Unspecified Strokes: Time Trends, Determinants, and Long-Term Prognosis in the General Population.

INTRODUCTION: In the absence of neuroimaging, a stroke is typically labelled as unspecified. While the majority of clinic-based stroke research focuses on hemorrhagic or ischemic stroke, in the general population, a substantial proportion of strokes remains unspecified. OBJECTIVE: To investigate time trends in the occurrence and determinants of unspecified strokes and differences in patient characteristics and survival compared to ischemic or hemorrhagic stroke. METHODS: We included 1,546 participants from the population-based Rotterdam Study who suffered a first-ever stroke during follow-up (1990-2016). We calculated the proportion of unspecified strokes per year and compared their characteristics between 3 time periods (1990-1999, 2000-2009, and 2010-2016) using a chi-square test, and furthermore investigated differences between unspecified, ischemic, and hemorrhagic stroke in patient characteristics and survival using age- and sex-adjusted survival curves. RESULTS: The occurrence of unspecified stroke among all strokes decreased from 75% in 1990 to 16% in 2016. Compared to the first time period (1991-1999), diagnosis of unspecified strokes was more often done by nursing home physicians (13 vs. 40%) and unspecified stroke patients had more often dementia (30 vs. 43%) in the last time period (2010-2016). Compared to patients with ischemic or hemorrhagic stroke, patients with unspecified stroke were on average older (84.3 vs. 78.5 years) and had more often physical impairments and dementia. Furthermore, patients with unspecified stroke had a lower survival probability up to 10 years after stroke than those with ischemic stroke. CONCLUSIONS: The proportion of unspecified strokes decreased drastically from 75 to 16% in the last decades. Patients who do not undergo neuroimaging and therefore are classified as unspecified stroke represent an older, more frail patient group that suffers more often from multimorbidities and poor long-term prognosis than those who do undergo neuroimaging and are thus classified as ischemic or hemorrhagic stroke.

Low ADAMTS13 activity is associated with an increased risk of ischemic stroke.

ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin motif repeats 13) has antithrombotic properties because it cleaves von Willebrand factor (VWF) in smaller, less active multimers. The aim of our study was to investigate prospectively the association between ADAMTS13 activity and ischemic stroke. We included 5941 individuals ≥55 years without a history of stroke or transient ischemic attack (TIA) of the Rotterdam Study, a population-based cohort study. ADAMTS13 activity was measured at inclusion with the FRETS-VWF73 assay and VWF antigen (VWF:Ag) levels by enzyme-linked immunosorbent assay. We assessed the association among ADAMTS13 activity, VWF:Ag levels, and ischemic stroke by Cox proportional hazard analysis. The added value of ADAMTS13 activity above the traditional risk factors for ischemic stroke risk prediction was examined by the C-statistic and the net reclassification improvement index (NRI). All individuals were followed for incident stroke or TIA. Over a median follow-up time of 10.7 years (56,403 total person-years), 461 participants had a stroke, 306 of which were ischemic. After adjustment for cardiovascular risk factors, individuals with ADAMTS13 activity in the lowest quartile had a higher risk of ischemic stroke (absolute risk, 7.3%) than did those in the reference highest quartile (absolute risk, 3.8%; hazard ratio, 1.65; 95% confidence interval [CI], 1.16-2.32). Adding ADAMTS13 to the model in prediction of ischemic stroke, increased the C-statistic by 0.013 (P = .003) and provided 0.058 (95% CI, -0.002 to 0.119) NRI. Low ADAMTS13 activity is associated with the risk of ischemic stroke and improves the accuracy of risk predictions for ischemic stroke beyond traditional risk factors.

Chronic Obstructive Pulmonary Disease and the Risk of Stroke. The Rotterdam Study.

