Joan Montaner

Hospital Universitario Virgen del Rocío, Hispalis, Andalusia, Spain

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Publications (343)1514.75 Total impact

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    ABSTRACT: Stroke remains one of the main causes of death and disability worldwide. The challenge of predicting stroke outcome has been traditionally assessed from a general point of view, where baseline non-modifiable factors such as age or stroke severity are considered the most relevant factors. However, after stroke occurrence, some specific complications such as hemorrhagic transformations or post stroke infections, which lead to a poor outcome, could be developed. An early prediction or identification of these circumstances, based on predictive models including clinical information, could be useful for physicians to individualize and improve stroke care. Furthermore, the addition of biological information such as blood biomarkers or genetic polymorphisms over these predictive models could improve their prognostic value. In this review, we focus on describing the different post-stroke complications that have an impact in short and long-term outcome across different time points in its natural history and on the clinical-biological information that might be useful in their prediction.
    No preview · Article · Jan 2016 · European Journal of Internal Medicine
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    ABSTRACT: The human immortalized brain endothelial cell line hCMEC/D3 is considered an in-vitro model of the blood-brain-barrier. We aimed to characterize changes in the secretome of hCMEC/D3 subjected to oxygen and glucose deprivation (OGD) to identify new proteins involved in ischemia-triggered blood-brain-barrier disruption and test their potential as blood biomarkers for ischemic stroke. Using a quantitative proteomic approach based on SILAC, 19 proteins were found differentially secreted between OGD and normoxia/normoglycemia conditions. Among the OGD-secreted proteins, protein folding was the main molecular function identified and for the main canonical pathways there was an enrichment in epithelial adherens junctions and aldosterone signaling. ANXA1, CLU, IGFBP2, PRDX3, TIMP2 and COL1A2 were validated by Western blot. Additionally, 5 replicated proteins were analyzed in human serum samples of 38 ischemic stroke patients, 18 stroke-mimicking conditions and 18 healthy controls. IGFBP2 was increased in strokes compared with stroke-mimicking patients (p<0.1). Significance: We characterized changes in the secretome of hCMEC/D3 cells after an ischemic insult and identified proteins associated with ischemia that might be involved in the disruption of the blood-brain barrier during cerebral ischemia by SILAC. Besides we analyzed the putative potential of the candidate proteins to become biomarkers for the diagnosis of ischemic stroke.
    Full-text · Article · Dec 2015 · Journal of proteomics
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    Full-text · Article · Dec 2015 · The Lancet Neurology
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    ABSTRACT: The involvement of apolipoproteins, such as the ApoE4 isoform, in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) highlights the fact that certain lipid carriers may participate in soluble β-amyloid (Aβ) transport. Our general aim was to characterize the soluble levels of the apolipoproteins apoE, apoA1 and apoJ/clusterin and their genotype status in patients with CAA. We analyzed the genotypes frequency of APOA1 (rs5069, rs670), CLU (rs11136000, rs1532278, rs7012010, rs9331888) and APOE (rs429358, rs7412) in a cohort of patients with CAA-associated intracerebral hemorrhage (ICH) (n = 59) and compared the results with those from hypertension-associated ICH (n = 42), AD patients (n = 73) and controls (n = 88). In a subgroup of patients, we also determined the plasma concentrations of apoE, apoA1 and apoJ/clusterin. We found increased plasma apoJ/clusterin levels in CAA patients compared to AD patients or controls after adjusting for sex and age (CAA vs. controls, p = 0.033; CAA vs. AD, p = 0.013). ApoA1 levels were not altered between groups, although a strong correlation was observed between plasma Aβ(1-40) and apoA1 among CAA patients (r = 0.583, p = 0.007). Regarding plasma apoE concentration, a robust association between circulating levels and genotype status was confirmed (p < 0.001). Whereas the APOE4 frequency was higher in AD (p < 0.001) and CAA (p = 0.013), the APOA1 and CLU genotypes were not different among groups. In the CAA cohort, the risk-linked CLU variant (C) rs11136000 was associated with white matter hyperintensities (p = 0.045) and the presence of lobar microbleeds (p = 0.023) on MRI. In summary, our findings suggest that apoA1 may act as a physiological transporter of Aβ(1-40) and that apoJ/clusterin appears to be a chaperone related to distinctive lesions in CAA brains.
