.30, 95% CI: 1.20, 4.30; HRCA-ICH: 1.40, 95% CI: 0.76, 2.53) and higher precision with CI (HRBA-CI: 1.30, 95% CI: 1.01,1.75; HRCA-CI:1.90, 95% CI: 1.48, 2.66). BA outperformed CA for prediction of ICH (AUC: 0.68 vs 0.53; Harrel's C: 0.72 vs 0.53) and for CI (AUC:0.63 vs 0.62; Harrel's C: 0.68 vs 0.67). CONCLUSIONS: Biological aging (delta biological aging) based on integrated physiology biomarkers provides a novel tool for monitoring and identification of persons at highest risk of cerebrovascular disease in advanced age with varying degrees of precision and magnitude for stroke subtypes. These variations are likely related to differences in pathophysiology of intracerebral hemorrhage and cerebral infarction. Wider validation and applicability require extension of these findings in other comparable samples and in clinical settings.

Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium.

BACKGROUND: Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. METHOD AND RESULTS: Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65-75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94-0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. CONCLUSIONS: For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

Appendectomy and the subsequent risk of cancer: A prospective population-based cohort study with long follow-up.

BACKGROUND: The appendix, an organ of immunological and microbiological importance, could be involved in the pathogenesis of cancers, but results are inconclusive. Our objective was to assess the association between appendectomy and the subsequent risk of cancer. METHODS: Data were obtained from the Rotterdam Study; a long-term prospective population-based study of individuals aged 55 years and older, of which the first cohort started in 1990 and included 7983 participants. Information on appendectomy was obtained through either medical interview at baseline or linkage with the national automated pathology center (PALGA). Cancer cases were pathology based. End of follow-up was January 1st, 2015. The association between appendectomy and risk of cancer was assessed using Cox proportional hazard models, adjusted for known confounders. RESULTS: Of 7135 included participants, 1373 (19.2%) had undergone an appendectomy and 1632 individuals developed cancer. After adjustment for age, sex, socioeconomic status, BMI, smoking, prevalent diabetes mellitus and alcohol intake, a history of appendectomy was associated with a significantly lower risk of cancer [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.75-0.98]. Subgroup analyses showed similar results for gastrointestinal cancer (HR 0.75, 95% CI 0.56-0.99), in particular colon cancer (HR 0.65, 95% 0.43-0.97), and cancer of the female reproductive organs (HR 0.35, 95% CI 0.15-0.80). CONCLUSION: Participants who underwent an appendectomy had a reduced risk of cancer in general after adjustment for potential confounders. Therefore, these results contradict earlier studies suggestive of an increased risk. Further research is necessary to replicate these results and reveal its underlying mechanism.

Sex steroids and markers of micro- and macrovascular damage among women and men from the general population.

AIMS: The contribution of sex hormones to micro- and macrovascular damage might differ among women and men. In particular, little is known about the association between sex hormones and small vessel disease. Therefore, we examined the association of total oestradiol, total testosterone, free-androgen index (FAI), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione levels with micro- and macrovascular diseases. METHODS AND RESULTS: This cross-sectional study included 2950 women and 2495 men from the population-based Rotterdam Study. As proxy of microvascular damage, we measured diameters of retinal arterioles and venules. Markers of macrovascular damage included carotid intima-media thickness and carotid plaque, coronary artery calcification (CAC), and peripheral artery disease. Linear and logistic regression models were used and adjusted for age, cardiovascular risk factors, and years since menopause. Associations with microvasculature: In women, total testosterone [mean difference per 1-unit increase in natural-log transformed total testosterone (95% confidence interval, CI): 2.59 (0.08-5.09)] and androstenedione [4.88 (1.82-7.95)] and in men DHEAS [2.80 (0.23-5.37)] and androstenedione [5.83 (2.19-9.46)] were associated with larger venular caliber. Associations with markers of large vessel disease: In women, higher total testosterone [-0.29 (-0.56 to -0.03)], FAI [-0.33 (-0.56 to -0.10)], and androstenedione levels [-0.33 (-0.64 to -0.02)] were associated with lower CAC burden and FAI [odds ratio (95% CI): 0.82 (0.71-0.94)] was associated with lower prevalence of plaque. CONCLUSION: A more androgenic profile was associated with more microvascular damage in both women and men. Among women, however, higher androgen levels were also associated with less macrovascular damage. Our findings suggest that androgens might have distinct effects on the vasculature, depending on the vascular bed and stages of the atherosclerosis process.

