Showing papers by "Peter J. Koudstaal published in 2016"
TL;DR: In the general population, a high microbleed count was associated with an increased risk for cognitive deterioration and dementia.
Abstract: Importance Cerebral microbleeds are hypothesized downstream markers of brain damage caused by vascular and amyloid pathologic mechanisms. To date, whether their presence is associated with cognitive deterioration in the general population remains unclear. Objective To determine whether microbleeds, and more specifically microbleed count and location, are associated with an increased risk for cognitive impairment and dementia in the general population. Design, Setting, and Participants The Rotterdam Study, a prospective population-based study set in the general community, assessed the presence, number, and location of microbleeds at baseline (August 2005 to December 2011) on magnetic resonance imaging studies of the brain in 4841 participants 45 years or older. Participants underwent neuropsychological testing at 2 points a mean (SD) of 5.9 (0.6) years apart and were followed up for incident dementia throughout the study period until January 1, 2013. The association of microbleeds with cognitive decline and dementia was studied using multiple linear regression, linear mixed-effects modeling, and Cox proportional hazards. Exposures Cerebral microbleed presence, location, and number. Main Outcomes and Measures Cognitive decline measured by a decrease in neuropsychological test battery scores (Mini-Mental State Examination, Letter Digit Substitution Task, Word Fluency Test, Stroop test, 15-word Verbal Learning Test, and Purdue Pegboard Test) and compound scores (eg, G factor, executive function, information processing speed, memory, motor speed) and dementia. Results In total, 3257 participants (1758 women [54.7%]; mean [SD] age, 59.6 [7.8] years) underwent baseline and follow-up cognitive testing. Microbleed prevalence was 15.3% (median [interquartile range] count, 1 [1-88]). The presence of more than 4 microbleeds was associated with cognitive decline. Lobar (with or without cerebellar) microbleeds were associated with a decline in executive functions (mean difference in z score, −0.31; 95% CI, −0.51 to −0.11; P = .003), information processing (mean difference in z score, −0.44; 95% CI, −0.65 to −0.22; P z score, −0.34; 95% CI, −0.64 to −0.03; P = .03), whereas microbleeds in other brain regions were associated with a decline in information processing and motor speed (mean difference in z score, −0.61; 95% CI, −1.05 to −0.17; P = .007). After a mean (SD) follow-up of 4.8 (1.4) years, 72 participants developed dementia, of whom 53 had Alzheimer dementia. The presence of microbleeds was associated with an increased risk for dementia after adjustment for age, sex, and educational level (hazard ratio, 2.02; 95% CI, 1.25-3.24), including Alzheimer dementia (hazard ratio, 2.10; 95% CI, 1.21-3.64). Conclusions and Relevance In the general population, a high microbleed count was associated with an increased risk for cognitive deterioration and dementia. Microbleeds thus mark the presence of diffuse vascular and neurodegenerative brain damage.
259 citations
TL;DR: The authors' APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region, and the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with TMEM106B (P=1·6 × 10−7) is noteworthy, because TMEM 106B variants have previously been associated with risk of frontotemporal dementia.
Abstract: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
241 citations
TL;DR: For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay.
Abstract: IMPORTANCE Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known. OBJECTIVE To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT. DESIGN, SETTING, AND PARTICIPANTS The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015. MAIN OUTCOMES AND MEASURES Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion. RESULTS Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours. CONCLUSION AND RELEVANCE For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion.
210 citations
TL;DR: The higher risk of dementia only in the increasing trajectory suggests depression might be a prodrome of dementia, which could not be captured by a single assessment of depressive symptoms.
177 citations
TL;DR: This study suggests that the filter-based Sentinel CPS use can lead to fewer and overall smaller new brain lesions, as assessed by MRI, and preservation of neurocognitive performance early after TAVI.
