Prestroke Physical Activity and Poststroke Cognitive Performance.

INTRODUCTION: Physical activity (PA) is associated with a lower risk of stroke and stroke mortality as well as a favorable stroke outcome. PA may also prevent general cognitive decline. Poststroke cognitive impairment is both common and disabling, and focusing on all possible preventive measures is important. Studies on the effect of PA on poststroke cognitive performance are sparse, however. We therefore aimed to examine the association between prestroke PA and poststroke cognitive performance. METHODS: We studied the correlation between prestroke PA and poststroke cognitive performance in a prespecified analysis in The Efficacy of Citalopram Treatment in Acute Ischemic Stroke (TALOS) trial. We used the Physical Activity Scale for the Elderly (PASE) to collect information on PA during the 7-day period before stroke. PA was quantified, and patients were stratified into quartiles based on their PASE score. Cognitive performance was measured using the Symbol Digit Modalities Test (SDMT) at 1 and 6 months and the Mini-Mental State Examination (MMSE) at 6 months. The functional outcome was assessed using the modified Rankin Scale (mRS). RESULTS: In total, 625 of 642 patients (97%) completed the PASE questionnaire. The median age was 69 (interquartile range [IQR]: 60-77), and the median PASE score was 137 (82-205). Higher prestroke PASE quartiles (2nd, 3rd, and 4th, each compared to the 1st) were independently associated with a higher SDMT score at 1 month in the both the univariable and multivariable analyses (2nd: 3.99 points, 95% confidence interval [CI]: 1.01-6.97; 3rd: 3.6, CI: 0.6-6.61; 4th: 4.1, CI: 0.95-7.24). This association remained at 6 months. PA was not statistically associated with the MMSE score or mRS. CONCLUSION: Higher prestroke PA was associated with a better cognitive performance as measured by the SDMT at 1 and 6 months poststroke. We found no significant association between prestroke PA and functional outcome. Our results are encouraging and support further investigations of PA as a protective measure against poststroke cognitive impairment.

Serotonergic Regulation and Cognition after Stroke: The Role of Antidepressant Treatment and Genetic Variation.

INTRODUCTION: Serotonin affects several brain functions including cognition. The serotonin transporter (SERT) regulates brain serotonin levels through reuptake into neurons. The gene encoding this transporter, the SERT gene, has several functional polymorphisms affecting the number of transporters and thereby the serotonin levels. SERT gene expression may be important for cognition and selective serotonin reuptake inhibitors (SSRI) may improve cognition post stroke. We therefore examined the association between SERT genotypes, cognitive function and early treatment with the SSRI citalopram among non-depressed Caucasian stroke patients. PATIENTS AND METHODS: SERT gene polymorphisms in 270 non-depressed first-ever acute ischemic stroke patients randomized to citalopram, n = 130, or placebo, n = 140, were investigated. Patients were genotyped for a length polymorphism (L = long and S = short allele) and a single nucleotide polymorphism (A/G substitution) dividing the L-allele into LA and LG. According to these genotypes, patients were further grouped according to low (S/S, LG/S and LG/LG), medium (S/LA and LG/LA), or high functional gene expression (LALA). Cognition was measured by the Symbol Digit Modalities Test (SDMT) at 1 and 6 months. Mean SDMT scores according to genotype and randomization groups were compared using multiple logistic regression adjusting for age, stroke severity, premorbid functional status, and vascular risk factors including smoking, hypertension, and diabetes. RESULTS: Stratified by genotype groups, there were no statistically significant differences in SDMT scores between randomization groups. Placebo-treated patients with low SERT expression genotypes, however, tended to have lower mean SDMT scores (at 1 month: 30.2, SD 10.8) compared to citalopram-treated patients (33.6, SD 13.7). Within the placebo group, the low genotype expression patients had significantly lower adjusted mean SDMT scores at 1 month compared to the high genotype expression patients (adjusted mean difference of -6 points, CI -12.0 to -0.05). We found similar results at 6 months, although not statistically significant. The genotype expression was not associated with SDMT scores among citalopram-treated patients. CONCLUSION: There was no difference in cognition between citalopram and placebo-treated patients according to the genotype group. Our results indicate, however, that low expression SERT genotype may contribute to reduced cognitive function post stroke as placebo-treated patients with low SERT expression tended to score lower on the SDMT. The significant difference in SDMT scores between low and high expression patients was present only in the placebo-treated group, thereby warranting further exploration of the potential effect of early citalopram treatment on cognitive functioning. Our results are preliminary and need replication in larger-scale studies.

