Joan Montaner

Hospital Universitario Virgen del Rocío, Hispalis, Andalusia, Spain

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Publications (330)1460.3 Total impact

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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.
    Journal of Neurochemistry 11/2015; DOI:10.1111/jnc.13419 · 4.28 Impact Factor
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    Alba Simats · Teresa García-Berrocoso · Joan Montaner ·
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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.
    Biochimica et Biophysica Acta 11/2015; DOI:10.1016/j.bbadis.2015.10.025 · 4.66 Impact Factor
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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.
    Cell Death & Disease 10/2015; 6(10):e1939. DOI:10.1038/cddis.2015.307 · 5.01 Impact Factor

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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.
    Journal of Alzheimer's disease: JAD 09/2015; 48(3). DOI:10.3233/JAD-143186 · 4.15 Impact Factor
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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.
    Mediators of Inflammation 09/2015; 2015(3):569714. DOI:10.1155/2015/569714 · 3.24 Impact Factor
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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.
    Journal of Medicinal Chemistry 08/2015; 58(16). DOI:10.1021/acs.jmedchem.5b00755 · 5.45 Impact Factor
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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.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2015; 35(10). DOI:10.1038/jcbfm.2015.180 · 5.41 Impact Factor
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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.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2015; DOI:10.1038/jcbfm.2015.172 · 5.41 Impact Factor
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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.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2015; DOI:10.1038/jcbfm.2015.169 · 5.41 Impact Factor
  • 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.
    Expert Opinion on Investigational Drugs 07/2015; 24(9). DOI:10.1517/13543784.2015.1065040 · 5.53 Impact Factor
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    ABSTRACT: DNA methylation is a heritable and stable epigenetic mark implicated in complex human traits. Epigenome-wide association studies (EWAS) using array-based technology are becoming widely used to identify differentially methylated sites associated with complex diseases. EWAS studies require large sample sizes to detect small effects, which increases project costs. In the present study we propose to pool DNA samples in methylation array studies as an affordable and accurate alternative to individual samples studies, in order to reduce economic costs or when low amounts of DNA are available. For this study, 20 individual DNA samples and 4 pooled DNA samples were analysed using the Illumina Infinium HumanMethylation450 BeadChip array to evaluate the efficiency of the pooling approach in EWAS studies. Statistical power calculations were also performed to discover the minimum sample size needed for the pooling strategy in EWAS. A total of 485,577 CpG sites across the whole genome were assessed. Comparison of methylation levels of all CpG sites between individual samples and their related pooled samples revealed highly significant correlations (rho > 0.99, p-val < 10(-16)). These results remained similar when assessing the 101 most differentially methylated CpG sites (rho > 0.98, p-val < 10(-16)). Also, it was calculated that n = 43 is the minimum sample size required to achieve a 95 % statistical power and a 10(-06) significance level in EWAS, when using a DNA pool strategy. DNA pooling strategies seems to accurately provide estimations of averaged DNA methylation state using array based EWAS studies. This type of approach can be applied to the assessment of disease phenotypes, reducing the amount of DNA required and the cost of large-scale epigenetic analyses.
    07/2015; 7(1):78. DOI:10.1186/s13148-015-0097-x
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    ABSTRACT: Lower respiratory tract infections frequently complicate stroke and adversely affect outcome. There is currently no agreed terminology or gold-standard diagnostic criteria for the spectrum of lower respiratory tract infections complicating stroke, which has implications for clinical practice and research. The aim of this consensus was to propose standardized terminology and operational diagnostic criteria for lower respiratory tract infections complicating acute stroke. Systematic literature searches of multiple electronic databases were undertaken. An evidence review and 2 rounds of consensus consultation were completed before a final consensus meeting in September 2014, held in Manchester, United Kingdom. Consensus was defined a priori