Abstract: Aims: Our aim was to determine whether use of the filter-based Sentinel (TM) Cerebral Protection System (CPS) during transcatheter aortic valve implantation (TAVI) can affect the early incidence of new brain lesions, as assessed by diffusion-weighted magnetic resonance imaging (DW-MRI), and neurocognitive performance. Methods and results: From January 2013 to July 2015, 65 patients were randomised 1:1 to transfemoral TAVI with or without the Sentinel CPS. Patients underwent DW-MRI and extensive neurological examination, including neurocognitive testing one day before and five to seven days after TAVI. Follow-up DW-MRI and neurocognitive testing was completed in 57% and 80%, respectively. New brain lesions were found in 78% of patients with follow-up MRI. Patients with the Sentinel CPS had numerically fewer new lesions and a smaller total lesion volume (95 mm(3) [IQR 10-257] vs. 197 mm(3) [95-525]). Overall, 27% of Sentinel CPS patients and 13% of control patients had no new lesions. Ten or more new brain lesions were found only in the control cohort (in 20% vs. 0% in the Sentinel CPS cohort, p=0.03). Neurocognitive deterioration was present in 4% of patients with Sentinel CPS vs. 27% of patients without (p=0.017). The filters captured debris in all patients with Sentinel CPS protection. Conclusions: Filter-based embolic protection captures debris en route to the brain in all patients undergoing TAVI. This study suggests that its use can lead to fewer and overall smaller new brain lesions, as assessed by MRI, and preservation of neurocognitive performance early after TAVI. Clinical Trial Registration: Dutch trial register-ID: NTR4236. URL http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=mistral
153 citations
TL;DR: Empirical and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells, and further expression studies in appropriate human tissues are needed to fully understand the underlying mechanisms.
Abstract: Summary Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p −6 ) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p −8 ), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2 ) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10 −8 ; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a ) are expressed in brain pericytes and mutant foxf2b −/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.
130 citations
TL;DR: A 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.
Abstract: 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...
104 citations
TL;DR: In this article, the authors present an updated prevalence estimate for incidental findings on brain magnetic resonance (MR) images and provide information on clinical relevance, including natural course, over a period of up to 9 years.
Abstract: Purpose To present an updated prevalence estimate for incidental findings on brain magnetic resonance (MR) images and provide information on clinical relevance, including natural course, over a period of up to 9 years. Materials and Methods This study was approved by the institutional review board and all participants gave informed consent. In a prospective population-based setting, structural brain MR imaging was performed in 5800 participants (mean age, 64.9 years; 3194 women [55.1%]). Trained reviewers recorded abnormalities, which were subsequently evaluated by neuroradiologists. The prevalence with 95% confidence interval (CI) of incidental findings was determined, and clinical management of findings that required the attention of a medical specialist was followed. Follow-up imaging in the study context provided information on the natural course of findings that were not referred. Results In 549 of 5800 participants (9.5% [95% CI: 8.7%, 10.3%]), incidental findings were found, of which meningiomas (143 of 5800; 2.5% [95% CI: 2.1%, 2.9%]) and cerebral aneurysms (134 of 5800; 2.3% [95% CI: 2.0%, 2.7%]) were most common. A total of 188 participants were referred to medical specialists for incidental findings (3.2% [95% CI: 2.8%, 3.7%]). Of these, 144 (76.6% [95% CI: 70.1%, 82.1%]) either underwent a wait-and-see policy or were discharged after the initial clinical visit. The majority of meningiomas and virtually all aneurysms not referred or referred but untreated remained stable in size during follow-up. Conclusion Incidental findings at brain MR imaging that necessitate further diagnostic evaluation occur in over 3% of the general middle-aged and elderly population, but are mostly without direct clinical consequences. © RSNA, 2016.
93 citations
TL;DR: In this paper, the authors investigated trajectories of cognition and daily functioning in preclinical dementia, during 18 years of follow-up, and found that various pathologic, environmental, and genetic factors may influence these trajectories.
Abstract: Introduction Although preclinical dementia is characterized by decline in cognition and daily functioning, little is known on their temporal sequence. We investigated trajectories of cognition and daily functioning in preclinical dementia, during 18 years of follow-up. Methods In 856 dementia cases and 1712 controls, we repetitively assessed cognition and daily functioning with memory complaints, mini-mental state examination (MMSE), instrumental activities of daily living (IADL), and basic activities of daily living (BADL). Results Dementia cases first reported memory complaints 16 years before diagnosis, followed by decline in MMSE, IADL, and finally BADL. Vascular dementia related to earlier decline in daily functioning but later in cognition, compared with Alzheimer's disease. Higher education related to larger preclinical cognitive decline, whereas apolipoprotein E ( APOE ) e4 carriers declined less in daily functioning. Discussion These results emphasize the long hierarchical preclinical trajectory of functional decline in dementia. Furthermore, they show that various pathologic, environmental, and genetic factors may influence these trajectories of decline.
