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Introduction: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Their role in the pathophysiology of dementia and potential as biomarkers remains undetermined. Methods: We conducted a single- (one-by-one) and multi-marker (joint) analysis to identify well-expressed circulating miRNAs in plasma (total = 591) associated with general cognition and incident dementia, for 1615 participants of the population-based Rotterdam Study. Results: During single-marker analysis, 47 miRNAs were nominally (P ≤.05) associated with cognition and 18 miRNAs were nominally associated with incident dementia, after adjustment for potential confounders. Three miRNAs were common between cognition and dementia (miR-4539, miR-372-3p, and miR-566), with multi-marker analysis revealing another common miRNA (miR-7106-5p). In silico analysis of these four common miRNAs led to several putative target genes expressed in the brain, highlighting the mitogen-activated protein kinase signaling pathway. Discussion: We provide population-based evidence on the relationship between circulatory miRNAs with cognition and dementia, including four common miRNAs that may elucidate downstream mechanisms. HIGHLIGHTS: MicroRNAs (miRNAs) are involved in the (dys)function of the central nervous system. Four circulating miRNAs in plasma are associated with cognition and incident dementia. Several predicted target genes of these four miRNAs are expressed in the brain. These four miRNAs may be linked to pathways underlying dementia. Although miRNAs are promising biomarkers, experimental validation remains essential.

Aim: Kushta-e-Murdarsang a herbo-mineral calx preparation was prepared as per classical and contemporary method and its physico-chemical and elemental analysis for standardization and safety evaluation (by heavy metal estimation) was performed. Methods: Murdarsang (Litharge mineral) was subjected to Mudabbar / Shodhan (processing) by Sheere- Madar (Latex of Calotropis gigantea Linn. R. Br. ex. Ait.) and calcined by classical and muffle furness method. Comparative Physico-chemical investigation for safety evaluation and standardization were done by X-ray diffraction (XRD), inductively coupled plasma mass spectrometry (ICP-MS), Atomic absorption spectroscopy (AAS) and other analytical parameters. Results: Both the sample Kushta-e-Murdarsang classical method (KM-CM) and Kushta-e-Murdarsang Muffle Furnace method (KM-MFM) passed specification tests as per Unani Medicine. Both the sample KM-CM and KM-MFM showed presence of heavy metals. In XRD analysis both the samples showed presence of Lead, sample KM-MFM revealed presence of Litharge syn- PbO phase, where KM-CM revealed presence of Lead syn- Pb, Galena syn- Pb S and Litharge syn- PbO phase. In ICP-MS analysis the Cadmium (Cd) content was 0.65 ppm and 0.65 ppm; Mercury (Hg) 54.17 ppm and 68.08 ppm and Arsenic (As) was 21.27 ppm and 0.11 ppm accordingly, in AAS analysis the Lead (Pb) content was 55.0 % and 51.4% in KM-MFM and KM-CM respectively. Conclusion: KM-MFM can be a better choice in respect of only ease of preparation, both the sample prepared by classical along with muffle furnace method contains heavy metal above permissible limit and KM-CM contain reduced quantity of heavy metal in respect of MF method. XRD and other standardization data for the formulation were set in. Key words: Murdarsang, Lead monoxide, Litharge, Unani Medicine, Kushta, Safety.

Early-life environmental factors have been suggested in the pathophysiology of dementia. Season of birth has previously been used as a proxy for these external exposures. We investigated the link between season of birth and the risk of dementia and further explored underlying pathways by studying structural brain changes on MRI. From the Dutch, population-based Rotterdam Study, 12,964 participants born between 1887 and 1960 were followed between 1990 and 2018 for dementia. Cox regression was conducted to assess the association between season of birth and dementia. In addition, we distinguished between mild and cold winters. The association of season of birth with structural brain markers on MRI was examined in 5237 participants. The risk of dementia in participants born in winter and fall was higher than of those born in summer (hazard ratio (HR) 1.15 [95% confidence interval (CI) 1.01–1.31] for winter and HR 1.17 [95% CI 1.01–1.33] for fall), especially for Alzheimer’s disease (HR 1.23 [1.06–1.43] for winter and HR 1.15 [95% CI 0.99–1.35] for fall). The risk was particularly increased for participants born in a cold winter. Except for slightly lower hippocampus in fall born participants (β − 0.03; 95% CI − 0.06 to 0.00), we did not find associations with brain imaging markers. In conclusion, winter and fall births were associated with a higher incidence of dementia, especially of AD. We did not find evidence for structural brain changes as an underlying mechanism. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00755-3.

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.

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.