Gait speed reference values in community-dwelling older adults - Cross-sectional analysis from the Rotterdam Study.

BACKGROUND: Gait speed is a simple, inexpensive and clinically useful marker of physical function in older adults. We aimed to establish gait speed reference values for community-dwelling older adults. To this end, we further explored the association of age, sex and height with gait speed. METHODS: This study included community-dwelling participants aged 50 years and over enrolled in the Rotterdam Study. Participants completed the gait protocol between 2009 and 2016. The mean gait speed was calculated for age and height groups, stratified by sex. Reference values for gait speed were calculated using a quantile regression model adjusted for sex, the non-linear effects of age and height, as well as the interaction between age and sex plus the interaction between age and height. RESULTS: The study population included 4656 Dutch participants with a mean (standard deviation) age of 67.7 (9.5) years, comprising 2569 (55.2%) women. The mean height of the participants was 1.69 (0.10) meters and the mean gait speed was 1.20 (0.20) m/s. Gait speed was lower with older age and greater with taller stature, but the effect of height disappeared above the age of 80 years. Sex did not affect gait speed after accounting for age and height. Age-, sex-, and height-specific reference values for gait speed are available for use at https://emcbiostatistics.shinyapps.io/GaitSpeedReferenceValues/. CONCLUSIONS: We found that height explains the commonly noted difference in usual gait speed between sexes and that neither height nor sex impacts gait speed in the very oldest adults. We developed reference values for usual gait speed in Western European community-dwelling older adults.

Differences Between MR Brain Region Segmentation Methods: Impact on Single-Subject Analysis.

For the segmentation of magnetic resonance brain images into anatomical regions, numerous fully automated methods have been proposed and compared to reference segmentations obtained manually. However, systematic differences might exist between the resulting segmentations, depending on the segmentation method and underlying brain atlas. This potentially results in sensitivity differences to disease and can further complicate the comparison of individual patients to normative data. In this study, we aim to answer two research questions: 1) to what extent are methods interchangeable, as long as the same method is being used for computing normative volume distributions and patient-specific volumes? and 2) can different methods be used for computing normative volume distributions and assessing patient-specific volumes? To answer these questions, we compared volumes of six brain regions calculated by five state-of-the-art segmentation methods: Erasmus MC (EMC), FreeSurfer (FS), geodesic information flows (GIF), multi-atlas label propagation with expectation-maximization (MALP-EM), and model-based brain segmentation (MBS). We applied the methods on 988 non-demented (ND) subjects and computed the correlation (PCC-v) and absolute agreement (ICC-v) on the volumes. For most regions, the PCC-v was good ( > 0.75 ), indicating that volume differences between methods in ND subjects are mainly due to systematic differences. The ICC-v was generally lower, especially for the smaller regions, indicating that it is essential that the same method is used to generate normative and patient data. To evaluate the impact on single-subject analysis, we also applied the methods to 42 patients with Alzheimer's disease (AD). In the case where the normative distributions and the patient-specific volumes were calculated by the same method, the patient's distance to the normative distribution was assessed with the z-score. We determined the diagnostic value of this z-score, which showed to be consistent across methods. The absolute agreement on the AD patients' z-scores was high for regions of thalamus and putamen. This is encouraging as it indicates that the studied methods are interchangeable for these regions. For regions such as the hippocampus, amygdala, caudate nucleus and accumbens, and globus pallidus, not all method combinations showed a high ICC-z. Whether two methods are indeed interchangeable should be confirmed for the specific application and dataset of interest.

