Validation of a prediction model for long-term outcome of aphasia after stroke.

BACKGROUND: About 30% of stroke patients suffer from aphasia. As aphasia strongly affects daily life, most patients request a prediction of outcome of their language function. Prognostic models provide predictions of outcome, but external validation is essential before models can be used in clinical practice. We aim to externally validate the prognostic model from the Sequential Prognostic Evaluation of Aphasia after stroKe (SPEAK-model) for predicting the long-term outcome of aphasia caused by stroke. METHODS: We used data from the Rotterdam Aphasia Therapy Study - 3 (RATS-3), a multicenter RCT with inclusion criteria similar to SPEAK, an observational prospective study. Baseline assessment in SPEAK was four days after stroke and in RATS-3 eight days. Outcome of the SPEAK-model was the Aphasia Severity Rating Scale (ASRS) at 1 year, dichotomized into good (ASRS-score of 4 or 5) and poor outcome (ASRS-score < 4). In RATS-3, ASRS-scores at one year were not available, but we could use six month ASRS-scores as outcome. Model performance was assessed with calibration and discrimination. RESULTS: We included 131 stroke patients with first-ever aphasia. At six months, 86 of 124 (68%) had a good outcome, whereas the model predicted 88%. Discrimination of the model was good with an area under the receiver operation characteristic curve of 0.87 (95%CI: 0.81-0.94), but calibration was unsatisfactory. The model overestimated the probability of good outcome (calibration-in-the-large α = - 1.98) and the effect of the predictors was weaker in the validation data than in the derivation data (calibration slope ß = 0.88). We therefore recalibrated the model to predict good outcome at six months. CONCLUSION: The original model, renamed SPEAK-12, has good discriminative properties, but needs further external validation. After additional external validation, the updated SPEAK-model, SPEAK-6, may be used in daily practice to discriminate between patients with good and patients with poor outcome of aphasia at six months after stroke. TRIAL REGISTRATION: RATS-3 was registered on January 13th 2012 in the Netherlands Trial Register: NTR3271 . SPEAK was not listed in a trial registry.

Genomewide association studies of stroke.

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

Catechol-O-methyltransferase Val158Met and the risk of dyskinesias in Parkinson's disease.

BACKGROUND: The A-allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability. METHODS: We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations. RESULTS: The A-allele of the COMT Val158Met polymorphism was related to an increased risk of developing dyskinesias during follow-up, in a dose-dependent manner (adjusted hazard ratios for the AG and AA genotypes [compared to GG]: 2.09 [95% confidence interval (CI), 1.07-4.06] and 2.81 [CI, 1.43-5.54], respectively). CONCLUSIONS: This finding suggests that genetic factors may affect susceptibility to dyskinesias in PD.

Strongly increased levels of fibrinogen elastase degradation products in patients with ischemic stroke.

Ischemic stroke is associated with leucocyte activation. Activated leucocytes release elastase, an enzyme that can degrade fibrinogen. Fibrinogen elastase degradation products (FgEDP) may serve as a specific marker of elastase proteolytic activity. In a case-control study of 111 ischemic stroke patients and 119 controls, significantly higher FgEDP levels were observed in cases than in controls, both in the acute phase and in the convalescent phase. Results were only slightly affected by adjustment for cardiovascular risk factors, C-reactive protein and fibrinogen. Our findings suggest that FgEDP might be involved in the pathogenesis of stroke.

Plasma folate concentration and cognitive performance: Rotterdam Scan Study.

BACKGROUND: Evidence is increasing for beneficial and independent effects of folate on cognitive function, but the underlying biologic mechanism is as yet unknown. OBJECTIVE: We examined the independent association of plasma folate concentration with cognitive performance and explored the nature of this association by evaluating brain-imaging markers for cerebrovascular disease and brain cell loss. DESIGN: In the population-based Rotterdam Scan Study, 1033 nondemented participants aged 60-90 y underwent extensive cognitive testing and brain imaging. We cross-sectionally examined the association between plasma folate concentration and cognitive test performance by multivariate linear regression. To evaluate the role of vascular or other mechanisms in this association, we subsequently studied whether plasma folate was related to the presence of white matter lesions and hippocampal and amygdalar volumes. RESULTS: After multivariate adjustment, the mean change in test score per 1-SD increase in plasma folate was 0.05 (95% CI: 0.01, 0.09) for global cognitive function, 0.08 (95% CI: 0.04, 0.13) for psychomotor speed, and 0.02 (95% CI: -0.04, 0.07) for memory function. Adjustment for homocysteine concentration only slightly diminished these associations. The odds ratio relating a 1-SD increase in plasma folate to the presence compared with the absence of severe white matter lesions was 0.79 (95% CI: 0.66, 0.94), whereas no relation was seen between folate status and hippocampal or amygdalar volume. CONCLUSIONS: Higher plasma folate concentrations are associated with better global cognitive function and better performance on tests of psychomotor speed, regardless of homocysteine concentration. These associations may be mediated by vascular mechanisms.

Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease.

BACKGROUND: Several lines of evidence suggest a role of inflammatory processes in Parkinson disease, although it is still unclear whether inflammation is a cause or rather a consequence of neurodegeneration. METHODS: In a prospective population-based cohort study among 6,512 participants aged >or=55 years, with repeated in-person examination, we evaluated the association between cumulative use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of Parkinson disease. Complete information on filled prescriptions was available from automated pharmacy records. Data were analyzed by means of Cox proportional hazards regression analysis, adjusted for age, sex, smoking habits and coffee consumption. RESULTS: After an average 9.4 years of follow-up, 88 new cases of Parkinson disease were detected. No association was found between use of NSAIDs and the risk of Parkinson disease (adjusted hazard ratio for any NSAID use, 1.50; 95% confidence interval, 0.95-2.37). CONCLUSION: Our findings do not support the hypothesis that NSAIDs might decrease the risk of Parkinson disease.

Screening tests for aphasia in patients with stroke: a systematic review.

Aphasia has a large impact on the quality of life and adds significantly to the costs of stroke care. Early recognition of aphasia in stroke patients is important for prognostication and well-timed treatment planning. We aimed to identify available screening tests for differentiating between aphasic and non-aphasic stroke patients, and to evaluate test accuracy, reliability, and feasibility. We searched PubMed, EMbase, Web of Science, and PsycINFO for published studies on screening tests aimed at assessing aphasia in stroke patients. The reference lists of the selected articles were scanned, and several experts were contacted to detect additional references. Of each screening test, we estimated the sensitivity, specificity, likelihood ratio of a positive test, likelihood ratio of a negative test, and diagnostic odds ratio (DOR), and rated the degree of bias of the validation method. We included ten studies evaluating eight screening tests. There was a large variation across studies regarding sample size, patient characteristics, and reference tests used for validation. Many papers failed to report on the consecutiveness of patient inclusion, time between aphasia onset and administration of the screening test, and blinding. Of the three studies that were rated as having an intermediate or low risk of bias, the DOR was highest for the Language Screening Test and ScreeLing. Several screening tools for aphasia in stroke are available, but many tests have not been verified properly. Methodologically sound validation studies of aphasia screening tests are needed to determine their usefulness in clinical practice.

Epidemiology of Parkinson's disease.

The causes of Parkinson's disease (PD), the second most common neurodegenerative disorder, are still largely unknown. Current thinking is that major gene mutations cause only a small proportion of all cases and that in most cases, non-genetic factors play a part, probably in interaction with susceptibility genes. Numerous epidemiological studies have been done to identify such non-genetic risk factors, but most were small and methodologically limited. Larger, well-designed prospective cohort studies have only recently reached a stage at which they have enough incident patients and person-years of follow-up to investigate possible risk factors and their interactions. In this article, we review what is known about the prevalence, incidence, risk factors, and prognosis of PD from epidemiological studies.

Subjective complaints precede Parkinson disease: the rotterdam study.

BACKGROUND: Neuronal degeneration and dopamine loss in the preclinical phase of Parkinson disease may produce subtle complaints before clinically recognizable symptoms emerge. OBJECTIVE: To examine whether subjective complaints of stiffness, slowness, tremors, or postural imbalance in persons without clinical signs of parkinsonism are related to an increased risk of future Parkinson disease. DESIGN: Population-based cohort study. We recorded subjective complaints of stiffness, slowness of movement, tremors, falling, or a feeling of imbalance in a standardized interview of 6038 participants without dementia in whom no parkinsonian signs were found on physical examination at baseline, and we studied them prospectively for the occurrence of incident Parkinson disease. SETTING: General population. PARTICIPANTS: A total of 6038 participants who were free of dementia and parkinsonian signs. MAIN OUTCOME MEASURES: Incident Parkinson disease. Participants were examined in person both at baseline (January 1990-June 1993) and at 2 follow-up visits (September 1993-December 1994 and April 1997-December 1999), and the cohort was continuously monitored through computerized linkage of the study database to general practitioners' medical records. We analyzed the data using Cox proportional hazards regression models. RESULTS: Participants who reported stiffness, tremors, or imbalance at baseline had a significantly increased risk of developing Parkinson disease during follow-up (for stiffness, hazard ratio, 2.11; 95% confidence interval, 1.25-3.55; P = .005; for tremors, hazard ratio, 2.09; 95% confidence interval, 1.12-3.90; P = .002; and for imbalance, hazard ratio, 3.47; 95% confidence interval, 1.69-7.00; P = .001). CONCLUSIONS: Subjective complaints of stiffness, tremors, and imbalance are associated with an increased risk of future Parkinson disease and may reflect early effects of dopamine shortage, even when standard neurological testing cannot yet demonstrate any motor symptoms.

Early effect of intra-arterial treatment in ischemic stroke on aphasia recovery in MR CLEAN.

OBJECTIVE: To investigate the effect of intra-arterial treatment (IAT) on early recovery from aphasia in acute ischemic stroke. We hypothesized that the early effect of IAT on aphasia is smaller than the effect on motor deficits. METHODS: We included patients with aphasia from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), in which 500 patients with a proximal anterior circulation stroke were randomized to usual care plus IAT (<6 hours after stroke, mainly stent retrievers) or usual care alone. We estimated the effect of IAT on the shift on the NIH Stroke Scale (NIHSS) item language and the NIHSS item motor arm at 24 hours and 1 week after stroke with multivariable ordinal logistic regression as a common odds ratio, adjusted for prognostic variables (acOR). Differences between the effect of IAT on aphasia and on motor deficits were tested in a multilevel model with a multiplicative interaction term. RESULTS: Of the 288 patients with aphasia, 126 were assigned to IAT and 162 to usual care alone. The acOR for improvement of language score at 24 hours was 1.65 (95% confidence interval [CI] 1.05-2.60), and at 1 week 1.86 (95% CI 1.18-2.94). The acOR for improvement of motor deficit at 24 hours was 2.44 (95% CI 1.54-3.88), and at 1 week 2.32 (95% CI 1.43-3.77). The effect of IAT on language deficits was significantly different from the effect on motor deficits at 24 hours and 1 week (p = 0.005 and p = 0.011). CONCLUSIONS: IAT results in better early recovery from aphasia than usual care alone. The early effect of IAT on aphasia is smaller than the effect on motor deficits. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute ischemic stroke IAT increases early recovery from aphasia and that the early effect on aphasia, as measured by the NIHSS, is smaller than the effect on motor deficits.

Prognosis of Parkinson disease: risk of dementia and mortality: the Rotterdam Study.

BACKGROUND: Most prognostic studies on Parkinson disease have been hospital based or have applied register-based case-finding methods. Potential under-representation of mild cases may have given biased results. OBJECTIVE: To evaluate whether Parkinson disease is associated with an increased risk of dementia and death. DESIGN: Population-based cohort study. Parkinson disease and dementia were assessed through in-person examination at baseline (1990-1993) and 2 follow-up visits (1993-1994 and 1997-1999). Computerized linkage to medical and municipality records provided additional information on disease outcomes and mortality. SETTING: General population. PARTICIPANTS: A total of 6969 participants, including 99 prevalent and 67 incident cases of Parkinson disease. MAIN OUTCOME MEASURES: Incident dementia and death. Adjusted hazard ratios were calculated through Cox proportional hazards regression analysis. RESULTS: Patients with Parkinson disease had an increased risk of dementia (hazard ratio, 2.8; 95% confidence interval, 1.8-4.4), which was especially pronounced in participants carrying at least 1 apolipoprotein E gene (APOE) epsilon2 allele (13.5; 4.5-40.6). Parkinson disease was associated with an increased mortality risk (1.8; 1.5-2.3). The association consistently diminished when analyses were sequentially restricted to patients with shorter disease duration and after adjustment for the occurrence of dementia. CONCLUSIONS: Especially patients with Parkinson disease who carry an APOE epsilon2 allele have an increased risk of developing dementia. Increased mortality risk in Parkinson disease is dependent on disease duration and is only modest in the absence of dementia.

Optimal timing of speech and language therapy for aphasia after stroke: more evidence needed.

Aphasia due to stroke affects communication and quality of life. Most stroke survivors with aphasia receive speech and language therapy. Although an early start of treatment is advocated in clinical practice, evidence for "The earlier, the better" in aphasia rehabilitation is weak. Hence, clinicians are faced with the dilemma of when to initiate intensive treatment: as early as possible, when most of the spontaneous recovery occurs but when patients are often ill, or later, when the patients' condition is more stabilized. Here we discuss whether aphasia outcome is affected by timing of treatment in relation to stroke onset and whether there is evidence for an optimal window of time during which language therapy should be provided. Findings from various rehabilitation research fields are discussed and combined to provide principles for future research.

Short Door-to-Needle Times in Acute Ischemic Stroke and Prospective Identification of Its Delaying Factors.

BACKGROUND: The clinical benefit of intravenous thrombolysis (IVT) in acute ischemic stroke is time dependent. Several studies report a short median door-to-needle time (DNT; 20 min), mainly in large tertiary referral hospitals equipped with a level 1 emergency department, a dedicated stroke team available 24/7, and on-site neuroimaging facilities. Meanwhile, in daily practice, the majority of stroke patients are admitted to secondary care hospitals, and in practice, even the generous benchmark of the American Heart Association (a DNT of 60 min in >80% of the cases) is met for a minority of patients treated with IVT. The first objective of our study was to investigate if, in a secondary care teaching hospital rather than a tertiary referral hospital, similar short DNTs can be accomplished with an optimized IVT protocol. Our second objective was to prospectively identify factors that delay the DNT in this setting. METHODS: A multicenter, consecutive cohort study of patients treated with IVT in one of two secondary care teaching hospitals. In both hospitals, data of consecutive stroke patients as well as median DNTs and factors delaying this were prospectively assessed for each patient. Multivariable logistic regression analysis was used to evaluate associations between patient-related and logistic factors with a delayed (i.e. exceeding 30 min) DNT. RESULTS: In total, 1,756 patients were admitted for ischemic stroke during the study period. Out of these, 334 (19.0%) patients were treated with IVT. The median DNT was 25 min (interquartile range: 20-35). A total of 71% (n = 238) had a DNT below 30 min. In 63% of the patients treated with IVT the DNT was delayed by at least one factor. Patients without any delaying factor had a 10 min shorter median DNT compared to patients with at least one delaying factor (p < 0.001). The following factors were independently associated with a delayed DNT: uncertainty about symptom onset, uncontrolled blood pressure, fluctuating neurological deficit, other treatment before IVT, uncertainty about (anti-)coagulation status, other patient-related factors, and incorrect triage. CONCLUSIONS: Short median DNTs can also be accomplished in secondary care. Despite the short DNTs, several delaying factors were identified that could direct future improvement measures. This study supports the view that as a performance measure, the current DNT targets are no longer ambitious enough and it adds to the knowledge of factors delaying the DNT.

[Chronic insomnia: not always psychophysiological]. / Chronische insomnie: niet altijd psychofysiologisch.

OBJECTIVE: To determine the sensitivity, specificity and the positive and negative predictive value of taking a detailed sleep history for making the diagnosis of psychophysiological insomnia. DESIGN: Retrospective case file study. METHOD: We examined 767 patients referred to the Amsterdam Centre for Sleep and Wake Disorders, and who underwent polysomnography for the first time between 1 January and 31 December 2010. We compared the probable diagnosis made following history-taking with the final diagnosis made after polysomnography. In this we differentiated between organic and non-organic insomnia. The sensitivity, specificity, positive and negative predictive values of the sleep history were calculated. RESULTS: In 24.8% of the 303 patients whose histories did not indicate organic insomnia, polysomnography showed there to be an organic cause. Primary causes were obstructive sleep apnoea (13.2%), upper airway resistance syndrome (5.4%), and periodic limb movement disorder (4.0%) or a combination of these. In the histories of 464 patients there were indications that the insomnia had an organic cause and in 325 of them this was confirmed by polysomnography. The sensitivity of detailed history taking to psychophysiological insomnia was 62.1%, the specificity 81.3%, the positive predictive value was 75.2% and the negative predictive value was 70.0%. In patients under the age of 40 with a score on the Epworth sleepiness scale < 10 (i.e. no hypersomnolence), a BMI < 25 kg/m2 and indications of psychophysiological insomnia, organic insomnia could not be demonstrated, with the exception of one parasomnia. CONCLUSION: History-taking only meant that the organic cause was missed in a substantial percentage of patients with insomnia, in particular in older patients with hypersomnolence and a high BMI.

Survival in Parkinson's disease. Relation with motor and non-motor features.

BACKGROUND: Survival in patients with Parkinson's disease is reduced as compared to the general population. We aimed to identify motor and non-motor features that predict mortality in Parkinson's disease. METHODS: A broad range of motor and non-motor features were assessed in a hospital-based cohort of 414 patients with Parkinson's disease, who underwent five annual follow-up examinations including vital status assessment. Multivariable Cox's proportional hazards regression analysis was used to evaluate the association between baseline characteristics and mortality risk. Stepwise regression with backward elimination was carried out to determine the best model to predict mortality in Parkinson's disease. RESULTS: After a mean follow-up period of 4.3 years, 49 (11.8%) patients had died. In the stepwise regression model, predictors of mortality in Parkinson's disease were higher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms. CONCLUSIONS: Higher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms are independent predictors of decreased survival in Parkinson's disease. Mortality in Parkinson's disease thus seems to be affected mainly by non-dopaminergic and non-motor features.

Rotterdam Aphasia Therapy Study (RATS)-3: "The efficacy of intensive cognitive-linguistic therapy in the acute stage of aphasia"; design of a randomised controlled trial.

BACKGROUND: Aphasia is a severely disabling condition occurring in 20 to 25% of stroke patients. Most patients with aphasia due to stroke receive speech and language therapy. Methodologically sound randomised controlled trials investigating the effect of specific interventions for patients with aphasia following stroke are scarce. The currently available evidence suggests that intensive speech and language therapy is beneficial for restoration of communication, but the optimal timing of treatment is as yet unclear.In the Rotterdam Aphasia Therapy Study-3 we aim to test the hypothesis that patients with aphasia due to stroke benefit more from early intensive cognitive-linguistic therapy than from deferred regular language therapy. METHODS/DESIGN: In a single blinded, multicentre, randomised controlled trial, 150 patients with first ever aphasia due to stroke will be randomised within two weeks after stroke to either early intensive cognitive-linguistic therapy (Group A) or deferred regular therapy (Group B). Group A will start as soon as possible, at the latest two weeks after stroke, with a four week period of one hour a day treatment with cognitive-linguistic therapy. In Group B professional speech and language therapy is deferred for four weeks. After this period, patients will follow the conventional procedure of speech and language therapy. Participants will be tested with an extensive linguistic test battery at four weeks, three months and six months after inclusion. Primary outcome measure is the difference in score between the two treatment groups on the Amsterdam-Nijmegen Everyday Language Test, a measure of everyday verbal communication, four weeks after randomisation. TRIAL REGISTRATION: This trial is registered in the Dutch Trial Register (http://www.trialregister.nl), NTR3271.