RATIONALE: Worldwide, chronic obstructive pulmonary disease (COPD) and stroke are leading causes of death. Increasing evidence suggests an association between both diseases, either caused by an increased atherosclerosis risk in patients with COPD or as a consequence of shared risk factors between stroke and COPD. OBJECTIVES: To examine the associations between COPD and subtypes of stroke in the general population and to explore the role of cardiovascular risk factors and exacerbations on these associations. METHODS: Within the prospective population-based Rotterdam Study, we followed 13,115 participants without history of stroke for occurrence of stroke. Follow up started in 1990 to 2008 and ended in 2012. COPD was related to stroke using a time-dependent Cox proportional hazard model. MEASUREMENTS AND MAIN RESULTS: COPD was diagnosed in 1,566 participants. During 126,347 person-years, 1,250 participants suffered a stroke, of which 701 were ischemic and 107 hemorrhagic. Adjusted for age, age squared, and sex, COPD was significantly associated with all stroke (hazard ratio [HR], 1.20; 95% confidence interval, 1.00-1.43), ischemic stroke (HR, 1.27; 1.02-1.59), and hemorrhagic stroke (HR, 1.70; 1.01-2.84). Adjusting for cardiovascular risk factors gave similar effect sizes. In contrast, additional adjusting for smoking attenuated the effect sizes: HR, 1.09 (0.91-1.31) for all stroke; HR, 1.13 (0.91-1.42) for ischemic stroke; and HR 1.53 (0.91-2.59) for hemorrhagic stroke. After an acute severe exacerbation, subjects with COPD had a 6.66-fold (2.42-18.20) increased risk of stroke. CONCLUSIONS: Our cohort study demonstrated a higher risk of both ischemic and hemorrhagic stroke in subjects with COPD and revealed the importance of smoking as a shared risk factor.

Cerebral Microbleeds Are Associated With an Increased Risk of Stroke: The Rotterdam Study.

BACKGROUND: Cerebral microbleeds are highly prevalent in people with clinically manifest cerebrovascular disease and have been shown to increase the risk of stroke recurrence. Microbleeds are also frequently found in healthy elderly, a population in which the clinical implication of microbleeds is unknown. METHODS AND RESULTS: In the population-based Rotterdam Study, the presence, number, and location of microbleeds were assessed at baseline on brain MRI of 4759 participants aged ≥45 years. Participants were followed for incident stroke throughout the study period (2005-2013). We used Cox proportional hazards to investigate if people with microbleeds were at increased risk of stroke in comparison with those without microbleeds, adjusting for demographic, genetic, and cardiovascular risk, and cerebrovascular imaging markers. Microbleed prevalence was 18.7% (median count 1 [1-111]). During mean follow-up of 4.9 years (standard deviation, 1.6) 93 strokes occurred (72 ischemic, 11 hemorrhagic, and 10 unspecified). Microbleed presence was associated with an increased risk of all strokes (hazard ratio, 1.93; 95% confidence interval, 1.25-2.99). The risk increased with greater microbleed count. In comparison with those without microbleeds, participants with microbleeds in locations suggestive of cerebral amyloid angiopathy (lobar with or without cerebellar microbleeds) were at increased risk of intracerebral hemorrhage (hazard ratio, 5.27; 95% confidence interval, 1.38-20.23). Microbleeds at other locations were associated with an increased risk of both ischemic stroke and intracerebral hemorrhage. CONCLUSIONS: Microbleeds on MRI are associated with an increased risk of stroke in the general population. Our results strengthen the notion that microbleeds mark progression of cerebrovascular pathology and represent a precursor of stroke.

Prestroke Vascular Pathology and the Risk of Recurrent Stroke and Poststroke Dementia.

BACKGROUND AND PURPOSE: Improved short-term survival after stroke has necessitated quantifying risk and risk factors of long-term sequelae after stroke (ie, recurrent stroke and dementia). This risk may be influenced by exposure to cardiovascular risk factors before the initial stroke. Within the population-based Rotterdam Study, we determined the long-term risk of recurrent stroke and dementia, and the proportion of recurrent strokes and poststroke dementia cases that are attributable to prestroke cardiovascular risk factors (ie, the population attributable risk). METHODS: We followed up 1237 patients with first-ever stroke and 4928 stroke-free participants, matched on age, sex, examination round, and stroke date (index date), for the occurrence of stroke or dementia. We calculated incidence rates in both groups and estimated the individual and combined population attributable risk of prestroke cardiovascular risk factors for both outcomes. RESULTS: Beyond 1 year after stroke, patients retained a 3-fold increased risk of recurrent stroke and an almost 2-fold increased risk of dementia compared with people without stroke. In total, 39% (95% confidence interval, 18%-66%) of recurrent strokes and 10% (95% confidence interval, 0%-91%) of poststroke dementia cases were attributable to prestroke cardiovascular risk factors. These percentages were similar for first-ever stroke and dementia in the matched stroke-free population. CONCLUSIONS: Long-term risks of recurrent stroke and poststroke dementia remain high and are substantially influenced by prestroke risk factors, emphasizing the need for optimizing primary prevention.

Anxiety and the Risk of Stroke: The Rotterdam Study.

BACKGROUND AND PURPOSE: It is unclear whether anxiety is a risk factor for stroke. We assessed the association between anxiety and the risk of incident stroke. METHODS: This population-based cohort study was based on 2 rounds of the Rotterdam Study. Each round was taken separately as baseline. In 1993 to 1995, anxiety symptoms were measured using the Hospital Anxiety and Depression Scale-Anxiety (HADS-A). In 2002 to 2004, anxiety disorders were assessed using the Munich version of the Composite International Diagnostic Interview. Participants were followed up for incident stroke until January 2012. RESULTS: In the sample undergoing HADS-A (N=2625; mean age at baseline, 68.4 years), 332 strokes occurred during 32 720 years of follow-up. HADS-A score was not associated with the risk of stroke during complete follow-up (adjusted hazard ratio, 1.02; 95% confidence interval, 0.74-1.43; for HADS-A≥8 compared with HADS-A <8), although we did find an increased risk after a shorter follow-up of 3 years (adjusted hazard ratio, 2.68; 95% confidence interval, 1.33-5.41). In the sample undergoing the Munich version of the Composite International Diagnostic Interview (N=8662; mean age at baseline, 66.1 years), 340 strokes occurred during 48 703 years of follow-up. Participants with any anxiety disorder had no higher risk of stroke than participants without anxiety disorder (adjusted hazard ratio, 0.95; 95% confidence interval, 0.64-1.43). We also did not observe an increased risk of stroke for the different subtypes of anxiety. CONCLUSIONS: Anxiety disorders were not associated with stroke in our general population study. Anxiety symptoms were only related to stroke in the short term, which needs further exploration.

Role of Prestroke Vascular Pathology in Long-Term Prognosis After Stroke: The Rotterdam Study.

BACKGROUND AND PURPOSE: Mortality after stroke remains high for years, mostly because of cardiovascular causes. Given that cardiovascular pathology plays an important role in causing the initial stroke, such prestroke pathology might also influence the prognosis after stroke. Within the population-based Rotterdam Study, we examined the proportion of deaths after stroke that are attributable to pre-existent cardiovascular risk factors before stroke (the population attributable risk). METHODS: We examined 1237 patients with first-ever stroke and 4928 stroke-free participants (between 1990 and 2012), matched on age, sex, examination round, and stroke date (index date). Cardiovascular risk factors measured on ≈4 years before index date were used as determinants. Participants were continuously followed up for mortality (≈6 years) after the index date. We calculated separate and combined population attributable risk of hypertension, total cholesterol, high-density lipoprotein-cholesterol, body mass index, diabetes mellitus, smoking, transient ischemic attack, and atrial fibrillation. RESULTS: Nine hundred and nineteen patients with stroke and 2654 stroke-free participants died. The combined population attributable risk in patients with stroke was 27% (95% confidence interval, 14%-45%) and in stroke-free participants was 19% (95% confidence interval, 12%-29%). Population attributable risks of diabetes mellitus, smoking, and atrial fibrillation were higher in patients with stroke than in the reference group because of a higher prevalence of risk factors. In addition, people with atrial fibrillation and stroke had a higher hazard ratio for death than those with only atrial fibrillation. CONCLUSIONS: One quarter of deaths after stroke could theoretically be prevented with rigorous cardiovascular prevention and treatment, but this should preferably start before stroke occurrence. In addition, research into factors explaining the remaining deaths needs to be encouraged.

Carotid Atherosclerotic Plaque Characteristics on Magnetic Resonance Imaging Relate With History of Stroke and Coronary Heart Disease.

BACKGROUND AND PURPOSE: Because atherosclerosis is a systemic disease, presence and composition on 1 location may relate to ischemic events in distant locations. We examined whether carotid atherosclerotic wall thickness, stenosis, and plaque composition are related to history of ischemic stroke and coronary heart disease (CHD). METHODS: From the population-based Rotterdam Study, 1731 asymptomatic participants (mean age, 72.4±9.1 years; 55% males) underwent magnetic resonance imaging of both carotid arteries. We assessed carotid wall thickness, stenosis and plaque composition, that is presence of intraplaque hemorrhage, lipid, and calcification. History of ischemic stroke and CHD was assessed until date of magnetic resonance imaging. The study was approved by the institutional review board, and all participants gave informed consent. Logistic regression analyses adjusted for age and traditional cardiovascular risk factors were used to study sex-specific associations between plaque characteristics and clinical events. RESULTS: We found that both carotid stenosis and intraplaque hemorrhage were associated with ischemic stroke in men but not in women (men: odds ratio [OR] for stenosis [per 10% increase]: 1.17 [95% CI, 1.06-1.30] and for intraplaque hemorrhage 2.39 [95% CI, 1.32-4.35]). In both men and women, carotid stenosis was associated with CHD (men: OR per 10% increase 1.12 [95% CI, 1.04-1.21] and women: OR, 1.17 [95% CI, 1.03-1.34]) and carotid wall thickness was associated with CHD (men: OR, 1.20 [95% CI, 1.03-1.39] and women: OR, 1.21 [95% CI, 0.88-1.65]). None of the plaque components was associated with CHD. CONCLUSIONS: Whereas carotid plaque thickness and stenosis are associated with the history of ischemic stroke and CHD, carotid intraplaque hemorrhage is associated with ischemic stroke, but not with CHD, providing novel insights into the pathogenesis of cardiovascular events.

White Matter Microstructure Improves Stroke Risk Prediction in the General Population.

BACKGROUND AND PURPOSE: The presence of subclinical vascular brain disease, including white matter lesions and lacunar infarcts, substantially increases the risk of clinical stroke. White matter microstructural integrity is considered an earlier, potentially better, marker of the total burden of vascular brain disease. Its association with risk of stroke, a focal event, remains unknown. METHODS: From the population-based Rotterdam Study, 4259 stroke-free participants (mean age: 63.6 years, 55.6% women) underwent brain magnetic resonance imaging, including diffusion magnetic resonance imaging, between 2006 and 2011. All participants were followed up for incident stroke until 2013. Cox proportional hazards models were used to associate markers of the microstructure of normal-appearing white matter with risk of stroke, adjusting for age, sex, white matter lesion volume, lacunar infarcts, and additionally for cardiovascular risk factors. Finally, we assessed the predictive value of white matter microstructural integrity for stroke beyond the Framingham Stroke Risk Profile. RESULTS: During 18 476 person-years of follow-up, 58 people experienced a stroke. Both lower fractional anisotropy and higher MD increased risk of stroke, independent of age, sex, cardiovascular risk factors, white matter lesion volume, and lacunar infarcts (hazard ratio per SD increase in: fractional anisotropy: 0.75 [95% confidence interval, 0.57-0.98] and MD: 1.50 [95% confidence interval, 1.08-2.09]). MD improved stroke prediction beyond the Framingham Stroke Risk Profile (continuous net reclassification improvement: 0.52 [95% confidence interval, 0.24-0.81]). CONCLUSIONS: Future stroke is predicted not only by prevalent vascular lesions but also by subtle alterations in the microstructure of normal-appearing white matter. Inclusion of this effect in risk prediction models produces a significant advantage in stroke prediction compared with the existing Framingham Stroke Risk Profile.

Higher Education Is Associated with a Lower Risk of Dementia after a Stroke or TIA. The Rotterdam Study.

BACKGROUND: Higher education is associated with a lower risk of dementia, possibly because of a higher tolerance to subclinical neurodegenerative pathology. Whether higher education also protects against dementia after clinical stroke or transient ischemic attack (TIA) remains unknown. METHODS: Within the population-based Rotterdam Study, 12,561 participants free of stroke, TIA and dementia were followed for occurrence of stroke, TIA and dementia. Across the levels of education, associations of incident stroke or TIA with subsequent development of dementia and differences in cognitive decline following stroke or TIA were investigated. RESULTS: During 124,862 person-years, 1,463 persons suffered a stroke or TIA, 1,158 persons developed dementia, of whom 186 developed dementia after stroke or TIA. Risk of dementia after a stroke or TIA, compared to no stroke or TIA, was highest in the low education category (hazards ratio [HR] 1.46, 95% CI 1.18-1.81) followed by intermediate education category (HR 1.36, 95% CI 1.03-1.81). No significant association was observed in the high education category (HR 0.62, 95% CI 0.25-1.54). In gender stratified analyses, decrease in risk of dementia with increasing education was significant only in men. CONCLUSION: Higher education is associated with a lower risk of dementia after stroke or TIA, particularly in men, which might be explained by a higher cognitive reserve.

Left-sided strokes are more often recognized than right-sided strokes: the Rotterdam study.

BACKGROUND AND PURPOSE: Left-sided strokes are reported to be more common than right-sided strokes, but it is unknown whether they occur more often or are simply recognized more easily by clinicians. In a large unselected community-dwelling population, we examined the frequency of clinical left- and right-sided strokes and transient ischemic attacks (TIAs) and compared it with the frequency of left- and right-sided infarcts on MRI. METHODS: This study was conducted within the population-based Rotterdam Study. Between 1990 and 2012, 13 894 participants were followed up for first-ever stroke and TIA. MRI scans were performed within a random subgroup of 5081 persons and were rated for the presence of supratentorial cortical and lacunar infarcts. We compared frequencies of left- and right-sided strokes, TIAs, or MRI infarcts using binomial and Fisher exact tests. RESULTS: After a mean follow-up of 9.6 (±6.0) years, 1252 patients had a stroke, of which 704 were ischemic, and 799 participants had a TIA. Within the subgroup with MRI, we identified 673 infarcts. Ischemic strokes were more frequently left-sided (57.7%; 95% confidence interval, 53.7-61.6) than right-sided, similar to TIAs (57.8% left-sided; 53.4-62.3). In contrast, we found no left-right difference in distribution of infarcts on MRI (51.9% left-sided; 48.1-55.6). CONCLUSIONS: Clinical ischemic strokes and TIAs are more frequently left-sided than right-sided, whereas this difference is not present for infarcts on MRI. This suggests that left-sided strokes and TIAs are more easily recognized. Consequently, there should be more attention for symptoms of right-sided strokes and TIAs.

Subjective memory complaints and the risk of stroke.

BACKGROUND AND PURPOSE: Persons with cognitive impairment, as assessed by cognitive tests, are at a higher risk of stroke. Subjective memory complaints might be an earlier marker for stroke, especially in persons with higher education. Their cognitive reserve might mask their cognitive impairment during cognitive testing. In a population-based setting, we investigated the association between subjective memory complaints and stroke. We simultaneously investigated the association between Mini-Mental State Examination and stroke. We also assessed whether these associations varied with educational level. METHODS: 9152 participants from the Rotterdam Study (baseline 1990-1993 or 2000-2001) completed the subjective memory complaints questionnaire and underwent Mini-Mental State Examination assessment. Subsequently, the entire cohort was followed for incident stroke until 2012. We used Cox proportional hazard models to estimate the associations between subjective memory complaints and Mini-Mental State Examination, with stroke. RESULTS: During a follow-up of 111 593 person years, 1134 strokes were identified, of which 663 were ischemic and 99 hemorrhagic. In the fully adjusted model, presence of subjective memory complaints was independently associated with a higher risk of stroke (hazard ratio, 1.20; 95% confidence interval, 1.04-1.39), but a higher Mini-Mental State Examination was not (hazard ratio per point increase, 0.99; 95% confidence interval, 0.95-1.02). The association between subjective memory complaints and risk of stroke was modified by educational level, with a higher risk of stroke in persons with a higher level of education (hazard ratio, 1.39; 95% confidence interval, 1.07-1.81). CONCLUSIONS: Subjective memory complaints might be an early indicator of stroke risk, especially in highly educated individuals.

The potential for prevention of dementia across two decades: the prospective, population-based Rotterdam Study.

BACKGROUND: Cardiovascular factors and low education are important risk factors of dementia. We provide contemporary estimates of the proportion of dementia cases that could be prevented if modifiable risk factors were eliminated, i.e., population attributable risk (PAR). Furthermore, we studied whether the PAR has changed across the last two decades. METHODS: We included 7,003 participants of the original cohort (starting in 1990) and 2,953 participants of the extended cohort (starting in 2000) of the Rotterdam Study. Both cohorts were followed for dementia until ten years after baseline. We calculated the PAR of overweight, hypertension, diabetes mellitus, cholesterol, smoking, and education. Additionally, we assessed the PAR of stroke, coronary heart disease, heart failure, and atrial fibrillation. We calculated the PAR for each risk factor separately and the combined PAR taking into account the interaction of risk factors. RESULTS: During 57,996 person-years, 624 participants of the original cohort developed dementia, and during 26,177 person-years, 145 participants of the extended cohort developed dementia. The combined PAR in the original cohort was 0.23 (95 % CI, 0.05-0.62). The PAR in the extended cohort was slightly higher at 0.30 (95 % CI, 0.06-0.76). The combined PAR including cardiovascular diseases was 0.25 (95 % CI, 0.07-0.62) in the original cohort and 0.33 (95 % CI, 0.07-0.77) in the extended cohort. CONCLUSIONS: A substantial part of dementia cases could be prevented if modifiable risk factors would be eliminated. Although prevention and treatment options of cardiovascular risk factors and diseases have improved, the preventive potential for dementia has not declined over the last two decades.

The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity.

BACKGROUND: An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. METHODS: Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. RESULTS: The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). CONCLUSIONS: The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

Cerebral vasomotor reactivity and risk of mortality: the Rotterdam Study.

BACKGROUND AND PURPOSE: Accumulating vascular pathology in cerebral arteries leads to impaired cerebral vasomotor reactivity. In turn, impaired cerebral vasomotor reactivity is a risk factor for stroke in clinical populations. It remains unclear whether impaired cerebral vasomotor reactivity also reflects more systemic vascular damage. We investigated whether cerebral vasomotor reactivity is associated with the risk of mortality, focusing particularly on cardiovascular mortality independent from stroke. METHODS: Between 1997 and 1999, 1695 participants from the Rotterdam Study underwent cerebral vasomotor reactivity measurements using transcranial Doppler. Follow-up was complete until January 1, 2011. We assessed the associations between cerebral vasomotor reactivity and mortality using Cox proportional hazards models, adjusting for age, sex, and blood pressure changes and subsequently for cardiovascular risk factors. We additionally censored for incident stroke. RESULTS: During 17 004 person-years, 557 participants died, of whom 181 due to a cardiovascular cause. In the fully adjusted model, the hazard ratio per SD decrease in vasomotor reactivity was 1.10 (95% confidence interval [CI], 1.01-1.19) for all-cause mortality, 1.09 (95% CI, 0.94-1.26) for cardiovascular mortality, and 1.10 (95% CI, 0.99-1.21) for noncardiovascular mortality. These associations remained unchanged after censoring for incident stroke. CONCLUSIONS: We found that lower cerebral vasomotor reactivity is associated with an increased risk of death. Incident stroke does not affect this association, suggesting that a lower cerebral vasomotor reactivity reflects a generally impaired vascular system.

A comparison of MR based segmentation methods for measuring brain atrophy progression.

Automated brain segmentation methods with a good precision and accuracy are required to detect subtle changes in brain volumes over time in clinical applications. However, the ability of established methods such as SIENA, US and kNN to estimate brain volume change have not been compared on the same data, nor been evaluated with ground-truth manual segmentations. We compared measurements of brain volume change between SIENA, US and kNN in terms of precision (repeatability) and accuracy (ground-truth) using one baseline and two repeated follow-up 1.5 T MRI scans after 4 years of 10 subjects. The coefficient of repeatability (brain volume/volume change) was larger for US (29.6 cc/2.84%) than for kNN (4.9 cc/0.31%) and SIENA (-/0.92%). In terms of absolute brain volume measurements US and kNN showed good correlation with the manual segmentations and with each other (all Spearman's correlation coefficients ρ≥0.96; all p<0.001). Concerning brain volume changes, SIENA showed a good (ρ=0.82; p=0.004), kNN a moderate (ρ=0.60; p=0.067) and US a weak (ρ=0.50; p=0.138) correlation with the manual segmentations. For measurements of volume change, SIENA-US (mean correlation coefficient and p-value: ρ=0.28; p=0.442) and US-kNN (ρ=0.17; p=0.641) showed a weak correlation, but correlation was fairly good for kNN-SIENA (ρ=0.65; p=0.048). In conclusion, US and kNN showed a good precision, accuracy and comparability for brain volume measurements. For measurements of volume change, SIENA showed the best performance. kNN is a good alternative if volume change measurements of other brain structures are required.

Global Brain Perfusion and the Risk of Transient Ischemic Attack and Ischemic Stroke: The Rotterdam Study.

Background The role of subtle disturbances of brain perfusion in the risk of transient ischemic attack ( TIA) or ischemic stroke remains unknown. We examined the association between global brain perfusion and risk of TIA and ischemic stroke in the general population. Methods and Results Between 2005 and 2015, 5289 stroke-free participants (mean age, 64.3 years; 55.6% women) from the Rotterdam Study underwent phase-contrast brain magnetic resonance imaging at baseline to assess global brain perfusion. These participants were followed for incident TIA or ischemic stroke until January 1, 2016. We investigated associations between global brain perfusion (mL of blood flow/100 mL of brain/min) and risk of TIA and ischemic stroke using Cox regression models with adjustment for age, sex, and cardiovascular risk factors. Additionally, we investigated whether associations were modified by retinal vessel calibers, small and large vessel disease, blood pressure, and heart rate. During a median follow-up of 7.2 years (36 103 person-years), 137 participants suffered a TIA and another 108 an ischemic stroke. We found that lower global brain perfusion was associated with a higher risk of TIA , but not with the risk of ischemic stroke (adjusted hazard ratio, 95% CI, per standard deviation decrease of global brain perfusion: 1.29, 1.07-1.55 for TIA and adjusted hazard ratio of 1.06, 0.87-1.30 for ischemic stroke). Across strata of wider arteriolar retinal calibers, lower brain perfusion was more prominently associated with TIA , but not with ischemic stroke. Conclusions In a community-dwelling population, impaired global brain perfusion increased the risk of TIA , but not of ischemic stroke.

Development of a Healthy Aging Score in the Population-Based Rotterdam Study: Evaluating Age and Sex Differences.

OBJECTIVES: To develop a healthy aging score (HAS), to assess age and sex differences in HAS, and to evaluate the association of the HAS with survival. DESIGN: Prospective population-based cohort. SETTING: Inhabitants of Ommoord, Rotterdam, The Netherlands. PARTICIPANTS: A total of 1405 men and 2122 women, mean (standard deviation) age 75.9 (6.4) years. MAIN MEASURES: We included 7 domains in the total score of HAS: chronic diseases, mental health, cognitive function, physical function, pain, social support, and quality of life; each scored 0, 1, or 2 in each domain. A total score (range 0-14) was constructed and was assessed continuously and in tertiles (13-14: healthy aging, 11-12: intermediate aging, 0-10: poor aging). Sex-specific change in the mean HAS was computed for the age categories of 65-69, 70-74, 75-79, 80-84, and ≥85 years. The association between HAS and mortality was assessed with Cox proportional hazards models. RESULTS: Mean follow-up was 8.6 (3.4) years. Men had poorer scores in the chronic disease domain than women. However, women had poorer mental health, worse physical function, more pain, and lower quality of life compared with men. The prevalence of healthy aging was higher in men (n = 396, 28.2%), than in women (n = 526, 24.8%). The mean (standard deviation) HAS was 11.1 (2.2) in men and 10.7 (2.3) in women. Mean HAS was higher in men than in women for all age categories. The ß for change in mean HAS across the 5 increasing age categories was -0.55 (-0.65 to -0.45) in men and -0.65 (-0.73 to -0.57) in women. The age-adjusted hazard ratio per unit increase in HAS with mortality was 0.86 (0.83-0.89) in men, and 0.89 (0.87-0.91) in women. CONCLUSIONS: Levels of HAS were lower in women compared with men, in all age categories. The HAS declined with increasing age for both sexes, albeit slightly steeper in women. The HAS was strongly associated with mortality in both sexes. A better understanding of population healthy aging and sex differences in this regard could aid to implement strategies for sustainable healthcare in aging populations.

Mid- to Late-Life Trajectories of Blood Pressure and the Risk of Stroke: The Rotterdam Study.

Hypertension is a major modifiable risk factor for stroke. Associations of blood pressure with incident stroke are mostly based on single or average blood pressure levels. However, this approach does not take into account long-term trajectories of blood pressure, which can vary considerably in the elderly. Within the population-based Rotterdam Study, we examined trajectories of systolic blood pressure in 6745 participants (60.0% women) over an age-range from 55 to 106 years and jointly modeled their risk of stroke and competing causes of death using joint latent class mixed modeling. Four trajectories were identified. Class 1 was characterized by blood pressure increasing gradually from on average 120 to 160 mm Hg over 5 decades (n=4938). Compared with this class, class 2, characterized by a similar midlife blood pressure, but a steep increase (n=822, increasing from 120 to 200 mm Hg), and class 4, characterized by a high midlife blood pressure (n=115; average 160 mm Hg) and had a higher risk of stroke and death. Class 3, characterized by a moderate midlife blood pressure (n=870; average 140 mm Hg), had a similar risk of death as class 1, but the highest risk of stroke. Assessing trajectories of blood pressure provides a more nuanced understanding of the associations between blood pressure, stroke, and mortality. In particular, high blood pressure and rapidly increasing blood pressure patterns are associated with a high risk of stroke and death, whereas moderately high blood pressure is only related to an increased risk of stroke. Future studies should explore the potential pathogenic significance of these patterns.

Genetic loci for serum lipid fractions and intracerebral hemorrhage.

BACKGROUND: Serum total cholesterol and its fractions are inversely associated with intracerebral hemorrhages (ICH) and their potential subclinical precursor, cerebral microbleeds. To ascertain whether there is a genetic basis for this inverse association, we studied established genetic loci for serum total, LDL, and HDL cholesterol, and triglycerides in their association with ICH and microbleeds. METHODS: Data on 161 genetic variants for serum lipids was collected in 9011 stroke-free participants (mean age 65.8, SD 10.2; 57.9% women) of the population-based Rotterdam Study. Participants were followed from baseline (1997-2005) up to 2013 for the occurrence of ICH. A subset of 4179 participants underwent brain MRI for microbleed assessment between 2005 and 2011. We computed genetic risk scores (GRS) for the joint effect of lipid variants. Cox proportional hazards and logistic regression models were used to investigate the association of GRS of lipid fractions with ICH and microbleeds. RESULTS: After a mean follow-up of 8.7 (SD 4.1) years, 67 (0.7%) participants suffered an ICH. Microbleed prevalence was 19.6%. Higher genetic load for high serum total and LDL cholesterol was associated with an increased risk of ICH. Higher genetic load for high serum LDL cholesterol was borderline associated with a higher prevalence of multiple lobar microbleeds. CONCLUSIONS: Genetic susceptibility for high serum total and LDL cholesterol is positively associated with incident ICH and borderline associated with multiple lobar microbleeds. We did not find a genetic basis for the previously reported inverse association between serum lipid levels and ICH.