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Background and purpose: Risk factors for stroke differ between women and men in general populations. However, little is known about sex differences in secondary prevention. We investigated if sex interacted with modifiable risk factors for stroke in a large arterial disease cohort. Methods: Within the prospective UCC-SMART study, 13,898 patients (35% women) with atherosclerotic disease or high-risk factor profile were followed up to 23 years for stroke incidence or recurrence. Hypertension, smoking, diabetes, overweight, dyslipidemia, high alcohol use, and physical inactivity were studied as risk factors. Association between these factors and ischemic and hemorrhagic stroke incidence or recurrence was studied in women and men using Cox proportional hazard models and Poisson regression models. Women-to-men relative hazard ratios (RHR) and rate differences (RD) were estimated for each risk factor. Left-truncated age was used as timescale. Results: The age-adjusted stroke incidence rate was lower in women than men (3.9 vs 4.4 per 1000 person-years), as was the age-adjusted stroke recurrence rate (10.0 vs 11.7). Hypertension and smoking were associated with stroke risk in both sexes. HDL cholesterol was associated with lower stroke incidence in women but not in men (RHR 0.49; CI 0.27–0.88; and RD 1.39; CI − 1.31 to 4.10). Overweight was associated with a lower stroke recurrence in women but not in men (RHR 0.42; CI 0.23–0.80; and RD 9.05; CI 2.78–15.32). Conclusions: In high-risk population, sex modifies the association of HDL cholesterol on stroke incidence, and the association of overweight on stroke recurrence. Our findings highlight the importance of sex-specific secondary prevention. [ABSTRACT FROM AUTHOR]

The purpose is to investigate the added prognostic value of coronary artery calcium (CAC), thoracic aortic calcium (TAC), and heart valve calcium scores for prediction of a combined endpoint of recurrent major cardiovascular events and cardiovascular interventions (MACE +) in patients with established cardiovascular disease (CVD). In total, 567 patients with established CVD enrolled in a substudy of the UCC-SMART cohort, entailing cardiovascular CT imaging and calcium scoring, were studied. Five Cox proportional hazards models for prediction of 4-year risk of MACE + were developed; traditional CVD risk predictors only (model I), with addition of CAC (model II), TAC (model III), heart valve calcium (model IV), and all calcium scores (model V). Bootstrapping was performed to account for optimism. During a median follow-up of 3.43 years (IQR 2.28–4.74) 77 events occurred (MACE+). Calibration of predicted versus observed 4-year risk for model I without calcium scores was good, and the c-statistic was 0.65 (95%CI 0.59–0.72). Calibration for models II–V was similar to model I, and c-statistics were 0.67, 0.65, 0.65, and 0.68 for model II, III, IV, and V, respectively. NRIs showed improvement in risk classification by model II (NRI 15.24% (95%CI 0.59–29.39)) and model V (NRI 20.00% (95%CI 5.59–34.92)), but no improvement for models III and IV. In patients with established CVD, addition of the CAC score improved performance of a risk prediction model with classical risk factors for the prediction of the combined endpoint MACE+. Addition of the TAC or heart valve score did not improve risk predictions. [ABSTRACT FROM AUTHOR]

Background/Aims: It has been hypothesized that cerebral hypoperfusion may contribute to cognitive deterioration. Patients with white matter lesions (WML) may be more vulnerable to a decrease in cerebral blood flow (CBF) due to an impaired autoregulation. We investigated the association between CBF and cognitive performance and whether WML modified this relation. Methods: Within the SMART-MR study, a cohort study among patients with manifest arterial disease, cross-sectional analyses were performed in 472 patients (mean age 57 ± 10 years, 77% male). Total CBF was measured with magnetic resonance angiography in the internal carotid arteries and basilar artery, and was expressed per 100 ml brain volume. Neuropsychological tests assessing executive functioning and memory were performed and composite scores were calculated. We used linear regression analyses, adjusted for age, sex, education and intelligence, to investigate the association between CBF and cognitive performance. Results: We found that WML modified the association between CBF and executive functioning (p for interaction <0.001); the association between lower CBF and worse performance on executive functioning became stronger and significant with increasing volumes of WML. Lower CBF was not associated with worse memory. Conclusion: Our results suggest that a combination of lower CBF and WML may impair executive functioning but not memory. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Context Depression is associated with an increased mortality risk. It is not known to what extent depression characteristics such as severity and length of exposure to depression contribute to the association with excess mortality. Objectives To investigate the association between depression severity and duration with mortality in community-living elderly. Design Two-wave prospective cohort study with 10-year follow-up of vital status. Assessment of depression at baseline and at three year follow-up (GMS-AGECAT). Cox proportional hazards analyses of mortality with depression according to severity and length of exposure, adjusted for demographic variables, physical illnesses, cognitive decline and functional disabilities. Setting and participants Randomly selected cohort of 3 746 non-demented older community-living persons in the city of Amsterdam. Main outcome measures Excess mortality of both the baseline cohort, and of non-demented subjects participating in both assessments (n = 1989). Results Both moderate (MHR 1.29, 95% CI 1.03–1.61) and severe depression (MHR 1.34, 95% CI 1.07–1.68) predicted 10-year mortality after multivariate adjustment. Chronic depression was associated with a 41% higher mortality risk in 6-year follow-up compared to subjects without depression. Conclusions Severity and chronicity of depression are associated with a higher mortality risk. In combination with other findings this is suggestive of a causal relationship and may have implications for both preventive and treatment strategies of late-life depression. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective:Low B-vitamin status and high levels of serum homocysteine are found in depressed inpatients, but results of population-based studies of this association are inconclusive. We investigated whether a low dietary intake of B6-9-12 vitamins and high levels of serum homocysteine are associated with depressive symptoms in elderly men.Methods:The study sample included a total of 332 men aged 70–90 years who were free from cardiovascular diseases and diabetes at baseline in 1990. Depressive symptoms were measured with the Zung Self-rating Depression Scale at baseline in 1990 and dietary factors with the crosscheck dietary history method in 1985 and 1990. Serum levels of homocysteine were obtained in 1985. Multiple linear and logistic regression analyses were performed.Results:Dietary intake of folate (−1.19, 95% CI −2.03; −0.36) and vitamin B6 (−2.09, 95% CI −2.92; −1.26) per standard deviation increase was associated with lower levels of serum homocysteine, while vitamin B12 was not associated with serum homocysteine. Intake of folate, vitamin B6, vitamin B12 and levels of serum homocysteine were not related to depressive symptoms.Conclusions:Our results do not support the hypothesis that a low dietary intake of B6-9-12 vitamins and high levels of serum homocysteine are related to depression in healthy elderly men.European Journal of Clinical Nutrition (2008) 62, 939–945; doi:10.1038/sj.ejcn.1602804; published online 30 May 2007 [ABSTRACT FROM AUTHOR]

Background: It is still not clear whether a low level of education increases the risk of developing Alzheimer's disease (AD). Two common problems in cohort studies involving an elderly population and a two-step diagnostic procedure are the loss to follow-up without data on the presence of AD, and the fact that, in general, people with higher levels of education perform better on traditional cognitive tests, such as the Mini-Mental State Examination (MMSE). Both phenomena may lead to misclassification, resulting in a biased association between level of education and AD. This study investigated to what extent these selection mechanisms may influence this association.Methods: In the community-based Amsterdam Study of the Elderly (AMSTEL) a cohort at risk for AD was selected of 3778 people aged 65-84 years. Level of education was expressed in two categories: low (primary education or less) versus high (partial secondary education to completed university education). At follow-up, a subsample of elderly people was selected for further diagnostic evaluation, using a memory test in addition to the MMSE. Clinical diagnoses of