Publications by authors named "Josep Puig"

105 Publications

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

Nat Commun 2021 May 10;12(1):2590. Epub 2021 May 10.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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% (CI [-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% (CI [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.
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http://dx.doi.org/10.1038/s41467-021-22786-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110812PMC
May 2021

Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome.

Microbiome 2021 May 7;9(1):104. Epub 2021 May 7.

Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona "Dr Josep Trueta", Girona, Spain.

Background: The gut microbiome and iron status are known to play a role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), although their complex interaction remains unclear.

Results: Here, we applied an integrative systems medicine approach (faecal metagenomics, plasma and urine metabolomics, hepatic transcriptomics) in 2 well-characterised human cohorts of subjects with obesity (discovery n = 49 and validation n = 628) and an independent cohort formed by both individuals with and without obesity (n = 130), combined with in vitro and animal models. Serum ferritin levels, as a markers of liver iron stores, were positively associated with liver fat accumulation in parallel with lower gut microbial gene richness, composition and functionality. Specifically, ferritin had strong negative associations with the Pasteurellaceae, Leuconostocaceae and Micrococcaea families. It also had consistent negative associations with several Veillonella, Bifidobacterium and Lactobacillus species, but positive associations with Bacteroides and Prevotella spp. Notably, the ferritin-associated bacterial families had a strong correlation with iron-related liver genes. In addition, several bacterial functions related to iron metabolism (transport, chelation, heme and siderophore biosynthesis) and NAFLD (fatty acid and glutathione biosynthesis) were also associated with the host serum ferritin levels. This iron-related microbiome signature was linked to a transcriptomic and metabolomic signature associated to the degree of liver fat accumulation through hepatic glucose metabolism. In particular, we found a consistent association among serum ferritin, Pasteurellaceae and Micrococcacea families, bacterial functions involved in histidine transport, the host circulating histidine levels and the liver expression of GYS2 and SEC24B. Serum ferritin was also related to bacterial glycine transporters, the host glycine serum levels and the liver expression of glycine transporters. The transcriptomic findings were replicated in human primary hepatocytes, where iron supplementation also led to triglycerides accumulation and induced the expression of lipid and iron metabolism genes in synergy with palmitic acid. We further explored the direct impact of the microbiome on iron metabolism and liver fact accumulation through transplantation of faecal microbiota into recipient's mice. In line with the results in humans, transplantation from 'high ferritin donors' resulted in alterations in several genes related to iron metabolism and fatty acid accumulation in recipient's mice.

Conclusions: Altogether, a significant interplay among the gut microbiome, iron status and liver fat accumulation is revealed, with potential significance for target therapies. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01052-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106161PMC
May 2021

Balloon guide catheter improvements in thrombectomy outcomespersist despite advances in intracranial aspiration technology.

J Neurointerv Surg 2021 Feb 25. Epub 2021 Feb 25.

Interventional Neuroradiology, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain.

Background: First-pass effect (FPE) has been established as a key metric for technical success and strongly correlates with better clinical outcomes. Most data supporting improved outcomes with the use of a balloon guide catheter (BGC) predate the advent of last-generation large-bore intracranial aspiration catheters. We aim to evaluate the impact of BGC in FPE and clinical outcomes in a large cohort of patients treated with contemporary technology.

Methods: Patients were recruited from the prospectively ongoing ROSSETTI registry. This registry includes all consecutive patients with anterior circulation large-vessel occlusion (LVO) from 10 comprehensive stroke centers in Spain. Demographic, clinical, angiographic, and clinical outcome data were compared between BGC and non-BGC groups. FPE was defined as the achievement of mTICI2c-3 after a single device pass.

Results: 426 patients were included out of which 271 (63.62%) used BCG. BGC-treated patients had higher FPE rate (45.8% vs 27.7%; P<0.001), higher final mTICI ≥2 c recanalization rate (76.8% vs 50.3%, respectively; P<0.001), shorter procedural time [median (IQR), 30 (19-58) vs 43 (33-71) min; P<0.001], higher NIHSS difference from admission to 24 hours [median (IQR), 8 (2-12) vs 3 (0-10); P=0.001], and lower mortality rate (17.6% vs 29.8%, P=0.026) compared with non-BGC patients. BGC use was an independent predictor of FPE (OR 2.197, 95% CI 1.436 to 3.361; P<0.001), and excellent clinical outcome at 3 months (OR 0.34, 95% CI 0.17 to 0.68; P=0.002).

Conclusions: Our results support the benefit of BGC use on angiographic and clinical outcomes in anterior circulation LVO ischemic stroke remain significant even when considering recent improvements in intracranial aspiration technology.
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http://dx.doi.org/10.1136/neurintsurg-2020-017027DOI Listing
February 2021

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

Gut 2021 Jan 29. Epub 2021 Jan 29.

Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain

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 ( 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.
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http://dx.doi.org/10.1136/gutjnl-2020-323371DOI Listing
January 2021

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

Cereb Cortex 2021 Mar;31(5):2466-2481

Computational Neuroscience Group, Center for Brain and Cognition, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.

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.
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http://dx.doi.org/10.1093/cercor/bhaa367DOI Listing
March 2021

Safety and efficacy of intravenous thrombolysis in stroke patients on prior antiplatelet therapy in the WAKE-UP trial.

