Long-term outcome of a pragmatic trial of multifaceted intervention (STROKE-CARD care) to reduce cardiovascular risk and improve quality-of-life after ischaemic stroke and transient ischaemic attack: study protocol.

BACKGROUND: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of incident cardiovascular events and recurrent stroke. Despite compelling evidence about the efficacy of secondary prevention, a substantial gap exists between risk factor management in real life and that recommended by international guidelines. We conducted the STROKE-CARD trial (NCT02156778), a multifaceted pragmatic disease management program between 2014 and 2018 with follow-up until 2019. This program successfully reduced cardiovascular risk and improved health-related quality of life and functional outcome in patients with acute ischaemic stroke or TIA within 12 months after the index event. To investigate potential long-term effects of STROKE-CARD care compared to standard care, an extension of follow-up is warranted. METHODS: We aim to include all patients from the STROKE-CARD trial (n = 2149) for long-term follow-up between 2019 and 2021 with the study visit scheduled 3-6 years after the stroke/TIA event. The co-primary endpoint is the composite of major recurrent cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, and vascular death) from hospital discharge until the long-term follow-up visit and health-related quality of life measured with the European Quality of Life-5 Dimensions (EQ-5D-3L) at the final visit. Secondary endpoints include overall mortality, long-term functional outcome, and target-level achievement in risk factor management. DISCUSSION: This long-term follow-up will provide evidence on whether the pragmatic post-stroke/TIA intervention program STROKE-CARD is capable of preventing recurrent cardiovascular events and improving quality-of-life in the long run. Trial registration clinicaltrials.gov: NCT04205006 on 19 December 2019.

Oxytocin receptor gene methylation as a molecular marker for severity of depressive symptoms in affective disorder patients.

BACKGROUND: Oxytocin (OXT) is a neuropeptide and hormone involved in emotional functioning and also seems to play a role in moderating the stress response. Both preclinical and clinical studies point to an increased methylation status of the Oxytocin receptor (OXTR) promoter region with concomitant deficits in social, cognitive and emotional functioning. We hypothesize that methylation levels (%) of the oxytocin receptor promoter region correlate with the severity of depression symptoms and/or with the severity of childhood trauma within this present sample of affective disorder patients. METHODOLOGY: Eight hundred forty six (846) affective disorder patients of Central European origin were recruited at the Department of Psychiatry and Psychotherapy of the Medical University Vienna, the Karl Landsteiner University for Health and Science and Zentren für seelische Gesundheit, BBRZ-Med Leopoldau. Psychiatric assessment included a semi-structured diagnostic interview (Schedules for Clinical Assessment in Neuropsychiatry), the Hamilton Depression Scale and the Childhood Trauma Questionnaire. Concomitantly DNA samples of peripheral blood cells were collected for Multiplexed and Sensitive DNA Methylation Testing. RESULTS: Our data suggests a positive but not significant association between OXTR promoter Exons 1-3 methylation levels and severity of depression symptoms as well as severity of emotional neglect in affective disorder patients and no association with childhood trauma. CONCLUSIONS: Our findings contribute to elucidate the role of OXTR in affective disorders, but further longitudinal studies in particular are necessary to broaden the current state of knowledge.

Time trends in stroke severity in the years 2005 to 2020: results from the Austrian Stroke Unit Registry.

BACKGROUND AND PURPOSE: With aging population, there is an increase of atrial fibrillation (AF) and other vascular risk factors. We investigated trends in stroke severity at hospital admission with respect to AF and other risk factors in a prospective national stroke registry from 2005 to 2020. METHODS: Data from the prospective Austrian Stroke Unit Registry were used to study demographic and clinical factors associated with the change in admission stroke severity over years. Time trends in admission stroke severity of patients with pre-stroke modified Rankin Score ≤ 3 were investigated with respect to clinical variables and predefined age groups 18-54, 55-64, 65-74, 75-84 and ≥ 85 years. Time trends were studied using robust generalized linear models assuming normal distribution with a log link. Stroke severity on admission was assessed according to the National Institutes of Health Stroke Scale Score (NIHSS). RESULTS: In total, 140,312 patients with acute ischemic stroke were included in the analysis. Within the study period, mean patients' age increased from 70 to 72 years (p < 0.001) and median NIHSS at admission decreased from 4 to 3 (p < 0.001). The frequency of AF increased from 25 to 32% (p < 0.001). The decrease in median admission NIHSS was evident in all relevant subgroups but more pronounced in patients with risk factors including AF, diabetes, hypercholesterolemia, smoking, elderly patients and those with pre-stroke disability. CONCLUSION: Despite an aging population and generally increasing AF frequency, we observed a consistent trend towards less disabling strokes on admission.

CT- versus MRI-Based Imaging for Thrombolysis and Mechanical Thrombectomy in Ischemic Stroke: Analysis from the Austrian Stroke Registry.

BACKGROUND AND PURPOSE: It is unclear whether a particular stroke imaging modality offers an advantage for the acute stroke treatment. The aim of this study was to compare procedure times, efficacy and safety of thrombolysis and/or thrombectomy based on computed tomography (CT) versus magnetic resonance imaging (MRI) acute stroke imaging. METHODS: Data of stroke patients who received intravenous thrombolysis (IVT) and/or mechanical thrombectomy (MT) were extracted from a nationwide, prospective stroke unit registry and categorized according to initial imaging modality. Study endpoints included procedure times, symptomatic intracerebral hemorrhage (sICH), early neurological improvement, 3-month functional outcome by modified Rankin Scale (mRS) and mortality. RESULTS: Stroke patients (n=16,799) treated with IVT and 2,248 treated with MT were included. MRI-guided patients (n=2,599) were younger, had less comorbidities and higher rates of strokes with unknown onset as compared to CT-guided patients. In patients treated with IVT, no differences were observed regarding the rates of functional outcome by mRS 0-1 (adjusted odds ratio [OR], 0.87; 95% confidence interval [CI], 0.71 to 1.05), sICH (adjusted OR, 0.82; 95% CI, 0.61 to 1.08), and mortality (adjusted OR, 0.88; 95% CI, 0.63 to 1.22). Patients undergoing MT selected by MRI as compared to CT showed equal rates of functional outcome by mRS 0-2 (adjusted OR, 0.87; 95% CI, 0.65 to 1.16), sICH (adjusted OR, 0.9; 95% CI, 0.51 to 1.69), and mortality (adjusted OR, 0.62; 95% CI, 0.35 to 1.09). MRI-guided patients showed a significant intrahospital delay of about 20 minutes in both the IVT and the MT group. CONCLUSIONS: This large non-randomized comparison study indicates that CT- and MRI-guided patient selection for IVT/MT may perform equally well in terms of functional outcome and safety.

Intravenous thrombolysis in stroke with admission NIHSS score 0 or 1.

BACKGROUND: Up to 30% of stroke patients initially presenting with non-disabling or mild deficits may experience poor functional outcome. Despite, intravenous thrombolysis remains controversial in this subgroup of stroke patients due to its uncertain risk benefit ratio. AIM: We aimed to analyze the real-world experience with intravenous thrombolysis in stroke patients presenting with very low NIHSS. METHODS: Data of stroke patients presenting with mild initial stroke severity (NIHSS 0-5) including vascular risk factors, stroke syndrome and etiology, early neurological deterioration, symptomatic intracerebral haemorrhage (sICH), and functional outcome by modified Rankin Scale were extracted from a large nationwide stroke registry and analysed. Patients were categorized and compared according to admission severity NIHSS 0-1 versus NIHSS 2-5 and intravenous thrombolysis use. RESULTS: Seven hundred and three (2%) of 35,113 patients presenting with NIHSS 0-1 and 6316 (13.9%) of 45,521 of patients presenting with NIHSS 2-5 underwent intravenous thrombolysis. In the NIHSS 0-1 group, intravenous thrombolysis was associated with early neurological deterioration (adjusted OR 8.84, CI 6.61-11.83), sICH (adjusted OR 9.32, CI 4.53-19.15) and lower rate of excellent outcome (mRS 0-1) at three months (adjusted OR 0.67, CI 0.5-0.9). In stroke patients with NIHSS 2-5, intravenous thrombolysis was associated with early neurological deterioration (adjusted OR 1.7, 1.47-1.98), sICH (adjusted OR 5.75, CI 4.45-7.45), and higher rate of excellent outcome (mRS 0-1) at three months (adjusted OR 1.21, CI 1.08-1.34). CONCLUSIONS: Among patients with NIHSS 0-1, intravenous thrombolysis did not increase the likelihood of excellent outcome. Moreover, potential signals of harm were observed. Further research seems to be warranted.

BDNF gene polymorphisms predicting treatment response to CBT-based rehabilitation of depression: to be submitted to: European Neuropsychopharmacology.

Genetic factors were shown to play a major role in both variation of treatment response and incidence of adverse effects to medication in affective disorders. Nevertheless, there is still a lack of therapygenetic studies, investigating the prediction of psychological therapy outcomes from genetic markers. Neuroplasticity and one of its mediators, brain-derived neurotrophic factor (BDNF), are potential research targets in this field. We aimed to investigate Tag SNP polymorphisms of the BDNF gene in depressed patients treated with cognitive behavioral therapy (CBT) in the context of a standardized 6-weeks outpatient rehabilitation program. Treatment response was assessed calculating the mean differences in BDI-II (Beck Depression Inventory) scores from admission to discharge. Six BDNF SNPs, including the Val66Met polymorphism (rs6265), were genotyped. Both genotypic data and BDI-II-scores at admission and discharge were available for 277 patients. Three SNPs, rs10501087 (p = 0.005, FDRp=0.015), rs11030104 (p = 0.006, FDRp=0.012), and the Val66Met polymorphism (rs6265, p<0.001, FDRp=0.006), were significantly associated with treatment response in depressed patients, even after multiple testing correction using the false discovery rate method (FDRp). We conclude that BDNF might serve as promising genetic marker for treatment response to psychological treatment in depression. However, due to our limited sample size, further studies are needed to disentangle the role of BDNF as potential therapygenetic marker.

Monoamino Oxidase A Gene Single-Nucleotide Polymorphisms and Methylation Status and the Risk of Violent Suicide Attempts in Affective Disorder Patients.

Background: When investigating the neurobiology of suicidal behavior, Monoamino Oxidase A (MAOA) is one of the prime suspects to consider. Interestingly, MAOA dysregulation has also been associated with violent behavior in previous publications. In the present study, we aimed to establish an association between polymorphisms of the MAOA gene and methylation status of the MAOA gene Exon I, and suicide attempts with violent methods in a sample of affective disorder patients. Methods: Eight hundred fourteen Caucasian affective disorder patients were assessed at the Department of Psychiatry and Psychotherapy of the Medical University Vienna, the Karl Landsteiner University for Health and Science and Zentren für seelische Gesundheit, BBRZ-Med Leopoldau. An assemblage of psychiatric interviews was performed (e.g., SCAN, HAMD, SBQ-R, CTQ) and DNA samples of peripheral blood cells were collected for Sequenom MassARRAY® iPLEX Gold genotyping and Multiplexed and Sensitive DNA Methylation Testing. Results: Female affective disorder patients with a history of violent suicide attempt were found to have a significantly increased frequency of the AA genotype in the rs5906957 single nucleotide polymorphism (p = 0.003). Furthermore, the MAOA gene exon I promoter region showed significantly decreased methylation in female violent suicide attempter(s) as opposed to female affective disorder patients who had no history of suicide attempt or no history of suicide attempt with violent method. Limitations: The small sample size hampers to reveal small genetic effects as to be expected in psychiatric disorders. Conclusions: This study offers promising findings about associations between the MAOA gene and violent suicide especially in women.

The Impact of COMT and Childhood Maltreatment on Suicidal Behaviour in Affective Disorders.