Background In a clinical setting, atrial fibrillation (AF) subgroups are defined, including paroxysmal, persistent, and permanent AF. These subgroups differ in terms of clinical characteristics, management strategy, and long-term outcomes. Application of clinical classifications in population-based settings is challenging as they are based on the duration of symptoms, recurrence, and treatment. Purpose We aim to develop an objective and standardized classification for AF patterns in the general population and examine the associated cardiovascular risk profiles and outcomes for the identified AF patterns. Methods Participants with only one reported AF episode were categorized as single-documented AF, if at least two separate AF episodes were reported as multiple-documented AF and as longstanding persistent AF if at least two consecutive ECG's at the research center showed AF, not followed by an ECG showing sinus rhythm. We fitted mixed effect models with age as time scale to characterize sex-specific cardiovascular risk factor trajectories preceding each AF pattern. We further used Cox proportional hazard modelling to describe the risk of coronary heart disease (CHD), heart failure (HF), stroke, and all-cause mortality following AF. Results We included 14,620 men and women aged ≥45 years. 1137 participants were categorized as single-documented AF, 208 as multiple-documented AF, and 57 as longstanding persistent AF. We identified significant differences in the preceding trajectories of weight, body mass index, systolic blood pressure, diastolic blood pressure, waist circumference, hip circumference, and waist-hip ratio with various AF patterns. In general, both men and women with persistent-elevated levels of these risk factors were prone to longstanding persistent AF. AF was associated with a large risk for subsequent CHD, HF, stroke, and mortality in the general population. Among the different AF patterns, single-documented AF conferred the largest risk of CHD [hazard ratio, 95% confidence interval: 1.92 (1.19–3.03)] and mortality [1.70 (1.41–2.07)] as compared to multiple-documented AF, and as compared to longstanding persistent AF [1.45 (0.72–2.90) and 3.66 (2.25–5.95), respectively]. Conclusion We developed a classification for AF patterns within a general population. We identified differences in risk factor trajectories preceding each AF pattern, which implies differences in pathophysiological mechanisms underlying AF. Participants with single-documented AF showed worse prognosis than those with multiple AF episodes. This might be due to the subgroup definition, since participants should live for a longer period of time to be categorized in the multiple-documented AF and longstanding persistent AF groups. This can also imply that participants suffering from multiple AF episodes are more frequently monitored, and treated for other risk factors. However, this could also suggest that singular AF episodes are not as innocent as commonly thought. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): - Erasmus MC Mrace grant. - Netherlands Organization for the Health Research and Development (ZonMw) Figure 1Figure 2. Progosis of various AF patterns

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); Purpose To evaluate the sex-specific predictive value of two cardiac biomarkers; N-terminal pro B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT), alongside traditional cardiovascular risk factors, for 10-year cardiovascular risk prediction in general population. Methods A total of 5430 participants (mean age 68.1 years; 59.9% women) free of cardiovascular disease (CVD), with blood sample measurements between 1997 and 2001 were included. We developed a ‘base’ model using cardiovascular risk factors used in the Pooled Cohort Equation (includes age, sex, systolic blood pressure, treatment of hypertension, total and high-density lipoprotein cholesterol levels, smoking, and diabetes) and then extended the ‘base’ model with NT-proBNP or hs-cTnT. These models were developed for coronary heart disease (CHD), stroke, and heart failure (HF) and also for composite CVD outcomes. To evaluate biomarkers’ added predictive value, c-statistic, and net reclassification improvement index (NRI) for events and non-events were calculated. NRI was calculated using cutoffs of 5%, 7.5% and 20% to categorize participants as low, borderline, intermediate, or high risk. Results Adding NT-proBNP to the ‘base’ model significantly improved c-statistic for all outcomes (increases ranged between 0.012-0.047), with the largest improvement in HF [0.026 (95% CI, 0.013, 0.040) for women and 0.047 (95% CI, 0.026, 0.069) for men]. Adding hs-TnT to ‘base’ model increased the c-statistic for CHD in women by 0.040 (95% CI, 0.013, 0.067) and for HF in men by 0.032 (95% CI, 0.005, 0.059). Improvments in reclassification by both biomarkers were mostly limited to modest improvemetns in reclassification of non-events [largest non-event NRI for global CVD in women (NT-proBNP: 11.8%; hs-cTnT: 10.5%) and for HF in men (NT-proBNP: 9.6%; hs-cTnT: 8.4%)]. Conclusion NT-proBNP improved model performance for prediction of all cardiovascular outcomes, in particular for HF, beyond traditional risk factors for both women and men. Hs-cTnT showed modest added predictive value beyond traditional risk factors for CHD among women and for HF among men. Imropovements in reclassification by both biomarkers were modest and not clinically relevant. Improvements of 10-year risk predictions Events Adding NT-proBNP Adding troponin T Delta c-statistic* Event NRI, % Non-event NRI, % Delta c-statistic* Event NRI, % Non-event NRI, % WomenASCVD Global CVD 0.012 (0.004, 0.020) 0.018 (0.010, 0.026) -1.7 (-5.0, 1.5)-0.8 (-3.8, 2.2) 5.4 (3.5, 7.2)11.8 (9.6, 14.1) 0.028 (0.009, 0.048)0.025 (0.009, 0.040) -0.4 (-7.1, 6.2)2.9 (-2.4, 8.3) 6.9 (3.9, 9.9)10.5 (7.3, 13.8) MenASCVD Global CVD 0.016 (0.005, 0.027)0.023 (0.012, 0.033) 0.7 (-2.3, 3.7)-0.3 (-3.0, 2.4) 5.2 (3.2, 7.2)7.2 (4.9, 9.4) 0.007 (-0.002, 0.016)0.011 (0.000, 0.021) -1.1 (-5.0, 2.7)-1.6 (-6.0, 2.8) 4.0 (1.2, 6.9)6.4 (3.1, 9.7) ASCVD comprises coronary heart disease and stroke; Global CVD comprises coronary heart disease, stroke and heart failure.

