Visit-to-visit blood pressure variability and the risk of stroke in the Netherlands: A population-based cohort study.

BACKGROUND: Apart from blood pressure level itself, variation in blood pressure has been implicated in the development of stroke in subgroups at high cardiovascular risk. We determined the association between visit-to-visit blood pressure variability and stroke risk in the general population, taking into account the size and direction of variation and several time intervals prior to stroke diagnosis. METHODS AND FINDINGS: From 1990 to 2016, we included 9,958 stroke-free participants of the population-based Rotterdam Study in the Netherlands. This is a prospective cohort study including participants aged 45 years and older. Systolic blood pressure (SBP) variability was calculated as absolute SBP difference divided by mean SBP over 2 sequential visits (median 4.6 years apart). Directional SBP variability was defined as SBP difference over 2 visits divided by mean SBP. Using time-varying Cox proportional hazards models adjusted for age, sex, mean SBP, and cardiovascular risk factors, hazard ratios (HRs) for stroke up to January 2016 were estimated per SD increase and in tertiles of variability. We also conducted analyses with 3-, 6-, and 9-year intervals between variability measurement and stroke assessment. These analyses were repeated for diastolic blood pressure (DBP). The mean age of the study population was 67.4 ± 8.2 years and 5,776 (58.0%) were women. During a median follow-up of 10.1 years, 971 (9.8%) participants had a stroke, including 641 ischemic, 89 hemorrhagic, and 241 unspecified strokes. SBP variability was associated with an increased risk of hemorrhagic stroke (HR per SD 1.27, 95% CI 1.05-1.54, p = 0.02) and unspecified stroke (HR per SD 1.21, 95% CI 1.09-1.34, p < 0.001). The associations were stronger for all stroke subtypes with longer time intervals; the HR for any stroke was 1.29 (95% CI 1.21-1.36, p < 0.001) at 3 years, 1.47 (95% CI 1.35-1.59, p < 0.001) at 6 years, and 1.38 (95%CI 1.24-1.51, p < 0.001) at 9 years. For DBP variability, we found an association with unspecified stroke risk. Both the rise and fall of SBP and the fall of DBP were associated with an increased risk for unspecified stroke. Limitations of the study include that, due to an average interval of 4 years between visits, our findings may not be generalizable to blood pressure variability over shorter periods. CONCLUSIONS: In this population-based study, we found that visit-to-visit blood pressure variation was associated with an increased risk of unspecified and hemorrhagic stroke, independent of direction of variation or mean blood pressure.

Circulatory MicroRNAs as Potential Biomarkers for Stroke Risk: The Rotterdam Study.

BACKGROUND AND PURPOSE: MicroRNAs (miRNAs) are post-transcriptionally regulators of gene expression that can be released extracellularly upon pathophysiological processes. By complementary binding of target transcripts, miRNAs can modulate the expression of an abundance of genes. Increasing evidence recognize miRNAs as promising biomarkers for complex traits, including cardiovascular disease and stroke. We conducted a longitudinal study to determine the association between circulatory miRNAs and incident stroke in a population-based setting. METHODS: Next-generation sequencing was used to measure expression levels of 2083 miRNAs in plasma samples, collected between 2002 and 2005, from 1914 stroke-free participants of the Rotterdam Study. Participants were assessed for incident stroke through continuous monitoring of medical records until January 1, 2016. Cox proportional hazards regression models adjusted for age, sex, and vascular risk factors were used to investigate the association between the levels of 591 miRNAs well-expressed in plasma and incident stroke. Furthermore, stroke subtype analysis was performed to assess the link between identified miRNAs and ischemic, hemorrhagic, and unspecified stroke. Subsequently, post hoc analyses were conducted to gain insight into the association between putative target genes of miRNAs and stroke. RESULTS: Of 1914 participants (mean age 71.5 years ±7.6; 57.7% women), 138 were diagnosed with incident stroke during a mean follow-up of 9.7±3.2 years. After adjusting for potential confounders, we found plasma levels of 3 miRNAs to be associated with incident stroke (false discovery rate-adjusted P<0.05). These include miR-6124 (hazard ratio, 1.66 [95% CI, 1.31-2.09]), miR-5196-5p (hazard ratio, 1.90 [95% CI, 1.39-2.61]), and miR-4292 (hazard ratio, 2.65 [95% CI, 1.62-4.34]). In silico analysis of the putative target genes of these miRNAs showed associations of variants in several target genes with stroke. CONCLUSIONS: This study indicates that plasma levels of 3 miRNAs are associated with the risk of stroke, proposing them as potential biomarkers for early detection of the disease.