AD were made according to DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria. To examine the extent to which loss to follow-up may have affected the results, a sensitivity analysis was performed comparing two extreme possibilities. Furthermore, to examine to what extent use of the MMSE only may have affected the results, the observed odds ratio (OR) was compared with the OR based on only those AD patients who were selected for diagnostics with the MMSE alone.Results: After an average of 3.2 years, 77 people had developed AD. Multivariate logistic regression analyses indicated that a low level of education was associated with incident AD (OR adjusted for age and sex 2.09; 95% CI: 1.29-3.38). The results of the sensitivity analysis still indicated that a low level of education was associated with incident AD. Screening with only the MMSE led to a higher OR than the one observed.Conclusion: Selective attrition and use of cognitive screening tests that are associated with educational level may influence the strength of the association between a low level of education and incident AD; however, it appears that these influences cannot completely explain this association. [ABSTRACT FROM AUTHOR]

Background: Population studies indicate that subjective memory complaints by elderly people are correlated with cognitive performance. These complaints have some predictive power regarding the development of dementia. The present study attempted to replicate this finding, and investigated which variables determine subjective memory complaints.Method: Participants in the Amsterdam Study of the Elderly (n = 2114; 65-84 years of age), who were not demented and had a normal MMSE score (> 23) at baseline, were re-examined after four years. Subjective complaints were measured using a previously developed scale. Dementia and depression were measured using the Geriatric Mental State Schedule (GMS). Premorbid intelligence was measured by the Dutch Adult Reading Test (DART).Results: Memory complaints at baseline contributed a small but significant amount of diagnostic information with respect to the prediction of future dementia. Depressive symptoms at baseline had no predictive value when these memory complaints were accounted for. Subjective memory complaints were associated with depression, baseline MMSE score, and premorbid intelligence.Conclusions: Subjective memory complaints are not just secondary to depression, but in part reflect realistic self-observations of cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Physical exercise in cancer patients is a promising intervention to improve cognition and increase brain volume, including hippocampal volume. We investigated whether a 6-month exercise intervention primarily impacts total hippocampal volume and additionally hippocampal subfield volumes, cortical thickness and grey matter volume in previously physically inactive breast cancer patients. Furthermore, we evaluated associations with verbal memory., Methods: Chemotherapy-exposed breast cancer patients (stage I-III, 2-4 years post diagnosis) with cognitive problems were included and randomized in an exercise intervention (n = 70, age = 52.5 ± 9.0 years) or control group (n = 72, age = 53.2 ± 8.6 years). The intervention consisted of 2x1 hours/week of supervised aerobic and strength training and 2x1 hours/week Nordic or power walking. At baseline and at 6-month follow-up, volumetric brain measures were derived from 3D T1-weighted 3T magnetic resonance imaging scans, including hippocampal (subfield) volume (FreeSurfer), cortical thickness (CAT12), and grey matter volume (voxel-based morphometry CAT12). Physical fitness was measured with a cardiopulmonary exercise test. Memory functioning was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R total recall) and Wordlist Learning of an online cognitive test battery, the Amsterdam Cognition Scan (ACS Wordlist Learning). An explorative analysis was conducted in highly fatigued patients (score of ≥ 39 on the symptom scale 'fatigue' of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), as previous research in this dataset has shown that the intervention improved cognition only in these patients., Results: Multiple regression analyses and voxel-based morphometry revealed no significant intervention effects on brain volume, although at baseline increased physical fitness was significantly related to larger brain volume (e.g., total hippocampal volume: R = 0.32, B = 21.7 mm 3 , 95 % CI = 3.0 - 40.4). Subgroup analyses showed an intervention