    No preview · Article · Dec 2015 · NeuroMolecular Medicine
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    ABSTRACT: Background: Intracerebral hemorrhage (ICH) is a devastating form of stroke and depending on the underlying cause, primary ICH is mainly caused by hypertension (HTN-ICH) or cerebral amyloid angiopathy (CAA-ICH). Currently, neuroimaging markers are required to identify the pattern for each etiology. The discovery of new biomarkers to improve the management of this pathology is therefore needed. Methods: A microarray analysis was carried out to analyze gene expression differences in blood samples from patients (>1.5 months since the last ICH event) who suffered a CAA-ICH and HTN-ICH, and controls. The results were replicated by quantitative polymerase chain reaction and the plasma protein level of the best candidate was measured with enzyme-linked immunosorbent assay. Results: The microarray analysis and the validation study revealed an increase in Golgin A8 Family, Member A (GOLGA8A) mRNA and protein levels in ICH cases compared to controls (P < .01), although no differences were found between specific ICH etiologies. GOLGA8A plasma levels were also associated with the presence of multiple hemorrhages (P < .05). Conclusions: The GOLGA8A level was increased in the blood of patients who suffered a primary ICH. We did not, however, find any candidate biomarker that distinguished CAA-ICH from HTN-ICH. The role of GOLGA8A in this fatal disorder has yet to be determined.
    No preview · Article · Dec 2015 · Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association
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    Preview · Article · Nov 2015 · Journal of the American Heart Association
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    ABSTRACT: Aim: We report the study of a familial rare disease with recurrent venous thromboembolic events that remained undiagnosed for many years using standard coagulation and hemostasis techniques. Methods: Exome sequencing was performed in three familial cases with venous thromboembolic disease and one familial control using NimbleGen exome array. Clot lysis experiments were performed to analyze the reasons of the altered fibrinolytic activity caused by the mutation found. Results: We found a mutation that consists of a R458C substitution on the fibrinogen alpha chain (FGA) gene confirmed in 13 new familial subjects that causes a rare subtype of dysfibrinogenemia characterized by venous thromboembolic events. The mutation was already reported to be associated with a fibrinogen variant called fibrinogen Bordeaux. Clot-lysis experiments showed a decreased and slower fibrinolytic activity in carriers of this mutation as compared to normal subjects, thus demonstrating an impaired fibrinolysis of fibrinogen Bordeaux. Conclusions: The exome sequencing and clot-lysis experiments might be powerful tools to diagnose idiopathic thrombophilias after an unsuccessful set of biochemical laboratory tests. Fibrinogen Bordeaux is associated with impaired fibrinolysis in this family with idiopathic thrombophilia.
    Preview · Article · Nov 2015 · Journal of atherosclerosis and thrombosis
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    ABSTRACT: A rapid differentiation of acute ischemic stroke and intracerebral hemorrhage is essential for an adequate treatment and to promote a better outcome. Our aim was to identify new plasma biomarkers to differentiate stroke subtypes and to combine their diagnostic ability with other biomarkers already described for this clinical indication. Plasma samples of ischemic stroke (36) and intracerebral hemorrhage (10) patients were screened using a 177 antibodies library and 11 showed different concentrations among stroke subtypes (p<0.05), mainly chemokines, growth factors and angiogenic factors. Five proteins were selected for replication in 16 ischemic stroke and 16 intracerebral hemorrhage patients, and Retinol binding protein 4 (RPB4), Apolipoprotein B100 and Pigment epithelial derived factor were replicated (p<0.05). These proteins, together with Glial fibrillary acidic protein (GFAP) and Receptor for advanced glycation end product, were tested in 38 ischemic stroke and 28 intracerebral hemorrhage samples. Finally, RBP4>61 μg/mL and GFAP<0.07 ng/mL showed a specificity of 100% for both subtypes. Moreover, after multivariate logistic regression analysis, RBP4>48.75 μg/mL (ORadj :6.09 (1.3-28.57), p=0.02) and GFAP<0.07 ng/mL (ORadj :0.03 (0.003-0.31, p=0.003) resulted in independent predictors of stroke subtype, improving discrimination by 29% (p<0.0001). Both biomarkers might be useful as diagnostic biomarkers to differentiate ischemic stroke and intracerebral hemorrhage. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Journal of Neurochemistry
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    ABSTRACT: Stroke is the third leading cause of death in industrialized countries and one of the largest causes of permanent disability worldwide. Therapeutic options to fight stroke are still limited and the only approved drug is tissue-plasminogen activator (tPA) and/or mechanical thrombectomy. Post-stroke inflammation is well known to contribute to the expansion of the ischemic lesion, whereas its resolution stimulates tissue repair and neuroregeneration processes. As inflammation highly influences susceptibility of stroke patients to overcome the disease, there is an increasing need to develop new diagnostic, prognostic and therapeutic strategies for post-stroke inflammation. This review provides a brief overview of the contribution of the inflammatory mechanisms to the pathophysiology of stroke. It specially focuses on the role of inflammatory biomarkers to help predicting stroke patients' outcome since some of those biomarkers might turn out to be targets to be therapeutically altered overcoming the urgent need for the identification of potent drugs to modulate stroke-associated inflammation. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.
    Full-text · Article · Nov 2015 · Biochimica et Biophysica Acta
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    ABSTRACT: Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), has a central role in the coordination of receptor crosstalk and the integration of signaling pathways essential for neuronal differentiation, survival and function. This protein is a shared downstream effector for neurotrophin- and ephrin-receptors signaling that also interacts with the N-methyl-d-aspartate type of glutamate receptors (NMDARs). Failures in neurotrophic support and glutamate signaling are involved in pathologies related to excitotoxicity and/or neurodegeneration, where different components of these dynamic protein complexes result altered by a combination of mechanisms. In the case of Kidins220/ARMS, overactivation of NMDARs in excitotoxicity and cerebral ischemia triggers its downregulation, which contributes to neuronal death. This key role in neuronal life/death decisions encouraged us to investigate Kidins220/ARMS as a novel therapeutic target for neuroprotection. As the main mechanism of Kidins220/ARMS downregulation in excitotoxicity is proteolysis by calpain, we decided to develop cell-penetrating peptides (CPPs) that could result in neuroprotection by interference of this processing. To this aim, we first analyzed in detail Kidins220/ARMS cleavage produced in vitro and in vivo, identifying a major calpain processing site in its C-terminal region (between amino acids 1669 and 1670) within a sequence motif highly conserved in vertebrates. Then, we designed a 25-amino acids CPP (Tat-K) containing a short Kidins220/ARMS sequence enclosing the identified calpain site (amino acids 1668-1681) fused to the HIV-1 Tat protein basic domain, able to confer membrane permeability to attached cargoes. Transduction of cortical neurons with Tat-K reduced Kidins220/ARMS calpain processing in a dose- and time-dependent manner upon excitotoxic damage and allowed preservation of the activity of pERK1/2 and pCREB, signaling molecules central to neuronal survival and functioning. Importantly, these effects were associated to a significant increase in neuronal viability. This Kidins220/ARMS-derived peptide merits further research to develop novel neuroprotective therapies for excitotoxicity-associated pathologies.
