Grupos Investigadores

Líneas de Investigación

  • Alteraciones conductales de la enfermedad de Alzheimer: depresión
  • Biomarcadores
  • Búsqueda de nuevas estrategias terapéuticas
  • Modelos experimentales basados en factores de riesgo de la enfermedad de Alzheimer
  • Neuroinflamación

Palabras Clave

  • Alzheimer
  • Amiloide
  • Canabinoides
  • Demencia
  • Depresión
  • Epigenética
  • Estrés
  • Metalolismo
  • Neuroimagen
  • Neuroprotección
  • Plasticidad sináptica
  • Tau

Publicaciones Científicas desde 2018

  • Autores: Pérez Silanes, Silvia; Martisová, Eva; Moreno Amatria, Esther; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1661-6596 Vol.25 N° 2 2024 págs. 799
    Resumen
    Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.
  • Autores: Ezkurdia Lasarte, Amaia; Ramírez Gil, María Javier; Solas Zubiaurre, Maite (Autor de correspondencia)
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.24 N° 5 2023 págs. 4354
    Resumen
    Alzheimer's disease (AD) is the main type of dementia and is a disease with a profound socioeconomic burden due to the lack of effective treatment. In addition to genetics and environmental factors, AD is highly associated with metabolic syndrome, defined as the combination of hypertension, hyperlipidemia, obesity and type 2 diabetes mellitus (T2DM). Among these risk factors, the connection between AD and T2DM has been deeply studied. It has been suggested that the mechanism linking both conditions is insulin resistance. Insulin is an important hormone that regulates not only peripheral energy homeostasis but also brain functions, such as cognition. Insulin desensitization, therefore, could impact normal brain function increasing the risk of developing neurodegenerative disorders in later life. Paradoxically, it has been demonstrated that decreased neuronal insulin signalling can also have a protective role in aging and protein-aggregation-associated diseases, as is the case in AD. This controversy is fed by studies focused on neuronal insulin signalling. However, the role of insulin action on other brain cell types, such as astrocytes, is still unexplored. Therefore, it is worthwhile exploring the involvement of the astrocytic insulin receptor in cognition, as well as in the onset and/or development of AD.
  • Autores: Perez-Gonzalez, M.; Solas Zubiaurre, Maite; Wu, Y.; et al.
    Revista: FRONTIERS IN CELLULAR NEUROSCIENCE
    ISSN: 1662-5102 Vol.17 N° 1170013 2023
  • Autores: García Ardanaz, Carlos; Ezkurdia Lasarte, Amaia; Bejarano, A.; et al.
    Revista: ACS CHEMICAL NEUROSCIENCE
    ISSN: 1948-7193 Vol.14 N° 11 2023 págs. 2074 - 2088
    Resumen
    c-Jun N-terminal kinases (JNKs) are a family of proteinkinasesactivated by a myriad of stimuli consequently modulating a vast rangeof biological processes. In human postmortem brain samples affectedwith Alzheimer ' s disease (AD), JNK overactivation has beendescribed; however, its role in AD onset and progression is stillunder debate. One of the earliest affected areas in the pathologyis the entorhinal cortex (EC). Noteworthy, the deterioration of theprojection from EC to hippocampus (Hp) point toward the idea thatthe connection between EC and Hp is lost in AD. Thus, the main objectiveof the present work is to address if JNK3 overexpression in the ECcould impact on the hippocampus, inducing cognitive deficits. Dataobtained in the present work suggest that JNK3 overexpression in theEC influences the Hp leading to cognitive impairment. Moreover, proinflammatorycytokine expression and Tau immunoreactivity were increased both inthe EC and in the Hp. Therefore, activation of inflammatory signalingand induction of Tau aberrant misfolding caused by JNK3 could be responsiblefor the observed cognitive impairment. Altogether, JNK3 overexpressionin the EC may impact on the Hp inducing cognitive dysfunction andunderlie the alterations observed in AD.
  • Autores: Sola Sevilla, Noemí; Mesa-Lombardo, A.; Aleixo, M.; et al.
    Revista: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
    ISSN: 1557-1890 Vol.18 N° 3 2023 págs. 529 - 550
    Resumen
    Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer's disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1 & beta;, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.
  • Autores: Belloch Perez, Francisco de Borja; Cortés Erice, María; Herzog, E.; et al.
    Revista: PROGRESS IN NEURO-PSYCHOPHARMACOLOGY AND BIOLOGICAL PSYCHIATRY
    ISSN: 0278-5846 Vol.121 2023 págs. 110640
    Resumen
    The NMDA antagonist ketamine demonstrated a fast antidepressant activity in treatment-resistant depression. Pre-clinical studies suggest that de novo synthesis of the brain-derived neurotrophic factor (BDNF) in the PFC might be involved in the rapid antidepressant action of ketamine. Applying a genetic model of impaired glutamate release, this study aims to further identify the molecular mechanisms that could modulate antide-pressant action and resistance to treatment.To that end, mice knocked-down for the vesicular glutamate transporter 1 (VGLUT1+/-) were used. We analyzed anhedonia and helpless behavior as well as the expression of the proteins linked to glutamate trans-mission in the PFC of mice treated with ketamine or the reference antidepressant reboxetine. Moreover, we analyzed the acute effects of ketamine in VGLUT1+/-mice pretreated with chronic reboxetine or those that received a PFC rescue expression of VGLUT1. Chronic reboxetine rescued the depressive-like phenotype of the VGLUT1+/-mice. In addition, it enhanced the expression of the proteins linked to the AMPA signaling pathway as well as the immature form of BDNF (pro-BDNF). Unlike WT mice, ketamine had no effect on anhedonia or pro-BDNF expression in VGLUT1+/-mice; it also failed to decrease phosphorylated eukaryote elongation factor 2 (p-eEF2). Nevertheless, we found that reboxetine administered as pretreatment or PFC overexpression of VGLUT1 did rescue the antidepressant-like activity of acute ketamine in the mice. Our results strongly suggest that not only do PFC VGLUT1 levels modulate the rapid-antidepressant action of ketamine, but also highlight a possible mechanism for antidepressant resistance in some patients.
  • Autores: Janeiro Arenas, Manuel Humberto; Solas Zubiaurre, Maite; Orbe Lopategui, Josune; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1661-6596 Vol.24 N° 24 2023 págs. 17557
    Resumen
    In this study, the plausible role of trimethylamine N-oxide (TMAO), a microbiota metabolite, was investigated as a link between peripheral inflammation and the inflammation of the central nervous system using different cell lines. TMAO treatment favored the differentiation of adipocytes from preadipocytes (3T3-L1 cell line). In macrophages (RAW 264.7 cell line), which infiltrate adipose tissue in obesity, TMAO increased the expression of pro-inflammatory cytokines. The treatment with 200 mu M of TMAO seemed to disrupt the blood-brain barrier as it induced a significant decrease in the expression of occludin in hCMECs. TMAO also increased the expression of pro-inflammatory cytokines in primary neuronal cultures, induced a pro-inflammatory state in primary microglial cultures, and promoted phagocytosis. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between peripheral and central inflammation. Thus, TMAO-decreasing compounds may be a promising therapeutic strategy for neurodegenerative diseases.
  • Autores: Villarejo-Galende, A.; García-Arcelay, E.; Piñol-Ripoll, G.; et al.
    Revista: FRONTIERS IN PSYCHIATRY
    ISSN: 1664-0640 Vol.14 N° 1290002 2023
    Resumen
    BackgroundLimited information is available on the active process of seeking medical help in patients with Alzheimer's disease (AD) at early stages. The aim of this study was to assess the phenomenon of medical help-seeking in early AD and to identify associated factors.MethodsA multicenter, non-interventional study was conducted including patients of 50-90 years of age with prodromal or mild AD (National Institute on Aging/Alzheimer's Association criteria), a Mini-Mental State Examination (MMSE) score >= 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5-1.0. A multivariate logistic regression analysis was conducted.ResultsA total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years, 50.3% were female, and 87.2% had a CDR-GS score of 0.5. Mean disease duration was 1.4 (1.8) years. Ninety-four (63.1%) patients sought medical help, mostly from neurologists. Patients with help-seeking intentions were mostly female (60.6%) with a CDR-GS score of 0.5 (91.5%) and had a greater awareness of diagnosis, poorer quality of life, more depressive symptoms, and a more severe perception of their condition than their counterparts. Lack of help-seeking intentions was associated with male sex (p = 0.003), fewer years of education (p = 0.005), a low awareness of diagnosis (p = 0.005), and a low emotional consequence of the condition (p = 0.016).ConclusionUnderstanding the phenomenon of active medical help-seeking may facilitate the design of specific strategies to improve the detection of cognitive impairment, especially in patients with a lower level of educational attainment and poor awareness of their condition.
  • Autores: Solas Zubiaurre, Maite (Autor de correspondencia); Vela Lumbreras, Silvia; Smerdou Picazo, Cristian; et al.
    Revista: ACS CHEMICAL NEUROSCIENCE
    ISSN: 1948-7193 Vol.14 N° 8 2023 págs. 1524 - 1534
    Resumen
    c-Jun N-terminal kinase 3 (JNK3) is suggested to play a key role in neurodegenerative disorders, especially in Alzheimer's disease (AD). However, it remains unclear whether JNK or amyloid beta (A beta) appears first in the disease onset. Postmortem brain tissues from four dementia subtypes of patients dementia, and AD) were used to measure activated JNK (pJNK) and A beta levels. pJNK expression is significantly increased in AD; however, similar pJNK expression was found in other dementias. Furthermore, there was a significant correlation, co-localization, and direct interaction between pJNK expression and A beta levels in AD. Significant increased levels of pJNK were also found in Tg2576 mice, a model of AD. In this line, A beta 42 intracerebroventricular injection in wild-type mice was able to induce a significant elevation of pJNK levels. JNK3 overexpression, achieved by intrahippocampal injection of an adeno-associated viral vector expressing this protein, was enough to induce cognitive deficiencies and precipitate Tau aberrant misfolding in Tg2576 mice without accelerating amyloid pathology. JNK3 overexpression may therefore be triggered by increased A beta. The latter, together with subsequent involvement of Tau pathology, may be underlying cognitive alterations in early stages of AD.
  • Autores: Dolcet Negre, Marta María; Imaz Aguayo, Laura; García de Eulate Ruiz, María Reyes; et al.
    Revista: JOURNAL OF ALZHEIMERS DISEASE
    ISSN: 1387-2877 Vol.93 N° 1 2023 págs. 125 - 140
    Resumen
    Background: Subjective cognitive decline (SCD) may represent a preclinical stage of Alzheimer's disease (AD). Predicting progression of SCD patients is of great importance in AD-related research but remains a challenge. Objective: To develop and implement an ensemble machine learning (ML) algorithm to identify SCD subjects at risk of conversion to mild cognitive impairment (MCI) or AD. Methods: Ninety-nine SCD patients were included. Thirty-two progressed to MCI/AD, while 67 remained stable. To minimize the effect of class imbalance, both classes were balanced, and sensitivity was taken as evaluation metric. Bagging and boosting ML models were developed by using socio-demographic and clinical information, Mini-Mental State Examination and Geriatric Depression Scale (GDS) scores (feature-set 1a); socio-demographic characteristics and neuropsychological tests scores (feature-set 1b) and regional magnetic resonance imaging grey matter volumes (feature-set 2). The most relevant variables were combined to find the best model. Results: Good prediction performances were obtained with feature-sets 1a and 2. The most relevant variables (variable importance exceeding 20%) were: Age, GDS, and grey matter volumes measured in four cortical regions of interests. Their combination provided the optimal classification performance (highest sensitivity and specificity) ensemble ML model, Extreme Gradient Boosting with over-sampling of the minority class, with performance metrics: sensitivity = 1.00, specificity = 0.92 and area-under-the-curve = 0.96. The median values based on fifty random train/test splits were sensitivity = 0.83 (interquartile range (IQR) = 0.17), specificity = 0.77 (IQR = 0.23) and area-under-the-curve = 0.75 (IQR = 0.11). Conclusion: A high-performance algorithm that could be translatable into practice was able to predict SCD conversion to MCI/AD by using only six predictive variables.
  • Autores: Maroto Garcia, Julia (Autor de correspondencia); Martinez-Escribano, A.; Delgado-Gil, V.; et al.
    Revista: CLINICA CHIMICA ACTA
    ISSN: 0009-8981 Vol.548 2023 págs. 117471
    Resumen
    Introduction: Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system. Although there is currently no definite cure for MS, new therapies have recently been developed based on a continuous search for new biomarkers. Development: MS diagnosis relies on the integration of clinical, imaging and laboratory findings as there is still no single pathognomonic clinical feature or diagnostic laboratory biomarker. The most commonly laboratory test used is the presence of immunoglobulin G oligoclonal bands (OCB) in cerebrospinal fluid of MS patients. This test is now included in the 2017 McDonald criteria as a biomarker of dissemination in time. Nevertheless, there are other biomarkers currently in use such as kappa free light chain, which has shown higher sensitivity and specificity for MS diagnosis than OCB. In addition, other potential laboratory tests involved in neuronal damage, demyelination and/or inflammation could be used for detecting MS.Conclusions: CSF and serum biomarkers have been reviewed for their use in MS diagnosis and prognosis to stablish an accurate and prompt MS diagnosis, crucial to implement an adequate treatment and to optimize clinical outcomes over time.
  • Autores: Badesso, Sara; Cartas-Cejudo, P.; Espelosín Azpilicueta, María; et al.
    Revista: PHARMACEUTICS
    ISSN: 1999-4923 Vol.15 N° 1 2023 págs. 82
    Resumen
    Docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the brain, is essential for successful aging. In fact, epidemiological studies have demonstrated that increased intake of DHA might lower the risk for developing Alzheimer's disease (AD). These observations are supported by studies in animal models showing that DHA reduces synaptic pathology and memory deficits. Different mechanisms to explain these beneficial effects have been proposed; however, the molecular pathways involved are still unknown. In this study, to unravel the main underlying molecular mechanisms activated upon DHA treatment, the effect of a high dose of DHA on cognitive function and AD pathology was analyzed in aged Tg2576 mice and their wild-type littermates. Transcriptomic analysis of mice hippocampi using RNA sequencing was subsequently performed. Our results revealed that, through an amyloid-independent mechanism, DHA enhanced memory function and increased synapse formation only in the Tg2576 mice. Likewise, the IPA analysis demonstrated that essential neuronal functions related to synaptogenesis, neuritogenesis, the branching of neurites, the density of dendritic spines and the outgrowth of axons were upregulated upon-DHA treatment in Tg2576 mice. Our results suggest that memory function in APP mice is influenced by DHA intake; therefore, a high dose of daily DHA should be tested as a dietary supplement for AD dementia prevention.
  • Autores: Villarejo-Galende, A.; Garcia-Arcelay, E.; Piñol-Ripoll, G.; et al.
    Revista: EUROPEAN JOURNAL OF NEUROLOGY
    ISSN: 1351-5101 Vol.30 N° Supl. 1 2023 págs. 438 - 439
  • Autores: García Osta, Ana María; Dong, J.; Moreno Aliaga, María Jesús; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.23 N° 3 2022 págs. 1211
    Resumen
    The cell cycle consists of successive events that lead to the generation of new cells. The cell cycle is regulated by different cyclins, cyclin-dependent kinases (CDKs) and their inhibitors, such as p27(Kip1). At the nuclear level, p27(Kip1) has the ability to control the evolution of different phases of the cell cycle and oppose cell cycle progression by binding to CDKs. In the cytoplasm, diverse functions have been described for p27(Kip1), including microtubule remodeling, axonal transport and phagocytosis. In Alzheimer's disease (AD), alterations to cycle events and a purported increase in neurogenesis have been described in the early disease process before significant pathological changes could be detected. However, most neurons cannot progress to complete their cell division and undergo apoptotic cell death. Increased levels of both the p27(Kip1) levels and phosphorylation status have been described in AD. Increased levels of A beta 42, tau hyperphosphorylation or even altered insulin signals could lead to alterations in p27(Kip1) post-transcriptional modifications, causing a disbalance between the levels and functions of p27(Kip1) in the cytoplasm and nucleus, thus inducing an aberrant cell cycle re-entry and alteration of extra cell cycle functions. Further studies are needed to completely understand the role of p27(Kip1) in AD and the therapeutic opportunities associated with the modulation of this target.
  • Autores: Arrondo, P.; Elia-Zudaire, O.; Martí Andrés, Gloria María (Autor de correspondencia); et al.
    Revista: ALZHEIMER'S RESEARCH & THERAPY
    ISSN: 1758-9193 Vol.14 N° 1 2022 págs. 98
    Resumen
    Introduction People with subjective cognitive decline (SCD) report cognitive deterioration. However, their performance in neuropsychological evaluation falls within the normal range. The present study aims to analyse whether structural magnetic resonance imaging (MRI) reveals grey matter changes in the SCD population compared with healthy normal controls (HC). Methods Parallel systematic searches in PubMed and Web of Science databases were conducted, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Quality assessment was completed using the Newcastle-Ottawa Scale (NOS). Results Fifty-one MRI studies were included. Thirty-five studies used a region of interest (ROI) analysis, 15 used a voxel-based morphometry (VBM) analysis and 10 studies used a cortical thickness (CTh) analysis. Ten studies combined both, VBM or CTh analysis with ROI analysis. Conclusions Medial temporal structures, like the hippocampus or the entorhinal cortex (EC), seemed to present grey matter reduction in SCD compared with HC, but the samples and results are heterogeneous. Larger sample sizes could help to better determine if these grey matter changes are consistent in SCD subjects.
  • Autores: Janeiro Arenas, Manuel Humberto; Ramírez Gil, María Javier; Solas Zubiaurre, Maite (Autor de correspondencia)
    Revista: CELLULAR AND MOLECULAR NEUROBIOLOGY
    ISSN: 0272-4340 Vol.42 N° 2 2022 págs. 377 - 387
    Resumen
    Recent investigations have increased the interest on the connection between the microorganisms inhabiting the gut (gut microbiota) and human health. An imbalance of the intestinal bacteria representation (dysbiosis) could lead to different diseases, ranging from obesity and diabetes, to neurological disorders including Alzheimer's disease (AD). The term "gut-brain axis" refers to a crosstalk between the brain and the gut involving multiple overlapping pathways, including the autonomic, neuroendocrine, and immune systems as well as bacterial metabolites and neuromodulatory molecules. Through this pathway, microbiota can influence the onset and progression of neuropathologies such as AD. This review discusses the possible interaction between the gut microbiome and AD, focusing on the role of gut microbiota in neuroinflammation, cerebrovascular degeneration and A beta clearance.
  • Autores: García Ardanaz, Carlos; Ramírez Gil, María Javier; Solas Zubiaurre, Maite (Autor de correspondencia)
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.23 N° 7 2022 págs. 3785
    Resumen
    The brain is one of the most energy-consuming organs in the body. Satisfying such energy demand requires compartmentalized, cell-specific metabolic processes, known to be complementary and intimately coupled. Thus, the brain relies on thoroughly orchestrated energy-obtaining agents, processes and molecular features, such as the neurovascular unit, the astrocyte-neuron metabolic coupling, and the cellular distribution of energy substrate transporters. Importantly, early features of the aging process are determined by the progressive perturbation of certain processes responsible for adequate brain energy supply, resulting in brain hypometabolism. These age-related brain energy alterations are further worsened during the prodromal stages of neurodegenerative diseases, namely Alzheimer's disease (AD), preceding the onset of clinical symptoms, and are anatomically and functionally associated with the loss of cognitive abilities. Here, we focus on concrete neuroenergetic features such as the brain's fueling by glucose and lactate, the transporters and vascular system guaranteeing its supply, and the metabolic interactions between astrocytes and neurons, and on its neurodegenerative-related disruption. We sought to review the principles underlying the metabolic dimension of healthy and AD brains, and suggest that the integration of these concepts in the preventive, diagnostic and treatment strategies for AD is key to improving the precision of these interventions.
  • Autores: Guerra-Hiraldo, J. D.; López-Jiménez, A.; Gasca-Salas, C.; et al.
    Revista: JOURNAL OF NEUROLOGY
    ISSN: 0340-5354 Vol.270 N° 1 2022 págs. 548 - 551
  • Autores: Lanz, M.; Janeiro Arenas, Manuel Humberto; Milagro Yoldi, Fermín Ignacio; et al.
    Revista: MECHANISMS OF AGEING AND DEVELOPMENT
    ISSN: 0047-6374 Vol.204 2022 págs. 111668
    Resumen
    It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases.
  • Autores: Solas Zubiaurre, Maite; Zamarbide González, Marta; García Ardanaz, Carlos; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.23 N° 21 2022 págs. 13591
    Resumen
    Obesity and aging are becoming increasingly prevalent across the globe. It has been established that aging is the major risk factor for Alzheimer's disease (AD), and it is becoming increasingly evident that obesity and the associated insulin resistance are also notably relevant risk factors. The biological plausibility of the link between high adiposity, insulin resistance, and dementia is central for understanding AD etiology, and to form bases for prevention efforts to decrease the disease burden. Several studies have demonstrated a strong association between short chain fatty acid receptor FFAR3 and insulin sensitivity. Interestingly, it has been recently established that FFAR3 mRNA levels are increased in early stages of the AD pathology, indicating that FFAR3 could play a key role in AD onset and progression. Indeed, in the present study we demonstrate that the ablation of the Ffar3 gene in Tg2576 mice prevents the development of cognitive deficiencies in advanced stages of the disease. Notably, this cognitive improvement is also maintained upon a severe metabolic challenge such as the exposure to high-fat diet (HFD) feeding. Moreover, FFAR3 deletion restores the brain hypermetabolism displayed by Tg2576 mice. Collectively, these data postulate FFAR3 as a potential novel target for AD.
  • Autores: Villarejo-Galende, A.; García-Arcelay, E.; Pinol-Ripoll, G.; et al.
    Revista: JOURNAL OF ALZHEIMERS DISEASE
    ISSN: 1387-2877 Vol.90 N° 2 2022 págs. 719 - 726
    Resumen
    Background: There is a need to better understand the experience of patients living with Alzheimer's disease (AD) in the early stages. Objective: The aim of the study was to evaluate the perception of quality of life in patients with early-stage AD. Methods: A multicenter, non-interventional study was conducted including patients of 50-90 years of age with prodromal or mild AD, a Mini-Mental State Examination (MMSE) score >= 22, and a Clinical Dementia Rating-Global score (CDR-GS) of 0.5-1.0. The Quality of Life in Alzheimer ' s Disease (QoL-AD) questionnaire was used to assess health-related quality of life. A battery of self-report instruments was used to evaluate different psychological and behavioral domains. Associations between the QoL-AD and other outcome measures were analyzed using Spearman's rank correlations. Results: A total of 149 patients were included. Mean age (SD) was 72.3 (7.0) years and mean disease duration was 1.4 (1.8) years. Mean MMSE score was 24.6 (2.1). The mean QoL-AD score was 37.9 (4.5). Eighty-three percent (n = 124) of patients had moderate-to-severe hopelessness, 22.1% (n = 33) had depressive symptoms, and 36.9% (n = 55) felt stigmatized. The quality of life showed a significant positive correlation with self-efficacy and negative correlations with depression, emotional and practical consequences, stigma, and hopelessness. Conclusion: Stigma, depressive symptoms, and hopelessness are frequent scenarios in AD negatively impacting quality of life, even in a population with short disease duration and minimal cognitive impairment.