effect in highly fatigued patients. Unexpectedly, these patients had significant reductions in hippocampal volume, compared to the control group (e.g., total hippocampal volume: B = -52.3 mm 3 , 95 % CI = -100.3 - -4.4)), which was related to improved memory functioning (HVLT-R total recall: B = -0.022, 95 % CI = -0.039 - -0.005; ACS Wordlist Learning: B = -0.039, 95 % CI = -0.062 - -0.015)., Conclusions: No exercise intervention effects were found on hippocampal volume, hippocampal subfield volumes, cortical thickness or grey matter volume for the entire intervention group. Contrary to what we expected, in highly fatigued patients a reduction in hippocampal volume was found after the intervention, which was related to improved memory functioning. These results suggest that physical fitness may benefit cognition in specific groups and stress the importance of further research into the biological basis of this finding., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The clinical relevance of cortical microinfarcts has recently been established; however, studies on microinfarcts in the deep gray matter are lacking. We examined the risk factors and MR imaging correlates of microinfarcts in the deep gray matter on 7T MR imaging and their relation to cognitive functioning., Materials and Methods: Within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, 213 patients (mean age, 68 [SD, 8] years) had a risk-factor assessment, 7T and 1.5T brain MR imaging, and a cognitive examination. Microinfarcts on 7T MR imaging were defined as lesions of <5 mm. Regression models were used to examine the age-adjusted associations among risk factors, MR imaging markers, and microinfarcts. Cognitive function was summarized as composite and domain-specific z scores., Results: A total of 47 microinfarcts were found in 28 patients (13%), most commonly in the thalamus. Older age, history of stroke, hypertension, and intima-media thickness were associated with microinfarcts. On 1.5T MR imaging, cerebellar infarcts (relative risk = 2.75; 95% CI, 1.4-5.33) and lacunes in the white (relative risk = 3.28; 95% CI, 3.28-6.04) and deep gray matter (relative risk = 3.06; 95% CI, 1.75-5.35) were associated with microinfarcts, and on 7T MR imaging cortical microinfarcts (relative risk = 2.33; 95% CI, 1.32-4.13). Microinfarcts were also associated with poorer global cognitive functioning (mean difference in the global z score between patients with multiple microinfarcts versus none = -0.97; 95% CI, -1.66 to -0.28, P = .006) and across all cognitive domains., Conclusions: Microinfarcts in the deep gray matter on 7T MR imaging were associated with worse cognitive functioning and risk factors and MR imaging markers of small-vessel and large-vessel disease. Our findings suggest that microinfarcts in the deep gray matter may represent a novel imaging marker of vascular brain injury., (© 2022 by American Journal of Neuroradiology.)

Perivascular spaces (PVS) are believed to be involved in brain waste disposal. PVS are associated with cerebral small vessel disease. At higher field strengths more PVS can be observed, challenging manual assessment. We developed a method to automatically detect and quantify PVS. A machine learning approach identified PVS in an automatically positioned ROI in the centrum semiovale (CSO), based on -resolution T2-weighted TSE scans. Next, 3D PVS tracking was performed in 50 subjects (mean age 62.9 years (range 27-78), 19 male), and quantitative measures were extracted. Maps of PVS density, length, and tortuosity were created. Manual PVS annotations were available to train and validate the automatic method. Good correlation was found between the automatic and manual PVS count: ICC (absolute/consistency) is 0.64/0.75, and Dice similarity coefficient (DSC) is 0.61. The automatic method counts fewer PVS than the manual count, because it ignores the smallest PVS (length <2 mm). For 20 subjects manual PVS annotations of a second observer were available. Compared with the correlation between the automatic and manual PVS, higher inter-observer ICC was observed (0.85/0.88), but DSC was lower (0.49 in 4 persons). Longer PVS are observed posterior in the CSO compared with anterior in the CSO. Higher PVS tortuosity are observed in the center of the CSO compared with the periphery of the CSO. Our fully automatic method can detect PVS in a 2D slab in the CSO, and extract quantitative PVS parameters by performing 3D tracking. This method enables automated quantitative analysis of PVS., (© 2022 The Author(s).)