Neuroregeneration and Vascular Protection by Citalopram in Acute Ischemic Stroke (TALOS).

Background and Purpose- Recent studies indicate a possible beneficial effect on neuroregeneration and vascular protection of selective serotonin reuptake inhibitors after stroke. We conducted a national multicentre study to explore these effects. Methods- The TALOS study (The Efficacy of Citalopram Treatment in Acute Stroke) is a Danish placebo-controlled, randomized, double-blind study of citalopram started within 7 days after symptom onset to detect improvement in functional outcomes and cardiovascular protection in nondepressed, first-ever ischemic stroke. Study medication was given as add-on to standard medical care and treatment duration and follow-up was 6 months. There were 2 coprimary outcomes: changes in functional disability from 1 to 6 months on the modified Rankin Scale, and a composite vascular end point of transient ischemic attack/stroke, myocardial infarction, or vascular mortality during the first 6 months. Results- We enrolled 642 patients randomized to either citalopram (n=319) or placebo (n=323). Median National Institutes of Health Stroke Scale was 5.3 (range, 0-27) versus 4.8 (range, 0-28) at admission. Improvement in functional recovery from 1 to 6 months occurred in 160 (50%) patients on citalopram and 136 (42%) on placebo (odds ratio, 1.27; 95% CI, 0.92-1.74; P=0.057). When dropouts before 31 days were excluded (n=90), the analysis population showed an odds ratio of 1.37 (95% CI, 0.97-1.91; P=0.07). During a median follow-up of 150 days, 23 (7%) patients in the citalopram group and 26 (8%) patients in the placebo group had a primary, vascular end point (hazard ratio, 0.89; 95% CI, 0.50-1.60; P=0.24). A total of 28 patients (4%) died (16 versus 12; P=0.42) during the study. Conclusions- Early citalopram treatment did not improve functional recovery in nondepressed ischemic stroke patients within the first 6 months, although a borderline statistical significant effect was observed in the analysis population. The risk of cardiovascular events was similar between treatment groups, and citalopram treatment was well tolerated. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01937182. URL: https://www.clinicaltrialsregister.eu/ . EudraCT number: 2013-002253-30.

The Serotonin Transporter Gene Polymorphisms and Risk of Ischemic Stroke.