Background The Coronary Artery Calcium (CAC) Score has emerged as a valuable tool in atherosclerotic cardiovascular disease (ASCVD) risk stratification. However, data on the relevance of arterial calcification in different vascular territories for ASCVD risk prediction is lacking. Purpose First, to assess the sex-specific distribution of arterial calcification in different vessel beds across ASCVD risk categories. Second, to determine the added value of arterial calcification in different vascular territories for ASCVD risk prediction. Methods From a large population-based study, 2,139 participants (mean age 69 years, 55% women) underwent non-contrast computed tomography to quantify CAC, aortic arch calcification (AAC), extracranial- (ECAC) and intracranial carotid artery calcification (ICAC), and vertebrobasilar artery calcification (VBAC). The outcome measure, incident ASCVD, composed of fatal and nonfatal myocardial infarction (MI), other coronary heart disease (CHD) mortality, and stroke. We fitted sex-specific prediction models according to the Pooled Cohort Equations (PCE), and categorized participants into low- ( Results The median follow-up for ASCVD was 9.3 years. Among women, 38% was classified as low-risk, 19% as borderline risk, 31% as intermediate risk, and 12% as high risk. Among men, 2% was classified as low-risk, 10% as borderline risk, 60% as intermediate risk, and 28% as high risk. With increasing risk of ASCVD, a larger burden of calcification was observed. In women, simultaneously adding calcification volumes in all vessel beds led to the largest increase in c statistic (from 0.71 to 0.75) for the prediction of ASCVD and the most beneficial reclassification (NRIe: 11%, NRIne: 2%). Among men, the addition of CAC alone most substantially improved the prediction of ASCVD (c statistic improved from 0.65 to 0.68, NRIe and NRIne were 4% and 14%, respectively). Conclusions Our findings suggest a potential role for comprehensive assessment of calcification in different vessel beds for ASCVD risk stratification in particular among women. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The Rotterdam Study is supported by Erasmus MC and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture, and Science; the Ministry of Health, Welfare, and Sports; European Commission; and the Municipality of Rotterdam. Dr. Kavousi is supported by the VENI grant (91616079) from ZonMw. Dr. Bos was supported by a fellowship of the BrightFocus Foundation (A2017424F). Oscar L. Rueda-Ochoa receives a scholarship from COLCIENCIAS-Colombia and support from Universidad Industrial de Santander,UIS-Colombia. None of the funders had any role in study design; study conduct; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article.

Background It is unclear to what extent the 2019 European Society of Cardiology (ESC), 2018 American College of Cardiology/ American Heart Association (ACC/AHA), 2016 US Preventive Services Task Force (USPSTF), and 2016 Canadian Cardiovascular Society (CCS) guidelines differ in assigning levels of evidence and classes of recommendations (LOE/class) to lipid-lowering treatment recommendations in primary prevention of cardiovascular disease (CVD). Purpose To compare LOE/class from four commonly used guidelines at population level. Methods A total of 7262 participants, aged 45–75 years of age and without history of CVD, from the prospective population-based Rotterdam Study were included. Per guideline, proportions of the population recommended statin therapy by LOE/class, sensitivity and specificity, and numbers needed to treat at 10 years (NNT10y) were calculated. Results Mean age was 61.1 (SD 6.9) years, and 58.2% were women. ESC, ACC/AHA, USPSTF and CCS strongly recommended statin use for a respective 33.8%, 48.1%, and 40.2% and 73.0% of the eligible population based on high-quality evidence, while in an additional 55.3%, 7.1%, 8.4% and 9.2% of participants statins use could or should be considered based on varying LOE/class. The sensitivity for treatment recommendations supported with strong, high quality evidence was 61.6% for ESC (“IA”), 74.6% for ACC/AHA (“IA or IB”), 69.4% for USPSTF (“USPSTF-B”) and 92.5% for CCS (“strong”). Specificity was highest for the ACC/AHA at 46.8% and lowest for ESC at 11.4%. Estimated NNT10y for those with the strongest LOE/class were comparable across all guidelines, ranging from 18 to 26 for moderate-intensity statin use, and 11 to 16 for high-intensity statin use. NNT10y reflective of recommendations supported with moderate strength of LOE/class varied substantially among guidelines for both moderate-intensity and high-intensity statin use, ranging from 33 for ESC and USPSTF to 91 for CCS. Conclusions Assigned LOE/class varied greatly among four clinical practice guidelines for primary prevention of CVD. Efforts for harmonized and comparable evidence grading system for clinical practice guidelines in primary prevention of CVD may reduce ambiguity, and reinforce updated evidence-based recommendations for appropriate treatment of populations for whom clear evidence for benefit of statin use is available. Funding Acknowledgement Type of funding source: None

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.