Neurol Res Pract 2020 20;2:40. Epub 2020 Nov 20.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Background: One quarter to one third of patients eligible for systemic thrombolysis are on antiplatelet therapy at presentation. In this study, we aimed to assess the safety and efficacy of intravenous thrombolysis in stroke patients on prescribed antiplatelet therapy in the WAKE-UP trial.

Methods: WAKE-UP was a multicenter, randomized, double-blind, placebo-controlled clinical trial to study the efficacy and safety of MRI-guided intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time. The medication history of all patients randomized in the WAKE-UP trial was documented. The primary safety outcome was any sign of hemorrhagic transformation on follow-up MRI. The primary efficacy outcome was favorable functional outcome defined by a score of 0-1 on the modified Rankin scale at 90 days after stroke, adjusted for age and baseline stroke severity. Logistic regression models were fitted to study the association of prior antiplatelet treatment with outcome and treatment effect of intravenous alteplase.

Results: Of 503 randomized patients, 164 (32.6%) were on antiplatelet treatment. Patients on antiplatelet treatment were older (70.3 vs. 62.8 years,  <  0.001), and more frequently had a history of hypertension, atrial fibrillation, diabetes, hypercholesterolemia, and previous stroke or transient ischaemic attack. Rates of symptomatic intracranial hemorrhage and hemorrhagic transformation on follow-up imaging did not differ between patients with and without antiplatelet treatment. Patients on prior antiplatelet treatment were less likely to achieve a favorable outcome (37.3% vs. 52.6%,  = 0.014), but there was no interaction of prior antiplatelet treatment with intravenous alteplase concerning favorable outcome ( = 0.355). Intravenous alteplase was associated with higher rates of favorable outcome in patients on prior antiplatelet treatment with an adjusted odds ratio of 2.106 (95% CI 1.047-4.236).

Conclusions: Treatment benefit of intravenous alteplase and rates of post-treatment hemorrhagic transformation were not modified by prior antiplatelet intake among MRI-selected patients with unknown onset stroke. Worse functional outcome in patients on antiplatelets may result from a higher load of cardiovascular co-morbidities in these patients.
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http://dx.doi.org/10.1186/s42466-020-00087-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678217PMC
November 2020

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

Stroke 2021 01 15;52(1):203-212. Epub 2020 Dec 15.

Calgary Stroke Program, Hotchkiss Brain Institute, Departments of Clinical Neurosciences and Radiology, Cumming School of Medicine, University of Calgary, Canada (T.O., B.K.M., M.H., M.N., A.A.-S., M.G., M.D.H., M.A., A.M.D.).

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.
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http://dx.doi.org/10.1161/STROKEAHA.120.029292DOI Listing
January 2021

Methionine transsulfuration pathway is upregulated in long-lived humans.

Free Radic Biol Med 2021 Jan 30;162:38-52. Epub 2020 Nov 30.

Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida (UdL-IRBLleida), Lleida, Catalonia, Spain. Electronic address:

Available evidences point to methionine metabolism as a key target to study the molecular adaptive mechanisms underlying differences in longevity. The plasma methionine metabolic profile was determined using a LC-MS/MS platform to systematically define specific phenotypic patterns associated with genotypes of human extreme longevity (centenarians). Our findings demonstrate the presence of a specific plasma profile associated with human longevity characterized by an enhanced transsulfuration pathway and tricarboxylic acid (TCA) cycle intermediates, as well as a reduced content of specific amino acids. Furthermore, our work reveals that centenarians maintain a strongly correlated methionine metabolism, suggesting an improved network integrity, homeostasis and more tightly regulated metabolism. We have discovered a particular methionine signature related to the condition of extreme longevity, allowing the identification of potential mechanisms and biomarkers of healthy aging.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.11.026DOI Listing
January 2021

RNA sequencing and Immunohistochemistry Reveal as a Stronger Marker of Survival than Molecular Subtypes in G-CIMP-negative Glioblastoma.

Clin Cancer Res 2021 Jan 26;27(2):645-655. Epub 2020 Oct 26.

Glioma and Neural Stem Cell Group, Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.

Purpose: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials.

Experimental Design: From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes.

Results: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype-negative patients, independently of clinical factors and methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes.

Conclusions: TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2141DOI Listing
January 2021

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

Stroke 2020 11 19;51(11):3232-3240. Epub 2020 Oct 19.

Department of Clinical Neurosciences (J.M.O., B.K.M., A.M.D., M.A.A., N.K., A.M., M.D.H., M.G.), University of Calgary, Canada.

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 (=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.
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http://dx.doi.org/10.1161/STROKEAHA.120.030227DOI Listing
November 2020

Obesity Impairs Short-Term and Working Memory through Gut Microbial Metabolism of Aromatic Amino Acids.

Cell Metab 2020 10;32(4):548-560.e7

Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain; Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), Girona, Spain; Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition (CIBEROBN), Madrid, Spain; Department of Medical Sciences, Faculty of Medicine, Girona University, Girona, Spain. Electronic address:

The gut microbiome has been linked to fear extinction learning in animal models. Here, we aimed to explore the gut microbiome and memory domains according to obesity status. A specific microbiome profile associated with short-term memory, working memory, and the volume of the hippocampus and frontal regions of the brain differentially in human subjects with and without obesity. Plasma and fecal levels of aromatic amino acids, their catabolites, and vegetable-derived compounds were longitudinally associated with short-term and working memory. Functionally, microbiota transplantation from human subjects with obesity led to decreased memory scores in mice, aligning this trait from humans with that of recipient mice. RNA sequencing of the medial prefrontal cortex of mice revealed that short-term memory associated with aromatic amino acid pathways, inflammatory genes, and clusters of bacterial species. These results highlight the potential therapeutic value of targeting the gut microbiota for memory impairment, specifically in subjects with obesity.
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http://dx.doi.org/10.1016/j.cmet.2020.09.002DOI Listing
October 2020

Glioblastoma TCGA Mesenchymal and IGS 23 Tumors are Identifiable by IHC and have an Immune-phenotype Indicating a Potential Benefit from Immunotherapy.

Clin Cancer Res 2020 12 30;26(24):6600-6609. Epub 2020 Sep 30.

Institut Catala d'Oncologia (ICO) Badalona, Badalona Applied Research Group in Oncology (B-ARGO Group), Institut Investigació Germans Trias i Pujol (IGTP), Badalona, Spain.

Purpose: Molecular subtype classifications in glioblastoma may detect therapy sensitivities. IHC would potentially allow the identification of molecular subtypes in routine clinical practice.

Experimental Design: Formalin-fixed, paraffin-embedded tumor samples of 124 uniformly treated, newly diagnosed patients with glioblastoma were submitted to RNA sequencing, IHC, and immune-phenotyping to identify differences in molecular subtypes associated with treatment sensitivities.

Results: We detected high molecular and IHC overlapping of the The Cancer Genome Atlas (TCGA) mesenchymal subtype with instrinsic glioma subtypes (IGS) cluster 23 and of the TCGA classical subtype with IGS cluster 18. IHC patterns, gene fusion profiles, and immune-phenotypes varied across subtypes. IHC revealed that the TCGA classical subtype was identified by high expression of EGFR and low expression of PTEN, while the mesenchymal subtype was identified by low expression of SOX2 and high expression of two antibodies, SHC1 and TCIRG1, selected on the basis of RNA differential transcriptomic expression. The proneural subtype was identified by frequent positive IDH1 expression and high Olig2 and Ki67 expression. Immune-phenotyping showed that mesenchymal and IGS 23 tumors exhibited a higher positive effector cell score, a higher negative suppressor cell score, and lower levels of immune checkpoint molecules. The cell-type deconvolution analysis revealed that these tumors are highly enriched in M2 macrophages, resting memory CD4 T cells, and activated dendritic cells, indicating that they may be ideal candidates for immunotherapy, especially with anti-M2 and/or dendritic cell vaccination.

Conclusions: There is a subset of tumors, frequently classified as mesenchymal or IGS cluster 23, that may be identified with IHC and could well be optimal candidates for immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2171DOI Listing
December 2020

Thrombectomy vs medical management in low NIHSS acute anterior circulation stroke.

Neurology 2020 12 28;95(24):e3364-e3372. Epub 2020 Sep 28.

From the Department of Clinical Neurosciences, Calgary Stroke Program (O.V., C.Z., M.N., A.M.D., B.K.M., M.D.H.), and Department of Community Health Sciences (C.Z., B.K.M., M.D.H.), Cumming School of Medicine, University of Calgary, Canada; International Clinical Research Centre, Stroke Research Program & Department of Neurology (O.V., P.C., R.M.), and Department of Medical Imaging (P.C.), St. Anne's University Hospital; Faculty of Medicine (O.V., P.C., R.M.), Masaryk University, Brno; Department of Neurology (O.V.), Faculty Hospital Ostrava; 2nd Medical Faculty (A.T.) and First Faculty of Medicine and General University Hospital (J.F.), Department of Neurology, Charles University, Prague; Department of Neurology, Faculty of Medicine (M.B.), University Hospital Ostrava, University Ostrava; Department of Radiology, 2nd Faculty of Medicine (M.R., R.P.), Charles University in Prague and Motol University Hospital; Department of Radiology (F.C.) and Department of Neurology-Comprehensive Stroke Center (D.C.), Masaryk Hospital, Usti nad Labem; Department of Neurology (M.N.), Hospital Ceske Budejovice; Neurocenter (L.J.), Regional Hospital Liberec; Department of Neurology (R.H.), Military University Hospital, Prague; Department of Neurology (M.K.), Na Homolce Hospital, Prague; Department of Neurology, Faculty of Medicine in Pilsen (P.S., V.R.), Charles University in Prague, Pilsen; Department of Neurology (R.J.), University Hospital Brno and Faculty of Medicine Masaryk University; Department of Neurology (D.V.), AGEL Research and Training Institute, Ostrava Vitkovice Hospital, Czech Republic; Institute of Diagnostic Imaging (IDI)-Research Unit (IDIR) (J.P.), Parc Sanitari Pere Virgili, Barcelona; Girona Biomedical Research Institute (IDIBGI)-Medical Imaging (J.P.), Hospital Universitari de Girona Dr. Josep Trueta, Girona, Spain; Department of Clinical Neurosciences (D.P.), University of Western Ontario; Lawson Health Research Institute and Robarts Research Institute (A.V.K.), London, Canada; and Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.F.), University of Florence, Italy.

Objective: To undertake an effectiveness and safety analysis of EVT in patients with LVO and NIH Stroke Scale (NIHSS) score ≤6 using datasets of multicenter and multinational nature.

