Mapping the interplay of atrial fibrillation, brain structure, and cognitive dysfunction.

INTRODUCTION: Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. Understanding the cognitive sequelae and brain structural changes associated with AF is vital for addressing ensuing health care needs. METHODS AND RESULTS: We examined 1335 stroke-free individuals with AF and 2683 matched controls using neuropsychological assessments and multimodal neuroimaging. The analysis revealed that individuals with AF exhibited deficits in executive function, processing speed, and reasoning, accompanied by reduced cortical thickness, elevated extracellular free-water content, and widespread white matter abnormalities, indicative of small vessel pathology. Notably, brain structural differences statistically mediated the relationship between AF and cognitive performance. DISCUSSION: Integrating a comprehensive analysis approach with extensive clinical and magnetic resonance imaging data, our study highlights small vessel pathology as a possible unifying link among AF, cognitive decline, and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies. Highlights We investigated neuropsychological and multimodal neuroimaging data of 1335 individuals with atrial fibrillation (AF) and 2683 matched controls. Our analysis revealed AF-associated deficits in cognitive domains of attention, executive function, processing speed, and reasoning. Cognitive deficits in the AF group were accompanied by structural brain alterations including reduced cortical thickness and gray matter volume, alongside increased extracellular free-water content as well as widespread differences of white matter integrity. Structural brain changes statistically mediated the link between AF and cognitive performance, emphasizing the potential of structural imaging markers as a diagnostic tool in AF-related cognitive decline.

Early effect of thrombolysis on structural brain network organisation after anterior-circulation stroke in the randomized WAKE-UP trial.

The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE-UP trial, comparing 127 imaging-selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio-topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network-informed imaging biomarkers and improved prognostication in ischemic stroke.

Independent external validation of a stroke recurrence score in patients with embolic stroke of undetermined source.

BACKGROUND: Embolic stroke of undetermined source (ESUS) accounts for a substantial proportion of ischaemic strokes. A stroke recurrence score has been shown to predict the risk of recurrent stroke in patients with ESUS based on a combination of clinical and imaging features. This study aimed to externally validate the performance of the ESUS recurrence score using data from a randomized controlled trial. METHODS: The validation dataset consisted of eligible stroke patients with available magnetic resonance imaging (MRI) data enrolled in the PreDAFIS sub-study of the MonDAFIS study. The score was calculated using three variables: age (1 point per decade after 35 years), presence of white matter hyperintensities (2 points), and multiterritorial ischaemic stroke (3 points). Patients were assigned to risk groups as described in the original publication. The model was evaluated using standard discrimination and calibration methods. RESULTS: Of the 1054 patients, 241 (22.9%) were classified as ESUS. Owing to insufficient MRI quality, three patients were excluded, leaving 238 patients (median age 65.5 years [IQR 20.75], 39% female) for analysis. Of these, 30 (13%) patients experienced recurrent ischaemic stroke or transient ischemic attack (TIA) during a follow-up period of 383 patient-years, corresponding to an incidence rate of 7.8 per 100 patient-years (95% CI 5.3-11.2). Patients with an ESUS recurrence score value of ≥ 7 had a 2.46 (hazard ratio (HR), 95% CI 1.02-5.93) times higher risk of stroke recurrence than patients with a score of 0-4. The cumulative probability of stroke recurrence in the low-(0-4), intermediate-(5-6), and high-risk group (≥ 7) was 9%, 13%, and 23%, respectively (log-rank test, χ2 = 4.2, p = 0.1). CONCLUSIONS: This external validation of a published scoring system supports a threshold of ≥ 7 for identifying ESUS patients at high-risk of stroke recurrence. However, further adjustments may be required to improve the model's performance in independent cohorts. The use of risk scores may be helpful in guiding extended diagnostics and further trials on secondary prevention in patients with ESUS. TRIAL REGISTRATION: Clinical Trials, NCT02204267. Registered 30 July 2014, https://clinicaltrials.gov/ct2/show/NCT02204267 .

Association of stroke lesion shape with newly detected atrial fibrillation - Results from the MonDAFIS study.

Paroxysmal Atrial fibrillation (AF) is often clinically silent and may be missed by the usual diagnostic workup after ischemic stroke. We aimed to determine whether shape characteristics of ischemic stroke lesions can be used to predict AF in stroke patients without known AF at baseline. Lesion shape quantification on brain MRI was performed in selected patients from the intervention arm of the Impact of standardized MONitoring for Detection of Atrial Fibrillation in Ischemic Stroke (MonDAFIS) study, which included patients with ischemic stroke or TIA without prior AF. Multiple morphologic parameters were calculated based on lesion segmentation in acute brain MRI data. Multivariate logistic models were used to test the association of lesion morphology, clinical parameters, and AF. A stepwise elimination regression was conducted to identify the most important variables. A total of 755 patients were included. Patients with AF detected within 2 years after stroke (n = 86) had a larger overall oriented bounding box (OBB) volume (p = 0.003) and a higher number of brain lesion components (p = 0.008) than patients without AF. In the multivariate model, OBB volume (OR 1.72, 95%CI 1.29-2.35, p < 0.001), age (OR 2.13, 95%CI 1.52-3.06, p < 0.001), and female sex (OR 2.45, 95%CI 1.41-4.31, p = 0.002) were independently associated with detected AF. Ischemic lesions in patients with detected AF after stroke presented with a more dispersed infarct pattern and a higher number of lesion components. Together with clinical characteristics, these lesion shape characteristics may help in guiding prolonged cardiac monitoring after stroke.

Long-term recovery of upper limb motor function and self-reported health: results from a multicenter observational study 1 year after discharge from rehabilitation.

BACKGROUND: Impaired motor functions after stroke are common and negatively affect patients' activities of daily living and quality of life. In particular, hand motor function is essential for daily activities, but often returns slowly and incompletely after stroke. However, few data are available on the long-term dynamics of motor recovery and self-reported health status after stroke. The Interdisciplinary Platform for Rehabilitation Research and Innovative Care of Stroke Patients (IMPROVE) project aims to address this knowledge gap by studying the clinical course of recovery after inpatient rehabilitation. METHODS: In this prospective observational longitudinal multicenter study, patients were included towards the end of inpatient rehabilitation after ischemic or hemorrhagic stroke. Follow-up examination was performed at three, six, and twelve months after enrollment. Motor function was assessed by the Upper Extremity Fugl-Meyer Assessment (FMA), grip and pinch strength, and the nine-hole peg test. In addition, Patient-Reported Outcomes Measurement Information System 10-Question Short Form (PROMIS-10) was included. Linear mixed effect models were fitted to analyze change over time. To study determinants of hand motor function, patients with impaired hand function at baseline were grouped into improvers and non-improvers according to hand motor function after twelve months. RESULTS: A total of 176 patients were included in the analysis. Improvement in all motor function scores and PROMIS-10 was shown up to 1 year after inpatient rehabilitation. FMA scores improved by an estimate of 5.0 (3.7-6.4) points per year. In addition, patient-reported outcome measures increased by 2.5 (1.4-3.6) and 2.4 (1.4-3.4) per year in the physical and mental domain of PROMIS-10. In the subgroup analysis non-improvers showed to be more often female (15% vs. 55%, p = 0.0155) and scored lower in the Montreal Cognitive Assessment (25 [23-27] vs. 22 [20.5-24], p = 0.0252). CONCLUSIONS: Continuous improvement in motor function and self-reported health status is observed up to 1 year after inpatient stroke rehabilitation. Demographic and clinical parameters associated with these improvements need further investigation. These results may contribute to the further development of the post-inpatient phase of stroke rehabilitation. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT04119479).

G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic.

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive neurodegenerative disease caused by point mutations in the gene for neuroserpin, a serine protease inhibitor of the nervous system. Different mutations are known that are responsible for mutant neuroserpin polymerization and accumulation as inclusion bodies in many cortical and subcortical neurons, thereby leading to cell death, dementia and epilepsy. Many efforts have been undertaken to elucidate the molecular pathways responsible for neuronal death. Most investigations have concentrated on analysis of intracellular mechanisms such as endoplasmic reticulum (ER) stress, ER-associated protein degradation (ERAD) and oxidative stress. We have generated a HEK-293 cell model of FENIB by overexpressing G392E-mutant neuroserpin and in this study we examine trafficking and toxicity of this polymerogenic variant. We observed that a small fraction of mutant neuroserpin is secreted via the ER-to-Golgi pathway, and that this release can be pharmacologically regulated. Overexpression of the mutant form of neuroserpin did not stimulate cell death in the HEK-293 cell model. Finally, when treating primary hippocampal neurons with G392E neuroserpin polymers, we did not detect cytotoxicity or synaptotoxicity. Altogether, we report here that a polymerogenic mutant form of neuroserpin is secreted from cells but is not toxic in the extracellular milieu.

Preserved structural connectivity mediates the clinical effect of thrombolysis in patients with anterior-circulation stroke.

Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke aims to restore compromised blood flow and prevent further neuronal damage. Despite the proven clinical efficacy of this treatment, little is known about the short-term effects of systemic thrombolysis on structural brain connectivity. In this secondary analysis of the WAKE-UP trial, we used MRI-derived measures of infarct size and estimated structural network disruption to establish that thrombolysis is associated not only with less infarct growth, but also with reduced loss of large-scale connectivity between grey-matter areas after stroke. In a causal mediation analysis, infarct growth mediated a non-significant 8.3% (CI95% [-8.0, 32.6]%) of the clinical effect of thrombolysis on functional outcome. The proportion mediated jointly through infarct growth and change of structural connectivity, especially in the border zone around the infarct core, however, was as high as 33.4% (CI95% [8.8, 77.4]%). Preservation of structural connectivity is thus an important determinant of treatment success and favourable functional outcome in addition to lesion volume. It might, in the future, serve as an imaging endpoint in clinical trials or as a target for therapeutic interventions.

Protocol for a multicenter observational prospective study of functional recovery from stroke beyond inpatient rehabilitation - The Interdisciplinary Platform for Rehabilitation Research and Innovative Care of Stroke Patients (IMPROVE).

INTRODUCTION: Stroke and its long-term consequences pose major challenges for the lives of those affected and healthcare systems. Neurological rehabilitation therefore primarily attempts to improve function in order to increase independence in activities of daily living, and to enable social participation. There is only scarce data on dynamics of functional recovery after patients discharge from inpatient neurological rehabilitation. Even less is known about the patient's perspective on long-term recovery from stroke. The Interdisciplinary Platform for Rehabilitation Research and Innovative Care of Stroke Patients (IMPROVE) aims to address this knowledge gap by providing new insights into the dynamics and extent of functional recovery from stroke beyond inpatient rehabilitation treatment. METHODS: We provide the protocol for an observational, longitudinal, multicenter study conducted in an Universitary Stroke Center in cooperation with five Neurological Rehabilitation Centers in Northern Germany. Patients who suffered from ischemic or hemorrhagic stroke will be enrolled by the end of inpatient rehabilitation and followed up to 1 year. In addition, a group of chronic stroke patients and a group of craniocerebral trauma patients will be enrolled as a comparison group. Data on stroke characteristics, vascular risk factors, co-morbidities, social support, and demographics will be recorded. Comprehensive clinical evaluation will be performed at baseline, three, six, and twelve months after enrollment. The assessments and scores used reflect the three components of the International Classification of Functioning, Disability and Health (ICF), some of them are tests regularly used in rehabilitation settings. Tests of motor function, cognition, and mood are included, as are tests of self-reported health-related quality of life. Primary outcome measure is a hand motor score, built by the sum of the hand items of the Fugl-Meyer Assessment as an objective measurement of hand function at 12 months after enrollment. Predictors of the primary outcome will be analyzed using linear regression analysis. PERSPECTIVE: The results of IMPROVE will inform about the long-term dynamics of functional stroke recovery after patients' discharge from inpatient rehabilitation and will provide insights into the association of clinical and demographic factors with recovery of function. TRIAL REGISTRATION: The protocol is registered at ClinicalTrials.gov (NCT04119479).