Background/Aim:To investigate the predictive ability of the previously established global cerebrovascular disease (CeVD) burden scale on long-term clinical outcomes in a longitudinal study of Asian elderly participants across the spectrum of cognitive impairment.Methods:A case-control study was conducted over a 2-year period involving participants with no cognitive impairment, cognitive impairment-no dementia (CIND), and Alzheimer's disease (AD). Annually, cognitive function was assessed with a comprehensive neuropsychological battery and the clinical dementia rating (CDR) scale was used to stage disease severity.Results:Of 314 participants, 102 had none/very mild CeVD, 31 mild CeVD, 94 moderate CeVD, and 87 severe CeVD at baseline. There was a 1.14 and 1.42 units decline per year on global cognitive z-scores in moderate and severe CeVD groups, respectively, compared to none/very mild CeVD. Moderate-severe CeVD predicted significant functional deterioration at year 2 (HR = 2.0, 95% CI = 1.2–3.4), and conversion to AD (HR = 6.3, 95% CI = 1.7–22.5), independent of medial temporal atrophy.Conclusion:The global CeVD burden scale predicts poor long-term clinical outcome independent of neurodegenerative markers. Furthermore, CeVD severity affects the rate of cognitive and functional deterioration. Hence, cerebrovascular burden, which is potentially preventable, is a strong prognostic indicator, both at preclinical and clinical stages of AD, independent of neurodegenerative processes.

textabstractBackground 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.

Background and aims Previous studies showed an independent association of low ankle-brachial index (ABI) with cognitive impairment. However, the association between low ABI and cognition in the presence of both cerebrovascular disease (CeVD) and neurodegeneration is lacking. We aimed at investigating a) the association of low ABI with markers of CeVD and cortical thickness, and b) whether the association of low ABI with cognition is influenced by these markers. Methods Data was drawn from the Epidemiology of Dementia In Singapore (EDIS) study where all participants (n = 832) underwent neuropsychological tests and 3T brain magnetic resonance imaging (MRI) to assess CeVD markers as well as cortical thicknesses. Cognitive function was expressed as a global composite z-score and domain-specific z-scores of a comprehensive neuropsychological battery. Results Multivariate analyses showed low ABI to be independently associated with intracranial stenosis [odds ratios (OR): 1.51; 95% confidence interval (CI):1.23–1.87] and lacunar infarcts [OR: 1.29; 95% CI: 1.06–1.57]. A low ABI was also independently associated with smaller cortical thickness globally [β: 0.09; 95% CI: 0.27–0.16] as well as with the limbic [β: 0.10; 95% CI: 0.03–0.17], temporal [β: 0.09; 95% CI: 0.02–0.15], parietal [β: 0.08; 95% CI: 0.02–0.15], and occipital [β: 0.09; 95% CI: 0.03–0.16] lobes. Low ABI was associated with worse performance in verbal memory [β: 0.06; 95% CI: 0.01–0.12], which became attenuated in the presence of MRI markers. Conclusions A low ABI is associated with MRI markers, and affects cognition in the presence of CeVD and neurodegeneration. Atherosclerosis should be targeted as a potentially modifiable risk factor to prevent cognitive disorders.

Background Cerebral small vessel disease (SVD) has been suggested to be more common in Asians compared with Caucasians. However, data from population-based studies in Asia are lacking. We report on the prevalence, risk factors and consequences of SVD from contemporary studies in three Asian countries using 3-Tesla MRI for the evaluation of SVD. Methods Clinical, cognitive and 3-Tesla brain MRI assessments were performed among participants of three studies from Singapore, Hong Kong and Korea. SVD markers include white matter hyperintensities (WMHs) using the modified Fazekas scale, lacunes and microbleeds. Cognition was assessed using the Mini Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Adjustments were made for age, sex and cardiovascular risk factors. Results A total of 1797 subjects were available for analysis (mean age: 70.1±6.3 years and 57% women). The prevalence of confluent WMH was 36.6%, lacunes, 24.6% and microbleeds, 26.9%. Presence of all three SVD markers showed a steeper increase with increasing age rising from 1.9% in the lowest to 46.2% in the highest 5-year age strata. The major risk factors for the increased severity of SVD markers were advancing age and hypertension. Moreover, increasing severity of SVD markers was independently associated with worse performance on MMSE and MoCA. Conclusion Elderly Asians have a high burden of SVD which was associated with cognitive dysfunction. This suggests that SVD markers should be a potential target for treatment in clinical trials so as to delay progression of cerebrovascular disease and potentially cognitive decline.

Background Thoracic aortic diameters have been associated with cardiovascular risk factors and atherosclerosis. However, limited evidence regarding the role of thoracic aortic diameters as risk markers for major cardiovascular outcomes among women and men exist. Purpose To evaluate the independent associations between crude and indexed ascending and descending aortic (AA and DA) diameters with major cardiovascular outcomes among women and men and to provide optimal cutoff values associated with increased cardiovascular risk. Methods and results 2178 women and men ≥55 years from the prospective population-based Rotterdam Study underwent multi-detector CT scan of thorax. Crude diameters of the AA and DA were measured and indexed by height, weight, body surface area (BSA) and body mass index (BMI). Incidence of stroke, coronary heart disease (CHD), heart failure (HF), cardiovascular and all-cause mortality were evaluated during 13 years of follow-up. Weight-, BSA-, or BMI-indexed AA diameters showed significant associations with total or cardiovascular mortality in both sexes and height-indexed values showed association with HF in women. Crude AA diameters were associated with stroke in men and HF in women. For DA, crude and almost all indexed diameters showed significant associations with either stroke, HF, cardiovascular or total mortality in women. Only weight-, BSA- and BMI-indexed values were associated with total mortality in men. For crude DA diameter, the risk for stroke increased significantly at the 75th percentile among men while the risks for HF and cardiovascular mortality increased at the 75th and 85th percentiles respectively in women. Conclusions Our study suggests a role for descending thoracic aortic diameter as a marker for increased cardiovascular risk, in particular for stroke, heart failure and cardiovascular mortality among women. The cut points for increased risk for several of cardiovascular outcomes were below the 95th percentile of the distribution of aortic diameters.

ObjectiveTo explore the additive effect of neurodegenerative diseases, measured by atrophy, on neurocognitive function in Asian dementia-free elderly with cerebrovascular disease (CeVD).MethodsThe present study employed a cross-sectional design and was conducted between 2010 and 2015 among community-dwelling elderly participants recruited into the study. Eligible participants were evaluated with an extensive neuropsychological battery and neuroimaging. The weighted CeVD burden scale comprising markers of both small- and large-vessel diseases was applied, with a score of ≥2, indicating significant CeVD burden. Cortical atrophy (CA) and medial temporal atrophy (MTA) were graded using the global cortical atrophy scale and Schelten’s scale, respectively. Global and domain-specific (attention, executive function, language, visuomotor speed, visuoconstruction, visual memory, and verbal memory) neurocognitive performance was measured using a locally validated neuropsychological battery (Vascular Dementia Battery, VDB).ResultsA total of 819 dementia-free participants were included in the analysis. Among none-mild CeVD subjects, there was no significant difference in the global cognitive performance across atrophy groups (no atrophy, CA, and CA+MTA). However, in moderate-severe CeVD subjects, CA+MTA showed significantly worse global cognitive performance compared with those with CA alone (mean difference=−0.35, 95% CI −0.60 to −0.11, p=0.002) and those without atrophy (mean difference=−0.46, 95% CI −0.74 to −0.19, pConclusions and relevanceAtrophy and moderate-severe CeVD burden showed an additive effect on global and domain-specific cognitive performance. This study highlights the importance of investigating the mechanisms of clinico-pathological interactions between neurodegenerative processes and vascular damage, particularly in the pre-dementia stage.

BackgroundRecently, using a counterfactual framework, a causal mediation analysis has been formalized to decompose the total effect of a time-fixed exposure on an outcome into four components that can be loosely defined as being components due to mediation only, interaction only, mediated interaction and neither. The interpretation of the estimated effect sizes is challenging when these components of the total effect are of the opposite sign compared with each other. Particularly, a negative mediated interaction might be intuitively difficult to conceptualize and, so far, lacks an easy-to-understand biological or mechanical interpretation.MethodsIn this paper, we focus on negative mediated interaction, and propose an interpretation using biological examples. For negative mediated interaction to be present, the effect of interaction on the outcome and the effect of the exposure on the mediator should be in opposite directions.ResultsIn this article, we give examples of biological and biochemical processes that may exhibit negative mediated interaction, such as drug treatment in clinical practice, allosteric effects of enzymes, different adaptations in the cardiovascular system and its effect on brain health, and antibiotic drug–drug interactions.ConclusionsWe aim to make researchers realize that negative-effect estimates might reflect relevant biological processes in the mechanism under study.