    Full-text · Article · Oct 2015 · Cell Death & Disease

  • No preview · Article · Oct 2015

  • No preview · Conference Paper · Sep 2015
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    ABSTRACT: Matrix metalloproteinases (MMPs) are a family of enzymes able to degrade components of the extracellular matrix, which is important for normal blood-brain barrier function. Their function is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). We investigated whether MMPs and TIMPs in cerebrospinal fluid (CSF) and plasma were altered in Alzheimer's disease (AD) and vascular dementia (VaD), and whether this effect was modified by presence of cerebral microbleeds in AD patients. In addition, we assessed associations of MMPs and TIMPs with CSF amyloid-β 1-42 (Aβ 42), tau, and tau phosphorylated at threonine-181 (p-tau). We measured MMP2, MMP9, and MMP10, and TIMP1 and TIMP2 in CSF and plasma of 52 AD patients, 26 matched controls, and 24 VaD patients. AD patients showed higher plasma MMP2 levels compared to VaD patients (p < 0.05), and higher CSF MMP10 levels compared to controls (p < 0.05). Microbleeds in AD were associated with lower CSF TIMP1, TIMP2 and MMP9 in a dose-response relation. In addition, CSF MMP2 was associated with p-tau (St.B 0.23, p < 0.05), and CSF MMP10 with tau (St.B 0.38, p < 0.001) and p-tau (St.B 0.40, p < 0.001). Our findings suggest involvement of MMP2 and MMP10 in AD pathology. Lower levels of TIMPs in AD patients with microbleeds suggest less MMP inhibition in patients with concurrent cerebral microbleeds, which may hypothetically lead to a more vulnerable blood-brain barrier in these patients.
    No preview · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
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    ABSTRACT: Inflammation has been associated with atherothrombotic stroke and recently with cardioembolic stroke. Different genetic risk factors have been specifically associated with the subtypes of ischemic stroke (cardioembolic, atherothrombotic, and lacunar). However, there are no studies that have generated genetic risk scores for the different subtypes of ischemic stroke using polymorphisms associated with inflammation. Methods. We have analyzed 68 polymorphisms of 30 inflammatory mediator genes in 2,685 subjects: 1,987 stroke cases and 698 controls. We generated a genetic scoring system with the most significant polymorphisms weighted by the odds ratio of every polymorphism and taken into consideration the stroke subtype. Results. Three polymorphisms, rs1205 (CRP gene), rs1800779, and rs2257073 (NOS3 gene), were associated with cardioembolic stroke (p value <0.05). The score generated was only associated with the cardioembolic stroke subtype (p value: 0.001) and was replicated in an independent cohort (p value: 0.017). The subjects with the highest score presented a cardioembolic stroke in 92.2% of the cases (p value: 0.002). Conclusion. The genetics of inflammatory markers is more closely associated with cardioembolic strokes than with atherothrombotic or lacunar strokes. The genetic risk scoring system could be useful in the prediction and differentiation of ischemic stroke; however, it might be specific to particular ischemic stroke subtypes.
    Full-text · Article · Sep 2015 · Mediators of Inflammation
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    ABSTRACT: This study describes CholesteroNitrone 2 as an antioxidant and neuroprotective agent against ischemic injury. Neuroprotection was assessed using in vitro and in vivo experimental ischemia models. The compound significantly increased cell viability, induced neuroprotection following ischemic reperfusion, and decreased neurological deficit scores in treated animals, supporting the next pre-clinical studies as a potential agent for the treatment of stroke.
    No preview · Article · Aug 2015 · Journal of Medicinal Chemistry
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    ABSTRACT: Endothelial progenitor cells (EPCs) are being investigated for advanced therapies, and matrix metalloproteinase 9 (MMP9) has an important role in stroke recovery. Our aim was to determine whether tissue MMP9 influences the EPC-induced angiogenesis after ischemia. Wild-type (WT) and MMP9-deficient mice (MMP9/KO) were subjected to cerebral ischemia and treated with vehicle or outgrowth EPCs. After 3 weeks, we observed an increase in the peri-infarct vessel density in WT animals but not in MMP9/KO mice; no differences were found in the vehicle-treated groups. Our data suggest that tissue MMP9 has a crucial role in EPC-induced vascular remodeling after stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 29 July 2015; doi:10.1038/jcbfm.2015.180.
    No preview · Article · Jul 2015 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
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    ABSTRACT: Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger's disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes. Binswanger's disease patients are a relatively homogeneous subgroup with hypoxic hypoperfusion, lacunar infarcts, and inflammation that act synergistically to disrupt the blood-brain barrier (BBB) and break down myelin. Identification of this subgroup can be facilitated by multimodal disease markers obtained from clinical, cerebrospinal fluid, neuropsychological, and imaging studies. This consensus statement identifies a potential set of biomarkers based on underlying pathologic changes that could facilitate diagnosis and aid patient selection for future collaborative treatment trials.Journal of Cerebral Blood Flow & Metabolism advance online publication, 22 July 2015; doi:10.1038/jcbfm.2015.172.
    Full-text · Article · Jul 2015 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
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    Full-text · Conference Paper · Jul 2015
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    ABSTRACT: Oxidative stress is a major brain injury mechanism after ischemic stroke. 12/15-lipoxygenase (12/15-LOX) is a key mediator of oxidative stress, contributing to neuronal cell death and vascular leakage. Nonetheless, the mechanism leading to its upregulation is currently unknown. We show here that Signal Transducers and Activators of Transcription (STATs), specifically STAT6 and possibly STAT1, increase transcription of 12/15-LOX in neuronal cells. Both p-STAT6 and -1 bound to specific STAT binding sites in the mouse 12/15-LOX promoter. Small interfering RNA (siRNA) knockdown showed STAT6 to be the dominant regulator, reducing 12/15-LOX promoter activation and cell death in oxidatively stressed HT22 cells. STAT6 siRNA efficiently prevented the increase of 12/15-LOX in murine primary neurons, both after induction of oxidative stress and after oxygen-glucose deprivation. Early activation of STAT6 and STAT1 in mice was consistent with a role in regulating 12/15-LOX in focal ischemia. Brains of human stroke patients showed increased p-STAT6 and p-STAT1 in the peri-infarct region, along with 12/15-LOX and markers of apoptosis. These results link STAT6 and STAT1 to the 12/15-LOX damage pathway and suggest disregulation of STAT-dependent transcription as injury mechanism in stroke. Selectively targeting STATs may thus be a novel therapeutic approach to reducing brain injury after a stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 15 July 2015; doi:10.1038/jcbfm.2015.169.
    No preview · Article · Jul 2015 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
  • Maria Irene Ayuso · Joan Montaner
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    ABSTRACT: Despite decades of research on neuroprotectants in the fight against ischemic stroke, no successful results have been obtained and new alternative approaches are urgently needed. Translation of effective candidate drugs in experimental studies to patients has systematically failed. However, some of those treatments or neuroprotectant diets which demonstrated only beneficial effects if given before (but not after) ischemia induction and discarded for conventional neuroprotection, could be rescued in order to apply an ‘advanced neuroprotection strategy’ (ADNES). Herein, the authors discuss how re-profiling those neuroprotective candidate drugs and diets with the best potential, some of which are mentioned in this article as an ADNES, may be a good approach for developing successful treatments that protect the brain against ischemic damage. This novel approach would try to protect the brain of patients who are at high risk of suffering a stroke, before damage occurs, in order to minimize brain injury by having the neuroprotectant drug or diet ‘on board’ if unfortunately stroke occurs.
    No preview · Article · Jul 2015 · Expert Opinion on Investigational Drugs

Publication Stats

9k Citations
1,514.75 Total Impact Points


  • 2014-2015
    • Hospital Universitario Virgen del Rocío
      Hispalis, Andalusia, Spain
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
  • 2004-2015
    • Autonomous University of Barcelona
      • Department of Medicine
      Cerdanyola del Vallès, Catalonia, Spain
    • Hospital Universitari de Bellvitge
      l'Hospitalet de Llobregat, Catalonia, Spain
  • 1999-2015
    • University Hospital Vall d'Hebron
      • • Department of Neurology
      • • Institut de Recerca
      Barcino, Catalonia, Spain
  • 2011-2014
    • VHIR Vall d’Hebron Research Institute
      Barcino, Catalonia, Spain
    • University of Coimbra
      • Department of Neurology
      Coímbra, Coimbra, Portugal
  • 2012
    • St George's, University of London
      • Stroke and Dementia Research Centre
      Londinium, England, United Kingdom
  • 2006-2012
    • Vall d’Hebron Institute of Oncology
      Barcino, Catalonia, Spain
  • 2004-2012
    • Hospital Valle Del Nalon
      Rianxo, Galicia, Spain
  • 2010
    • University of Newcastle
      Newcastle, New South Wales, Australia
    • University of Barcelona
      • Department of Medicine
      Barcino, Catalonia, Spain
  • 2009
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany