Correlation of Cognitive Reappraisal and the Microstructural Properties of the Forceps Minor: A Deductive Exploratory Diffusion Tensor Imaging Study.

Cognitive reappraisal (CR) is a mechanism for emotion regulation, and the prefrontal cortex (PFC) plays a central role in the regulation of emotions. We tested the hypothesis of an association between CR function and microstructural properties of forceps minor (a commissural bundle within the PFC) in healthy subjects (HS). We analyzed a population of 65 young HS of a public dataset. The diffusion tensor imaging (DTI) sequence of every subject was analyzed to extract the derived shape (diameter and volume) and DTI metrics in terms of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) of the forceps minor. The CR subscale of the German version of the Emotion Regulation Questionnaire (ERQ) was used for CR assessment. The Shapiro-Wilk test was applied to test the assumption of normality in all these parameters, adopting a statistical threshold at p < 0.05. Whenever appropriate a non-parametric two-tailed partial correlation analysis was applied to test for correlations between the CR ERQ score and the derived shape and DTI metrics, including age and sex as confounders, adopting a statistical threshold at p < 0.05. The non-parametric two-tailed partial correlation analysis revealed a mildly significant correlation with FA (ρ = 0.303; p = 0.016), a weakly significant negative correlation with MD (ρ = - 0.269; p = 0.033), and a mildly significant negative correlation with RD (ρ = - 0.305; p = 0.015). These findings suggest a correlation between DTI microstructural properties of forceps minor and CR.

Unraveling the gut-brain connection: The association of microbiota-linked structural brain biomarkers with behavior and mental health.

AIM: The gut microbiota can influence human behavior. However, due to the massive multiple-testing problem, research into the relationship between microbiome ecosystems and the human brain faces drawbacks. This problem arises when attempting to correlate thousands of gut bacteria with thousands of brain voxels. METHODS: We performed brain magnetic resonance imaging (MRI) scans on 133 participants and applied machine-learning algorithms (Ridge regressions) combined with permutation tests. Using this approach, we were able to correlate specific gut bacterial families with brain MRI signals, circumventing the difficulties of massive multiple testing while considering sex, age, and body mass index as confounding factors. RESULTS: The relative abundance (RA) of the Selenomonadaceae, Clostridiaceae, and Veillonellaceae families in the gut was associated with altered cerebellar, visual, and frontal T2-mapping and diffusion tensor imaging measures. Conversely, decreased relative abundance of the Eubacteriaceae family was also linked to T2-mapping values in the cerebellum. Significantly, the brain regions associated with the gut microbiome were also correlated with depressive symptoms and attentional deficits. CONCLUSIONS: Our analytical strategy offers a promising approach for identifying potential brain biomarkers influenced by gut microbiota. By gathering a deeper understanding of the microbiota-brain connection, we can gain insights into the underlying mechanisms and potentially develop targeted interventions to mitigate the detrimental effects of dysbiosis on brain function and mental health.

Early and Delayed Infarct Growth in Patients Undergoing Mechanical Thrombectomy: A Prospective, Serial MRI Study.

BACKGROUND: We studied the evolution over time of diffusion weighted imaging (DWI) lesion volume and the factors involved on early and late infarct growth (EIG and LIG) in stroke patients undergoing endovascular treatment (EVT) according to the final revascularization grade. METHODS: This is a prospective cohort of patients with anterior large artery occlusion undergoing EVT arriving at 1 comprehensive stroke center. Magnetic resonance imaging was performed on arrival (pre-EVT), <2 hours after EVT (post-EVT), and on day 5. DWI lesions and perfusion maps were evaluated. Arterial revascularization was assessed according to the modified Thrombolysis in Cerebral Infarction (mTICI) grades. We recorded National Institutes of Health Stroke Scale at arrival and at day 7. EIG was defined as (DWI volume post-EVT-DWI volume pre-EVT), and LIG was defined as (DWI volume at 5d-DWI volume post-EVT). Factors involved in EIG and LIG were tested via multivariable lineal models. RESULTS: We included 98 patients (mean age 70, median National Institutes of Health Stroke Scale score 17, final mTICI≥2b 86%). Median EIG and LIG were 48 and 63.3 mL in patients with final mTICI<2b, and 3.6 and 3.9 cc in patients with final mTICI≥2b. Both EIG and LIG were associated with higher National Institutes of Health Stroke Scale at day 7 (ρ=0.667; P<0.01 and ρ=0.614; P<0.01, respectively). In patients with final mTICI≥2b, each 10% increase in the volume of DWI pre-EVT and each extra pass leaded to growths of 9% (95% CI, 7%-10%) and 14% (95% CI, 2%-28%) in the DWI volume post-EVT, respectively. Furthermore, each 10% increase in the volume of DWI post-EVT, each extra pass, and each 10 mL increase in TMax6s post-EVT were associated with growths of 8% (95% CI, 6%-9%), 9% (95% CI, 0%-19%), and 12% (95% CI, 5%-20%) in the volume of DWI post-EVT, respectively. CONCLUSIONS: Infarct grows during and after EVT, especially in nonrecanalizers but also to a lesser extent in recanalizers. In recanalizers, number of passes and DWI volume influence EIG, while number of passes, DWI, and hypoperfused volume after the procedure determine LIG.

Adjunct Thrombolysis Enhances Brain Reperfusion following Successful Thrombectomy.

OBJECTIVE: This study was undertaken to investigate whether adjunct alteplase improves brain reperfusion following successful thrombectomy. METHODS: This single-center, randomized, double-blind, placebo-controlled study included 36 patients (mean [standard deviation] = 70.8 [13.5] years old, 18 [50%] women) with large vessel occlusion undergoing thrombectomy resulting in near-normal (expanded Thrombolysis in Cerebral Infarction [eTICI] b50/67/2c, n = 23, 64%) or normal angiographic reperfusion (eTICI 3, n = 13, 36%). Seventeen patients were randomized to intra-arterial alteplase (0.225mg/kg), and 19 received placebo. At 48 hours, patients had brain perfusion/diffusion-weighted magnetic resonance imaging (MRI) and MRI-spectroscopy. The primary outcome was the difference in the proportion of patients with areas of hypoperfusion on MRI. Secondary outcomes were the infarct expansion ratio (final to initial infarction volume), and the N-acetylaspartate (NAA) peak relative to total creatine as a marker of neuronal integrity. RESULTS: The prevalence of hypoperfusion was 24% with intra-arterial alteplase, and 58% with placebo (adjusted odds ratio = 0.20, 95% confidence interval [CI] = 0.04-0.91, p = 0.03). Among 14 patients with final eTICI 3 scores, hypoperfusion was found in 1 of 7 (14%) in the alteplase group and 3 of 7 (43%) in the placebo group. Abnormal brain perfusion was associated with worse functional outcome at day 90. Alteplase significantly reduced the infarct expansion ratio compared with placebo (median [interquartile range (IQR)] = 0.7 [0.5-1.2] vs 3.2 [1.8-5.7], p = 0.01) and resulted in higher NAA peaks (median [IQR] = 1.13 [0.91-1.36] vs 1.00 [0.74-1.22], p < 0.0001). INTERPRETATION: There is a high prevalence of areas of hypoperfusion following thrombectomy despite successful reperfusion on angiography. Adjunct alteplase enhances brain reperfusion, which results in reduced expansion of the infarction and improved neuronal integrity. ANN NEUROL 2022;92:860-870.

Magnetic resonance imaging as a predictor of therapeutic response to pasireotide in acromegaly.

OBJECTIVE: Hyperintensity signal in T2-weighted magnetic resonance imaging (MRI) has been related to better therapeutic response during pasireotide treatment in acromegaly. The aim of the study was to evaluate T2 MRI signal intensity and its relation with pasireotide therapeutic effectiveness in real-life clinical practice. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective multicentre study including acromegaly patients treated with pasireotide. Adenoma T2-weighted MRI signal at diagnosis was qualitatively classified as iso-hyperintense or hypointense. Insulin-like growth factor (IGF-I), growth hormone (GH) and tumour volume reduction were assessed after 6 and 12 months of treatment and its effectiveness evaluated according to baseline MRI signal. Hormonal response was considered 'complete' when normalization of IGF-I levels was achieved. Significant tumour shrinkage was defined as a volume reduction of ≥25% from baseline. RESULTS: Eighty-one patients were included (48% women, 50 ± 1.5 years); 93% had previously received somatostatin receptor ligands (SRLs) treatment. MRI signal was hypointense in 25 (31%) and hyperintense in 56 (69%) cases. At 12 months of follow-up, 42/73 cases (58%) showed normalization of IGF-I and 37% both GH and IGF-I. MRI signal intensity was not associated with hormonal control. 19/51 cases (37%) presented a significant tumour volume shrinkage, 16 (41%) from the hyperintense group and 3 (25%) from the hypointense. CONCLUSIONS: T2-signal hyperintensity was more frequently observed in pasireotide treated patients. Almost 60% of SRLs resistant patients showed a complete normalization of IGF-I after 1 year of pasireotide treatment, regardless of the MRI signal. There was also no difference in the percentage tumour shrinkage over basal residual volume between the two groups.

Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study.

INTRODUCTION: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. METHODS: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0-1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. RESULTS: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954-1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932-0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989-0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9-96%) of the treatment effect. CONCLUSION: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

Aortic valve Replacement compared to Transcatheter Implant and its relationship with COgnitive Impairment (ARTICO) evaluated with neuropsychological and advanced neuroimaging: a longitudinal cohort study.

BACKGROUND: Aortic stenosis is the most common valvulopathy in Western countries. The treatment of choice had been surgery aortic valve replacement (SAVR), but the improvement in endovascular approaches as transcatheter aortic valve implantation (TAVI), initially reserved for patients with very high surgical risk, has been extended to high and intermediate, and recently also to low-risk patients. Stroke and vascular cognitive impairment are the most important complications. It is not entirely clear which technique is best to avoid these complications as well as their impact. Our goal is to evaluate changes in cognitive performance in the early (1-month) and late (1-year) postoperative period in patients undergoing SAVR or TAVI, by extensive neuropsychological study (NRP) and advanced Magnetic Resonance Imaging (MRI). Specifically, to compare early and late cognitive changes after the intervention between both groups, the occurrence of stroke during follow-up and to compare the appearance of silent vascular lesions and changes in brain activity and functional connectivity with functional MRI during follow-up between both groups. METHODS/DESIGN: Prospective longitudinal cohort study. A non-selected representative sample of 80 subjects, 40 SAVR and 40 TAVI to obtain a final sample of 36 eligible subjects in each group, ranging from 70 to 85 years old, with indication for aortic replacement and intermediate or high surgical risk will be studied. At baseline, within one month before the treatment, all individuals will undergo an extensive NRP and advanced MRI study. These studies will also be performed 1-month and 1-year after treatment, to assess the appearance of new vascular lesions, as well as changes in cognitive performance with respect to baseline. DISCUSSION: This study aims to evaluate changes in cognitive performance as well as both clinical and silent vascular events occurring in the early (1-month) and late (1-year) periods after SAVR and TAVI. We will also analyze the correlation between neuropsychological and neuroimaging approaches in order to evaluate cognition. Therefore, it may provide high-quality data of cognitive changes and vascular events for both techniques, and be useful to tailor interventions to individual characteristics and ultimately aiding in decision-making. TRIAL REGISTRATION: This study is register in Clinicaltrials.gov (NCT05235529) on 11th February 2022.

The effect of external stimulation on functional networks in the aging healthy human brain.

Understanding the brain changes occurring during aging can provide new insights for developing treatments that alleviate or reverse cognitive decline. Neurostimulation techniques have emerged as potential treatments for brain disorders and to improve cognitive functions. Nevertheless, given the ethical restrictions of neurostimulation approaches, in silico perturbation protocols based on causal whole-brain models are fundamental to gaining a mechanistic understanding of brain dynamics. Furthermore, this strategy could serve to identify neurophysiological biomarkers differentiating between age groups through an exhaustive exploration of the global effect of all possible local perturbations. Here, we used a resting-state fMRI dataset divided into middle-aged (N =310, <65 years) and older adults (N =310, $\geq $65) to characterize brain states in each group as a probabilistic metastable substate (PMS) space. We showed that the older group exhibited a reduced capability to access a metastable substate that overlaps with the rich club. Then, we fitted the PMS to a whole-brain model and applied in silico stimulations in each node to force transitions from the brain states of the older- to the middle-aged group. We found that the precuneus was the best stimulation target. Overall, these findings could have important implications for designing neurostimulation interventions for reversing the effects of aging on whole-brain dynamics.

The Longitudinal Changes in Subcutaneous Abdominal Tissue and Visceral Adipose Tissue Volumetries Are Associated with Iron Status.

Excess iron is known to trigger adipose tissue dysfunction and insulin resistance. Circulating markers of iron status have been associated with obesity and adipose tissue in cross-sectional studies. We aimed to evaluate whether iron status is linked to changes in abdominal adipose tissue longitudinally. Subcutaneous abdominal tissue (SAT) and visceral adipose tissue (VAT) and its quotient (pSAT) were assessed using magnetic resonance imaging (MRI), at baseline and after one year of follow-up, in 131 (79 in follow-up) apparently healthy subjects, with and without obesity. Insulin sensitivity (euglycemic- hyperinsulinemic clamp) and markers of iron status were also evaluated. Baseline serum hepcidin (p = 0.005 and p = 0.002) and ferritin (p = 0.02 and p = 0.01)) were associated with an increase in VAT and SAT over one year in all subjects, while serum transferrin (p = 0.01 and p = 0.03) and total iron-binding capacity (p = 0.02 and p = 0.04) were negatively associated. These associations were mainly observed in women and in subjects without obesity, and were independent of insulin sensitivity. After controlling for age and sex, serum hepcidin was significantly associated with changes in subcutaneous abdominal tissue index (iSAT) (ß = 0.406, p = 0.007) and visceral adipose tissue index (iVAT) (ß = 0.306, p = 0.04), while changes in insulin sensitivity (ß = 0.287, p = 0.03) and fasting triglycerides (ß = -0.285, p = 0.03) were associated with changes in pSAT. These data indicated that serum hepcidin are associated with longitudinal changes in SAT and VAT, independently of insulin sensitivity. This would be the first prospective study evaluating the redistribution of fat according to iron status and chronic inflammation.

Carotid Artery Plaque Calcifications: Lessons From Histopathology to Diagnostic Imaging.

The role of calcium in atherosclerosis is controversial and the relationship between vascular calcification and plaque vulnerability is not fully understood. Although calcifications are present in ≈50% to 60% of carotid plaques, their association with cerebrovascular ischemic events remains unclear. In this review, we summarize current understanding of carotid plaque calcification. We outline the role of calcium in atherosclerotic carotid disease by analyzing laboratory studies and histopathologic studies, as well as imaging findings to understand clinical implications of carotid artery calcifications. Differences in mechanism of calcium deposition express themselves into a wide range of calcification phenotypes in carotid plaques. Some patterns, such as rim calcification, are suggestive of plaques with inflammatory activity with leakage of the vasa vasourm and intraplaque hemorrhage. Other patterns such as dense, nodular calcifications may confer greater mechanical stability to the plaque and reduce the risk of embolization for a given degree of plaque size and luminal stenosis. Various distributions and patterns of carotid plaque calcification, often influenced by the underlying systemic pathological condition, have a different role in affecting plaque stability. Modern imaging techniques afford multiple approaches to assess geometry, pattern of distribution, size, and composition of carotid artery calcifications. Future investigations with these novel technologies will further improve our understanding of carotid artery calcification and will play an important role in understanding and minimizing stroke risk in patients with carotid plaques.

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.

Whole-Brain Dynamics in Aging: Disruptions in Functional Connectivity and the Role of the Rich Club.

Normal aging causes disruptions in the brain that can lead to cognitive decline. Resting-state functional magnetic resonance imaging studies have found significant age-related alterations in functional connectivity across various networks. Nevertheless, most of the studies have focused mainly on static functional connectivity. Studying the dynamics of resting-state brain activity across the whole-brain functional network can provide a better characterization of age-related changes. Here, we employed two data-driven whole-brain approaches based on the phase synchronization of blood-oxygen-level-dependent signals to analyze resting-state fMRI data from 620 subjects divided into two groups (middle-age group (n = 310); age range, 50-64 years versus older group (n = 310); age range, 65-91 years). Applying the intrinsic-ignition framework to assess the effect of spontaneous local activation events on local-global integration, we found that the older group showed higher intrinsic ignition across the whole-brain functional network, but lower metastability. Using Leading Eigenvector Dynamics Analysis, we found that the older group showed reduced ability to access a metastable substate that closely overlaps with the so-called rich club. These findings suggest that functional whole-brain dynamics are altered in aging, probably due to a deficiency in a metastable substate that is key for efficient global communication in the brain.

Obesity-associated deficits in inhibitory control are phenocopied to mice through gut microbiota changes in one-carbon and aromatic amino acids metabolic pathways.

BACKGROUND: Inhibitory control (IC) is critical to keep long-term goals in everyday life. Bidirectional relationships between IC deficits and obesity are behind unhealthy eating and physical exercise habits. METHODS: We studied gut microbiome composition and functionality, and plasma and faecal metabolomics in association with cognitive tests evaluating inhibitory control (Stroop test) and brain structure in a discovery (n=156), both cross-sectionally and longitudinally, and in an independent replication cohort (n=970). Faecal microbiota transplantation (FMT) in mice evaluated the impact on reversal learning and medial prefrontal cortex (mPFC) transcriptomics. RESULTS: An interplay among IC, brain structure (in humans) and mPFC transcriptomics (in mice), plasma/faecal metabolomics and the gut metagenome was found. Obesity-dependent alterations in one-carbon metabolism, tryptophan and histidine pathways were associated with IC in the two independent cohorts. Bacterial functions linked to one-carbon metabolism (thyX,dut, exodeoxyribonuclease V), and the anterior cingulate cortex volume were associated with IC, cross-sectionally and longitudinally. FMT from individuals with obesity led to alterations in mice reversal learning. In an independent FMT experiment, human donor's bacterial functions related to IC deficits were associated with mPFC expression of one-carbon metabolism-related genes of recipient's mice. CONCLUSION: These results highlight the importance of targeting obesity-related impulsive behaviour through the induction of gut microbiota shifts.

Thrombus Migration and Fragmentation After Intravenous Alteplase Treatment: The INTERRSeCT Study.

BACKGROUND AND PURPOSE: There is interest in what happens over time to the thrombus after intravenous alteplase. We study the effect of alteplase on thrombus structure and its impact on clinical outcome in patients with acute stroke. METHODS: Intravenous alteplase treated stroke patients with intracranial internal carotid artery or middle cerebral artery occlusion identified on baseline computed tomography angiography and with follow-up vascular imaging (computed tomography angiography or first run of angiography before endovascular therapy) were enrolled from INTERRSeCT study (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography). Thrombus movement after intravenous alteplase was classified into complete recanalization, thrombus migration, thrombus fragmentation, and no change. Thrombus migration was diagnosed when occlusion site moved distally and graded according to degrees of thrombus movement (grade 0-3). Thrombus fragmentation was diagnosed when a new distal occlusion in addition to the primary occlusion was identified on follow-up imaging. The association between thrombus movement and clinical outcome was also evaluated. RESULTS: Among 427 patients in this study, thrombus movement was seen in 54% with a median time of 123 minutes from alteplase administration to follow-up imaging, and sub-classified as marked (thrombus migration grade 2-3 + complete recanalization; 27%) and mild to moderate thrombus movement (thrombus fragmentation + thrombus migration grade 0-1; 27%). In patients with proximal M1/internal carotid artery occlusion, marked thrombus movement was associated with a higher rate of good outcome (90-day modified Rankin Scale, 0-2) compared with mild to moderate movement (52% versus 27%; adjusted odds ratio, 5.64 [95% CI, 1.72-20.10]). No difference was seen in outcomes between mild to moderate thrombus movement and no change. In M1 distal/M2 occlusion, marked thrombus movement was associated with improved 90-day good outcome compared with no change (70% versus 56%; adjusted odds ratio, 2.54 [95% CI, 1.21-5.51]). CONCLUSIONS: Early thrombus movement is common after intravenous alteplase. Marked thrombus migration leads to good clinical outcomes. Thrombus dynamics over time should be further evaluated in clinical trials of acute reperfusion therapy.

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).

Higher agreement in endovascular treatment decision-making than in parametric quantifications among automated CT perfusion software packages in acute ischemic stroke.

BACKGROUND AND OBJECTIVE: Estimates of parameters used to select patients for endovascular thrombectomy (EVT) for acute ischemic stroke differ among software packages for automated computed tomography (CT) perfusion analysis. To determine impact of these differences in decision making, we analyzed intra-observer and inter-observer agreement in recommendations about whether to perform EVT based on perfusion maps from 4 packages. METHODS: Perfusion CT datasets from 63 consecutive patients with suspected acute ischemic stroke were retrospectively postprocessed with 4 packages of Minerva, RAPID, Olea, and IntelliSpace Portal (ISP). We used Pearson correlation coefficients and Bland-Altman analysis to compare volumes of infarct core, penumbra, and mismatch calculated by Minerva and RAPID. We used kappa analysis to assess agreement among decisions of 3 radiologists about whether to recommend EVT based on maps generated by 4 packages. RESULTS: We found significant differences between using Minerva and RAPID to estimate penumbra (67.39±41.37mL vs. 78.35±45.38 mL, p < 0.001) and mismatch (48.41±32.03 vs. 61.27±32.73mL, p < 0.001), but not of infarct core (p = 0.230). Pearson correlation coefficients were 0.94 (95%CI:0.90-0.96) for infarct core, 0.87 (95%CI:0.79-0.91) for penumbra, and 0.72 (95%CI:0.57-0.83) for mismatch volumes (p < 0.001). Limits of agreements were (-21.22-25.02) for infarct core volumes, (-54.79-32.88) for penumbra volumes, and (-60.16-34.45) for mismatch volumes. Final agreement for EVT decision-making was substantial between Minerva vs. RAPID (k = 0.722), Minerva vs. Olea (k = 0.761), and RAPID vs. Olea (k = 0.782), but moderate for ISP vs. the other three. CONCLUSIONS: Despite quantitative differences in estimates of infarct core, penumbra, and mismatch using 4 software packages, their impact on radiologists' decisions about EVT is relatively small.

Prevalence of Ipsilateral Nonstenotic Carotid Plaques on Computed Tomography Angiography in Embolic Stroke of Undetermined Source.

Background and Purpose- Embolic stroke of undetermined source (ESUS) constitutes a large proportion of acute ischemic stroke. It is crucial to identify possible stroke etiologies in this patient subgroup to individually tailor secondary stroke prevention strategies. This study aimed to assess the prevalence of carotid plaques causing <50% stenosis in ESUS patients on computed tomography angiography and the association of these plaques with ipsilateral strokes. Methods- Patients from INTERRSeCT-a multicenter prospective study of patients with acute ischemic stroke-were included in this study if their stroke etiology was not large artery atherosclerosis (>50% stenosis), and neck computed tomography angiography was obtained. Degree of stenosis (<30% versus 30%-50%), maximum plaque thickness, degree of plaque calcification (<50% versus ≥50%), plaque irregularity, ulceration, hypodensity, carotid web, and focal vessel outpouching were assessed for both carotid arteries on computed tomography angiography. Prevalence of carotid plaques with <50% stenosis (nonstenotic plaques), ipsilateral and contralateral to the stroke, in ESUS patients was determined and compared with non-ESUS patients. Features of these plaques with versus without ipsilateral stroke in ESUS patients were compared. Uni- and multivariable logistic regression was performed to determine associations between nonstenotic carotid plaque, plaque characteristics, and ipsilateral stroke in ESUS patients. Results- Four hundred forty-six patients were included in the study (median age, 73 years; 218 men), 138 of which were ESUS patients (median age, 70 years; 61 men). Nonstenotic carotid plaques (with <50% stenosis) were present in 54 of 138 (39.1%) ESUS patients. Twelve (8.7%) patients had bilateral carotid plaques. Forty (60.6%) of these plaques were ipsilateral and 26 (39.4%) contralateral to the side of the stroke (P=0.004). Nonstenotic carotid plaques were significantly associated with ipsilateral strokes (adjusted odds ratio, 1.83 [95% CI, 1.05-3.18]). Conclusions- In patients with ESUS, nonstenotic carotid plaques were significantly more common on the side of the ischemic stroke, suggesting that these plaques could be a potential stroke etiology in patients in whom the ischemic stroke is classified currently as ESUS.

Clinical Course of Acute Ischemic Stroke Due to Medium Vessel Occlusion With and Without Intravenous Alteplase Treatment.

BACKGROUND AND PURPOSE: Available data on the clinical course of patients with acute ischemic stroke due to medium vessel occlusion (MeVO) are mostly limited to those with M2 segment occlusions. Outcomes are generally better compared with more proximal occlusions, but many patients will still suffer from severe morbidity. We aimed to determine the clinical course of acute ischemic stroke due to MeVO with and without intravenous alteplase treatment. METHODS: Patients with MeVO (M2/M3/A2/A3/P2/P3 occlusion) from the INTERRSeCT (The Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography) and PRoveIT (Precise and Rapid Assessment of Collaterals Using Multi-Phase CTA in the Triage of Patients With Acute Ischemic Stroke for IA Therapy) studies were included. Baseline characteristics and clinical outcomes were summarized using descriptive statistics. The primary outcome was a modified Rankin Scale score of 0 to 1 at 90 days, describing excellent functional outcome. Secondary outcomes were the common odds ratio for a 1-point shift across the modified Rankin Scale and functional independence, defined as modified Rankin Scale score of 0 to 2. We compared outcomes between patients with versus without intravenous alteplase treatment and between patients who did and did not show recanalization on follow-up computed tomography angiography. Logistic regression was used to provide adjusted effect-size estimates. RESULTS: Among 258 patients with MeVO, the median baseline National Institutes of Health Stroke Scale score was 7 (interquartile range: 5-12). A total of 72.1% (186/258) patients were treated with intravenous alteplase and in 41.8% (84/201), recanalization of the occlusion (revised arterial occlusive lesion score 2b/3) was seen on follow-up computed tomography angiography. Excellent functional outcome was achieved by 50.0% (129/258), and 67.4% (174/258) patients gained functional independence, while 8.9% (23/258) patients died within 90 days. Recanalization was observed in 21.4% (9/42) patients who were not treated with alteplase and 47.2% (75/159) patients treated with alteplase (P=0.003). Early recanalization (adjusted odds ratio, 2.29 [95% CI, 1.23-4.28]) was significantly associated with excellent functional outcome, while intravenous alteplase was not (adjusted odds ratio, 1.70 [95% CI, 0.88-3.25]). CONCLUSIONS: One of every 2 patients with MeVO did not achieve excellent clinical outcome at 90 days with best medical management. Early recanalization was strongly associated with excellent outcome but occurred in <50% of patients despite intravenous alteplase treatment.

Quantitative Signal Intensity in Fluid-Attenuated Inversion Recovery and Treatment Effect in the WAKE-UP Trial.

Background and Purpose- Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods- FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results- FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 (P=0.169) and shift analysis (P=0.086) but reached significance for mRS score of 0 to 2 (P=0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions- In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset.

Brain BOLD MRI O2 and CO2 stress testing: implications for perioperative neurocognitive disorder following surgery.

BACKGROUND: Mechanical ventilation to alter and improve respiratory gases is a fundamental feature of critical care and intraoperative anesthesia management. The range of inspired O2 and expired CO2 during patient management can significantly deviate from values in the healthy awake state. It has long been appreciated that hyperoxia can have deleterious effects on organs, especially the lung and retina. Recent work shows intraoperative end-tidal (ET) CO2 management influences the incidence of perioperative neurocognitive disorder (POND). The interaction of O2 and CO2 on cerebral blood flow (CBF) and oxygenation with alterations common in the critical care and operating room environments has not been well studied. METHODS: We examine the effects of controlled alterations in both ET O2 and CO2 on cerebral blood flow (CBF) in awake adults using blood oxygenation level-dependent (BOLD) and pseudo-continuous arterial spin labeling (pCASL) MRI. Twelve healthy adults had BOLD and CBF responses measured to alterations in ET CO2 and O2 in various combinations commonly observed during anesthesia. RESULTS: Dynamic alterations in regional BOLD and CBF were seen in all subjects with expected and inverse brain voxel responses to both stimuli. These effects were incremental and rapid (within seconds). The most dramatic effects were seen with combined hyperoxia and hypocapnia. Inverse responses increased with age suggesting greater risk. CONCLUSIONS: Human CBF responds dramatically to alterations in ET gas tensions commonly seen during anesthesia and in critical care. Such alterations may contribute to delirium following surgery and under certain circumstances in the critical care environment. TRIAL REGISTRATION: ClincialTrials.gov NCT02126215 for some components of the study. First registered April 29, 2014.