Gestational hypertensive disorders may lead to vascular changes in the offspring. We examined the associations of maternal blood pressure development and hypertensive disorders during pregnancy with microvasculature adaptations in the offspring in childhood. This study was performed as part of the Generation R Study in Rotterdam, the Netherlands (2002–2012), among 3,748 pregnant mothers and their children for whom information was available on maternal blood pressure in different periods of pregnancy and gestational hypertensive disorders. Childhood retinal arteriolar and venular calibers were assessed at the age of 6 years. We found that higher maternal systolic and diastolic blood pressures in early pregnancy were associated with childhood retinal arteriolar narrowing (P < 0.05). Higher maternal systolic blood pressure in late pregnancy, but not in middle pregnancy, was associated with childhood narrower retinal venular caliber (standard deviation score per standardized residual increase in systolic blood pressure: −0.05; 95% confidence interval: −0.08, −0.01). Paternal blood pressure was not associated with childhood retinal vessel calibers. Children of mothers with gestational hypertensive disorders tended to have narrower retinal arteriolar caliber (standard deviation score: −0.13, 95% confidence interval: −0.27, 0.01). Our results suggest that higher maternal blood pressure during pregnancy is associated with persistent microvasculature adaptations in their children. Further studies are needed to replicate these observations.

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Aims: To examine the diagnostic utility of the National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network (NINDS-CSN) neuropsychological battery in memory clinics comparing controls with patients with no cognitive impairment (NCI), patients with cognitive impairment-no dementia (CIND) at varying severity levels (mild/moderate), and patients with dementia. Methods: A total of 405 participants with NCI, CIND or dementia were assessed with the NINDS-CSN battery. The discriminatory properties of all three protocols (5, 30 and 60 min) before and after education stratification (none/primary vs. secondary/above) were examined by receiver operating characteristic curves. Results: Overall, the shorter protocols are equivalent to the longer protocol in diagnosing dementia, regardless of education. To discriminate between nondementia groups, before education stratification, the 5-min protocol showed varied discriminatory properties between different diagnostic/severity groups. After stratification, the 5-min protocol was broadly equivalent to the longer protocols in lower-education groups [area under the curve (AUC) range: 0.77-0.87] but was less accurate in the higher-education groups (AUC range: 0.68-0.78). The 30- and 60-min protocol constantly showed moderate-to-excellent differentiating capacities regardless of education (AUC range: 0.80-0.90). Conclusion: The NINDS-CSN neuropsychological battery can be applied in memory clinics and effectively discriminate between cognitively intact individuals and those with cognitive impairments of varying severity. Furthermore, level of education should be taken into consideration when choosing protocols with different lengths for cognitive assessment.

Purpose To investigate the association of passive tobacco smoke exposure with early-onset myopia among three-year-old children in Singapore. Methods Pregnant mothers who attended their first trimester clinic at two major maternity units were recruited into the GUSTO birth cohort. The current analysis comprised 572 three-year-old children, who underwent cycloplegic autorefraction and axial length (AL) measurements. Myopia was defined as spherical equivalent (SE) of ≤−0.50 diopters (D). Either parent completed questionnaires describing their child's exposure to passive smoke at six months, one and two years of age. Results There were 197 children (36.2%) who were exposed to passive smoke from birth to before six months. Compared to non-exposed children, children exposed to any passive smoke from birth to before six months experienced greater myopia prevalence (adjusted OR = 2.79; 95% CI: 1.24–6.29; p = 0.01). The odds of myopia in a child was greater if a smoker smokes at home, in the family car, or in the presence of the child (adjusted OR = 3.95; 95% CI: 1.41–11.09; p < 0.01) compared to non-exposed child. In contrast to myopia, childhood exposure to passive smoke did not systematically shift mean values for SE or AL. Conclusions In this prospective birth cohort study, we found that childhood exposure to passive smoke from birth to before six months slightly increased the risk of early-onset myopia. This may indicate a delayed response to passive smoke exposure before six months and the development of myopia at three years of age. Our study is limited by the small number of myopic children at this young age. Thus, larger prospective studies using more objective cotinine level measures are required to fully establish and understand the influence of tobacco smoke on refractive development in older children.