as ≥75% agreement between the consensus group members. Consensus was reached for the following: (1) stroke-associated pneumonia (SAP) is the recommended terminology for the spectrum of lower respiratory tract infections within the first 7 days after stroke onset; (2) modified Centers for Disease Control and Prevention (CDC) criteria are proposed for SAP as follows-probable SAP: CDC criteria met, but typical chest x-ray changes absent even after repeat or serial chest x-ray; definite SAP: CDC criteria met, including typical chest x-ray changes; (3) there is limited evidence for a diagnostic role of white blood cell count or C-reactive protein in SAP; and (4) there is insufficient evidence for the use of other biomarkers (eg, procalcitonin). Consensus operational criteria for the terminology and diagnosis of SAP are proposed based on the CDC criteria. These require prospective evaluation in patients with stroke to determine their reliability, validity, impact on clinician behaviors (including antibiotic prescribing), and clinical outcomes. © 2015 American Heart Association, Inc.
    Stroke 06/2015; 46(8). DOI:10.1161/STROKEAHA.115.009617 · 5.72 Impact Factor
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    ABSTRACT: Cerebral stroke induces massive Th1-shifted inflammation both in the brain and the periphery, contributing to the outcome of stroke. A Th1-type response is neurotoxic whereas a Th2-type response is accompanied by secretion of anti-inflammatory cytokines, such as interleukin-4 (IL-4). Interleukin-33 (IL-33) is a cytokine known to induce a shift towards the Th2-type immune response, polarize macrophages/microglia towards the M2-type, and induce production of anti-inflammatory cytokines. We found that the plasma levels of the inhibitory IL-33 receptor, sST2, are increased in human stroke and correlate with a worsened stroke outcome, suggesting an insufficient IL-33-driven Th2-type response. In mouse, peripheral administration of IL-33 reduced stroke-induced cell death and improved the sensitivity of the contralateral front paw at 5 days post injury. The IL-33-treated mice had increased levels of IL-4 in the spleen and in the peri-ischemic area of the cortex. Neutralization of IL-4 by administration of an IL-4 antibody partially prevented the IL-33-mediated protection. IL-33 treatment also reduced astrocytic activation in the peri-ischemic area and increased the number of Arginase-1 immunopositive microglia/macrophages at the lesion site. In human T-cells, IL-33 treatment induced IL-4 secretion, and the conditioned media from IL-33-exposed T-cells reduced astrocytic activation. This study demonstrates that IL-33 is protective against ischemic insult by induction of IL-4 secretion and may represent a novel therapeutic approach for the treatment of stroke. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 06/2015; 49. DOI:10.1016/j.bbi.2015.06.013 · 5.89 Impact Factor
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    ABSTRACT: Blood pressure (BP) variability is associated with stroke risk, but less is known about subclinical cerebral small vessel disease (CSVD). We aimed to determine whether CSVD relates to short-term BP variability independently of BP levels and also, whether they improve CSVD discrimination beyond clinical variables and office BP levels. This was a cohort study on asymptomatic hypertensives who underwent brain magnetic resonance imaging and 24-hour ambulatory BP monitoring. Office and average 24-hour, daytime and nighttime BP levels, and several metrics of BP variability (SD, weighted SD, coefficient of variation, and average real variability [ARV]) were calculated. Definition of CSVD was based on the presence of lacunar infarcts and white matter hyperintensity grades. Multivariate analysis and integrated discrimination improvement were performed to assess whether BP variability and levels were independently associated with CSVD and improved its discrimination. Four hundred eighty-seven individuals participated (median age, 64; 47% women). CSVD was identified in 18.9%, related to age, male sex, diabetes mellitus, use of treatment, ambulatory BP monitoring-defined BP levels, and ARV of systolic BP at any period. The highest prevalence (33.7%) was found in subjects with both 24-hour BP levels and ARV elevated. BP levels at any period and ARV (24 hours and nocturnal) emerged as independent predictors of CSVD, and discrimination was incrementally improved although not to a clinically significant extent (integrated discrimination improvement, 5.31%, 5.17% to 5.4%). Ambulatory BP monitoring-defined BP levels and ARV of systolic BP relate to subclinical CSVD in hypertensive individuals. © 2015 American Heart Association, Inc.
    Hypertension 06/2015; 66(3). DOI:10.1161/HYPERTENSIONAHA.115.05440 · 6.48 Impact Factor
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    ABSTRACT: No neuroprotective or neurorestorative therapies have been approved for ischemic stroke. Bone marrow mononuclear cell intra-arterial transplantation improves recovery in experimental models of ischemic stroke. This trial aims to test safety and efficacy of intra-arterial injection of autologous bone marrow mononuclear cell in ischemic stroke patients. Multicenter, prospective, phase II, randomized, controlled (non-treated group as control), assessor-blinded clinical trial. Seventy-six stroke patients will be enrolled. Patients fulfilling clinical and radiological criteria (e.g. age between 18 and 80 years, middle cerebral artery ischemic stroke with a National Institutes of Health Stroke Scale score of 6-20 within one- to seven-days from stroke onset and no lacunar stroke) will be randomized to intervention or control group (1 : 1). Bone marrow harvest and intra-arterial injection of autologous bone marrow mononuclear cell will be done in the intervention group with two different doses (2 × 10(6) /kg or 5 × 10(6) /kg in 1 : 1 proportion). Patients will be stratified at randomization by National Institutes of Health Stroke Scale score. Patients will be followed up for two-years. The primary outcome is the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days. Secondary outcomes include National Institutes of Health Stroke Scale and Barthel scores at six-months, infarct volume, mortality, and seizures. This is the first trial to explore efficacy of different doses of intra-arterial bone marrow mononuclear cell in moderate-to-severe acute ischemic stroke patients. The trial is registered as NCT02178657. © 2015 World Stroke Organization.
    International Journal of Stroke 06/2015; 10(7). DOI:10.1111/ijs.12520 · 3.83 Impact Factor
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    ABSTRACT: The majority of patients with ischaemic cerebrovascular disease (CVD) are not protected from further vascular events with antiplatelet therapy. Measurement of inhibition of platelet function ex vivo on antiplatelet therapy, using laboratory tests that correlate with the clinical effectiveness of these agents, would potentially enable physicians to tailor antiplatelet therapy to suit individuals. A systematic review of the literature was performed to collate all available data on ex vivo platelet function/reactivity in CVD patients, especially those treated with aspirin, dipyridamole or clopidogrel. Particular emphasis was paid to information from commonly available whole blood platelet function analysers (PFA-100®, VerifyNow® and Multiplate®). Data on pharmacogenetic mechanisms potentially influencing high on-treatment platelet reactivity (HTPR) on antiplatelet therapy in CVD were reviewed. Two-hundred forty-nine potentially relevant articles were identified; 93 manuscripts met criteria for inclusion. The prevalence of ex vivo HTPR in CVD varies between 3–62% with aspirin monotherapy, 8–61% with clopidogrel monotherapy and 56–59% when dipyridamole is added to aspirin in the early, subacute or late phases after TIA/stroke onset. The prevalence of HTPR on aspirin was higher on the PFA-100 than on the VerifyNow in one study (p < 0.001). Furthermore, the prevalence of HTPR on aspirin was lower when one used ‘novel longitudinal’ rather than ‘cross-sectional, case–control’ definitions of HTPR on the PFA early after TIA or stroke (p = 0.003; 1 study). Studies assessing the influence of genetic polymorphisms on HTPR in CVD patients are limited, and need validation in large multicentre studies. Available data illustrate that an important proportion of CVD patients have ex vivo HTPR on their prescribed antiplatelet regimen, and that the prevalence varies depending on the definition and assay used. Large, adequately-sized, prospective multicentre collaborative studies are urgently needed to determine whether comprehensive assessment of HTPR at high and low shear stress with a range of user-friendly whole blood platelet function testing platforms, in conjunction with pharmacogenetic data, improves our ability to predict the risk of recurrent vascular events in CVD patients, and thus enhance secondary prevention following TIA or ischaemic stroke.
    Platelets 06/2015; 26(5). DOI:10.3109/09537104.2015.1049139 · 2.98 Impact Factor
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    ABSTRACT: High blood pressure accelerates normal aging stiffness process. Arterial stiffness (AS) has been previously associated with impaired cognitive function and dementia. Our aims are to study how cognitive function and status (mild cognitive impairment, MCI and normal cognitive aging, NCA) relate to AS in a community-based population of hypertensive participants assessed with office and 24-hour ambulatory blood pressure measurements. Six hundred ninety-nine participants were studied, 71 had MCI and the rest had NCA. Office pulse pressure (PP), carotid-femoral pulse wave velocity, and 24-hour ambulatory PP monitoring were collected. Also, participants underwent a brain magnetic resonance to study cerebral small-vessel disease (cSVD) lesions. Multivariate analysis-related cognitive function and cognitive status to AS measurements after adjusting for demographic, vascular risk factors, and cSVD. Carotid-femoral pulse wave velocity and PP at different periods were inversely correlated with several cognitive domains, but only awake PP measurements were associated with attention after correcting for confounders (beta=-0.22, 95% confidence interval (CI) -0.41, -0.03). All ambulatory PP measurements were related to MCI, which was independently associated with nocturnal PP (odds ratio (OR)=2.552, 95% CI 1.137, 5.728) and also related to the presence of deep white matter hyperintensities (OR=1.903, 1.096, 3.306). Therefore, higher day and night ambulatory PP measurements are associated with poor cognitive outcomes.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 May 2015; doi:10.1038/jcbfm.2015.90.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 05/2015; DOI:10.1038/jcbfm.2015.90 · 5.41 Impact Factor
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    ABSTRACT: Vascular dementia is the second most common type of dementia after Alzheimer's disease (AD). Subcortical ischemic vascular disease refers to a form of vascular cognitive impairment characterized by the presence of diffuse white matter hyperintensities (WMHs) and multiple lacunar infarcts. These neuroimaging findings are mainly caused by cerebral small-vessel disease (cSVD) and relate to aging and cognitive impairment, but they can also be silent and highly prevalent in otherwise healthy individuals. We aimed to review studies on blood and cerebrospinal fluid (CSF) markers related to the presence of WMHs and lacunar infarcts that have been conducted in the past in large population-based studies and in high-risk selected patients (such as those with vascular risk factors, vascular cognitive impairment, or AD). Relevant associations with the presence and progression of cSVD have been described in the blood for markers related to inflammatory processes, endothelial damage and coagulation/fibrinolysis processes, etc. Also, different combinations of CSF markers might help to differentiate between etiologic types of dementia. In the future, to translate these findings into clinical practice and use biomarkers to early diagnosis and monitoring vascular cognitive impairment would require the replication of candidate markers in large-scale, multicenter, and prospectively designed studies.Journal of Cerebral Blood Flow & Metabolism advance online publication, 22 April 2015; doi:10.1038/jcbfm.2015.68.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2015; DOI:10.1038/jcbfm.2015.68 · 5.41 Impact Factor
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    ABSTRACT: Matrix metalloproteases MMP-2 and MMP-9 have been implicated in the physiologic catabolism of Alzheimer amyloid-β (Aβ). Conversely, their association with vascular amyloid deposits, blood-brain barrier disruption, and hemorrhagic transformations after ischemic stroke also highlights their involvement in pathologic processes. To better understand this dichotomy, recombinant human (rh) MMP-2 and MMP-9 were incubated with Aβ40 and Aβ42 and the resulting proteolytic fragments assessed via immunoprecipitation and quantitative mass spectrometry. Both MMPs generated Aβ fragments truncated only at the C-terminus, ending at positions 34, 30 and 16. Using deuterated homologues as internal standards, we observed limited and relatively slow degradation of Aβ42 by rhMMP-2 while the enzyme cleaved >80% of Aβ40 during the first hour of incubation. rhMMP-9 was significantly less effective, particularly in degrading Aβ1-42, although the targeted peptide bonds were identical. Using Aβ1-34 and Aβ1-30, we demonstrated that these peptides are also substrates for both MMPs, cleaving Aβ1-34 to produce Aβ1-30 first and Aβ1-16 subsequently. Consistent with the kinetics observed with full-length Aβ, rhMMP-9 degraded only a minute fraction of Aβ1-34 and was even less effective in producing Aβ1-16. Further degradation of Aβ1-16 by either MMP-2 or MMP-9 was not observed even after prolonged incubation times. Notably, all MMP-generated C-terminally truncated Aβ fragments were highly soluble, did not exhibit fibrillogenic properties or induce cytotoxicity in human cerebral microvascular endothelial or neuronal cells supporting the notion that these truncated Aβ species are associated with clearance mechanisms rather than being key elements in the fibrillogenesis process. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 04/2015; 290(24). DOI:10.1074/jbc.M114.610931 · 4.57 Impact Factor

Publication Stats

8k Citations
1,460.30 Total Impact Points


  • 2014-2015
    • Hospital Universitario Virgen del Rocío
      Hispalis, Andalusia, Spain
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
  • 2006-2015
    • Vall d’Hebron Institute of Oncology
      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
  • 2010
    • University of Newcastle
      Newcastle, New South Wales, Australia
  • 2004-2010
    • Hospital Valle Del Nalon
      Rianxo, Galicia, Spain
  • 2009
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany