Circadian rhythms in the efficacy of intravenous alteplase in patients with acute ischemic stroke and middle cerebral artery occlusion

Peer ReviewedPostprint (author's final draft

Intracranial atherosclerotic plaque enhancement and long-term risk of future strokes: A prospective, longitudinal study

Background and Purpose The prognostic significance of postcontrast enhancement of intracranial atheromatous plaque is uncertain. Prospective, long-term follow-up studies in Caucasians, using a multicenter design, are lacking. We aimed to evaluate whether this radiological sign predicts long-term new stroke in symptomatic and asymptomatic intracranial atherosclerotic disease (ICAD) patients. Methods This was a prospective, observational, longitudinal, multicenter study. We included a symptomatic and an asymptomatic cohort of ICAD patients that underwent 3T MRI including high-resolution sequences focused on the atheromatous plaque. We evaluated grade of stenosis, plaque characteristics, and gadolinium enhancement ratio (postcontrast plaque signal/postcontrast corpus callosum signal). The occurrence of new events was evaluated at 3, 6, 9, and 12 months and annually thereafter. The association between plaque characteristics and new stroke was studied using Cox multiple regression survival analysis and Kaplan-Meier curves. Results Forty-eight symptomatic and 13 asymptomatic patients were included. During 56.3 ± 16.9 months, 11 patients (18%) suffered a new event (seven ischemic, two hemorrhagic, and two transient ischemic attacks). A receiver operating characteristic curve identified an enhancement ratio of >1.77 to predict a new event. In a multivariable Cox regression, postcontrast enhancement ratio >1.77 (hazard ratio [HR]= 3.632; 95% confidence interval [CI], 1.082-12.101) and cerebral microbleeds (HR = 5.244; 95% CI, 1.476-18.629) were independent predictors of future strokes. Patients with a plaque enhancement ratio >1.77 had a lower survival free of events (p < .05). Conclusions High intracranial postcontrast enhancement is a long-term predictor of new stroke in ICAD patients. Further studies are needed to elucidate whether postcontrast enhancement reflects inflammatory activity of intracranial atheromatous plaque.This study has been funded by the Spanish Ministry of Science, via FIS project PI13/02544, PI16/01396, and PI19/01398 and through the INVICTUS PLUS research network RD16/0019. Beatriz Gómez-Vicente received a research contract from the Junta de Castilla y León and European Social Fund, Spain. María Hernandez-Perez was funded by The Instituto de Salud Carlos III, Spain (JR17/00006)

Aterosclerosis intracraneal asintomática: prevalencia, factores clínicosy biomarcadores asociados

INTRODUCCIÓN: El ictus constituye la segunda causa de mortalidad global en España (la primera causa en mujeres) y la primera de discapacidad. Aproximadamente un 6-10% de los ictus isquémicos en nuestra población son debidos a la aterosclerosis intracraneal, y se considera que ésta es la principal causa de ictus isquémico a nivel mundial, debido a su alta prevalencia en países asiáticos. Dada la importancia creciente de la prevención primaria del ictus y la ausencia de estudios sobre la fase asintomática de esta patología en nuestro medio, el estudio Barcelona- AsIA (Asymptomatic Intracranial Atherosclerosis study) se diseñó para conocer la prevalencia de aterosclerosis intracraneal asintomática en una población caucásica con riesgo vascular moderado-alto, estudiar su impacto pronóstico, e identificar factores clínicos, biológicos y genéticos asociados a su desarrollo, progresión y expresión clínica. Asimismo, se diseñó para comparar dichos factores con los asociados a la presencia de aterosclerosis extracraneal asintomática en la misma población. En la presente tesis se expone el diseño y los principales resultados de la fase transversal del estudio Barcelona-AsIA. MÉTODOS: El estudio Barcelona-AsIA constituye el primer trabajo centrado el estudio de la aterosclerosis intracraneal asintomática en población caucásica. Se trata de un estudio transversal y longitudinal, observacional y de base poblacional. Se incluyeron prospectivamente 933 sujetos mayores de 50 años con riesgo vascular moderado-alto y sin enfermedad cerebrovascular previa, seleccionados de una forma aleatoria en nuestra área sanitaria de 600.000 habitantes. En la visita basal se recogieron variables demográficas, socioeconómicas y clínicas, y se obtuvieron muestras sanguíneas para estudio de marcadores biológicos y genéticos. Se realizó un Eco-Doppler de troncos supra-aórticos y transcraneal para detectar la presencia de lesiones ateroscleróticas extra e intracraneales, confirmando estas últimas mediante angioresonancia magnética. En la fase longitudinal del estudio se evaluará durante 3 años el impacto pronóstico de la aterosclerosis intracraneal asintomática en la aparición de eventos vasculares cerebrales, cardiacos y periféricos, y en la muerte de origen vascular. RESULTADOS/DISCUSIÓN: La fase transversal del estudio ha permitido determinar que la prevalencia de aterosclerosis intracraneal asintomática de cualquier grado en una población caucásica con riesgo vascular moderado-alto y sin antecedentes de ictus es del 8.6%, y que la prevalencia de aterosclerosis intracraneal de grado moderado-grave es del 3.3%. Los factores clínicos asociados a la presencia y mayor gravedad de la aterosclerosis intracraneal fueron la edad, la diabetes y el síndrome metabólico. La resistencia insulínica se mostró como un factor íntimamente relacionado con el desarrollo de lesiones ateroscleróticas a nivel intracraneal, más que a nivel extracraneal. Los niveles séricos del marcador de disfunción endotelial ADMA y de la molécula inflamatoria resistina también se asociaron de forma independiente a la presencia de aterosclerosis intracraneal asintomática en nuestra población. El presente trabajo ha dado luz a un vacío existente en la literatura ya que nos ha permitido conocer la prevalencia de aterosclerosis intracraneal asintomática en población caucásica, desconocida hasta ahora. Además, el hallazgo de los principales factores de riesgo asociados a la presencia y gravedad de la aterosclerosis intracraneal desde su fase pre-clínica, nos ayudará a detectar a los sujetos en riesgo de presentar esta patología en nuestra población. La evaluación del impacto pronóstico de la presencia de aterosclerosis intracraneal asintomática durante la fase longitudinal del estudio ASIA podrá ser útil para diseñar estrategias sanitarias coste-efectivas en el campo de la prevención primaria de la enfermedad cerebrovascular sintomátiINTRODUCTION: Stroke is the second cause of mortality and the first cause of disability in Spain. Around 6-10% of ischemic strokes in our population are caused by large artery intracranial atherosclerosis (ICAD). Moreover, ICAD is considered the major cause of ischemic stroke worldwide, due to the high prevalence of this entity in Asian populations. Owing to the importance of developing stroke primary prevention strategies, Barcelona-AsIA (Asymptomatic Intracranial Atherosclerosis) study was designed to determine the prevalence of asymptomatic ICAD in a stroke-free Caucasian population with moderate-high vascular risk, to study its prognostic impact and to identify clinical, molecular and genetic factors associated with its development, progression and clinical expression. We also aimed to compare these factors with the presence of asymptomatic extracranial atherosclerosis in the same population. In this doctoral thesis we present the design and first results of the transversal phase of Barcelona-AsIA study. METHODS: Barcelona-AsIA study is the first study on asymptomatic ICAD in a Caucasian population. This is a population-based, prospective and long-term follow-up observational study. We included 933 subjects older than 50 years, with a moderate-high vascular risk and without history of stroke, randomly selected from our reference population of 600.000. At baseline visit we registered clinical, demographic and anthropometric data, and we collected blood samples to study biological and genetic markers. All individuals underwent a complete extracranial and transcranial color-coded duplex to identify the presence and severity of carotid atherosclerosis and intracranial stenoses. Intracranial stenoses were also assessed by magnetic resonance angiography. In the longitudinal phase of the study we will evaluate the prognosis impact of asymptomatic intracranial atherosclerosis on the risk of suffering major ischemic vascular events and vascular death. RESULTS/DISCUSSION: Prevalence of asymptomatic intracranial atherosclerosis of any degree in a Caucasian population with moderate-high vascular risk and without history of stroke was 8.6%, and prevalence of moderate-severe intracranial lesions was 3.3%. Age, diabetes and metabolic syndrome were risk factors independently associated with the presence and higher severity of asymptomatic intracranial atherosclerosis. Insulin resistance was found to be an important factor associated with the development of intracranial atherosclerosis, more than with extracranial atherosclerosis. High levels of serum biomarkers ADMA (marker of endothelial dysfunction) and resistin (inflammatory marker) were independently associated with the presence of isolated intracranial atherosclerosis and combined intracranial-extracranial atherosclerosis respectively. The present study has allowed us to determine the prevalence of asymptomatic intracranial atherosclerosis in a Caucasian population, which was unknown until now. Moreover, the finding of the main clinical and biological risk factors associated with intracranial atherosclerosis from its preclinical stage will allow us to detect individuals at risk in our population. The evaluation of the prognosis impact of asymptomatic intracranial atherosclerosis in the longitudinal phase of Barcelona-AsIA study will allow us to evaluate cost-effectiveness in the field of stroke primary prevention

Reported prestroke physical activity is associated with vascular endothelial growth factor expression and good outcomes after stroke

Physical activity (PhA) prior to stroke has been associated with good outcomes after the ischemic insult, but there is scarce data on the involved molecular mechanisms. Methods: We studied consecutive acute ischemic stroke patients admitted to a single tertiary stroke center. Pre-stroke PhA was evaluated with the International Physical Activity Questionnaire (METS-minute/week). We studied several circulating angiogenic and neurogenic factors at different time-points: Vascular Endothelial Growth Factor (VEGF), Granulocyte Colony-Stimulating Factor (G-CSF) and Brain-Derived Neurotrophic Factor (BDNF) at admission, day 7, and at 3 months. We considered good functional outcome at 3 months (mRS = 2) as primary endpoint, and final infarct volume as secondary outcome. Results: We studied 83 patients with at least two time-point serum determinations (mean age 69.6 years, median NIHSS 17 at admission). Patients more physically active before stroke had a significantly higher increment of serum Vascular Endothelial Growth Factor (VEGF) at 7th day when compared to less active patients. This increment was an independent predictor of good functional outcome at 3 months and was associated with smaller infarct volume in multivariate analyses adjusted for relevant covariates. We did not find independent associations of G-CSF or BDNF levels neither with level of pre-stroke PhA nor with stroke outcomes. Conclusions: Although there are probably more molecular mechanisms by which physical activity exerts its beneficial effects in stroke outcomes, our observation regarding the potential role of VEGF is plausible and in line with previous experimental studies. Further research in this field is needed.Peer ReviewedPostprint (author's final draft

Reported prestroke physical activity is associated with vascular endothelial growth factor expression and good outcomes after stroke

Physical activity (PhA) prior to stroke has been associated with good outcomes after the ischemic insult, but there is scarce data on the involved molecular mechanisms. Methods: We studied consecutive acute ischemic stroke patients admitted to a single tertiary stroke center. Pre-stroke PhA was evaluated with the International Physical Activity Questionnaire (METS-minute/week). We studied several circulating angiogenic and neurogenic factors at different time-points: Vascular Endothelial Growth Factor (VEGF), Granulocyte Colony-Stimulating Factor (G-CSF) and Brain-Derived Neurotrophic Factor (BDNF) at admission, day 7, and at 3 months. We considered good functional outcome at 3 months (mRS = 2) as primary endpoint, and final infarct volume as secondary outcome. Results: We studied 83 patients with at least two time-point serum determinations (mean age 69.6 years, median NIHSS 17 at admission). Patients more physically active before stroke had a significantly higher increment of serum Vascular Endothelial Growth Factor (VEGF) at 7th day when compared to less active patients. This increment was an independent predictor of good functional outcome at 3 months and was associated with smaller infarct volume in multivariate analyses adjusted for relevant covariates. We did not find independent associations of G-CSF or BDNF levels neither with level of pre-stroke PhA nor with stroke outcomes. Conclusions: Although there are probably more molecular mechanisms by which physical activity exerts its beneficial effects in stroke outcomes, our observation regarding the potential role of VEGF is plausible and in line with previous experimental studies. Further research in this field is needed.Peer Reviewe

Impact of COVID-19 outbreak on ischemic stroke admissions and in-hospital mortality in North-West Spain

Background and purpose Spain has been one of the countries heavily stricken by COVID-19. But this epidemic has not affected all regions equally. We analyzed the impact of the COVID-19 pandemic on hospital stroke admissions and in-hospital mortality in tertiary referral hospitals from North-West Spain.Methods Spanish multicenter retrospective observational study based on data from tertiary hospitals of the NORDICTUS network. We recorded the number of patients admitted for ischemic stroke between 30 December 2019 and 3 May 2020, the number of IVT and EVT procedures, and in-hospital mortality.Results In the study period, 2737 patients were admitted with ischemic stroke. There was a decrease in the weekly mean admitted patients during the pandemic (124 vs. 173, p<0.001). In-hospital mortality of stroke patients increased significantly (9.9% vs. 6.5%, p = 0.003), but there were no differences in the proportion of IVT (17.3% vs. 16.1%, p = 0.405) or EVT (22% vs. 23%, p = 0.504).Conclusion We found a decrease in the number of ischemic stroke admissions and an increase in in-hospital mortality during the COVID-19 epidemic in this large study from North-West Spain. There were regional changes within the network, not fully explained by the severity of the pandemic in different regions.Peer reviewe

Feeding Ecology of the Cuvier’s Gazelle (<i>Gazella cuvieri</i>, Ogilby, 1841) in the Sahara Desert

Knowledge of the feeding ecology of ungulates in arid biomes offers an interesting model for understanding the drought resistance of large desert-adapted herbivores, a crucial issue in the face of increasing desertification due to climate change. To assess the feeding ecology of the endangered Cuvier’s gazelle (Gazella cuvieri) in the Sahara desert, we used a multi-method approach combining faecal samples, direct observations, and the recording of indirect signs of feeding. We hypothesised that browser behaviour is the best foraging strategy for species living in hyper-arid environments, mainly due to long periods without grazing opportunities. Complementarily, we explored the effects of the main environmental descriptors (rainfalls and NDVI) on feeding patterns and diet quality. We found that Cuvier’s diets are based mainly on acacias (Vachellia tortilis, V. flava) and occasionally on the annual forb Anastatica hierochuntica. In total, eighteen species (five trees, nine shrubs, three herbs, and one grass) belonging to fifteen families were recorded. Our result confirmed the browsers’ characteristic of this species, reaffirming its ability to settle in a hostile environment. Acacias stand out as key species consumed at the southernmost limit of their range; hence, future conservation plans and strategies should take this into account for the survival of Cuvier’s gazelle in desert environments

Feeding Ecology of the Cuvier's Gazelle (Gazella cuvieri, Ogilby, 1841) in the Sahara Desert