Background To examine the association of diabetes and diabetic retinopathy (DR) with retinal ganglion cell (RGC) loss. Design Observational case-control study. Participants Type 2 diabetes cases and age-gender matched controls without diabetes. Methods Spectral-domain optical coherence tomography (OCT) parameters of RGCs were calculated after automated segmentation of macular scans. DR severity was graded on fundus photographs using the modified Airlie House Classification system. Generalized estimating equation was used to compare OCT parameters between cases and controls, adjusted for covariates. Main outcome measures Average ganglion cell-inner plexiform layer (GC-IPL) and average retinal nerve fibre layer (RNFL) thicknesses. Results We analyzed 227 cases and 227 controls. The mean age (years) of cases was 58.3 and controls was 58.1 (P = 0.13). Among cases, 101 had none, 25 had mild and 101 had moderate or severe DR. Compared with controls, GC-IPL and RNFL were thinner in all cases [mean difference (95% confidence interval [CI]): GC-IPL -4.49 µm (-2.92; -6.06), RNFL -0.93 µm (-0.09; -1.85)], including cases with no DR [mean difference (95% CI), GC-IPL -4.37 µm (-2.72; -6.02), RNFL -1.06 µm (-0.10; -2.02)]. Cases with any DR had thinner GC-IPL than controls [mean difference (95% CI): GC-IPL -4.81 µm (-2.12; -7.50)]. Among cases, subjects with moderate or severe DR had thinner GC-IPL than subjects with no DR [mean difference (95% CI): GC-IPL -2.07 µm (-0.08; -4.07)]. Conclusions RGC loss is present in subjects with diabetes and no DR, and is progressive in moderate or severe DR. RGC neuronal damage in diabetes and DR can be clinically detected using OCT.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in working-age adults. Patients with diabetes often develop DR despite appropriate control of systemic risk factors, suggesting the involvement of other pathogenic factors. We hypothesize that the plasma metabolic signature of DR is distinct and resolvable from that of diabetes alone. A nested population-based case-control metabonomic study was first performed on 40 DR cases and 40 control subjects with diabetes using gas chromatography–mass spectrometry. Eleven metabolites were found to be correlated with DR, and the majority were robust when adjusted for metabolic risk factors and confounding kidney disease. The metabolite markers 2-deoxyribonic acid; 3,4-dihydroxybutyric acid; erythritol; gluconic acid; and ribose were validated in an independent sample set with 40 DR cases, 40 control subjects with diabetes, and 40 individuals without diabetes. DR cases and control subjects with diabetes were matched by HbA1c in the validation set. Activation of the pentose phosphate pathway was identified from the list of DR metabolite markers. The identification of novel metabolite markers for DR provides insights into potential new pathogenic pathways for this microvascular complication and holds translational value in DR risk stratification and the development of new therapeutic measures.

Background Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition. Objective To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments. Methods Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z-scores on the battery were derived and used to assess overall and significant (≥0.5 standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported. Results The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64-0.78] & 0.73 [0.66-0.80] for overall decline; 0.78 [0.70-0.85] & 0.80 [0.73-0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively). Conclusion There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change.

Item does not contain fulltext Increasing evidence shows that thinner retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), assessed on optical coherence tomography (OCT), are reflecting global brain atrophy. Yet, little is known on the relation of these layers with specific brain regions. Using voxel-based analysis, we aimed to unravel specific brain regions associated with these retinal layers. We included 2,235 persons (mean age: 67.3 years, 55% women) from the Rotterdam Study (2007-2012) who had gradable retinal OCT images and brain magnetic resonance imaging (MRI) scans, including diffusion tensor (DT) imaging. Thicknesses of peripapillary RNFL and perimacular GCL were measured using an automated segmentation algorithm. Voxel-based morphometry protocols were applied to process DT-MRI data. We investigated the association between retinal layer thickness with voxel-wise gray matter density and white matter microstructure by performing linear regression models. We found that thinner RNFL and GCL were associated with lower gray matter density in the visual cortex, and with lower fractional anisotropy and higher mean diffusivity in white matter tracts that are part of the optic radiation. Furthermore, thinner GCL was associated with lower gray matter density of the thalamus. Thinner RNFL and GCL are associated with gray and white matter changes in the visual pathway suggesting that retinal thinning on OCT may be specifically associated with changes in the visual pathway rather than with changes in the global brain. These findings may serve as a basis for understanding visual symptoms in elderly patients, patients with Alzheimer's disease, or patients with posterior cortical atrophy.

__Background:__ Plasma homocysteine levels are increasingly studied as a potential risk factor for dementia. Elevated homocysteine levels have been linked with gray and white matter volume reduction among individuals with mild cognitive impairment and Alzheimer's disease. However, the effects of homocysteine on brain changes in preclinical stages of dementia remain unexplored. __Objective:__ To examine the association of elevated homocysteine levels with markers of neurodegeneration, i.e., white and gray matter volume in an elderly population. __Methods:__ The study included 768 participants (mean age: 69.6±6.5 years, 51.3% women) from the Epidemiology of Dementia In Singapore study. Participants underwent a brain MRI scan and blood tests. Serum homocysteine was measured using competitive immunoassay. Cortical thickness and subcortical structural volume were quantified using FreeSurfer whereas white matter volume was quantified using a previous validated method. __Results:__ Higher homocysteine levels were significantly associated with decreased global white matter volume [mean difference (β) in volume (ml) per micromole per liter (μmol/l) increase in homocysteine levels: - 0.555, 95% Confidence Interval (CI): - 0.873; - 0.237], decreased parietal cortical thickness [β in thickness (μm) per μmol/l increase in homocysteine levels:- 1.429, 95% CI: - 2.781; - 0.077], and smaller volumes of the thalamus [β: - 0.017, 95% CI: - 0.026; - 0.008], brainstem [β: - 0.037, 95% CI: - 0.058; - 0.016], and accumbens [β: - 0.004, 95% CI: - 0.006; - 0.002]. __Conclusion:__ Higher homocysteine levels were associated with cerebral atrophy. Further studies are required to assess whether lowering plasma homocysteine levels may prevent neurodegenerative changes or delay progression of clinical symptoms before the development of dementia.

This study explores whether the Mini-Mental State Examination (MMSE) could reliably exclude definite dementia and dementia-free cases from requiring more extensive neuropsychological investigations in memory clinic settings in Singapore. Patients with memory complaints referred for possible dementia underwent the MMSE, followed by standardized neuropsychological and clinical assessments which led to a consensus diagnosis. MMSE cut-off points were derived stratified for education (less and equal/above primary level). Results show that after education stratification, using an optimal Positive Likelihood Ratio (PLR) and optimal Negative Likelihood Ratio (NLR), a higher percentage of patients were correctly identified as having dementia or dementia-free, with minimal misclassification rate. The finding suggests the MMSE can be used to exclude patients not requiring full neuropsychological assessments in a memory clinic.

Background and Purpose— The present study sought to examine the association between the burden of cerebrovascular disease (CeVD) as assessed by multimodal magnetic resonance imaging and neurocognitive function. Methods— Cognitively impaired patients and controls were tested on an extensive neuropsychological battery and underwent multimodal brain magnetic resonance imaging. CeVD markers determined from magnetic resonance imaging included the presence of multiple lacunes, multiple cerebral microbleeds, and moderate or severe white matter hyperintensities as markers for small-vessel disease and cortical stroke and intracranial stenosis as markers for large-vessel disease. A weighted CeVD burden score was constructed, and its association with global and domain-specific cognitive performance was investigated. Results— A total of 305 cases and 94 controls were included in the analysis. A graded association of CeVD burden with neurocognitive function was found. Moreover, a clear threshold of CeVD burden was associated with severe impairment. White matter hyperintensities was associated with global neurocognitive deficits, whereas microbleeds were associated with domain-specific impairments. Conclusions— The weighted CeVD burden score comprising markers of both small- and large-vessel diseases were associated with deficits in both global and domain-specific neurocognitive function. Additional studies are needed to validate the use of this CeVD burden score for the prediction of dementia.

Background Fetal exposure to maternal smoking is associated with an adverse cardiovascular risk profile in later life. Early microvasculature adaptations might be part of the underlying mechanisms for these associations. Aims The aim of this study was to examine the influence of maternal smoking during pregnancy on retinal vessel calibers in children. Study design We performed a population-based prospective cohort study among 3564 school-age children. Maternal smoking patterns during pregnancy were assessed by questionnaires. Outcome measures At the median age of 6.0 years (95% range 5.8, 8.0 years), we measured childhood retinal vessel calibers from retinal photographs. Results No differences were observed in childhood retinal arteriolar and venular calibers among offspring from mothers who smoked in the first trimester and mothers who continued smoking throughout pregnancy, as compared to mothers who did not smoke during pregnancy. Also, no dose-dependent associations of the number of cigarettes smoked during pregnancy with childhood retinal vessel calibers were present. Conclusion Maternal smoking during pregnancy did not influence childhood retinal arteriolar and venular calibers. The mechanisms linking fetal smoke exposure with cardiovascular risk factors in later life may include other mechanisms than structural microvasculature adaptations.

Objectives:To investigate the presence of neuropsychiatric symptoms (NPS) and sub-syndromes in elderly community-dwelling Asians with varying severity of cognitive impairment.Methods:Chinese and Malay participants (n = 613) from the Epidemiology of Dementia in Singapore (EDIS) Study aged ≥ 60 years underwent clinical examination, neuropsychological testing, and NPS assessment using the Neuropsychiatric Inventory (NPI). Diagnosis of no cognitive impairment (NCI), cognitive impairment-no dementia (CIND), including CIND-mild and CIND-moderate, and dementia were made using established criteria.Results:A significant increase in the numbers of NPS was observed accompanying with increasing severity of cognitive impairment (p < 0.001). Compared to those with NCI/CIND-mild, participants with CIND-moderate [Odds ratio (OR): 4.2, 95% confidence interval (CI): 1.8–10.0] or dementia [OR: 9.2, 95% CI: 2.3–36.0] were more likely to have two or more neuropsychiatric sub-syndromes. Participants with CIND-moderate were more likely to have hyperactivity [OR: 2.0, 95% CI: 1.0–3.8] and apathy [OR: 2.9, 95% CI: 1.0–8.4] sub-syndromes, whereas patients with dementia were more likely to have psychosis [OR: 6.9, 95% CI: 2.4–20.1], affective (OR: 8.7, 95% CI: 1.8–42.9), and hyperactivity (OR: 5.4, 95% CI: 1.8–16.1). Furthermore, executive dysfunction and visual memory impairment were associated with the presence of three neuropsychiatric sub-syndromes; whist language and visuomotor speed impairment were related to the presence of two sub-syndromes. By contrast, impairment in attention, verbal memory, and visuoconstruction were not associated with any of the sub-syndromes.Conclusions:The presence of NPS and sub-syndromes increase with increasing severities of cognitive impairment, and different neuropsychiatric syndromes are associated with specific impairment on cognitive domains in community-dwelling Asian elderly.