  • Autores: Zamarbide González, Marta; Martínez Pinilla, Eva; Gil Bea, Francisco Javier; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.23 N° 7 2022 págs. 3533
    Resumen
    The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD) patients at different stages of the disease and, second, to assess whether genetic inactivation of the Ffar3 gene could affect the phenotypic features of the APP(swe) mouse model. The expression of transcripts for FFA receptors in postmortem human hippocampal samples and in the hippocampus of wild-type and transgenic mice was analyzed by RT-qPCR. We generated a double transgenic mouse, FFA3R(-/-)/APP(swe), to perform cognition studies and to assess, by immunoblotting A beta and tau pathologies and the differential expression of synaptic plasticity-related proteins. For the first time, the occurrence of the FFA3R in the human hippocampus and its overexpression, even in the first stages of AD, was demonstrated. Remarkably, FFA3R(-/-)/APP(swe) mice do not have the characteristic memory impairment of 12-month-old APP(swe) mice. Additionally, this newly generated transgenic line does not develop the most important Alzheimer's disease (AD)-related features, such as amyloid beta (A beta) brain accumulations and tau hyperphosphorylation. These findings are accompanied by increased levels of the insulin-degrading enzyme (IDE) and lower activity of the tau kinases GSK3 beta and Cdk5. We conclude that the brain FFA3R is involved in cognitive processes and that its inactivation prevents AD-like cognitive decline and pathological hallmarks.
  • Autores: Toledano, R. (Autor de correspondencia); Martínez-Álvarez, R.; Jiménez Huete, Adolfo; et al.
    Revista: NEUROLOGÍA (BARCELONA. ED. IMPRESA)
    ISSN: 0213-4853 Vol.37 N° 5 2022 págs. 334 - 345
    Resumen
    Objective: Stereoelectroencephalography (SEEG) is a technique for preoperative evaluation of patients with difficult-to-localise refractory focal epilepsy (DLRFE), enabling the study of deep cortical structures. The procedure, which is increasingly used in international epilepsy centres, has not been fully developed in Spain. We describe our experience with SEEG in the preoperative evaluation of DLRFE. Material and methods: In the last 8 years, 71 patients with DLRFE were evaluated with SEEG in our epilepsy centre. We prospectively analysed our results in terms of localisation of the epileptogenic zone (EZ), surgical outcomes, and complications associated with the procedure. Results: The median age of the sample was 30 years (range, 4-59 years); 27 patients (38%) were women. Forty-five patients (63.4%) showed no abnormalities on brain MR images. A total of 627 electrodes were implanted (median, 9 electrodes per patient; range, 1-17), and 50% of implantations were multilobar. The EZ was identified in 64 patients (90.1%), and was extratemporal or temporal plus in 66% of the cases. Follow-up was over one year in 55 of the 61 patients undergoing surgery: in the last year of follow-up, 58.2% were seizure-free (Engel Epilepsy Surgery Outcome Scale class I) and 76.4% had good outcomes (Engel I-II). Three patients (4.2%) presented brain haemorrhages. Conclusion: SEEG enables localisation of the EZ in patients in whom this was previously impossible, offering better surgical outcomes than other invasive techniques while having a relatively low rate of complications.
  • Autores: Villarejo Galende, A.; García-Arcelay, E.; Pinol-Ripoll, G.; et al.