Objectives: Stroke is the second most common cause of death and a major cause of disability. Besides the physical consequences, depressive symptoms are frequent in the aftermath after stroke. Every year, approximately 15 million stroke survivors worldwide are at risk of developing post-stroke depression. In this study we describe the natural course of depressive symptoms in stroke patients over a long-period of time post stroke and identify associated determinants., Materials and Methods: From the Second Manifestations of ARTerial disease-Memory, depression and aging (SMART-Medea) study, an observational prospective cohort study, we selected patients with cerebrovascular disease, and used the biannually collected data of the Patient Health Questionnaire-9 for depressive symptoms. A score of ≥10 indicated the presence of depressive symptoms. A multinomial logistic regression analysis was used to identify prognostic determinants for courses of depressive symptoms after stroke., Results: During a mean follow-up time of 7.9 years, 62% of the 172 participants was never depressed, 19% had a single episode and 19% had recurrent depressive symptoms. Physical function was associated with increased risk for single episode and recurrent depressive symptoms (OR=1.06 [1.01-1.11]). OR's for social, mental and (vascular) comorbidities variables were not significant. Participants' physical function was only measured at baseline. Several relevant variables were not present in this dataset, including information about clinical events during follow-up., Conclusion: Nearly 40% of the participants are confronted with depressive symptoms on the long-term. Physical function plays a substantial part for stroke survivors in the development of these symptoms., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Intracranial atherosclerosis, a major risk factor for ischemic stroke, is thought to have different atherogenic mechanisms than extracranial atherosclerosis. Studies investigating their relationship in vivo are sparse and report inconsistent results. We studied the relationship between intracranial atherosclerosis and extracranial atherosclerosis in a cohort of patients with a history of vascular disease., Materials and Methods: Within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART) study, cross-sectional analyses were performed in 130 patients (mean age, 68 ± 9 years) with a history of vascular disease and with assessable 7T intracranial vessel wall MR imaging data. Intracranial atherosclerosis burden was defined as the number of intracranial vessel wall lesions in the circle of Willis and its major branches. Age- and sex-adjusted unstandardized regression coefficients ( b -value) were calculated with intracranial atherosclerosis burden as the dependent variable and extracranial atherosclerosis markers as independent variables., Results: Ninety-six percent of patients had ≥1 vessel wall lesion, with a mean intracranial atherosclerosis burden of 8.5 ± 5.7 lesions. Significant associations were observed between higher intracranial atherosclerosis burden and carotid intima-media thickness ( b = 0.53 lesions per +0.1  mm; 95% CI, 0.1-1.0 lesions), 50%-100% carotid stenosis versus no stenosis ( b = 6.6 lesions; 95% CI, 2.3-10.9 lesions), ankle-brachial index ≤ 0.9 versus >0.9 ( b = 4.9 lesions; 95% CI, 1.7-8.0 lesions), and estimated glomerular filtration rate ( b = -0.77 lesions per +10 mL/min; 95% CI, -1.50 to -0.03 lesions). No significant differences in intracranial atherosclerosis burden were found among different categories of vascular disease., Conclusions: Intracranial atherosclerosis was associated with various extracranial markers of atherosclerosis, not supporting a different etiology., (© 2019 by American Journal of Neuroradiology.)

Background and Purpose: High resolution 7T MRI is increasingly used to investigate hippocampal subfields in vivo, but most studies rely on manual segmentation which is labor intensive. We aimed to evaluate an automated technique to segment hippocampal subfields and the entorhinal cortex at 7T MRI., Materials and Methods: The cornu ammonis (CA)1, CA2, CA3, dentate gyrus, subiculum, and entorhinal cortex were manually segmented, covering most of the long axis of the hippocampus on 0.70-mm(3) T2-weighted 7T images of 26 participants (59 ± 9 years, 46% men). The automated segmentation of hippocampal subfields approach was applied and evaluated by using leave-one-out cross-validation., Results: Comparison of automated segmentations with corresponding manual segmentations yielded a Dice similarity coefficient of >0.75 for CA1, the dentate gyrus, subiculum, and entorhinal cortex and >0.54 for CA2 and CA3. Intraclass correlation coefficients were >0.74 for CA1, the dentate gyrus, and subiculum; and >0.43 for CA2, CA3, and the entorhinal cortex. Restricting the comparison of the entorhinal cortex segmentation to a smaller range along the anteroposterior axis improved both intraclass correlation coefficients (left: 0.71; right: 0.82) and Dice similarity coefficients (left: 0.78; right: 0.77). The accuracy of the automated segmentation versus a manual rater was lower, though only slightly for most subfields, than the intrarater reliability of an expert manual rater, but it was similar to or slightly higher than the accuracy of an expert-versus-manual rater with ∼170 hours of training for almost all subfields., Conclusions: This work demonstrates the feasibility of using a computational technique to automatically label hippocampal subfields and the entorhinal cortex at 7T MRI, with a high accuracy for most subfields that is competitive with the labor-intensive manual segmentation. The software and atlas are publicly available: http://www.nitrc.org/projects/ashs/., (© 2016 by American Journal of Neuroradiology.)