Methods: We pooled patients with anterior circulation occlusion from 3 prospective international cohorts. Patients were eligible if presentation occurred within 12 hours from last known well and baseline NIHSS ≤6. Primary outcome was modified Rankin Scale (mRS) score 0-1 at 90 days. Secondary outcomes included neurologic deterioration at 24 hours (change in NIHSS of ≥2 points), mRS 0-2 at 90 days, and 90-day all-cause mortality. We used propensity score matching to adjust for nonrandomized treatment allocation.

Results: Among 236 patients who fit inclusion criteria, 139 received EVT and 97 received medical management. Compared to medical management, the EVT group was younger (65 vs 72 years; < 0.001), had more proximal occlusions ( < 0.001), and less frequently received concurrent IV thrombolysis (57.7% vs 71.2%; = 0.04). After propensity score matching, clinical outcomes between the 2 groups were not significantly different. EVT patients had an 8.6% (95% confidence interval [CI] -8.8% to 26.1%) higher rate of excellent 90-day outcome, despite a 22.3% (95% CI, 3.0%-41.6%) higher risk of neurologic deterioration at 24 hours.

Conclusions: EVT for LVO in patients with low NIHSS score was associated with increased risk of neurologic deterioration at 24 hours. However, both EVT and medical management resulted in similar proportions of excellent clinical outcomes at 90 days.

Classification Of Evidence: This study provides Class III evidence that for patients with acute anterior circulation ischemic strokes and LVO with NIHSS < 6, EVT and medical management result in similar outcomes at 90 days.
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http://dx.doi.org/10.1212/WNL.0000000000010955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836655PMC
December 2020

Bariatric Surgery-Induced Changes in Intima-Media Thickness and Cardiovascular Risk Factors in Class 3 Obesity: A 3-Year Follow-Up Study.

Obesity (Silver Spring) 2020 09 9;28(9):1663-1670. Epub 2020 Aug 9.

Department of Radiology (IDI), Girona Biomedical Research Institute (IDIBGI), Hospital Universitari de Girona Dr Josep Trueta, Girona, Spain.

Objective: The impact of weight loss induced by bariatric surgery (BS) and nonsurgical approaches on cardiovascular risk factors (CVRFs) has not been fully elucidated. We assessed the effects of BS and a nonsurgical approach on carotid intima-media thickness (CIMT) and CVRFs in participants with class 3 obesity.

Methods: A total of 87 participants with obesity (59 women; 46 [37-52] years old; BMI, 43 [40-47]) and 75 controls were recruited; 21 (25%) participants with obesity underwent BS. BMI, blood pressure, cholesterol, triglycerides, fasting plasma glucose, C-reactive protein, CIMT, and Framingham Risk Score were measured at baseline and at 3-year follow-up. Independent factors for reduction in CIMT were analyzed. The literature on the effects of BS and CIMT was reviewed.

Results: After BS, BMI decreased from 45.45 to 27.28 (P < 0.001), and mean CIMT decreased from 0.64 mm (0.56-0.75 mm) to 0.54 mm (0.46-0.65) mm (P < 0.012), equivalent to 0.005 mm/kg of weight lost. At 3-year follow-up, participants who had undergone BS had similar CIMT and CVRFs to the control group. No changes in CVRFs were seen related to the nonsurgical approach. BMI reduction after BS had the strongest independent association with decreased CIMT.

Conclusions: Weight loss after BS decreases CIMT and CVRFs in middle-aged participants with class 3 obesity, resulting in CIMT similar to that observed in lean participants.
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http://dx.doi.org/10.1002/oby.22905DOI Listing
September 2020

Robotic-assisted transrectal MRI-guided biopsy. Technical feasibility and role in the current diagnosis of prostate cancer: an initial single-center experience.

Abdom Radiol (NY) 2020 12 23;45(12):4150-4159. Epub 2020 Jul 23.

Department of Computer Science, Applied Mathematics and Statistics, University of Girona, 17003, Girona, Spain.

Objectives: To evaluate the potential clinical and technical utility to manage in practice the use of a robotic MRI in-bore-targeted prostate biopsies in the current work-up of prostate cancer diagnosis.

Methods: Thirty patients with a single cancer suspicious lesion interpreted on MRI using PI-RADSv2.1 category ≥ 3 underwent in-bore robotic transrectal MRI remote-controlled-guided biopsy. It was analyzed the technical success, clinical details, biopsy findings in correlation with the MRI examination, complications and cancer detection rate (CDR).

Results: The overall CDR for any cancer was 73% (22/30). It was 86% (19/22) for significant tumors (Gleason score of more than 6 or maximum cancer core length greater than 3 mm for Gleason 6) and 77% (17/22) for tumors with Gleason > 6. CDR for biopsy-naïve patients was 89% (16/18) and 50% (6/12) for patients with prior negative transrectal ultrasound-guided biopsies. The CDR for PI-RADS > 3 was 92% (22/24). All the lesions (n = 30) were reachable with the robotic MRI device. A self-limited rectal hemorrhagic complication was reported.

Conclusion: This initial data show that a robotic MRI-guided biopsy could be useful, efficient and feasible procedure in the new paradigm to diagnose significant prostate cancer in selected patients.
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http://dx.doi.org/10.1007/s00261-020-02665-6DOI Listing
December 2020

The Aging Imageomics Study: rationale, design and baseline characteristics of the study population.

Mech Ageing Dev 2020 07 11;189:111257. Epub 2020 May 11.

Canon Medical Systems Europe, Zoetermeer, The Netherlands.

Biomarkers of aging are urgently needed to identify individuals at high risk of developing age-associated disease or disability. Growing evidence from population-based studies points to whole-body magnetic resonance imaging's (MRI) enormous potential for quantifying subclinical disease burden and for assessing changes that occur with aging in all organ systems. The Aging Imageomics Study aims to identify biomarkers of human aging by analyzing imaging, biopsychosocial, cardiovascular, metabolomic, lipidomic, and microbiome variables. This study recruited 1030 participants aged ≥50 years (mean 67, range 50-96 years) that underwent structural and functional MRI to evaluate the brain, large blood vessels, heart, abdominal organs, fat, spine, musculoskeletal system and ultrasonography to assess carotid intima-media thickness and plaques. Patients were notified of incidental findings detected by a certified radiologist when necessary. Extensive data were also collected on anthropometrics, demographics, health history, neuropsychology, employment, income, family status, exposure to air pollution and cardiovascular status. In addition, several types of samples were gathered to allow for microbiome, metabolomic and lipidomic profiling. Using big data techniques to analyze all the data points from biological phenotyping together with health records and lifestyle measures, we aim to cultivate a deeper understanding about various biological factors (and combinations thereof) that underlie healthy and unhealthy aging.
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http://dx.doi.org/10.1016/j.mad.2020.111257DOI Listing
July 2020

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

Stroke 2020 06 7;51(6):1743-1749. Epub 2020 May 7.

From the Department of Clinical Neurosciences (J.M.O., M.A., A.D., S.B.C., M.D.H., B.K.M., M.G.), University of Calgary, Canada.

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 (=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.
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http://dx.doi.org/10.1161/STROKEAHA.120.029404DOI Listing
June 2020

Magnetic Resonance Imaging Biomarkers of Brain Connectivity in Predicting Outcome after Mild Traumatic Brain Injury: A Systematic Review.

J Neurotrauma 2020 08 24;37(16):1761-1776. Epub 2020 Apr 24.

Department of Radiology, Perioperative and Pain Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

There is growing interest in developing magnetic resonance imaging (MRI) biomarkers of brain connectivity from resting-state functional (rs-fMRI) and diffusion tensor imaging (DTI) to aid in the diagnosis and management of patients with mild traumatic brain injury (mTBI). To determine whether early MRI biomarkers of brain connectivity are useful in predicting outcome after mTBI, we conducted a systematic review using the following inclusion criteria: 1) patients aged >16 years with mTBI, 2) MRI performed during the first month post-injury, 3) outcome measure available, 4) control group, and 5) original article published in a peer-reviewed journal. Of the 1351 citations identified, 14 studies met inclusion criteria (5 rs-fMRI and 10 DTI; 680 patients with mTBI vs. 436 controls) including those where MRI was performed from <12 h to 1 month post-injury. The most common clinical outcome measure used in these studies was symptom burden using the Rivermead Post-Concussion Questionnaire. The most frequently studied brain connectivity MRI biomarkers were global functional connectivity, default-mode network, and fractional anisotropy (FA). Despite the scant evidence and considerable methodological heterogeneity observed among studies, we conclude that brain connectivity MRI biomarkers obtained within 1 month of injury may be potentially useful in predicting outcome in mTBI. Further longitudinal studies are needed to evaluate the effect of mTBI on MRI-based brain connectivity biomarkers and examine how incorporation of these tests can inform the clinical care of individual mTBI patients.
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http://dx.doi.org/10.1089/neu.2019.6623DOI Listing
August 2020

The APOA1bp-SREBF-NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients.

Clin Nutr 2020 11 8;39(11):3408-3418. Epub 2020 Mar 8.

Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona "Dr Josep Trueta", Departament de Ciències Mèdiques, University of Girona, Girona Biomedical Research Institute (IdibGi), Girona, Spain; CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Background & Aims: Atherosclerosis is characterized by an inflammatory disease linked to excessive lipid accumulation in the artery wall. The Notch signalling pathway has been shown to play a key regulatory role in the regulation of inflammation. Recently, in vitro and pre-clinical studies have shown that apolipoprotein A-I binding protein (AIBP) regulates cholesterol metabolism (SREBP) and NOTCH signalling (haematopoiesis) and may be protective against atherosclerosis, but the evidence in humans is scarce.

Methods: We evaluated the APOA1bp-SREBF-NOTCH axis in association with atherosclerosis in two well-characterized cohorts of morbidly obese patients (n = 78) within the FLORINASH study, including liver transcriptomics, H NMR plasma metabolomics, high-resolution ultrasonography evaluating carotid intima-media thickness (cIMT), and haematological parameters.

Results: The liver expression levels of APOA1bp were associated with lower cIMT and leukocyte counts, a better plasma lipid profile and higher circulating levels of metabolites associated with lower risk of atherosclerosis (glycine, histidine and asparagine). Conversely, liver SREBF and NOTCH mRNAs were positively associated with atherosclerosis, liver steatosis, an unfavourable lipid profile, higher leukocytes and increased levels of metabolites linked to inflammation and CVD such as branched-chain amino acids and glycoproteins. APOA1bp and NOTCH signalling also had a strong association, as revealed by the negative correlations among APOA1bp expression levels and those of all NOTCH receptors and jagged ligands.

Conclusions: We here provide the first evidence in human liver of the putative APOA1bp-SREBF-NOTCH axis signalling pathway and its association with atherosclerosis and inflammation.
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http://dx.doi.org/10.1016/j.clnu.2020.02.034DOI Listing
November 2020

Brain BOLD MRI O and CO stress testing: implications for perioperative neurocognitive disorder following surgery.

Crit Care 2020 03 4;24(1):76. Epub 2020 Mar 4.

Department of Anesthesiology, Perioperative and Pain Medicine, Max Rady College of Medicine, University of Manitoba, 2nd Floor, Harry Medovy House, 671 William Ave., Winnipeg, MB, R3E 0Z2, Canada.

Background: Mechanical ventilation to alter and improve respiratory gases is a fundamental feature of critical care and intraoperative anesthesia management. The range of inspired O and expired CO 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) CO management influences the incidence of perioperative neurocognitive disorder (POND). The interaction of O and CO 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 O and CO 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 CO and O 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.
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http://dx.doi.org/10.1186/s13054-020-2800-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057494PMC
March 2020

From "Time is Brain" to "Imaging is Brain": A Paradigm Shift in the Management of Acute Ischemic Stroke.

J Neuroimaging 2020 09 10;30(5):562-571. Epub 2020 Feb 10.

Department of Radiology, University of Manitoba, Winnipeg, Manitoba, Canada.

Arterial recanalization to restore the blood supply and limit the brain damage is the primary goal in the management of acute ischemic stroke (AIS). Since the publication of pivotal randomized clinical trials in 2015, endovascular thrombectomy has become part of the standard of care in selected cases of AIS from large-vessel occlusions up to 6 hours after the onset of symptoms. However, the association between endovascular reperfusion and improved functional outcome is not strictly time dependent. Rather than on rigid time windows, candidates should be selected based on vascular and physiologic information. This approach places imaging data at the center of treatment decisions. Advances in imaging-based management of AIS provide crucial information about vessel occlusion, infarct core, ischemic penumbra, and degree of collaterals. This information is invaluable in identifying patients who are likely to benefit from reperfusion therapies and excluding those who are unlikely to benefit or are at risk of adverse effects. The approach to reperfusion therapies continues to evolve, and imaging is acquiring a greater role in the diagnostic work-up and treatment decisions as shown in recent clinical trials with extended time window. The 2018 American Heart Association/American Stroke Association guidelines reflect a paradigm shift in the management of AIS from "Time is Brain" to "Imaging is Brain." This review discusses the essential role of multimodal imaging developing from recent trials on therapy for AIS.
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http://dx.doi.org/10.1111/jon.12693DOI Listing
September 2020

Spatial normalization of multiple sclerosis brain MRI data depends on analysis method and software package.

Magn Reson Imaging 2020 05 30;68:83-94. Epub 2020 Jan 30.

Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, MB, Canada; Department of Radiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Division of Diagnostic Imaging, Health Sciences Centre, Winnipeg, MB, Canada; Department of Psychological and Brain Sciences, Krieger School of Arts & Sciences, Johns Hopkins University, Baltimore, MD, USA. Electronic address:

Background: Spatially normalizing brain MRI data to a template is commonly performed to facilitate comparisons between individuals or groups. However, the presence of multiple sclerosis (MS) lesions and other MS-related brain pathologies may compromise the performance of automated spatial normalization procedures. We therefore aimed to systematically compare five commonly used spatial normalization methods for brain MRI - including linear (affine), and nonlinear MRIStudio (LDDMM), FSL (FNIRT), ANTs (SyN), and SPM (CAT12) algorithms - to evaluate their performance in the presence of MS-related pathologies.

Methods: 3 Tesla MRI images (T1-weighted and T2-FLAIR) were obtained for 20 participants with MS from an ongoing cohort study (used to assess a real dataset) and 1 healthy control participant (used to create a simulated lesion dataset). Both raw and lesion-filled versions of each participant's T1-weighted brain images were warped to the Montreal Neurological Institute (MNI) template using all five normalization approaches for the real dataset, and the same procedure was then repeated using the simulated lesion dataset (i.e., total of 400 spatial normalizations). As an additional quality-assurance check, the resulting deformations were also applied to the corresponding lesion masks to evaluate how each processing pipeline handled focal white matter lesions. For each normalization approach, inter-subject variability (across normalized T1-weighted images) was quantified using both mutual information (MI) and coefficient of variation (COV), and the corresponding normalized lesion volumes were evaluated using paired-sample t-tests.

Results: All four nonlinear warping methods outperformed conventional linear normalization, with SPM (CAT12) yielding the highest MI values, lowest COV values, and proportionately-scaled lesion volumes. Although lesion-filling improved spatial normalization accuracy for each of the methods tested, these effects were small compared to differences between normalization algorithms.

Conclusions: SPM (CAT12) warping, ideally combined with lesion-filling, is recommended for use in future MS brain imaging studies requiring spatial normalization.
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http://dx.doi.org/10.1016/j.mri.2020.01.016DOI Listing
May 2020

Validation of an automated ASPECTS method on non-contrast computed tomography scans of acute ischemic stroke patients.

Int J Stroke 2020 07 18;15(5):528-534. Epub 2019 Dec 18.

Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.

Background: The Alberta Stroke Program Early CT Score (ASPECTS) is a systematic method of assessing the extent of early ischemic change on non-contrast computed tomography in patients with acute ischemic stroke. Our objective was to validate an automated ASPECTS scoring method we recently developed on a large data set.

Materials And Methods: We retrospectively collected 602 acute ischemic stroke patients' non-contrast computed tomography scans. Expert ASPECTS readings on non-contrast computed tomography were compared to automated ASPECTS. Statistical analyses on the total ASPECTS, region level ASPECTS, and dichotomized ASPECTS (≤4 vs. >4) score were conducted.

Results: In total, 602 scans were evaluated and 6020 (602 × 10) ASPECTS regions were scored. Median time from stroke onset to computed tomography was 114 min (interquartile range: 73-183 min). Total ASPECTS for the 602 patients generated by the automated method agreed well with expert readings (intraclass correlation coefficient): 0.65 (95% confidence interval (CI): 0.60-0.69). Region level analysis showed that the automated method yielded accuracy of 81.25%, sensitivity of 61.13% (95% CI: 58.4%-63.8%), specificity of 86.56% (95% CI: 85.6%-87.5%), and area under curve of 0.74 (95% CI: 0.73-0.75). For dichotomized ASPECTS (≤4 vs. >4), the automated method demonstrated sensitivity 97.21% (95% CI: 95.4%-98.4%), specificity 57.81% (95% CI: 44.8%-70.1%), accuracy 93.02%, and area under the curve of 0.78 (95% CI: 0.74-0.81). For each individual region (M1-6, lentiform, insula, and caudate), the automated method demonstrated acceptable performance.

Conclusion: The automated system we developed approached the stroke expert in performance when scoring ASPECTS on non-contrast computed tomography scans of acute ischemic stroke patients.
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http://dx.doi.org/10.1177/1747493019895702DOI Listing
July 2020

Comparison of different methods of thrombus permeability measurement and impact on recanalization in the INTERRSeCT multinational multicenter prospective cohort study.

Neuroradiology 2020 Mar 12;62(3):301-306. Epub 2019 Nov 12.

Calgary Stroke Program, Departments of Clinical Neurosciences, Radiology and Community Health Sciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Purpose: To compare the association of different measures of intracranial thrombus permeability on non-contrast computerized tomography (NCCT) and computed tomography angiography (CTA) with recanalization with or without intravenous alteplase.

Methods: Patients with anterior circulation occlusion from the INTERRSeCT study were included. Thrombus permeability was measured on non-contrast CT and CTA using the following methods: [1] automated method, mean attenuation increase on co-registered thin (< 2.5 mm) CTA/NCCT; [2] semi-automated method, maximum attenuation increase on non-registered CTA/NCCT (ΔHUmax); [3] manual method, maximum attenuation on CTA (HUmax); and [4] visual method, residual flow grade. Primary outcome was recanalization with intravenous alteplase on the revised AOL scale (2b/3). Regression models were compared using C-statistic, Akaike (AIC), and Bayesian information criterion (BIC).

Results: Four hundred eighty patients were included in this analysis. Statistical models using methods 2, 3, and 4 were similar in their ability to discriminate recanalizers from non-recanalizers (C-statistic 0.667, 0.683, and 0.634, respectively); method 3 had the least information loss (AIC = 483.8; BIC = 492.2). A HU ≥ 89 measured with method 3 provided optimal sensitivity and specificity in discriminating recanalizers from non-recanalizers [recanalization 55.4% (95%CI 46.2-64.6) when HU > 89 vs. 16.8% (95%CI 13.0-20.6) when HU ≤ 89]. In sensitivity analyses restricted to patients with co-registered CTA/NCCT (n = 88), methods 1-4 predicted recanalization similarly (C-statistic 0.641, 0.688, 0.640, 0.648, respectively) with Method 2 having the least information loss (AIC 104.8, BIC 109.8).

Conclusion: Simple methods that measure thrombus permeability are as reliable as complex image processing methods in discriminating recanalizers from non-recanalizers.
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http://dx.doi.org/10.1007/s00234-019-02320-yDOI Listing
March 2020

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

Stroke 2020 01 30;51(1):209-215. Epub 2019 Oct 30.

From the Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum (B.C., A.N., C.G., G.T.), University Medical Center Hamburg-Eppendorf, Germany.

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 (=0.169) and shift analysis (=0.086) but reached significance for mRS score of 0 to 2 (=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.
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http://dx.doi.org/10.1161/STROKEAHA.119.027390DOI Listing
January 2020

Serotonin Reuptake Inhibitor Drugs Are Associated with Contrast Extravasation and Clinical Outcome in Patients with Intracerebral Haemorrhage.

Eur Neurol 2019 25;81(5-6):254-261. Epub 2019 Oct 25.

Stroke Unit, Department of Neurology, Girona Biomedical Research Institute (IDIBGI), Hospital Universitari Dr Josep Trueta, Girona, Spain.

Background: Antidepressants that inhibit the reuptake of serotonin (SRIs) have been related to the appearance of intracerebral haemorrhage (ICH). Some studies have described bigger haematoma volumes in these patients. So far, no studies have demonstrated an association between SRIs and contrast extravasation (CE). We propose to investigate the relationship of SRIs with CE and clinical outcome.

Patients And Methods: We aimed a prospective registry of 294 patients with ICH. All previous treatments were registered, including SRIs intake. The presence of CE and the number of spot sign in CT angiography were collected. Early neurological deterioration (END) and late neurological deterioration (LND) were registered. Follow-up was completed at day 90.

Results: Two hundred and ninety-four patients were included, mean age 66.5 years, 27.6% female. A total of 28 (9.5%) were taking SRIs at the time of the ICH. This group of patients presented statistically significantly more CE (46.4 vs. 19.9%, p = 0.012), ≥2 spot sign (25 vs. 6.8%, p = 0.017), END (46.4 vs. 25.2%, p = 0.018) and LND (14.3 vs. 4.9%, p = 0.032). In addition, this group of patients showed a tendency to have higher mortality (32.1 vs. 22.2%, p = 0.553) and a lower functional independence (modified Rankin Scale 0-2) at day 90 (25 vs. 36.5%, p = 0.230). In the multivariate analysis, SRIs intake was identified as an independent predictor of CE (adjusted OR 3.37; 95% CI 1.033-10.989; p = 0.044) together with hematoma volume at baseline and alcohol use.

Conclusions: In our studied population, previous SRIs intake in patients with ICH was independently associated to CE. Further studies are needed to confirm this association.
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http://dx.doi.org/10.1159/000503561DOI Listing
July 2020

Imaging-based Selection for Endovascular Treatment in Stroke.

Radiographics 2019 10;39(6):1696-1713

From the Neuroimaging Advanced and Exploratory Laboratory, Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, NY 10029 (K.N., Y.S.); Departments of Neurology (P.K.), Neurosurgery (C.J.P.), and Radiology (A.V.), University of Cincinnati Medical Center, Cincinnati, Ohio; and Department of Radiology, University of Manitoba, Winnipeg, MB, Canada (J.P.).

Treatment of acute ischemic stroke (AIS) has evolved significantly in the past few years. Endovascular treatment (EVT) is now proved to be efficacious up to 24 hours from onset in properly selected patients. The recently updated 2018 American Heart Association-American Stroke Association guidelines reflect the important role of imaging in triage and patient selection for EVT of AIS. Pretreatment imaging in patients with acute stroke should allow assessment for intracranial hemorrhage and demonstrate the extent of early ischemic changes, the presence of large arterial occlusion, and in some cases potential salvageable tissue before the decision to proceed with EVT. The authors review how multimodality imaging can be used for EVT selection in the context of the recent guidelines. They highlight the importance of having streamlined imaging workflows that are integrated with clinical decision making to maximize treatment efficiency. Knowledge of the various imaging criteria including perfusion imaging used for EVT selection is highlighted. The authors discuss variable imaging paradigms used for selection of patients in the early and late windows (who present before vs after 6 hours from onset of symptoms), as reflected in the latest guidelines and in relation to their level of evidence. Finally, they focus on challenges in the subgroups of patients who were excluded from recent EVT trials and with limited evidence to prove the efficacy of EVT, such as patients with low NIHSS (National Institutes of Health Stroke Scale) score, distal occlusion, or large ischemic core. RSNA, 2019 See discussion on this article by Leslie-Mazwi.
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http://dx.doi.org/10.1148/rg.2019190030DOI Listing
October 2019

Clinical Characteristics and Outcome of Patients with Lacunar Infarcts and Concurrent Embolic Ischemic Lesions.

Clin Neuroradiol 2020 Sep 3;30(3):511-516. Epub 2019 Jun 3.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Purpose: Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI).

Methods: All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions.

Results: Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and-among those randomized-had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011).

Conclusion: Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts.
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http://dx.doi.org/10.1007/s00062-019-00800-5DOI Listing
September 2020

Glycated Hemoglobin, but not Insulin Sensitivity, is Associated with Memory in Subjects with Obesity.

Obesity (Silver Spring) 2019 06 15;27(6):932-942. Epub 2019 Apr 15.

Department of Diabetes, Endocrinology and Nutrition, Girona Biomedical Research Institute, Dr. Josep Trueta University Hospital, Center for Physiopathology of Obesity and Nutrition, Girona, Spain.

Objective: Obesity has been related to later-life dementia. Serum glucose levels and insulin resistance are known to influence cognition in individuals with diabetes. This study aimed to evaluate memory function in middle-aged individuals with obesity in association with glucose metabolism and brain iron content.

Methods: This was a cross-sectional case-control study including 121 participants aged 27.2 to 66.6 years (56 without obesity, 65 with obesity) stratified according to sex and menopausal status. Insulin sensitivity, body composition, brain iron content, and memory function were evaluated by euglycemic hyperinsulinemic clamp, dual-energy x-ray absorptiometry, magnetic resonance relaxometry (R2*), and California Verbal Learning Test, respectively.

Results: Women with obesity, but not men, had lower scores in some California Verbal Learning Tests in association with metabolic parameters and increased brain iron content compared with controls. Fasting plasma glucose, glycated hemoglobin (HbA1c; within normal range), and R2* were negatively associated with memory scores, whereas insulin sensitivity showed positive associations. Remarkably, only HbA1c levels and R2* in the right inferior fronto-orbital region remained significant after controlling for age, sex, education, and BMI.

Conclusions: Impairments in memory function in middle-aged women with obesity are associated with HbA1c levels and brain iron content independently of insulin sensitivity. These results may have implications in the design of therapeutic strategies in women with obesity.
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http://dx.doi.org/10.1002/oby.22457DOI Listing
June 2019