Mental health in people with Parkinson's disease during the COVID-19 pandemic: potential for targeted interventions?

The COVID-19 pandemic has introduced a myriad of challenges to the social life and care of people with Parkinson's disease (PD), which could potentially worsen mental health problems. We used baseline data of the PRIME-NL study (N = 844) to examine whether the association between COVID-19 stressors and mental health is disproportionately large in specific subgroups of people with PD and to explore effects of hypothetical reductions in COVID-19 stressors on mental health and quality of life. The mean (SD) age of the study population was 70.3 (7.8) years and 321 (38.0%) were women. The linear regression effect estimate of the association of COVID-19 stressors with mental health was most pronounced in women, highly educated people, people with advanced PD and people prone to distancing or seeking social support. Smaller effect estimates were found in people scoring high on confrontive coping or planful problem solving. The parametric G-formula method was used to calculate the effects of hypothetical interventions on COVID-19 stressors. An intervention reducing stressors with 50% in people with above median MDS-UPDRS-II decreased the Beck Depression Inventory in this group from 14.7 to 10.6, the State-Trait Anxiety Inventory from 81.6 to 73.1 and the Parkinson's Disease Quality of Life Questionnaire from 35.0 to 24.3. Insights from this cross-sectional study help to inform tailored care interventions to subgroups of people with PD most vulnerable to the impact of COVID-19 on mental health and quality of life.

Age-dependent sex differences in calcium and phosphate homeostasis.

BACKGROUND: Sex differences in calcium and phosphate have been observed. We aimed to assess a relation with age. METHODS: We used the laboratory values of serum calcium, phosphate and albumin from three different samples ( 2005, 2010 and 2014 years) using the hospital information system of Erasmus MC, Rotterdam. The samples were divided into three age groups: 1-17, 18-44 and ≥45 years. Sex differences in calcium and phosphate were analyzed using ANCOVA, adjusting for age and serum albumin. Furthermore, sex by age interactions were determined and we analyzed differences between age groups stratified by sex. RESULTS: In all three samples there was a significant sex × age interaction for serum calcium and phosphate, whose levels were significantly higher in women compared to men above 45 years. No sex differences in the younger age groups were found. In men, serum calcium and phosphate levels were highest in the youngest age group compared to age groups of 18-44 and ≥45 years. In women, serum calcium levels were significantly higher in the age group 1-17 and the age group ≥45 years compared to the 18-44 years age group. In women, serum phosphate was different between the three different age groups with highest level in the group 1-17 years and lowest in the group 18-44 years. CONCLUSION: There are age- dependent sex differences in serum calcium and phosphate. Furthermore, we found differences in serum calcium and phosphate between different age groups. Underlying mechanisms for these age- and sex- differences are not yet fully elucidated.

Cognitive and physical impairment and the risk of stroke - A prospective cohort study.

The manifestation of cognitive and physical impairment in stroke patients before the acute event suggests accumulating subclinical vascular pathology in the brain. We investigated whether impairments in cognitive and physical functioning were associated with an increased stroke risk. Between 2002 and 2008, 8,519 stroke-free non-demented participants from the population-based Rotterdam Study underwent cognition and physical assessments including Mini-Mental State Examination, 15-word learning test, Stroop test, letter-digit substitution test, verbal fluency test, Purdue pegboard test and questionnaires on basic and instrumental activities of daily living (BADL; IADL). Principal component analysis was used to derive global cognition (G-factor). Incident stroke was assessed through continuous monitoring of medical records until 2016. Among 8,519 persons (mean age 66.0 years; 57.8% women), 489 suffered a stroke during mean follow-up of 8.7 years (SD: 2.9). Worse G-factor was associated with higher stroke risk (Hazard Ratio 1.21, 95% CI: 1.06-1.38), largely driven by unspecified stroke. Likewise, worse scores on 15-word learning test, Stroop test, Purdue pegboard test, IADL, and BADL were associated with higher risk of stroke. Thus both worse cognitive and physical functioning were associated with a higher stroke risk, in particular unspecified stroke and persons with worse memory, information processing, executive function, and motor function.

Orientation Prior and Consistent Model Selection Increase Sensitivity of Tract-Based Spatial Statistics in Crossing-Fiber Regions.

The goal of this paper is to increase the statistical power of crossing-fiber statistics in voxelwise analyses of diffusion-weighted magnetic resonance imaging (DW-MRI) data. In the proposed framework, a fiber orientation atlas and a model complexity atlas were used to fit the ball-and-sticks model to diffusion-weighted images of subjects in a prospective population-based cohort study. Reproducibility and sensitivity of the partial volume fractions in the ball-and-sticks model were analyzed using TBSS (tract-based spatial statistics) and compared to a reference framework. The reproducibility was investigated on two scans of 30 subjects acquired with an interval of approximately three weeks by studying the intraclass correlation coefficient (ICC). The sensitivity to true biological effects was evaluated by studying the regression with age on 500 subjects from 65 to 90 years old. Compared to the reference framework, the ICC improved significantly when using the proposed framework. Higher t-statistics indicated that regression coefficients with age could be determined more precisely with the proposed framework and more voxels correlated significantly with age. The application of a fiber orientation atlas and a model complexity atlas can significantly improve the reproducibility and sensitivity of crossing-fiber statistics in TBSS.

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Questionnaire survey on cardiologists' view and management of coronary microvascular disease in clinical practice.

OBJECTIVE: We aimed to assess the opinion of Dutch cardiologists on coronary microvascular disease (CMD) and its management in clinical practice, and to assess the need for a CMD guideline among Dutch cardiologists. METHODS: We developed an online questionnaire including different aspects of CMD which was reviewed by an expert panel. The questionnaire was distributed by e­mail among all members of the Dutch Society of Cardiology. RESULTS: A total of 103 cardiologists (70% male) completed the questionnaire (response rate: 10%). Median age and years of experience as a cardiologist were 49 ± 15 and 12 ± 12 years, respectively. Overall, 93% of the cardiologists had considered the CMD diagnosis, 85% had ever made such a diagnosis, 90% had treated a patient with CMD, and 61% had referred patients to tertiary care. The median (interquartile range) self-rated knowledge level was 7.0 (2.0) (scale of 0-10). 84% rated their knowledge as sufficient (>5.5) and 58% viewed CMD as a disease entity. Overall, 61% and 17%, respectively, agreed that evidence-based diagnostic and treatment modalities for CMD do not exist, while 56% believed that CMD patients have a higher risk for cardiovascular disease and mortality. Finally, 82% of the responders stated that a CMD guideline is needed, and 91% wanted to receive the guideline once developed. DISCUSSION: Fifty-eight per cent of the responders recognise CMD as a separate disease entity. Our study underscores the need for a dedicated CMD guideline for Dutch cardiology practice. However, the response rate was low (10%), and it is likely that mainly cardiologists interested in CMD have participated in our study.

Diet as a risk factor for antimicrobial resistance in community-acquired urinary tract infections in a middle-aged and elderly population: a case-control study.

OBJECTIVES: There is an ongoing debate as to what extent antimicrobial resistance (AMR) can be transmitted from animals to humans via the consumption of animal products. Because epidemiological data on the role of diet in AMR in humans are lacking, we investigated this association between diet and AMR for different antimicrobial drugs in Escherichia coli (E. coli) in urinary tract infections (UTIs). METHODS: Susceptibility of E. coli in urinary cultures and information on diet (with food frequency questionnaires) were obtained from participants of the Rotterdam study, a population-based prospective cohort study. The association between intake of several food groups (meat, seafood, eggs, dairy products, crops) and resistance of E. coli to several antimicrobial drugs (amoxicillin, amoxicillin-clavulanic acid, trimethoprim, sulfamethoxazole-trimethoprim, first-generation cephalosporins, cefotaxime, nitrofurantoin, norfloxacin) was studied. RESULTS: Urinary cultures with E. coli were obtained from 612 individuals, of whom 481 (78.6%) were women. Resistance rates varied from 246/611 (40.3%) for amoxicillin and 167/612 (27.3%) for trimethoprim to only 29/612 (4.7%) for nitrofurantoin and 16/462 (3.5%) for cefotaxime. A higher intake of chicken was associated with cefotaxime resistance (OR 2.18; 95% CI 1.05-4.51 per tertile increase); a higher intake of pork was associated with norfloxacin resistance (OR 1.42; 95% CI 1.04-1.95 per quartile increase). In contrast, a higher intake of cheese was associated with lower AMR to amoxicillin (OR 0.84; 95% CI 0.72-0.99 per quartile increase) and amoxicillin-clavulanic acid (OR 0.67; 95% CI 0.53-0.86 per quartile increase). CONCLUSIONS: These findings support the hypothesis that diet may play a role in the AMR of E. coli in UTIs.

Erythrocyte sedimentation rate as an independent prognostic marker for mortality: a prospective population-based cohort study.

BACKGROUND: A very high erythrocyte sedimentation rate (ESR) is usually an indication of underlying pathology. Additionally, a moderately elevated ESR may also be attributable to biological ageing. Whether the ESR is a prognostic factor for mortality, regardless of age, has been scarcely investigated. Therefore, the objective was to analyse the association between elevated ESR levels and the risk of mortality in a prospective cohort of the general population. METHODS: We studied data from the Rotterdam Study (1990-2014). ESR levels were measured at baseline and individuals were followed until death or end of study. Associations between moderately (20-50 mm h-1 ) and markedly (>50 mm h-1 ) elevated ESR levels and all-cause mortality were assessed using multivariate Cox proportional hazard models. RESULTS: In total, 5226 participants were included, and the mean age was 70.3 years. During a median follow-up time of 14.9 years, 3749 participants died (71.7%). After adjustment, both a moderately elevated ESR and a markedly elevated ESR were associated with a significantly higher risk of overall mortality [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.12-1.35 and HR 1.89, 95% CI 1.38-2.60, respectively]. Although the ESR becomes higher with age, in a group aged above 75 years, without any comorbidities, an ESR > 20 mm h-1 remained associated with a significantly increased risk of mortality (HR 1.29, 95%CI 1.01-1.64). CONCLUSION: An elevated ESR is an independent prognostic factor for mortality. Despite the fact that ESR increases with age, it remains associated with an increased risk of mortality and warrants close follow-up.

Transfer learning by feature-space transformation: A method for Hippocampus segmentation across scanners.

Many successful approaches in MR brain segmentation use supervised voxel classification, which requires manually labeled training images that are representative of the test images to segment. However, the performance of such methods often deteriorates if training and test images are acquired with different scanners or scanning parameters, since this leads to differences in feature representations between training and test data. In this paper we propose a feature-space transformation (FST) to overcome such differences in feature representations. The proposed FST is derived from unlabeled images of a subject that was scanned with both the source and the target scan protocol. After an affine registration, these images give a mapping between source and target voxels in the feature space. This mapping is then used to map all training samples to the feature representation of the test samples. We evaluated the benefit of the proposed FST on hippocampus segmentation. Experiments were performed on two datasets: one with relatively small differences between training and test images and one with large differences. In both cases, the FST significantly improved the performance compared to using only image normalization. Additionally, we showed that our FST can be used to improve the performance of a state-of-the-art patch-based-atlas-fusion technique in case of large differences between scanners.

Erratum to: Epidemiology of Dementia: The Burden on Society, the Challenges for Research.

The name of the Chapter 1 author had been inadvertently mentioned as M. Arfan Ikram.

Professional occupation and the risk of Parkinson's disease.

BACKGROUND AND PURPOSE: Creativity in Parkinson's disease (PD) is strongly related to dopaminergic activity and medication. We hypothesized that patients with PD, including those who are in the pre-diagnostic phase of PD, are prone to choose highly structured 'conventional' professional occupations and avoid highly creative 'artistic' occupations. METHODS: At baseline of the population-based Rotterdam Study, we asked 12 147 individuals aged ≥45 years about their latest occupation and categorized occupations according to the RIASEC model. Participants underwent baseline and follow-up (median 11 years) examinations for PD. We determined associations of artistic (versus any other occupation) and conventional (versus any other occupation) occupations with PD. Additionally, we pooled our results with a recently published case-control study (Radboud Study). RESULTS: At baseline, conventional occupations were common [n = 4356 (36%)], whereas artistic occupations were rare [n = 137 (1%)]. There were 217 patients with PD, including 91 with prevalent PD and 126 with incident PD. The risk of PD varied substantially across occupational categories (chi-square, 14.61; P = 0.01). The penalized odds ratio (OR) of artistic occupations for PD was 0.19 [95% confidence interval (CI), 0.00-1.31; P = 0.11], whereas the OR of conventional occupations for PD was 1.23 (95% CI, 0.95-1.66; P = 0.10). The direction and magnitude of ORs were similar in cross-sectional and longitudinal subsamples. Pooled ORs across the Rotterdam and Radboud Studies were 0.20 (95% CI, 0.08-0.52; P < 0.001) for artistic and 1.23 (95% CI, 0.92-1.67; P = 0.08) for conventional occupations. CONCLUSIONS: The risk of PD varies substantially by choice of professional occupation. Our findings suggest that dopaminergic degeneration affects choice of occupation, which may start in the pre-diagnostic phase of PD.

Epidemiology of Dementia: The Burden on Society, the Challenges for Research.

Dementia is among the leading causes of death and disability. Due to the ageing population, its prevalence is expected to nearly triple worldwide by 2050, urging the development of preventive and curative interventions. Various modifiable risk factors have been identified in community-based cohort studies, but insight into the underlying pathophysiological mechanisms is lacking. Clinical trials have thus far failed in the development of disease-modifying therapy in patients with dementia, thereby triggering a shift of focus toward the presymptomatic phase of disease. The extensive preclinical disease course of Alzheimer's disease warrants reliable, easily obtainable biomarkers to aid in timely application of preventive strategies, selecting participants for neuroprotective trials, and disease monitoring in trials and clinical practice. Biomarker and drug discovery may yield the fruits from technology-driven developments in the field of genomics, epigenetics, metabolomics, and brain imaging. In that context, bridging the gap between translational and population research may well prove a giant leap toward development of successful preventive and curative interventions against dementia.

A spatio-temporal reference model of the aging brain.

Both normal aging and neurodegenerative disorders such as Alzheimer's disease (AD) cause morphological changes of the brain. It is generally difficult to distinguish these two causes of morphological change by visual inspection of magnetic resonance (MR) images. To facilitate making this distinction and thus aid the diagnosis of neurodegenerative disorders, we propose a method for developing a spatio-temporal model of morphological differences in the brain due to normal aging. The method utilizes groupwise image registration to characterize morphological variation across brain scans of people with different ages. To extract the deformations that are due to normal aging we use partial least squares regression, which yields modes of deformations highly correlated with age, and corresponding scores for each input subject. Subsequently, we determine a distribution of morphologies as a function of age by fitting smooth percentile curves to these scores. This distribution is used as a reference to which a person's morphology score can be compared. We validate our method on two different datasets, using images from both cognitively normal subjects and patients with Alzheimer disease (AD). Results show that the proposed framework extracts the expected atrophy patterns. Moreover, the morphology scores of cognitively normal subjects are on average lower than the scores of AD subjects, indicating that morphology differences between AD subjects and healthy subjects can be partly explained by accelerated aging. With our methods we are able to assess accelerated brain aging on both population and individual level. A spatio-temporal aging brain model derived from 988 T1-weighted MR brain scans from a large population imaging study (age range 45.9-91.7y, mean age 68.3y) is made publicly available at www.agingbrain.nl.