Peter J. Koudstaal

High von Willebrand Factor Levels Increase the Risk of Stroke The Rotterdam Study

Background and Purpose— Many studies have investigated the role of plasma von Willebrand factor level in coronary heart disease, but few have investigated its role in stroke. The aim of this study was to determine if von Willebrand factor levels are associated with the risk of stroke. Methods— The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged ≥55 years. We included 6 250 participants who were free from stroke at baseline (1997 to 2001) and for whom blood samples were available. Follow-up for incident stroke was complete up to January 1, 2005. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally with models adjusted for other potential confounders including ABO blood group. A subgroup analysis was performed in participants without atrial fibrillation. Effect modification by sex was tested on a multiplicative and on an additive scale. Results— During an average follow-up time of 5.0 years, 290 first-ever strokes occurred, of which 197 were classified as ischemic. The risk of stroke increased with increasing von Willebrand factor levels (age- and sex-adjusted hazard ratios per SD increase in von Willebrand factor level: 1.12 [95% CI, 1.01 to 1.25] for stroke, 1.13 [95% CI, 0.99 to 1.29] for ischemic stroke). Adjustments for additional confounders slightly attenuated the association. The association was also present in subjects without atrial fibrillation and did not differ between sexes. Conclusion— High von Willebrand factor levels are associated with stroke risk in the general population.

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

BackgroundCardiovascular 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.MethodsWe 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.ResultsDuring 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.ConclusionsA 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.

Platelet-mediated erythromelalgic, cerebral, ocular and coronary microvascular ischemic and thrombotic manifestations in patients with essential thrombocythemia and polycythemia vera: A distinct aspirin-responsive and coumadin-resistant arterial thrombophilia

Microvascular circulation disturbances including erythromelalgia, its microvascular ischemic complications, and migraine-like atypical or typical transient ischemic cerebral, ocular, and coronary ischemic attacks are specific clinical manifestations in patients with essential thrombocythemia (ET), and polycythemia vera (PV) associated with thrombocythemia. Thrombocythemia (ET and PV) patients with microvascular disturbances have shortened platelet survival, increased β-thromboglobulin (β-tg), platelet factor 4 (PF4), and thrombomoduline (TM) levels, and increased urinary thromboxane B2 (TxB2) excretion indicating platelet-mediated processes in vivo. Inhibition of platelet cyclooxygenase (COX 1) by aspirin is followed by relief of microvascular disturbances, correction of shortened platelet survival, and return of plasma levels of β-tg, PF4, TM levels and TxB2 excretion to normal. The transient ischemic attacks and thrombotic complications in thrombocythemia are very likely caused by hypersensitive platelets produced by spontaneously proliferating enlarged megakaryocytes in the bone marrow of ET and PV patients. In contrast to normal platelets in healthy individuals the circulating hypersensitive thrombocythemic platelets spontaneously activate and secrete their products, thus forming aggregates that transiently plug the microcirculation, or result in occlusive platelet thrombi in arterioles or small arteries. Clear evidence is presented that the microvascular transient ischemic and occlusive thrombotic complications in thrombocythemia patients are relieved by treatment with aspirin and by reduction of platelet counts to normal (<400 × 109/l), but not by coumadin. In patients with thrombocythemia associated with PV, increased hematocrit and whole blood viscosity aggravate the platelet-mediated microvascular ischemic and thrombotic syndrome of thrombocythemia to major arterial and venous thrombotic complications. Correction of hematocrit and blood viscosity by phlebotomy significantly reduces the major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated microvascular circulation disturbances in PV patients because thrombocythemia persists. Complete relief and prevention of microvascular and major thrombosis in PV patients are obtained by treatment with low-dose aspirin on top of phlebotomy or by treatment with the platelet lowering agents, anagrelide, interferon or hydroxyurea.