Altres ajuts: Fundació Zoo Barcelona PRIC 2017The Sahara desert is home to the greatest diversity of ungulates of all deserts. In this harsh environment, the endangered Cuvier's gazelle finds at the southernmost limit of its distribution a key population for its survival. A better understanding of the feeding ecology of the species may improve our understanding of the biological requirements for implementing conservation measures. In this study, we analysed the diet and feeding strategy of a desert population by combining different approaches such as faecal sampling, recording indirect signs of feeding, and direct observations of individuals. Our results revealed that Cuvier's gazelles displayed a feeding behaviour similar to that of browsing ruminants, with acacias as key species for the survival of the species in the harsh environment of the Sahara. Consequently, the current increasing grazing pressure in remote areas and on acacias calls for measures to mitigate this emerging and possibly worsening impact due to imminent climate change. Knowledge of the feeding ecology of ungulates in arid biomes offers an interesting model for understanding the drought resistance of large desert-adapted herbivores, a crucial issue in the face of increasing desertification due to climate change. To assess the feeding ecology of the endangered Cuvier's gazelle (Gazella cuvieri) in the Sahara desert, we used a multi-method approach combining faecal samples, direct observations, and the recording of indirect signs of feeding. We hypothesised that browser behaviour is the best foraging strategy for species living in hyper-arid environments, mainly due to long periods without grazing opportunities. Complementarily, we explored the effects of the main environmental descriptors (rainfalls and NDVI) on feeding patterns and diet quality. We found that Cuvier's diets are based mainly on acacias (Vachellia tortilis, V. flava) and occasionally on the annual forb Anastatica hierochuntica. In total, eighteen species (five trees, nine shrubs, three herbs, and one grass) belonging to fifteen families were recorded. Our result confirmed the browsers' characteristic of this species, reaffirming its ability to settle in a hostile environment. Acacias stand out as key species consumed at the southernmost limit of their range; hence, future conservation plans and strategies should take this into account for the survival of Cuvier's gazelle in desert environments

Dislipidemias y prevención del ictus: recomendaciones del Grupo de Estudio de Enfermedades Cerebrovasculares de la Sociedad Española de Neurología

Objective: We present an update of the Spanish Society of Neurology's recommendations for prevention of both primary and secondary stroke in patients with dyslipidaemia. Development: We performed a systematic review to evaluate the main aspects of the management of dyslipidaemias in primary and secondary stroke prevention and establish a series of recommendations. Conclusions: In primary prevention, the patient's vascular risk should be determined in order to define target values for low-density lipoprotein cholesterol. In secondary prevention after an atherothrombotic stroke, a target value <55 mg/dL is recommended; in non-atherothombotic ischaemic strokes, given the unclear relationship with dyslipidaemia, target value should be established according to the vascular risk group of each patient. In both primary and secondary prevention, statins are the drugs of first choice, and ezetimibe and/or PCSK9 inhibitors may be added in patients not achieving the target value.Objetivo: Actualizar las recomendaciones de la Sociedad Española de Neurología para la prevención del ictus, tanto primaria como secundaria en pacientes con dislipidemia. Desarrollo: Se ha realizado una revisión sistemática en Pubmed evaluando los principales aspectos relacionados con el manejo de las dislipidemias en la prevención primaria y secundaria del ictus, elaborándose una serie de recomendaciones relacionadas con los mismos. Conclusiones: En prevención primaria se recomienda determinar el riesgo vascular del paciente con el fin de definir los objetivos de LDLc. En prevención secundaria tras un ictus de origen aterotrombótico se recomienda un objetivo de LDLc < 55 mg/dl, mientras que en ictus isquémicos de origen no aterotrombótico dado que su relación con dislipidemias es incierta se establecerán los objetivos en base al grupo de riesgo vascular de cada paciente. Tanto en prevención primaria como secundaria las estatinas son los fármacos de primera elección, pudiendo asociarse ezetimiba y/o inhibidores de PCSK9 en aquellos casos que no alcancen los objetivos terapéuticos

RP11-362K2.2 : RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis

Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p-value 3.90 x 10(-8)) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p-value 6.10 x 10(-8)) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer's disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-beta, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases.Peer reviewe