The extracellular deposition of β-amyloid (Aβ) is one of the major characteristics in Alzheimer´s disease (AD). The “spreading hypothesis” suggests that a pathological protein (similar to prions) spreads over the entire brain. The aim of the present study was to use organotypic brain slices of postnatal day 8–10 mice. Using collagen hydrogels, we applied different Aβ peptides onto brain slices and analyzed spreading as well as glial reactions after eight weeks of incubation. Our data showed that from all tested Aβ peptides, human Aβ₄₂ had the most potent activity to spread over into adjacent “target” areas. This effect was potentiated when brain slices from transgenic AD mice (APP_SweDI) were cultured. When different brain areas were connected to the “target slice” the spreading activity was more intense, originating from ventral striatum and brain stem. Reactive glial-fibrillary acidic protein (GFAP) astrogliosis increased over time, but Aβ depositions co-localized only with Iba1+ microglia but not with astrocytes. Application of human Aβ₄₂ did not cause a degeneration of cholinergic neurons. We concluded that human Aβ₄₂ spreads over into other “target areas”, causing activation of glial cells. Most of the spread Aβ₄₂ was taken up by microglia, and thus toxic free Aβ could not damage cholinergic neurons.

Introduction: The progression of diabetes status in post-stroke patients remains under-investigated, particularly regarding new treatments for type II diabetes mellitus (DM II), like glucagon-like peptide 1 receptor agonists (GLP-1-RA) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, which have not been studied in the post-stroke setting. Patients and methods: Eight hundred eighty-four consecutive ischemic stroke patients recruited to our prospective STROKE-CARD Registry were assessed concerning their glycemic status at baseline (normoglycemia, prediabetes, DM II) and change over time within 1 year follow-up. Multivariate logistic regression was performed to identify factors associated with transitioning from normoglycemia to prediabetes or DM II. Additionally, we reviewed ongoing clinical trials for GLP-1-RA and SGLT-2 inhibitors in the context of acute ischemic stroke. Results: At baseline, 44.6% (n = 394) of individuals had normoglycemia, 33.9% (n = 300) were prediabetic, and 21.5% had DM II (n = 190). After 1 year, normoglycemia decreased by 12.1 percentage points (n = 107), whereas prediabetes and DM II increased by 10.2 percentage (n = 90) points and 1.9 percentage points (n = 17), respectively. Statin therapy was the only significant risk factor for progression. 23.4% (n = 207) of our cohort would have met eligibility criteria for a recent trial on semaglutide in obese non-diabetics with prior cardiovascular disease. However, only one ongoing trial aims at evaluating short-term cardiovascular risk reduction in stroke patients. Discussion: GPrediabetes and DM II are frequent in ischemic stroke patients. Even within an intensified post-stroke disease management setting, a considerable amount of stroke survivors convert to prediabetes or DM II within the first year. Our results demonstrate a notable proportion of patients qualifying inclusion in studies examining the efficacy of GLP-1-RA agonists and SGLT-2 inhibitors in secondary prevention. Conclusion: Given the high prevalence and progression of prediabetes and DM II in stroke survivors, there is a need for clinical trials evaluating the use of GLP-1-RA and SGLT-2 inhibitors in this population.

Background: Recent advances in acute stroke therapy improved short-term outcome, but some of this benefit may be lost due to post-stroke complications, including fractures. Aims: We assessed the incidence of fractures before and after stroke and transient ischemic attack (TIA), the risk factors for fractures, and the consequences for mortality, functional outcome, and quality of life. Methods: Consecutive patients with acute ischemic stroke or TIA from the prospective STROKE-CARD Registry and the randomized controlled STROKE-CARD trial and its long-term follow-up were analyzed. We prospectively assessed all fractures using self-report and documentation, records of hospitals and general practitioners, and electronic health records with all radiographs. Results: A total of 2513 patients were included (median age = 72 years (interquartile range, IQR = 61–79), 39.2% female). In the first year after the event, 145 individuals (5.8%, 95% confidence interval (CI) = 4.9%–6.7%) experienced 152 fractures corresponding to an incidence rate of 61.87 (95% CI = 52.04–71.71) per 1000 person-years. Rates were similar after stroke and TIA (60.84 and 72.28 per 1000 person-years). The incidence of fractures was more than five times higher compared to the general population (age- and sex-adjusted hazard ratio (HR) for first fracture 5.36, 95% CI = 2.49–11.52). The risk of fractures 1 year before stroke/TIA was also increased (HR = 2.99, 95% CI = 1.39–6.42). Stroke/TIA further increased the risk of fractures as documented by a comparison between fractures 1 year before and 1 year after the event (age- and sex-adjusted risk ratio = 1.69, 95% CI = 1.10–2.58). The main risk factors for fractures were falls and osteoporosis. Fracture after stroke/TIA was associated with death (adjusted odds ratio (aOR) = 2.16, 95% CI = 1.20–3.89), inability to walk (aOR = 2.06, 95% CI = 1.08–3.93), and poor quality of life. Conclusions: Patients with ischemic stroke and TIA are at high risk for future fractures. Fracture after stroke/TIA is strongly associated with death, poor functional outcome, and reduced health-related quality of life. Therefore, there is a need to incorporate fracture prevention into post-stroke care to improve patient outcomes. Trial Registration: STROKE-CARD Registry (NCT04582825, https://clinicaltrials.gov/study/NCT04582825 ); STROKE-CARD trial (NCT02156778, https://clinicaltrials.gov/study/NCT02156778 ); STROKE-CARD long-term follow-up (NCT04205006, https://clinicaltrials.gov/study/NCT04205006 ).

Background: Women show higher age‐standardized mortality rates for ischemic stroke. Nevertheless, women are underrepresented in secondary stroke prevention trials. Our analysis investigated contributors to reduced study participation among women in a comprehensive stroke center in Austria. Methods: The population‐based Tyrolean Stroke Pathway database was used to describe sex distribution in patients with ischemic stroke in the region and at the study site. Screening logs from 3 secondary stroke prevention studies at the Medical University of Innsbruck were analyzed containing information on age, self‐reported sex, and causes for nonparticipation. Binary and multinomial logistic regression were performed to calculate odds ratios (ORs) and 95% CIs. Results: Women constituted 45.6% of all patients with ischemic stroke in the federal region and 43.1% at the study site. Of 4511 patients screened, 68.1% were included in at least 1 stroke trial, 39.5% of whom were female. Screened women were older than screened men, median age (interquartile range) of 76 (66–83) versus 72 (61–80) years. Women showed higher odds than men of receiving comfort terminal care (OR, 1.53 [95% CI, 1.14–2.05]), being unable to provide informed consent (OR, 1.95 [95% CI, 1.54–2.47]) due to aphasia (OR, 2.79 [95% CI, 1.91–4.06]) or cognitive impairment (OR, 1.96 [95% CI, 1.30–2.95]), and being ineligible for study participation based on inclusion and exclusion criteria (OR, 1.28 [95% CI, 1.04–1.58]). When adjusting for age, women were not more likely than men to refuse study participation (OR, 1.09 [95% CI, 0.84–1.43]). Conclusions: Female sex was associated with higher odds of exclusion from studies due to comorbidities and more severe neurological deficits. However, in our analysis women were not more likely to refuse study participation.