The inconsistent findings on the association between COMT (catecholamine-O-methyl-transferase) and suicidal behaviour gave reason to choose a clear phenotype description of suicidal behaviour and take childhood maltreatment as environmental factor into account. The aim of this candidate-gene-association study was to eliminate heterogeneity within the sample by only recruiting affective disorder patients and find associations between COMT polymorphisms and defined suicidal phenotypes. In a sample of 258 affective disorder patients a detailed clinical assessment (e.g. CTQ, SCAN, HAMD, SBQ-R, VI-SURIAS, LPC) was performed. DNA of peripheral blood samples was genotyped using TaqMan® SNP Genotyping Assays. We observed that the haplotype GAT of rs737865, rs6269, rs4633 is significantly associated with suicide attempt (p = 0.003 [pcorr = 0.021]), and that there is a tendency towards self-harming behaviour (p = 0.02 [pcorr = 0.08]) and also NSSI (p = 0.03 [pcorr = 0.08]), though the p values did not resist multiple testing correction. The same effect we observed with the 4-marker slide window haplotype, GATA of rs737865, rs6269, rs4633, rs4680 (p = 0.009 [pcorr = 0.045]). The findings support an association between the COMT gene and suicidal behaviour phenotypes with and without childhood maltreatment as environmental factor.

Influence of CRHR1 Polymorphisms and Childhood Abuse on Suicide Attempts in Affective Disorders: A GxE Approach.

Background: Previous studies have shown that the hypothalamus-pituitary-adrenal-axis (HPA-axis) is closely involved in the development of affective disorders. Given that early life events are also linked to dysregulation of the same system, there might be an association between childhood adversities and suicidal behavior in affective disorders, moderated by HPA-axis genes. We aimed to investigate a potential association between childhood trauma and previous suicide attempts in affective disorder patients, moderated by variants of the corticotropin-releasing hormone receptor 1 (CRHR1) gene. Methods: The current pilot study is part of an ongoing study on suicidal behavior in affective disorders (VieSAD). Two hundred fifty eight Caucasian affective disorder patients were assessed at the Department of Psychiatry and Psychotherapy of the Medical University Vienna and the Karl Landsteiner University for Health and Science. An assemblage of psychiatric interviews was performed (e.g., SCAN, HAMD, SBQ-R, CTQ) and DNA samples of peripheral blood cells were genotyped with TaqMan® SNP Genotyping Assays (rs7209436, rs4792887, rs110402, rs242924, and rs242939). Results: Neither genetic, nor haplotypic associations between CRHR1 polymorphisms and previous suicide attempts could be established for the present sample. Using a binary logistic regression model, significant gene-environment-interactions were found for the single nucleotide polymorphisms (SNPs) rs7209436 and rs110402, reflecting the impact of childhood trauma and CRHR1 polymorphisms on previous suicide attempts. Limitations: A larger sample size will be required to ultimately elucidate the link between childhood trauma and the HPA axis in suicidal behavior. Conclusion: This pilot study presents promising gene-environment-interaction findings in affective disorder patients with a history of suicide attempts.

Influence of Sex on Suicidal Phenotypes in Affective Disorder Patients with Traumatic Childhood Experiences.

OBJECTIVES: In the current study, we aimed to investigate the impact of childhood trauma on suicidal behaviour phenotypes in a group of patients with diagnosed affective disorder (unipolar or bipolar affective disorder). PATIENTS AND METHODS: Patients with and without a history of childhood abuse, measured by Childhood Trauma Questionnaire (CTQ), were assessed to explore risks for suicidal behaviour (including suicide attempt, self-harm and non-suicidal self-injury). The tested sample consisted of 258 patients (111 males and 147 females, in-patients and out-patients at the Department of Psychiatry and Psychotherapy, Medical University of Vienna and University Hospital Tulln, Lower Austria). Psychiatric diagnoses were derived from the SCAN (Schedules for Clinical Assessment in Neuropsychiatry) interview. In addition, patients were administered the Lifetime Parasuicidal Count (LPC), Suicidal Behaviour Questionnaire (SBQ-R), and Viennese Suicide Risk Assessment Scale (VISURIAS) questionnaires. RESULTS: In contrast to male suicide attempters, female suicide attempters showed both significantly higher total CTQ scores (p<0.001), and higher CTQ subscores (emotional, physical and sexual abuse, as well as emotional and physical neglect) in comparison to the non-suicidal control group. Besides, females with a history of self-harming behaviour (including suicidal intention) and Non-Suicidal-Self Injury (NSSI) had significantly higher CTQ total scores (p<0.001) than the control group. CONCLUSION: These findings suggest gender differences in suicidal behaviour after being exposed to childhood trauma.