Exploring vascular contributions to cognitive impairment and dementia (ENIGMA): protocol for a prospective observational study.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is common. However, the underlying pathophysiology remains largely unknown. Understanding the role of microvascular changes and finding markers that can predict PSCI, could be a first step towards better screening and management of PSCI. Capillary dysfunction is a pathological feature of cerebral small vessel disease and may play a role in the mechanisms underlying PSCI. Extracellular vesicles (EVs) are secreted from cells and may act as disease biomarkers. We aim to investigate the role of capillary dysfunction in PSCI and the associations between EV characteristics and cognitive function one year after acute ischemic stroke (AIS) and transient ischemic attack (TIA). METHODS: The ENIGMA study is a single-centre prospective clinical observational study conducted at Aarhus University Hospital, Denmark. Consecutive patients with AIS and TIA are included and followed for one year with follow-up visits at three and 12 months. An MRI is performed at 24 h and 12 months follow-up. EV characteristics will be characterised from blood samples drawn at 24 h and three months follow-up. Cognitive function is assessed three and 12 months after AIS and TIA using the Repeatable Battery for the Assessment of Neuropsychological Status. DISCUSSION: Using novel imaging and molecular biological techniques the ENIGMA study will provide new knowledge about the vascular contributions to cognitive decline and dementia. TRIAL REGISTRATION: The study is retrospectively registered as an ongoing observational study at ClinicalTrials.gov with the identifier NCT06257823.

Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

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.

Impact of prestroke physical activity and citalopram treatment on poststroke depressive symptoms: a secondary analysis of data from the TALOS randomised controlled trial in Denmark.

OBJECTIVES: To investigate the association between prestroke physical activity and depressive symptoms up to 6 months after stroke and examine if citalopram treatment modified the association. DESIGN: A secondary analysis of data from the multicentre randomised controlled trial The Efficacy of Citalopram Treatment in Acute Ischemic Stroke (TALOS). SETTING AND PARTICIPANTS: TALOS was conducted at multiple stroke centres in Denmark from 2013 to 2016. It enrolled 642 non-depressed patients with first-ever acute ischaemic stroke. Patients were eligible for this study if a prestroke physical activity level was assessed by the Physical Activity Scale for the Elderly (PASE). INTERVENTIONS: All patients were randomised to citalopram or placebo for 6 months. OUTCOMES: Depressive symptoms 1 and 6 months after stroke measured on the Major Depression Inventory (MDI) ranging from 0 to 50. RESULTS: A total of 625 patients were included. Median (IQR) age was 69 (60-77) years, 410 (65.6%) were men, 309 (49.4 %) received citalopram and median (IQR) prestroke PASE score was 132.5 (76-197). Higher prestroke PASE quartile, compared with the lowest PASE quartile, was associated with fewer depressive symptoms both after 1 month (mean difference third quartile -2.3 (-4.2, -0.5), p=0.013, mean difference fourth quartile -2.4 (-4.3, -0.5), p=0.015) and 6 months after stroke (mean difference third quartile -3.3 (-5.5, -1.2), p=0.002, mean difference fourth quartile -2.8 (-5.2, -0.3), p=0.027). There was no interaction between citalopram treatment and prestroke PASE score on poststroke MDI scores (p=0.86). CONCLUSIONS: A higher prestroke physical activity level was associated with fewer depressive symptoms 1 and 6 months after stroke. Citalopram treatment did not seem to modify this association. TRIAL REGISTRATION NUMBERS: NCT01937182 (ClinicalTrials.gov) and 2013-002253-30 (EUDRACT).

Too risky, too large, too late, or too mild-Reasons for not treating ischemic stroke patients and the related outcomes.

Background: Despite effective treatments, many patients are still not offered reperfusion therapy for acute ischemic stroke. Methods: We present a single-center observational study on acute ischemic stroke patients, who presented as candidates for reperfusion therapy but were deemed ineligible after work-up. Reasons for non-treatment were obtained by studying patient files and subsequently grouped into "too risky" (e.g., anticoagulant use, comorbidities), "too large" (large infarct), "too late" (late presentation of stroke and wake-up strokes), or "too mild" (clinically mild/remitting symptoms). Modified Rankin scale (mRS) score was prospectively collected in all patients by a structured telephone interview. All non-treated patients with a National Institute of Health Stroke Scale (NIHSS) score of 0-5 were compared with a similar cohort that was treated. Results: Of 529 patients with acute ischemic stroke arriving as reperfusion therapy candidates, 198 (37.4%) were not treated. The majority (42%) were not treated due to admission outside the treatment window (too late) and 24% had absolute contraindications (too risky). Only 8% was excluded because their infarct was too large [median Alberta Stroke Program Early CT score 3 (2-4)]. In the "too mild" group (14%) the percentage of patients not being independent at 90 days was 30%. The adjusted odds ratio for a better outcome (lower mRS) among treated patients with NIHSS 0-5 compared with non-treated was 1.93 (95% confidence interval 1.15-3.23). Conclusion: Presenting outside the treatment window is still the most common reason for not receiving therapy. Our study suggests a benefit of thrombolysis for patients with mild symptoms.

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.