90 citations
TL;DR: Thyroid function is not related to vascular brain disease as assessed by MRI, suggesting a role for thyroid hormone in nonvascular pathways leading to dementia, and high and high-normal thyroid function is associated with increased dementia risk.
Abstract: Objective: To study the role of thyroid function in dementia, cognitive function, and subclinical vascular brain disease with MRI. Methods: Analyses were performed within the Rotterdam Study (baseline 1997), a prospective, population-based cohort. We evaluated the association of thyroid-stimulating hormone (TSH) and free thyroxine with incident dementia using Cox models adjusted for age, sex, cardiovascular risk factors, and education. Absolute risks were calculated accounting for death as a competing risk factor. Associations of thyroid function with cognitive test scores and subclinical vascular brain disease (white matter lesions, lacunes, and microbleeds) were assessed with linear or logistic regression. Additionally, we stratified by sex and restricted analyses to normal thyroid function. Results: We included 9,446 participants with a mean age of 65 years. During follow-up (mean 8.0 years), 601 participants had developed dementia. Higher TSH was associated with lower dementia risk in both the full and normal ranges of thyroid function (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.83–0.98; and HR 0.76, 95% CI 0.64–0.91, respectively). This association was independent of cardiovascular risk factors. Dementia risk was higher in individuals with higher free thyroxine (HR 1.04, 95% CI 1.01–1.07). Absolute 10-year dementia risk decreased from 15% to 10% with higher TSH in older women. Higher TSH was associated with better global cognitive scores ( p = 0.021). Thyroid function was not related to subclinical vascular brain disease as indicated by MRI. Conclusions: High and high-normal thyroid function is associated with increased dementia risk. Thyroid function is not related to vascular brain disease as assessed by MRI, suggesting a role for thyroid hormone in nonvascular pathways leading to dementia.
70 citations
01 Jan 2016
TL;DR: In the general male population the future occurrence of stroke may be predicted using easy obtainable information from medical history and physical examination, and measurement of pulse rate, body mass index, blood lipids, fibrinogen level and ECG characteristics do not contribute to the risk stratification of stroke and have no value in the screening for stroke in the generalmale population.
TL;DR: The incidence of parkinsonism in general and of PD in particular, decreased between 1990 and 2011, and competitive event rates were lower in the 2000 subcohort, and mortality rates among persons with parkinsonist remained stable.
Abstract: We investigated trends in the incidence of parkinsonism and Parkinson disease (PD) by comparing data from the first 2 subcohorts of the Rotterdam Study, a prospective, population-based cohort study (first subcohort: baseline 1990 with 10 years of follow-up; second subcohort, baseline 2000 with 10 years of follow-up). From the baseline years, we observed differences in the second subcohort that were associated with a lower risk of PD for some but not all baseline risk factors. Participants in both subcohorts were followed for a maximum of 10 years and monitored for the onset of parkinsonism, the onset of dementia, or death, until January 1, 2011. We used Poisson regression models to compare the incidences of parkinsonism, both overall and by cause (PD and secondary causes), and competitive events (incident dementia and death) as well as the mortality of parkinsonism patients in the 2 subcohorts. In the 1990 subcohort, there were 182 cases of parkinsonism (84 of which were PD) during 57,052 person-years. In the 2000 subcohort, we observed 28 cases of parkinsonism (10 with PD) during 22,307 person-years. The overall age- and sex-adjusted incidence of parkinsonism was lower in the 2000 subcohort (incidence rate ratio = 0.55, 95% confidence interval: 0.36, 0.81), and PD incidence declined sharply (incidence rate ratio = 0.39, 95% confidence interval: 0.19, 0.72). Competitive event rates were lower in the 2000 subcohort, and mortality rates among persons with parkinsonism remained stable. These findings suggest that the incidence of parkinsonism in general, and of PD in particular, decreased between 1990 and 2011.
TL;DR: NT-proBNP reflecting subclinical CVD is associated with dementia, particularly vascular dementia, and can be a useful marker of imminent cognitive-decline and dementia in absence of clinical CVD.
Abstract: Background The N-terminal pro B-type natriuretic peptide (NT-proBNP) has a well-documented prognostic value for cardiovascular disease (CVD) and higher levels are associated with cognitive-dysfunction in patients with CVD. However, how NT-proBNP relates to incident dementia and cognitive-decline in community-dwelling persons is unknown. Methods Between 1997 and 2001, serum NT-proBNP was measured in 6040 participants (mean age 69 years, 57% women) free of heart-failure and dementia from the Rotterdam Study. Participants were continuously followed-up for incident dementia until 2012, for 56 616 person-years. Cognition was assessed at baseline and reassessed between 2002 and 2006 by Letter-Digit-Substitution-task, Stroop test and Word-Fluency test. Associations of NT-proBNP with dementia (555 cases), Alzheimer9s disease (357 cases) and vascular dementia (32 cases) were assessed linearly, and in quartiles using Cox regression. Associations of NT-proBNP with cognitive-decline were assessed using multiple linear regression. All analyses were repeated after excluding patients with CVD. Results Higher NT-proBNP was associated with a higher risk of dementia, even after excluding patients with CVD and adjusting for cardiovascular risk factors, HR per SD 1.27 (95% CI 1.13 to 1.44). Associations were particularly strong for vascular dementia, HR per SD 2.04 (95% CI 1.18 to 3.55), but also for Alzheimer9s disease when comparing the second and third quartile with first. Higher NT-proBNP was cross-sectionally associated with poorer performance in multiple cognitive tests but longitudinally only in Letter-Digit-Substitution-task. Conclusions NT-proBNP reflecting subclinical CVD is associated with dementia, particularly vascular dementia. NT-proBNP can be a useful marker of imminent cognitive-decline and dementia in absence of clinical CVD.
TL;DR: Increased glucose on admission and impaired fasting glucose in the first week after stroke onset are associated with unfavorable short-term outcome after IAT of acute ischemic stroke.
TL;DR: In this paper, the longitudinal relation between cerebral vasoreactivity (CVR) and the risk of dementia in the general population was determined in nondemented participants who underwent transcranial Doppler with induced hypercapnia from 1997 to 1999, as part of the ongoing population-based Rotterdam Study.
Abstract: Objective—Cerebral vasoreactivity (CVR) is a key factor in maintenance of continuous cerebral perfusion and a marker of (micro)vascular damage. We aimed to determine the longitudinal relation between CVR and the risk of dementia in the general population. Approach and Results—We determined CVR in nondemented participants who underwent transcranial Doppler with induced hypercapnia from 1997 to 1999, as part of the ongoing population-based Rotterdam Study. We used a Cox model to determine the risk of dementia in relation to CVR, adjusted for age, sex, cardiovascular risk factors, and carotid intima-media thickness. We furthermore determined decline on a cognitive test battery in relation to CVR, using linear mixed models. Among 1629 participants (mean±SD age 70.6±6.2 years, 46.2% female) with a mean follow-up of 11.5 years, 209 were diagnosed with dementia, of whom 171 had Alzheimer disease. Higher CVR at baseline was associated with lower risk of dementia (adjusted hazard ratio, 95% confidence interval, pe...
TL;DR: Serum apoE is associated with long-term risk of Alzheimer's disease in the general population, independent of APOE genotype.
TL;DR: There was no evidence for a differential effect of thrombectomy for acute ischemic stroke by type of stent, and possible interactions between stent type and treatment with multiple regression models.
Abstract: Background and Purpose— Intra-arterial treatment by means of retrievable stents has been proven safe and effective. In MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the choice of the type of thrombectomy device was left to the discretion of the interventionist. The aim of this study was to explore the differences in functional outcome, neurological recovery, reperfusion, extent of infarction, and adverse events according to stent type and make.
Methods— The primary outcome was functional outcome at 90 days, assessed with the modified Rankin Scale (mRS). Neuroimaging outcomes included occlusion on computed tomographic angiography at 24 hours, infarct volume at 5 to 7 days, and modified thrombolysis in cerebral infarction scores. Safety outcomes included death within 90 days and any symptomatic intracerebral hemorrhage. We analyzed possible interactions between stent type and treatment with multiple regression models. Treatment effects were adjusted for patient age, stroke severity, and collateral score.
Results— Of the 500 patients included in the trial, 233 were allocated to intervention. Of these, 124 (53%) were first treated with Trevo (adjusted common odds ratio for shift on the mRS [acOR, 1.98; 95% confidence interval, 1.30–2.92]), 31 (13%) with Solitaire (acOR, 1.90; 95% confidence interval, 0.97–3.73), 40 (17%) with other retrievable stents or mechanical devices (acOR, 0.96; 95% confidence interval, 0.51–3.93], and 38 (16%) could not be treated. There was no interaction between device and treatment effect on functional outcome and all other secondary and safety outcomes.
Conclusions— We found no evidence for a differential effect of thrombectomy for acute ischemic stroke by type of stent.
Clinical Trial Registration— URL: . Unique identifier: [ISRCTN10888758][1].
[1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN10888758
TL;DR: 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.
Abstract: 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.
TL;DR: Although rare, arterial dissections, CADASIL, arteriovenous malformations, venous sinus thrombosis, moyamoya disease, and vasculitis can lead to serious symptoms.
Abstract: With 16.9 million people who suffered a first-ever stroke in 2010 worldwide, stroke is a very common vascular disease. Epidemiologic studies have played an essential role in assessing this burden and in detecting the risk factors for stroke. Primary prevention of these risk factors, primarily hypertension, smoking, diabetes, and atrial fibrillation, has reduced the incidence in high-income countries. However, stroke remains a major cause of death and disability, and therefore research should be continued.
Subarachnoid hemorrhages are less prevalent than strokes but have an even higher risk of death. Similar to stroke, epidemiologic studies identified smoking and hypertension as its most important risk factors, together with excessive alcohol intake.
Although rare, arterial dissections, CADASIL, arteriovenous malformations, venous sinus thrombosis, moyamoya disease, and vasculitis can lead to serious symptoms. The burden and risk factors of those rare diseases are more challenging to assess. Whenever possible, they should be recognized in a timely manner for their increased risk of stroke, but most often they are diagnosed only at the time of stroke.
Some cerebrovascular abnormalities do not result in immediate symptoms. This subclinical cerebrovascular disease includes silent infarcts, white-matter lesions, and microbleeds, and is incidentally found by neuroimaging. These lesions are not innocent, as several epidemiologic studies have associated subclinical cerebrovascular disease with an increased risk of stroke, cognitive decline, dementia, and death.
TL;DR: Self-efficacy, fear, and response- efficacy were determinants of intention to change health-related behavior after TIA or ischemic stroke and should be taken into account in the development of future interventions promoting health- related behavior change in these group of patients.
TL;DR: Careful recording the features of the attack in patients with TMB can provide important information about the risk of future vascular events, and characteristics of TMB that predicted a low risk of vascular complications were not identified.
Abstract: Patients with transient monocular blindness (TMB) can present with many different symptoms, and diagnosis is usually based on the history alone. In this study, we assessed the risk of vascular complications according to different characteristics of TMB. We prospectively studied 341 consecutive patients with TMB. All patients were interviewed by a single investigator with a standardized questionnaire; reported symptoms were classified into predefined categories. We performed Cox regression analyses with adjustment for baseline vascular risk factors. During a mean follow-up of 4.0 years, the primary outcome event of vascular death, stroke, myocardial infarction, or retinal infarction occurred in 60 patients (annual incidence 4.4 %, 95 % confidence interval (CI) 3.4–5.7). An ipsilateral ischemic stroke occurred in 14 patients; an ipsilateral retinal infarct in six. Characteristics of TMB independently associated with subsequent vascular events were: involvement of only the peripheral part of the visual field (hazard ratio (HR) 6.5, 95 % CI 3.0–14.1), constricting onset of loss of vision (HR 3.5, 95 % CI 1.0–12.1), downward onset of loss of vision (HR 1.9, 95 % CI 1.0–3.5), upward resolution of loss of vision (HR 2.0, 95 % CI 1.0–4.0), and the occurrence of more than three attacks (HR 1.7, 95 % CI 1.0–2.9). We could not identify characteristics of TMB that predicted a low risk of vascular complications. In conclusion, careful recording the features of the attack in patients with TMB can provide important information about the risk of future vascular events.
TL;DR: Future stroke is predicted not only by prevalent vascular lesions but also by subtle alterations in the microstructure of normal-appearing white matter, which produces a significant advantage in stroke prediction compared with the existing Framingham Stroke Risk Profile.
Abstract: 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.
Journal Article•
TL;DR: Cerebral hypoperfusion is associated with an increased risk of cognitive decline and dementia in the general population and the findings suggest preservation and restoration of cerebral perfusion may limit cognitive decline.
Abstract: Objective: To determine the association between cerebral perfusion and risk of dementia in the general population.
Background: Cerebral hypoperfusion has been associated with brain atrophy and cognition in various cross-sectional studies, and could be a promising target for prevention of dementia. Yet, it remains uncertain whether hypoperfusion precedes cognitive decline or is merely a consequence of reduced metabolic demand due to atrophy.
Methods: As part of the ongoing population-based Rotterdam study, we measured cerebral blood flow by 2D phase-contrast MRI in non-demented participants. Perfusion was calculated as flow in mL/100gram/minute. We used a Cox hazard model to determine the risk of dementia in relation to perfusion, adjusting for total intracranial volume, age, sex, cardiovascular risk factors and APOE genotype. We repeated the analyses for Alzheimer’s disease only, and after excluding those with stroke or >50[percnt] carotid artery stenosis. Finally, we determined deterioration in scores on a cognitive assessment battery during two consecutive examination rounds, in relation to perfusion.
Results: Out of 4744 participants (mean±SD age 63.6±10.8 years, 55.2[percnt] women) with a mean follow-up of 4.9 years, 82 participants developed dementia, of whom 59 (72.0[percnt]) had Alzheimer’s disease. Those with higher cerebral perfusion had lower risk of developing dementia (adjusted HR,95[percnt]CI, per SD increase 0.69,0.53-0.90;p=0.006), and Alzheimer’s disease only (aHR 0.65,0.48-0.89;p=0.008). This was similar after excluding those with stroke or >50[percnt] carotid artery stenosis, and similar after excluding dementia cases occurring within 3 years of follow-up. Amongst 3224 alive and non-demented participants whose follow-up extended beyond the next examination round (after on average 5.9 years), higher cerebral perfusion at baseline was associated with less decline in global cognition (p=0.02).
Conclusion: Cerebral hypoperfusion is associated with an increased risk of cognitive decline and dementia in the general population. These findings suggest preservation and restoration of cerebral perfusion may limit cognitive decline. Disclosure: Dr. Wolters has nothing to disclose. Dr. Zonneveld has nothing to disclose. Dr. Koudstaal has nothing to disclose. Dr. Hofman has nothing to disclose. Dr. Vernooij has nothing to disclose. Dr. Ikram has nothing to disclose.
TL;DR: The clinical usefulness of a recently proposed non-motor risk score for PD (the PREDICT-PD risk score) in the population-based Rotterdam Study is investigated and it is found that it only slightly improves long-term prediction of PD in the community.
Abstract: At present, there are no validated methods to identify persons who are at increased risk for Parkinson Disease (PD) from the general population. We investigated the clinical usefulness of a recently proposed non-motor risk score for PD (the PREDICT-PD risk score) in the population-based Rotterdam Study. At baseline (1990), we constructed a weighted risk score based on 10 early nonmotor features and risk factors in 6492 persons free of parkinsonism and dementia. We followed these persons for up to 20 years (median 16.1 years) for the onset of PD until 2011. We studied the association between the PREDICT-PD risk score and incident PD using competing risk regression models with adjustment for age and sex. In addition, we assessed whether the PREDICT-PD risk score improved discrimination (C-statistics) and risk classification (net reclassification improvement) of incident PD beyond age and sex. During follow-up, 110 persons were diagnosed with incident PD. The PREDICT-PD risk score was associated with incident PD (hazard ratio [HR] = 1.30; 95 % confidence interval [1.06; 1.59]) and yielded a small, non-significant improvement in overall discrimination (ΔC-statistic = 0.018[−0.005; 0.041]) and risk classification (net reclassification improvement = 0.172[−0.017; 0.360]) of incident PD. In conclusion, the PREDICT-PD risk score only slightly improves long-term prediction of PD in the community.
TL;DR: One quarter of deaths after stroke could theoretically be prevented with rigorous cardiovascular prevention and treatment, but this should preferably start before stroke occurrence.
Abstract: 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, diabete...
TL;DR: Genetic variants for PD are associated with the risk of incident PD in the general population and with impairment in daily functioning in individuals without clinical parkinsonism, but do not improve the clinical prediction of PD.
TL;DR: Genetic susceptibility for high serum total and LDL cholesterol is positively associated with incident ICH and borderline associated with multiple lobar microbleeds, and the previously reported inverse association between serum lipid levels and ICH was not found.
TL;DR: Anxiety disorders were not associated with stroke in the authors' general population study, and anxiety symptoms were only related to stroke in the short term, which needs further exploration.
Abstract: 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.
TL;DR: Nonfocal symptoms are present in one out of 5 patients with TIA or ischemic stroke, in particular when located in the posterior circulation, which is a heterogeneous etiology.
Abstract: Background: Transient ischemic attacks (TIAs) accompanied by nonfocal symptoms are associated with a higher risk of cardiovascular events, in particular cardiac events. Reported frequencies of TIAs accompanied by nonfocal symptoms range from 18 to 53%. We assessed the occurrence of nonfocal symptoms in patients with TIA or minor ischemic stroke in a neurological outpatient clinic in terms of clinical determinants, cardiac history, and atrial fibrillation (AF). Methods: We included 1,265 consecutive patients with TIA or minor stroke who visited the outpatient clinic. During these visits, we systematically asked for nonfocal symptoms. Nonfocal symptoms included decreased consciousness, amnesia, positive visual phenomena, non-rotatory dizziness, and paresthesias. Relative risks for the presence of nonfocal symptoms in relation to clinical determinants, AF, and cardiac history were calculated. Results: In 243 (19%) of 1,265 patients, TIA or minor ischemic stroke was accompanied by one or more nonfocal symptoms. Non-rotatory dizziness, paresthesia, and amnesia were the most common nonfocal symptoms. In patients with an event of the posterior circulation or obesity, the qualifying TIA or minor stroke was more frequently accompanied by nonfocal symptoms, and in patients with significant carotid stenosis, nonfocal symptoms occurred less frequently. AF was related only with amnesia. Conclusion: Nonfocal symptoms are present in one out of 5 patients with TIA or ischemic stroke, in particular when located in the posterior circulation. A cardiac history or AF was not directly related to nonfocal symptoms. A heterogeneous etiology is suggested.
TL;DR: It is unlikely that the decline in smoking prevalence drove a change in the incidence of parkinsonism in the Rotterdam Study, and the discrepant findings of the study by Savica et al compared with previous studies highlight the lack of insight on causality of risk factors for Parkinsonism and PD.
Abstract: __To the Editor__ We read with interest the article by Savica et al, who described an increase in the incidence rate of parkinsonism in the Rochester Epidemiology Project between 1976 and 2005. This finding contradicts our recently reported observation that the incidence rate of parkinsonism was lower in a subcohort of the Rotterdam Study that was followed up between 2000 and 2011 compared with a subcohort that was followed up between 1990 and 2000.2 Similarly, a UK primary care study previously reported a significant decline in Parkinson disease (PD) incidence rates between 1999 and 2009.
Savica et al1 hypothesized that the changes observed in the Rochester Epidemiology Project could be attributed to a decrease in the prevalence of smoking in the second half of the 20th century, but they were unable to test this hypothesis in their cohort. Within the Rotterdam Study, we assessed smoking habits at baseline of both subcohorts (1990 and 2000). As expected, we observed that the ageand sex-adjusted prevalence of current smoking was lower across all ages (55-106 years) in the subcohort that started in 2000.
During follow-up, incident parkinsonism was diagnosed in 182 of 6752 persons in the subcohort that started in 1990, and in 28 of 2440 persons in the subcohort that started in 2000. The age- and sex-adjusted incidence rate (IR) of parkinsonism for smokers was similar in both subcohorts (IR, 0.63; 95% CI,0.43-0.91 in the 1990 subcohort; IR, 0.61; 95% CI, 0.27-1.44 in the 2000 subcohort). The age- and sex-adjusted incidence rate ratio (IRR) for parkinsonism of persons in the 2000 subcohort vs the 1990 subcohort was 0.55 (95% CI, 0.36-0.81). After additional adjustment for smoking status, the IRR remained virtually unchanged (IRR, 0.57; 95% CI, 0.37-0.84). Unfortunately, the small number of PD cases in the 2000 subcohort prevented PD-specific analyses on the effect of smoking. We conclude that it is unlikely that the decline in smoking prevalence drove a change in the incidence of parkinsonism in the Rotterdam Study.
The discrepant findings of the study by Savica et al compared with previous studies, including the Rotterdam Study, highlight the lack of insight on causality of risk factors for parkinsonism and PD. For smoking in particular, causality of its inverse association with the risk for parkinsonism and PD remains highly contentious, and the inference that the increase in parkinsonism incidence in the Rochester Epidemiology Project can be attributed to a decline in smoking may shift focus from other putative etiological factors. To better understand factors that drive differential trends in the incidence of parkinsonism across populations, there is an urgent need for cross-cohort collaboration, similar to recently initiated efforts for dementia.