Introduction: Complications may secondarily impair functional outcome after stroke and transient ischemic attack (TIA). Here, we estimated the population-level impact of complications on long-term functional outcome to describe their combined impact and identify the most impactful complications. Patients and methods: Patients admitted for acute ischemic stroke or TIA (ABCD2 score ⩾ 3) and discharged without severe disability were followed-up for occurence of 12 in-hospital and 26 post-discharge complications. Population-level impact of complications on the primary endpoint of non-excellent functional outcome (modified Rankin Scale (mRS) > 1) at end of follow-up 12 months after stroke was assessed by population attributable fraction (PAF). This cohort study was performed at a single European comprehensive stroke center and nested within a randomized controlled trial of intensified post-stroke care, STROKE-CARD. Results: Among 1705 patients aged 69.4 ± 13.6 years (59.8% male), 36.8% (95% confidence interval: 34.5, 39.2) had non-excellent outcome at 12 months, 21.3% (19.4, 23.3) had unfavorable outcome (mRS > 2), and functional worsening occurred in-hospital in 2.6% (2.0, 3.6) and post-discharge in 20.3% (18.4, 22.3). Non-excellent 1-year functional outcome was predicted in-hospital by occurrence of recurrent stroke, neurological worsening, and infections (PAF: 0.6%–3.2%). Post-discharge, 12 complications significantly predicted outcome, and pain, severe fatigue, falls, and depression were most impactful (PAF: 5.4%–13.0%). Together, in-hospital complications accounted for 7.6% and post-discharge complications for 31.8% of non-excellent outcome, whereas acute therapy (thrombolysis and/or thrombectomy) and STROKE-CARD care accounted for 8.0% and 14.5% of excellent outcomes. In moderate and severe stroke (NIHSS > 5), acute therapy was the strongest predictor of excellent outcome (PAF: 29.1%). Results were consistent or stronger in patients with TIA, without prestroke disability, or in the regional catchment area, and when focusing on unfavorable outcome or worsening in mRS. Discussion: Complications were responsible for more than one third of non-excellent 1-year functional outcome with pain, severe fatigue, depression, and falls most impactful. Complications rivaled the impact of acute therapy and determined functional outcome after TIA as well as after stroke. Conclusion: Effective prevention and treatment of complications may substantially improve long-term functional outcomes after stroke and TIA.

Background: An increased risk of femoral fractures after ischemic stroke (IS) and transient ischemic attack (TIA) has been shown previously. However, it remains unclear whether the ischemic cerebral event is directly associated with the risk of femoral fractures. Aims: The aim of this study was (1) to assess the association between the frequency of femoral fractures in patient with IS and TIA, and (2) to compare the risk of femoral fractures to the Austrian general population. Methods: Population-based observational secondary analysis of the Austrian Stroke Cohort to assess the incidence of femoral fractures in the year after IS/TIA compared with the year before, and both intervals compared with the Austrian general population. All patients ⩾20 years treated for IS/TIA in Austria between 1 January 2016 and 31 December 2018 were identified using medical record linkage. Patient trajectories were reconstructed from 1 January 2015 to 31 December 2019 to have a 1-year observational period before and after the event. Femoral fractures within 1 year after IS/TIA compared to 1 year before IS/TIA were analyzed using McNemar test and Cox regression analysis considering sex and age. The 1-year age- and sex-adjusted relative risk of femoral fractures was calculated for patients with IS/TIA and compared to the Austrian general population. Results: A total of 48,996 survivors of IS (n = 34,997) and TIA (n = 13,999) were included. The incidence of femoral fractures increased significantly from the year before the IS/TIA (8.9 per 1000 person-years, 95% CI 7.7–10.2) to the year after the event (11.8 per 1000 person-years, 95% CI 10.1–13.5; p = 0.022). Compared to the Austrian general population including 21.1 million patient-years at risk and 37,436 femoral fractures, the risk of femoral fractures was increased both in the year before (RR 2.08, 95% CI 2.06–2.11) and after (RR 3.52, 95% CI 3.48–3.56) the IS/TIA. Conclusion: The risk of femoral fractures was found to be increased in the year following an IS/TIA, indicating a direct association with the IS/TIA event. Data access statement: Reconstruction of medical record linkage and individual patient trajectory reconstruction were reported previously. Data from individual patient trajectories was used for this analysis.