INTRODUCTION: Serotonin is known as a neurotransmitter; however, it also plays an important role in platelet aggregation as it is released upon platelet activation. The serotonin transporter (SERT) is responsible for the uptake of serotonin into platelets. Functional polymorphisms in the SERT gene may influence platelet activity, as they result in different levels of transporters and thereby different levels of serotonin in platelets. SERT gene polymorphisms have thus been associated with the risk of myocardial infarction. A similar association may exist between SERT gene polymorphisms and stroke. However, to our knowledge, this potential association has not previously been studied. We therefore aimed to investigate the association between polymorphisms in the SERT gene and the risk of ischemic stroke/transitory ischemic attack (TIA). MATERIALS AND METHODS: We conducted a case-control study including 834 consecutively admitted first-ever Caucasian ischemic stroke patients/TIA from Aarhus University Hospital, Denmark and 571 healthy controls. The control group comprised a sample from the Danish working population, who were all employees in the public sector in the Central Denmark Region. Two polymorphisms, the length variation (short = S/long = L) in the serotonin-transporter-linked polymorphic region and a single-nucleotide (A/G) polymorphism (rs25531) were studied. The genotypes were grouped according to the functional activity: SS, SLG and LGLG (low expression), SLA, LGLA (medium expression), and LALA (high expression). Data were analyzed using logistic regression and results presented as OR with 95% CI. RESULTS: The high-expression genotype was associated with a lower risk of ischemic stroke/TIA when compared to both the medium expression genotype (OR 0.72, 95% CI 0.56-0.93) and the low-expression genotype (OR 0.75, 95% CI 0.55-1.01) as well as the combination of the low and medium expression genotypes (OR 0.73, 95% CI 0.58-0.93). The lower OR estimates associated with the high-expression genotype were consistent across all stroke subtypes, although not statistically significant. The results remained virtually unchanged, although not reaching statistical significance, when adjusting for age and gender. CONCLUSION: The presence of the high expression SERT genotype (LALA) may be associated with a lower risk of ischemic stroke/TIA. This is, to our knowledge, the first study examining the SERT gene polymorphisms and the risk of stroke. The present results raise interesting considerations for future personalized medicine potential, and we argue that further larger-scale studies with sufficient power to study subgroups according to stroke etiology and stroke-onset age are needed.

Acute ischemic stroke and measurement of apixaban and rivaroxaban: an observational cohort implementation study.

Background: Treatment with intravenous thrombolysis for acute ischemic stroke is contraindicated with intake of apixaban/rivaroxaban in the last 48 hours. Recent European Stroke Organization guidelines suggest that thrombolysis can be considered if anti-factor Xa activity (AFXa) is <0.5 × 103 IU/L with low-molecular-weight (LMWH) or unfractionated heparin (UFH) calibrated assays. Some centers also use apixaban/rivaroxaban-calibrated AFXa assays to identify patients with low drug concentrations. Objectives: To prospectively evaluate the first year of implementation of drug-calibrated AFXa assays at our center with 2500 yearly admittances with suspected stroke. Methods: Samples were analyzed on Sysmex CS-5100 instruments with Innovance anti-Xa reagents. Thrombolysis could be considered with drug concentrations <25 µg/L. Patients were registered in an institutionally approved quality register. Outcomes included (1) the number of patients receiving thrombolysis after drug measurement, (2) turn-around time for drug concentration measurements, and (3) sensitivity of LMWH/UFH AFXa to apixaban and rivaroxaban. Results: Apixaban or rivaroxaban was measured in 148 samples, and 4 patients who previously would have been ineligible for thrombolysis were treated with thrombolysis. In total, thrombolysis was administered in 123 patient episodes in the study period. The median turn-around time for the drug measurements was 38 minutes. Apixaban concentrations of 25 µg/L and 50 µg/L corresponded to LMWH/UFH AFXa of 0.13 and 0.27 × 103 IU/L, respectively. There were too few rivaroxaban results for regression analysis. Conclusion: Implementation of apixaban and rivaroxaban measurements led to a small increase in the number of patients receiving thrombolysis. Excluding significant concentrations of apixaban or rivaroxaban using LMWH/UFH AFXa may be feasible.

Predictors for wellbeing and characteristics of mental health after stroke.

BACKGROUND: Poor mental health after stroke is common and complex. We aimed to identify predictors of poor wellbeing and to examine the overlap of poor wellbeing, fatigue, and depression. METHOD: Consecutive first-ever ischemic stroke-patients filled in questionnaires on wellbeing, fatigue, and depression at baseline and at one and six months. The World Health Organization 5-Item Wellbeing-Index (WHO-5), the Major Depression Inventory, and the Multidimensional Fatigue Inventory were used. Patients were genotyped according to serotonin-transporter gene polymorphisms. Multivariable logistic regression was used to identify potential predictors of poor wellbeing (WHO-5 score <50). Overlap between wellbeing, fatigue, and depression was examined using an Euler diagram. RESULTS: We included 919 patients. The prevalence of poor wellbeing was 279 (30.4%) six months after stroke. Living alone at stroke onset was the strongest predictor of poor wellbeing with a mutually adjusted odds ratio of 1.53 (95% confidence interval (CI): 1.03 to 2.28) at one month and 1.77 (CI: 1.13 to 2.76) at six months. Severe stroke at admission also predicted poor wellbeing at six months. Abnormal fatigue occurred in half and incorporated almost all patients with poor wellbeing. Less than 5% fulfilled the criteria for depression at any point and almost all of these patients had poor wellbeing and abnormal fatigue. Antidepressants were used by 292 (31.8%) during follow-up. LIMITATIONS: Cognitive impairment was not measured and could interact with wellbeing post-stroke. CONCLUSION: Living alone strongly predicted poor wellbeing after stroke. Satisfactory mental health-recovery seems to require psychosocial interventions when indicated in combination with antidepressant treatment.

Antiplatelet effects of citalopram in patients with ischaemic stroke: A randomized, placebo-controlled, double-blind study.

We evaluated the effect of SSRI treatment on platelet aggregation in patients with ischaemic stroke and included patients from the randomized double-blind controlled study of citalopram in acute ischaemic stroke (TALOS). Patients on clopidogrel were included 6 months after acute ischaemic stroke. Platelet parameters, including P2Y12 platelet reactivity using the VerifyNow System, were measured at the last day of study treatment and repeated after a 14-day wash-out period. A total of 60 patients were included (n = 32 randomized to citalopram). Platelet aggregation levels did not differ between the citalopram group (mean 116, 95% CI 89 to 143) and the placebo group (mean 136, 95% CI 109 to 163) (On-treatment, p = 0.14). Similarly, there was no significant change in platelet aggregation in the citalopram group from on-treatment to post-treatment (mean difference 2.0; 95% CI -18 to 14). Platelet count, size and turnover were not affected by SSRI treatment. In conclusion, SSRI therapy did not lead to statistically significant inhibition of platelet aggregation in ischaemic stroke patients treated with clopidogrel.

TALOS: a multicenter, randomized, double-blind, placebo-controlled trial to test the effects of citalopram in patients with acute stroke.

RATIONALE: Selective Serotonin Reuptake Inhibitors (SSRI) are effective in the treatment of post-stroke depression and may have potential neuroprotective and vascular effects. Data from registry studies have further indicated a protective effect against recurrent ischemic events, but also an increased risk of bleeding in patients with ischemic stroke. Therefore, prospective studies are needed to determine the effects of SSRI treatment after acute ischemic stroke. AIMS AND DESIGN: TALOS is an investigator-initiated, national multicenter randomized- and placebo-controlled, double-blind trial testing citalopram in acute ischemic stroke. We hypothesize that citalopram treatment initiated in the acute phase after ischemic stroke will improve outcome assessed by the modified Rankin Score (mRS) and reduce the risk of death from vascular causes, transient ischemic attack (TIA)/stroke and myocardial infarction. STUDY OUTCOMES: There are two co-primary effect variables: (i) Functional status at six-months, measured by the modified Rankin Scale, and (ii) Vascular death, TIA/stroke and myocardial infarction. Secondary effect variables include: (i) Single primary outcomes; (ii) The Barthel Index; (iii) Mini Mental State Examination at six-months; (iv) Final infarct size (Magnetic Resonance Imaging). DISCUSSION: SSRI treatment is well tolerated and overall beneficial in the wake of stroke; it may also be neuroprotective and prevent new vascular events.

[Anticoagulant therapy in stroke patients]. / Antikoagulansbehandling og apopleksi.

Stroke is a common disease, which is associated with high morbidity and high mortality. Up to 25% of cerebral ischaemic infarcts are caused by cardio-embolic events, most commonly associated with atrial fibrillation. It has previously been shown that antithrombotic therapy is insufficiently used in patients at increased risk of stroke. This article reviews evidence and practical management of anticoagulant therapy in stroke patients and provides an update on risk stratification for thromboembolism and bleeding complications in patients with atrial fibrillation.