Fiabilidad interexaminador de un sistema de segmentación semiautomàtica para el cálculo del volumen del bulbo y tracto olfatorio mediante resonancia magnética

El transtorn de l'olfacte a la malaltia d'Alzheimer (MA) és freqüent i precoç. Per determinar la relació entre la MA i el volum del bulb i tracte olfactori, és necessari un instrument que ens permeti realitzar el càlcul d'aquest volum a partir d'imatges obtingudes per ressonància magnètica. S'ha desenvolupat un software específic i s'ha realitzat un estudi observacional i transversal de fiabilitat en una mostra de pacients. S'ha calculat el volum de forma semiautomàtica per dos observadors independents. El coeficient de correlació intraclasse obtingut ens permet concloure que la fiabilitat interexaminador és apropiada.El trastorno del olfato en la enfermedad de Alzheimer (EA) es frecuente y precoz. Para determinar la relación entre la EA y el volumen del bulbo y tracto olfatorio, es necesario un instrumento que nos permita realizar el cálculo de dicho volumen a partir de imágenes obtenidas por resonancia magnética. Se ha desarrollado un software específico y se ha realizado un estudio observacional y transversal de fiabilidad en una muestra de pacientes. Se ha calculado el volumen de forma semiautomática por dos observadores independientes. El coeficiente de correlación intraclase obtenido nos permite concluir que la fiabilidad interexaminador es apropiada

Evaluación de la eficacia y seguridad del tratamiento con tetratiomolibdato de amonio en la enfermedad de Wilson con afectación neurológica

El tractament actual de la malaltia de Wilson amb afectació neurològica és controvertit. Els fàrmacs actuals s'associen a risc de deteriorament neurològic (50% amb penicilamina i 26% amb trientine). El nou medicament tetratiomolibdat s'està estudiant perquè sembla tenir menor freqüència d'empitjorament neurològic. S'associa a efectes secundaris lleus i generalment reversibles. A la nostra sèrie de cinc pacients vàrem observar una milloria significativa dels símptomes després del tractament amb tetratiomolibdat. No es va detectar cap empitjorament neurològic. En dos casos va haver també una millora radiològica. Un pacient va presentar lleu anèmia, leucopènia i elevació de les transaminases reversible.: El tratamiento actual de la enfermedad de Wilson con síntomas neurológicos es controvertido. Los fármacos actuales parecen asociarse a riesgo de empeoramiento neurológico (50% con penicilamina y 26% con trientine). El nuevo medicamento tetratiomolibdato está siendo investigado porque parece presentar menor empeoramiento neurológico. Se asocia a efectos secundarios leves y generalmente reversibles. En nuestra serie de cinco pacientes hubo una mejoría significativa de los síntomas tras el tratamiento con tetratiomolibdato. No se detectó ningún empeoramiento neurológico. En dos casos existió también mejoría radiológica. Un paciente presentó leve anemia, leucopenia y elevación de transaminasas que fue reversible

Blood Biomarkers to Predict Long-Term Mortality after Ischemic Stroke

Altres ajuts: This work has been funded by La Fundació La Marató (Reg. 84/240 proj. 201702).Stroke is a major cause of disability and death globally, and prediction of mortality represents a crucial challenge. We aimed to identify blood biomarkers measured during acute ischemic stroke that could predict long-term mortality. Nine hundred and forty-one ischemic stroke patients were prospectively recruited in the Stroke-Chip study. Post-stroke mortality was evaluated during a median 4.8-year follow-up. A 14-biomarker panel was analyzed by immunoassays in blood samples obtained at hospital admission. Biomarkers were normalized and standardized using Z -scores. Multiple Cox regression models were used to identify clinical variables and biomarkers independently associated with long-term mortality and mortality due to stroke. In the multivariate analysis, the independent predictors of long-term mortality were age, female sex, hypertension, glycemia, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Independent blood biomarkers predictive of long-term mortality were endostatin > quartile 2, tumor necrosis factor receptor-1 (TNF-R1) > quartile 2, and interleukin (IL)-6 > quartile 2. The risk of mortality when these three biomarkers were combined increased up to 69%. The addition of the biomarkers to clinical predictors improved the discrimination (integrative discriminative improvement (IDI) 0.022 (0.007-0.048), p quartile 3 was an independent predictor of mortality due to stroke. Altogether, endostatin, TNF-R1, and IL-6 circulating levels may aid in long-term mortality prediction after stroke

Endocannabinoid levels in peripheral blood mononuclear cells of multiple sclerosis patients treated with dimethyl fumarate.

The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.post-print1392 K

Comparison of the impact of atrial fibrillation on the risk of early death after stroke in women versus men

BACKGROUND: Atrial fibrillation (AF) is considered a predictive factor of poor clinical outcome in patients with an ischemic stroke (IS). This study addressed whether the impact of AF on the in-hospital mortality after first ever IS is different according to the patient’s gender. METHODS: We prospectively studied 1678 patients with first ever IS consecutively admitted to two University Hospitals. We recorded demographic data, vascular risk factors, and the stroke severity (NIHSS) at admission analyzing their impact on the in-hospital mortality and on the combined mortality-dependency at discharge using a Cox proportional hazards model. Two variable interactions between those factors independently related to in-hospital mortality and combined mortality-dependency at discharge were tested. RESULTS: Overall in-hospital mortality was 11.3%. Cox proportional hazards model showed that NIHSS at admission (HR: 1.178 [95% CI 1.149–1.207]), age (HR: 1.044 [95% CI 1.026–1.061]), AF (HR: 1.416 [95% CI 1.048–1.913]), male gender (HR: 1.853 [95% CI 1.323–2.192) and ischemic heart disease (HR: 1.527 [95% CI 1.063–2.192]) were independent predictors of in-hospital mortality. A significant interaction between gender and AF was found (p = 0.017). Data were stratified by gender, showing that AF was an independent predictor of poor outcome just for woman (HR: 2.183 [95% CI 1.403–3.396]; p < 0.001). The independent predictors of combined mortality-disability at discharge were NIHSS at admission (HR: 1.052 [95% CI 1.041–1.063]), age (HR: 1.011 [95% CI 1.004–1.018]), AF (HR: 1.197 [95% CI 1.031–1.390]), ischemic heart disease (HR: 1.222 [95% CI 1.004–1.488]), and smoking (HR: 1.262 [95% CI 1.033–1.541]). CONCLUSIONS: The impact of AF is different in the twogenders and appears as a specific ischemic stroke predictor of in-hospital mortality just for women

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 x 10(-5) were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 x 10(-8)) were characterized by in silica functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 x 10(-8); odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 x 10(-8), OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silica studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.Peer reviewe

Association of Mortality and Risk of Epilepsy With Type of Acute Symptomatic Seizure After Ischemic Stroke and an Updated Prognostic Model

IMPORTANCE: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. OBJECTIVE: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. EXPOSURES: Type of acute symptomatic seizure. MAIN OUTCOMES AND MEASURES: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). RESULTS: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. CONCLUSIONS AND RELEVANCE: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

[Background] Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient’s prognosis.[Objectives] To investigate the association between genetically determined natural hemostatic factors’ levels and increased risk of HT after r-tPA treatment.[Methods] Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT.[Results] Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10−11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10−10; rs1421067 (CHD9), P = 1.81 × 10−14; and rs34780449, near ROBO1 gene, P = 1.64 × 10−8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10−14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [−0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05).[Conclusion] We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.This study is supported in part by the National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141291. G.T.-S. is supported by the Pla Estratègic de Recerca i Innovació en Salut grant from the Catalan Department of Health for junior research personnel (SLT017/20/000100). M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. E.M. is supported by a Río Hortega Contract (CM18/00198) from the ISCIII. J.C.-M. is supported by an Agència de Gestió d’Ajuts Universitaris i de Recerca Contract (FI_DGR 2020, grant number 2020FI_B1 00157) cofinanced by the European Social Fund. C.G.-F. is supported by a Sara Borrell Contract (CD20/00043) from ISCIII and Fondo Europeo de Desarrollo Regional (ISCIII- FEDER). M.L. is supported by a Contratos Predoctorales de Formación en Investigación en Salud Contract from the ISCIII (FI19/00309).Peer reviewe

Table_3_A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype.DOCX

[Background] Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification.[Methods] Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10−8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort.[Results] We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension.[Conclusion] The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.Peer reviewe