Long-term trajectories of decline in cognition and daily functioning before and after stroke.

OBJECTIVE: Although knowledge on poststroke cognitive and functional decline is increasing, little is known about the possible decline of these functions before stroke. We determined the long-term trajectories of cognition and daily functioning before and after stroke. METHODS: Between 1990 and 2016, we repeatedly assessed cognition (Mini-Mental State Examination (MMSE), 15-Word Learning, Letter-Digit Substitution, Stroop, Verbal Fluency, Purdue Pegboard) and basic and instrumental activities of daily living (BADL and IADL) in 14 712 participants within the population-based Rotterdam Study. Incident stroke was assessed through continuous monitoring of medical records until 2018. We matched participants with incident stroke to stroke-free participants (1:3) based on sex and birth year. Trajectories of cognition and daily functioning of patients who had a stroke 10 years before and 10 years after stroke and the corresponding trajectories of stroke-free individuals were constructed using adjusted linear mixed effects models. RESULTS: During a mean follow-up of 12.5±6.8 years, a total of 1662 participants suffered a first-ever stroke. Patients who had a stroke deviated from stroke-free controls up to 10 years before stroke diagnosis in cognition and daily functioning. Significant deviations before stroke were seen in scores of MMSE (6.4 years), Stroop (5.7 years), Purdue Pegboard (3.8 years) and BADL and IADL (2.2 and 3.0 years, respectively). CONCLUSION: Patients who had a stroke have steeper declines in cognition and daily functioning up to 10 years before their first-ever stroke compared with stroke-free individuals. Our findings suggest that accumulating intracerebral pathology already has a clinical impact before stroke.

Orthostatic Hypotension: A Prodromal Marker of Parkinson's Disease?

BACKGROUND: Orthostatic hypotension is common in patients with Parkinson's disease (PD). However, it remains unknown whether orthostatic hypotension is a marker of prodromal PD or more advanced disease. The objectives of this study were to assess whether orthostatic hypotension is a prodromal marker of PD in the general population. METHODS: This study was embedded in the Rotterdam Study, a large prospective population-based cohort in the Netherlands. We measured orthostatic hypotension in 6910 participants. First, we determined the relation between prevalent PD and orthostatic hypotension using logistic regression. Second, we followed PD-free participants for the occurrence of PD until 2016 and studied the association between orthostatic hypotension and the risk of PD using Cox proportional hazards models. All models were adjusted for age and sex. RESULTS: At baseline, the mean age ± standard deviation of the study population was 69.0 ± 8.8 years, and 59.1% were women. Orthostatic hypotension was present in 1245 participants (19.8%), and 62 participants (1.0%) had PD at the time of orthostatic hypotension measurement. Participants with PD were significantly more likely to have orthostatic hypotension (odds ratio, 1.88; 95% confidence interval, 1.09-3.24). During a median (interquartile range) follow-up of 16.1 years (8.5-22.7 years), 122 participants were diagnosed with incident PD. Orthostatic hypotension at baseline was not associated with an increased risk of PD (hazard ratio, 0.97; 95% confidence interval, 0.59-1.58). CONCLUSIONS: Our study suggests that orthostatic hypotension is common in patients with PD, but that orthostatic hypotension is not associated with an increased risk of PD and thus is not a prodromal marker of PD in the general population. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Physical Exercise Interventions Targeting Cognitive Functioning and the Cognitive Domains in Nondementia Samples: A Systematic Review of Meta-Analyses.

OBJECTIVE: We investigated whether physical exercise interventions improve cognitive functioning in nondementia populations. METHODS: We conducted a systematic review of meta-analyses including only randomized controlled trials (RCTs). Two reviewers completed a systematic search of PubMed, Embase, PsychInfo, and Cochrane Controlled Register of Trials. Study characteristics, effect size data, and heterogeneity estimates were extracted and presented in tabular form. Methodological quality was assessed by 2 reviewers using the AMSTAR-2 checklist. The validity of results was considered based on AMSTAR-2 scores and study characteristics. RESULTS: We included 11 meta-analyses: 6 focused on disease-free older adults and 5 on mild cognitive impairment (MCI) excluding dementia. These meta-analyses summarized 97 unique RCTs. Methodological quality ranged from critically low to high. For overall cognitive functioning, which was the outcome of 6 meta-analyses, 1 showed improvement due to exercise interventions in disease-free older adults (g = 0.29, P < .01), while 2 reported nonsignificant effects. In patients with MCI, 3 meta-analyses reported significant benefits of exercise interventions on overall cognitive functioning (g = 0.25-0.57, P < .01). For cognitive domains such as attention and memory, there was limited evidence of beneficial effects of exercise demonstrated in either disease-free or MCI samples. CONCLUSIONS: Exercise may improve overall cognitive functioning in disease-free older adults, but there is too little high-quality evidence to conclude whether this is achieved through improvement in any of the specific cognitive domains assessed. There is clearer evidence that exercise may improve cognitive functioning in MCI, but again there is limited evidence across most cognitive domains.

Time Trends in Survival Following First Hemorrhagic or Ischemic Stroke Between 1991 and 2015 in the Rotterdam Study.

Background and Purpose- The introduction of stroke units and the implementation of evidence-based interventions have been a breakthrough in the management of patients with stroke over the past decade. Survival following stroke is an important indicator in monitoring stroke burden. Recent data on survival by stroke subtype in the general population is scarce. We assessed (1) recent temporal time trends in survival; (2) age-standardized death rates; (3) survival probabilities at 6 months, 1, 2, and 3 years following first hemorrhagic or ischemic stroke. Methods- Within the population-based Rotterdam Study between 1991 and 2015, we assessed time trends in survival among 162 with first-ever hemorrhagic and 988 patients with first-ever ischemic stroke across 3 time periods (1991-1998; 1999-2007; 2008-2015) using time-varying Cox regression model and calculated age-standardized death rates according to the European 2010 census population. Results- In the hemorrhagic stroke group, a total of 144 deaths occurred during 386 person-years. Following a hemorrhagic stroke, we observed similar mortality rates over the years with 30 per 100 person-years in 2015 compared with 25/100 person-years in 1991. Similarly, compared with the earliest study period (1991-1998), mortality rates remained unchanged in the latest study period (2008-2015; hazard ratio, 0.97 [95% CI, 0.61-1.57]; P=0.93). In the ischemic stroke group, a total of 711 deaths occurred during 4897 person-years. We observed a decline in mortality rates in 2015 (11 per 100 person-years) compared with 1991 (29/100 person-years). This translated to favorable trends in the latest study period 2008 to 2015 (hazard ratio, 0.71 [95% CI, 0.56-0.90]; P<0.01). Conclusions- Survival following ischemic stroke has improved over the past decade, while no change was observed in survival following hemorrhagic stroke.

Quantitative Gait Impairments in Patients With Stroke or Transient Ischemic Attack: A Population-Based Approach.

BACKGROUND AND PURPOSE: Gait is a complex process involving various cortical and subcortical brain regions. An acute stroke or transient ischemic attack (TIA) may disrupt white and gray matter integrity and, therefore, affect gait in patients without evident neurological signs. We determined whether patients with stroke and TIA experience subtle changes in global gait and several independent gait domains. METHODS: In the population-based Rotterdam Study, 4456 participants (median age, 65 years; 55% women) underwent detailed quantitative gait assessment (GAITRite) between 2009 and 2016. We summarized 30 gait parameters into a global gait score and 7 mutually independent gait domains. First, we assessed the association between prior stroke or TIA and global and domain-specific gait using linear regression models adjusted for age, sex, vascular risk factors, and cognition. Subsequently, we repeated the analysis stratified by the presence of different neurological symptoms in a subgroup of participants with ischemic stroke after study entry. RESULTS: Compared with participants without prior stroke, patients with stroke had a worse global gait (SD, -0.49 [95% CI, -0.64 to -0.34]), especially in the gait domains Pace, Phases, and Turning. The detrimental effect of stroke on gait was amplified in participants with worse cognition. No gait differences were found between participants with and without prior TIA. Ischemic stroke patients without lower limb weakness, loss of coordination, or visuospatial problems still had a worse gait compared with participants without stroke. Stratification by different stroke symptoms showed that different gait domains were affected in each group. CONCLUSIONS: Prior stroke without neurological signs that affect gait is still associated with gait difficulties compared with individuals without stroke. Our study suggests that stroke not only has a direct impact on gait through neurological impairments but also includes an indirect effect possibly through disruption of gray and white matter integrity and accelerated neurodegeneration.

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.

Vitamin D Status and Risk of Stroke: The Rotterdam Study.

Background and Purpose- Recent findings suggest that vitamin D, a neuroprotective prohormone, is involved in the pathogenesis of cardiovascular disease. However, previous studies investigating the association between vitamin D and stroke have shown inconsistent findings. In view of these discrepancies, we determined the association of vitamin D status with stroke using data from a population-based study. Methods- Within the RS (Rotterdam Study), an ongoing prospective population-based study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2008 in 9680 participants (56.8% women) aged ≥45 years. We assessed a history of stroke at baseline and subsequently followed for incident stroke until January 1, 2016. Regression models were used to investigate the association of serum 25-hydroxyvitamin D with prevalent and incident stroke separately, adjusted for age, sex, study cohort, season of blood sampling, and other cardiovascular risk factors. Results- Of 9680 participants, 339 had a history of stroke at baseline. Serum 25-hydroxyvitamin D concentration was associated with prevalent stroke, adjusted odds ratio per SD decrease, 1.31; 95% CI, 1.14-1.51. After excluding participants with prevalent stroke, we followed 9338 participants for a total of 98 529 person-years. During follow-up, 735 participants developed a stroke. Lower serum 25-hydroxyvitamin D concentration was not associated with a higher stroke risk, adjusted hazard ratio per SD decrease, 1.06; 95% CI, 0.97-1.16. However, severe vitamin D deficiency did show a significant association: hazard ratio, 1.25; 95% CI, 1.05-1.50. Conclusions- In this population-based cohort, we found an association between vitamin D and prevalent stroke. Only severe vitamin D deficiency was associated with incident stroke. This suggests that lower vitamin D levels do not lead to a higher stroke risk but are instead a consequence of stroke.

Lifetime risk and multimorbidity of non-communicable diseases and disease-free life expectancy in the general population: A population-based cohort study.

BACKGROUND: Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk factors on this risk. METHODS AND FINDINGS: Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam Study aged 45 years and older who were free from NCDs at baseline for incident stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease. We quantified occurrence/co-occurrence and remaining lifetime risk of any NCD in a competing risk framework. We additionally studied the lifetime risk of any NCD, age at onset, and overall life expectancy for strata of 3 shared risk factors at baseline: smoking, hypertension, and overweight. During 75,354 person-years of follow-up from a total of 9,061 participants (mean age 63.9 years, 60.1% women), 814 participants were diagnosed with stroke, 1,571 with heart disease, 625 with diabetes, 1,004 with chronic respiratory disease, 1,538 with cancer, and 1,065 with neurodegenerative disease. NCDs tended to co-occur substantially, with 1,563 participants (33.7% of those who developed any NCD) diagnosed with multiple diseases during follow-up. The lifetime risk of any NCD from the age of 45 years onwards was 94.0% (95% CI 92.9%-95.1%) for men and 92.8% (95% CI 91.8%-93.8%) for women. These risks remained high (>90.0%) even for those without the 3 risk factors of smoking, hypertension, and overweight. Absence of smoking, hypertension, and overweight was associated with a 9.0-year delay (95% CI 6.3-11.6) in the age at onset of any NCD. Furthermore, the overall life expectancy for participants without these risk factors was 6.0 years (95% CI 5.2-6.8) longer than for those with all 3 risk factors. Participants aged 45 years and older without the 3 risk factors of smoking, hypertension, and overweight at baseline spent 21.6% of their remaining lifetime with 1 or more NCDs, compared to 31.8% of their remaining life for participants with all of these risk factors at baseline. This difference corresponds to a 2-year compression of morbidity of NCDs. Limitations of this study include potential residual confounding, unmeasured changes in risk factor profiles during follow-up, and potentially limited generalisability to different healthcare settings and populations not of European descent. CONCLUSIONS: Our study suggests that in this western European community, 9 out of 10 individuals aged 45 years and older develop an NCD during their remaining lifetime. Among those individuals who develop an NCD, at least a third are subsequently diagnosed with multiple NCDs. Absence of 3 common shared risk factors is associated with compression of morbidity of NCDs. These findings underscore the importance of avoidance of these common shared risk factors to reduce the premature morbidity and mortality attributable to NCDs.