Serum Lipid Levels and the Risk of Intracerebral Hemorrhage: The Rotterdam Study

Objective—Low serum total cholesterol levels are associated with an increased risk of symptomatic intracerebral hemorrhage and with presence of asymptomatic cerebral microbleeds. The relative contribution of lipid fractions to these associations is unclear and requires investigation. We determined whether serum HDL-cholesterol, LDL-cholesterol, and triglycerides are associated with risk of intracerebral hemorrhage and presence of cerebral microbleeds. Methods and Results—Nine thousand sixty-eight stroke-free community-dwelling persons aged ≥55 were followed from baseline (1990–2001) up to January 1, 2009, of whom 85 suffered from intracerebral hemorrhage during follow-up. Brain MRI was carried out in 789 healthy participants, of whom 162 had cerebral microbleeds. Triglycerides were strongly and inversely associated with intracerebral hemorrhage, independently of HDL-cholesterol, LDL-cholesterol, and potential confounders [hazard ratio for highest versus lowest quartile: 0.20 (0.06–0.69)]. Triglycerides were also associated with deep or infratentorial microbleeds [odds ratio for highest versus lowest quartile: 0.37 (0.14–0.96)], but not with strictly lobar microbleeds. No associations were found for HDL-cholesterol or LDL-cholesterol. Conclusion—Low serum triglyceride levels were associated with an increased risk of intracerebral hemorrhage and with the presence of deep or infratentorial cerebral microbleeds. This provides novel insights into the role of lipid fractions, particularly triglycerides, in the etiology of intracerebral hemorrhage.

Retinal Vascular Calibers and the Risk of Intracerebral Hemorrhage and Cerebral Infarction The Rotterdam Study

Background and Purpose— Narrower retinal arteriolar calibers and wider venular calibers are associated with cardiovascular disease, including cerebral infarction. We investigated the association between retinal vascular calibers and the long-term risk for stroke and its subtypes with particular focus on intracerebral hemorrhage. Methods— We included 5518 participants (aged ≥55 years) from the prospective population-based Rotterdam Study who were stroke-free at baseline (1990–1993) and of whom digital retinal images were available. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally for potential confounders. Arteriolar and venular calibers were entered both separately and simultaneously in the models. Results— During an average follow-up of 11.5 years, 623 participants developed a first-ever stroke (50 hemorrhagic, 361 ischemic, 212 unspecified). Larger venular caliber was independently associated with an increased risk for stroke (hazard ratio [HR] per SD increase: 1.20; 95% confidence interval [CI]: 1.09 to 1.33), cerebral infarction (HR: 1.28; 95% CI: 1.13 to 1.46), and intracerebral hemorrhage (HR: 1.53; 95% CI: 1.09 to 2.15). Much weaker, only borderline significant associations were found between arteriolar caliber and risk for stroke (HR per SD decrease: 1.12; 95% CI: 0.99 to 1.23), cerebral infarction (HR: 1.12; 95% CI, 0.98 to 1.27), and intracerebral hemorrhage (HR: 1.25; 95% CI: 0.87 to 1.79). Retinal vascular calibers were strongly associated with lobar hemorrhages and oral anticoagulant-related hemorrhages. Conclusion— Larger retinal venular caliber is associated with an increased risk for stroke in the general population and, in particular, with an increased risk for intracerebral hemorrhage.

Determinants, MRI Correlates, and Prognosis of Mild Cognitive Impairment: The Rotterdam Study

Mild cognitive impairment (MCI) marks a transitional stage between healthy aging and dementia, but the understanding of MCI in the general population remains limited. We investigated determinants, MRI-correlates, and prognosis of MCI within the population-based Rotterdam Study. Firstly, we studied age, APOE-ε4 carriership, waist circumference, hypertension, diabetes mellitus, total and HDL-cholesterol levels, smoking, and stroke as potential determinants of MCI. Determinants were assessed cross-sectionally at baseline (2002-2005) and up to 7 years prior to baseline (1997-2001). Secondly, we compared volumetric, microstructural, and focal MRI-correlates in persons with and without MCI. Thirdly, we followed participants for incident dementia and mortality until 2012. Out of 4,198 participants, 417 had MCI, of whom 163 amnestic and 254 non-amnestic MCI. At baseline, older age, APOE-ε4 carriership, lower total cholesterol levels, and stroke were associated with MCI. Additionally, lower HDL-cholesterol levels and smoking were related to MCI when assessed 7 years prior to baseline. Persons with MCI, particularly those with non-amnestic MCI, had larger white matter lesion volumes, worse microstructural integrity of normal-appearing white matter, and a higher prevalence of lacunes, compared to cognitively healthy participants. MCI was associated with an increased risk of dementia (hazard ratio (HR) 3.98, 95% confidence interval (CI) 2.97;5.33), Alzheimers disease (HR 4.03, 95% CI 2.92;5.56), and mortality (HR 1.54, 95% CI 1.28;1.85). In conclusion, we found that several vascular risk factors and MRI-correlates of cerebrovascular disease were related to MCI in the general population. Participants with MCI had an increased risk of dementia, including Alzheimers disease, and mortality.

Genetic determinants of von Willebrand factor plasma levels and the risk of stroke: the Rotterdam Study

Summary.  Background:  High von Willebrand factor (VWF) plasma levels are associated with an increased risk of stroke. VWF levels are strongly heritable. A previous meta‐analysis of five large genome‐wide association studies identified single‐nucleotide polymorphisms (SNPs) within eight genetic loci as determinants of VWF levels. Whether these SNPs are associated with stroke risk is not known. The aim of our study was to investigate the association between genetic determinants of VWF levels and stroke risk.

Plasma β amyloid and impaired CO2-induced cerebral vasomotor reactivity

Abstract Amyloid β (Aβ) may disturb cerebral autoregulation by damaging the wall of small cerebral blood vessels and by direct negative vasoactive properties. We assessed whether previous and concurrent plasma Aβ 1–40 and Aβ 1–42 levels were associated with an impaired CO 2 -induced cerebral vasomotor response. In the longitudinal population-based Rotterdam Study we measured plasma Aβ levels and cerebral vasomotor reactivity to hypercapnia with transcranial Doppler ultrasonography (TCD) in 441 people, aged 60–90 years. We performed age and sex adjusted logistic regression analysis. Plasma Aβ levels assessed on average 6.5-year before TCD were linearly associated with an impaired CO 2 -induced cerebral vasomotor response (odds ratio 1.48 (95%CI 1.19;1.84) per standard deviation increase in Aβ 1–40 , and 1.36 (95%CI 1.09;1.70) per standard deviation increase in Aβ 1–42 ). Such an association was not present for Aβ assessed concurrently with the TCD measurement. Persons whose plasma Aβ 1–40 levels had decreased in the 6.5-year period preceding TCD measurements were more likely to have an impaired CO 2 -induced vasomotor reactivity. Overall our observations are most compatible with plasma Aβ levels representing vascular Aβ deposits years later resulting in impaired CO 2 -induced vasomotor reactivity.

Efficacy of early cognitive-linguistic treatment for aphasia due to stroke: A randomised controlled trial (Rotterdam Aphasia Therapy Study-3)

Introduction One third of patients with acute stroke have aphasia. The majority receive speech and language therapy. There is evidence for a beneficial effect of speech and language therapy on restoring communication, but it is unknown whether and how efficacy of speech and language therapy is influenced by timing of treatment. We studied whether speech and language therapy early after stroke by way of intensive cognitive-linguistic treatment is more effective than no speech and language therapy in the Rotterdam Aphasia Therapy Study-3, a multicentre randomised single-blind trial. Methods and patients Stroke patients with first-ever aphasia were randomised within 2 weeks of onset to either 4 weeks of early intensive cognitive-linguistic treatment (1 h/day) or no language treatment. Hereafter, both groups received regular speech and language therapy. Primary outcome was the score on the Amsterdam-Nijmegen Everyday Language Test, measuring everyday verbal communication, 4 weeks after randomisation. Secondary outcomes were Amsterdam-Nijmegen Everyday Language Test at 3 and 6 months. The study was powered to detect a clinically relevant difference of four points on the Amsterdam-Nijmegen Everyday Language Test. Results Of the 152 included patients, 80 patients were allocated to intervention. Median treatment intensity in the intervention-group was 24.5 h. The adjusted difference between groups in mean Amsterdam-Nijmegen Everyday Language Test-scores 4 weeks after randomisation was 0.39, 95% confidence interval: [−2.70 to 3.47], p = 0.805. No statistically significant differences were found at 3 and 6 months after randomisation either. Conclusion Four weeks of intensive cognitive-linguistic treatment initiated within 2 weeks of stroke is not more effective than no language treatment for the recovery of post-stroke aphasia. Our results exclude a clinically relevant effect of very early cognitive-linguistic treatment on everyday language.

Late neurological recovery of paraplegia after endovascular repair of an infected thoracic aortic aneurysm.

Spinal cord ischemia is a potentially devastating complication after thoracic endovascular aorta repair (TEVAR). Patients with spinal cord ischemia after TEVAR often develop paraplegia, which is considered irreversible, and have significant increased postoperative morbidity and mortality. We report the case of a patient with unusual late complete neurologic recovery of acute-onset paraplegia after TEVAR for an infected thoracic aortic aneurysm.