Relationship of Von Willebrand Factor with carotid artery and aortic arch calcification in ischemic stroke patients.

BACKGROUND: Large population studies have revealed that increased von Willebrand Factor (VWF) levels are associated with an increased risk of ischemic stroke. In previous studies VWF was associated with atherosclerosis in healthy individuals. However, it is yet unknown what the association is between atherosclerosis and VWF levels in patients with ischemic stroke. OBJECTIVES: The aim of our study was to determine the association of atherosclerosis, measured with recent developed techniques, and VWF levels in a large, well characterized, cohort of ischemic stroke patients and to determine the prognostic value. METHODS: We included 925 consecutive patients with transient ischemic attack (TIA) or ischemic stroke. Calcification volumes (mm(3)) were scored in the aortic arch and both carotid arteries using multidetector computed tomography (CT) angiography. VWF antigen (VWF:Ag) levels were measured using ELISA. RESULTS: Mean VWF:Ag levels were significantly higher in the presence of calcification in either the aortic arch (1.47 vs. 1.37 IU/ml [P = 0.039]) or the carotid arteries (1.49 vs. 1.34 IU/ml [P = 0.001]). Patients with a large artery atherosclerosis ischemic stroke had significantly higher VWF:Ag levels then the other TOAST subtypes (P < 0.0001). High VWF:Ag levels were associated with an unfavorable outcome (modified Rankin Scale >2 vs. ≤2; 1.64 vs. 1.41 IU/ml, [P < 0.0001]). CONCLUSION: Our study showed a strong association between the extent of atherosclerosis in both the aortic arch and the carotid arteries and VWF levels in patients with TIA or ischemic stroke. Higher VWF levels are found in large artery atherosclerosis and are associated with a poor outcome.

Association of two single nucleotide polymorphisms from genomewide association studies with clinical phenotypes of cerebral ischemia.

BACKGROUND: Recent genomewide association studies have revealed an association between two single nucleotide polymorphisms, rs11833579 and rs12425791, and ischemic stroke. AIM: To gain more insight in pathophysiological mechanisms underlying the found associations by exploring relationships between these single nucleotide polymorphisms and clinical and radiological characteristics of patients with cerebral ischemia. METHODS: Our cohort consisted of 660 Caucasian patients with cerebral ischemia; from all patients detailed clinical and radiological data were available. Etiologic subtype of cerebral ischemia was determined according to the TOAST classification and an alternative classification. We studied associations between risk alleles and etiologic subtype, duration of ischemia, occurrence of multiple events, functional outcome and findings on CT-angiography by means of logistic regression analysis. RESULTS: The risk allele of rs11833579 was associated with an atherothrombotic etiology of cerebral ischemia, but not with other etiologic subtypes. Risk alleles of both single nucleotide polymorphisms were related to events of shorter duration (<24 h), the risk allele of rs11833579 with occurrence of multiple events. There was no association between single nucleotide polymorphism and clinical outcome. Both single nucleotide polymorphismswere associated with presence of stenotic calcifications and stenosis >30% in a symptomatic artery on CT-angiography. CONCLUSIONS: This is the first study to show an association of rs11833579 with multiple episodes of cerebral ischemia of atherothrombotic origin, and of rs11833579 and rs12425791 with short duration of ischemia. Also, we found an association of both single nucleotide polymorphisms with atherosclerotic lesions in the extracranial vessels on CT-angiography. Together this suggests a relationship between the two single nucleotide polymorphisms and large artery pathology.