    Revista: NEUROLOGY
    ISSN: 0028-3878 Vol.98 N° 18 2022 págs. * - *
  • Autores: Tordera Baviera, Rosa María (Autor de correspondencia); Cortés Erice, María
    Revista: REVIEWS OF PHYSIOLOGY BIOCHEMISTRY AND PHARMACOLOGY
    ISSN: 0303-4240 Vol.180 2021 págs. 1 - 47
    Resumen
    Histone deacetylases (HDACs) are a family of 18 members that participate in the epigenetic regulation of gene expression. In addition to histones, some HDACs also deacetylate transcription factors and specific cytoplasmic proteins. Monocytes, as part of the innate immune system, maintain tissue homeostasis and help fight infections and cancer. In these cells, HDACs are involved in multiple processes including proliferation, migration, differentiation, inflammatory response, infections, and tumorigenesis. Here, a systematic description of the role that most HDACs play in these functions is reviewed. Specifically, some HDACs induce a pro-inflammatory response and play major roles in host defense. Conversely, other HDACs reprogram monocytes and macrophages towards an immunosuppressive phenotype. The right balance between both types helps monocytes to respond correctly to the different physiological/pathological stimuli. However, aberrant expressions or activities of specific HDACs are associated with autoimmune diseases along with other chronic inflammatory diseases, infections, or cancer. This paper critically reviews the interesting and extensive knowledge regarding the role of some HDACs in these pathologies. It also shows that as yet, very little progress has been made toward the goal of finding effective HDAC-targeted therapies. However, given their obvious potential, we conclude that it is worth the effort to develop monocyte-specific drugs that selectively target HDAC subtypes with the aim of finding effective treatments for diseases in which our innate immune system is involved.
  • Autores: Janeiro Arenas, Manuel Humberto; García Ardanaz, Carlos; Sola Sevilla, Noemí; et al.
    Revista: ADVANCES IN LABORATORY MEDICINE / AVANCES EN MEDICINA DE LABORATORIO
    ISSN: 2628-491X Vol.2 N° 1 2021 págs. 27 - 37
    Resumen
    Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease. AD is the main cause of dementia worldwide and aging is the main risk factor for developing the illness. AD classical diagnostic criteria rely on clinical data. However, the development of a biological definition of AD using biomarkers that reflect the underling neuropathology is needed. Content: The aim of this review is to describe the main outcomes when measuring classical and novel biomarkers in biological fluids or neuroimaging. Summary: Nowadays, there are three classical biomarkers for the diagnosis of AD: Aß42, t-Tau and p-Tau. The diagnostic use of cerebrospinal fluid biomarkers is limited due to invasive collection by lumbar puncture with potential side effects. Plasma/serum measurements are the gold standard in clinics, because they are minimally invasive and, in consequence, easily collected and processed. The two main proteins implicated in the pathological process, Aß and Tau, can be visualized using neuroimaging techniques, such as positron emission tomography. Outlook: As it is currently accepted that AD starts decades before clinical symptoms could be diagnosed, the opportunity to detect biological alterations prior to clinical symptoms would allow early diagnosis or even perhaps change treatment possibilities.
  • Autores: Toledano Illán, Carlos (Autor de correspondencia); Esparragosa Vázquez, Inés; Zelaya Huerta, M. V. ; et al.
    Revista: JOURNAL OF NEUROLOGY
    ISSN: 0340-5354 Vol.268 N° 6 2021 págs. 2256 - 2258
  • Autores: Fernández Matarrubia, Marta (Autor de correspondencia); Goñi Mateos, Leticia; Rognoni Trueba, María Teresa; et al.
    Revista: JOURNAL OF ALZHEIMERS DISEASE
    ISSN: 1387-2877 Vol.79 N° 3 2021 págs. 1257 - 1268
    Resumen
    Background: Available evidence on the association of physical activity (PA) or sedentary behavior with cognitive decline is inconclusive. Objective: To assess the association between an active lifestyle score and leisure-time physical activity (LTPA) and changes in cognitive function in the Seguimiento Universidad de Navarra (SUN) prospective cohort. Methods: Cognitive function was evaluated in a subsample of 806 participants of the SUN cohort study using the validated Telephone Interview for Cognitive Status-modified (STICS-m) questionnaire at baseline and after 6 years. LTPA was evaluated with a previously validated 17-item self-administered questionnaire and with information on sedentary lifestyles. We also calculated a multidimensional 8-item PA score. Multivariable linear regression analysis evaluated the association between PA and changes in cognitive function and its interaction by APOE genotype. Results: Mean age of participants was 66 (SD 5.3) years and 69.7% were male. When stratifying by APOE variants, no significant associations between the active lifestyle score or LTPA and changes in cognitive performance over time were found among APOE epsilon 4 carriers. However, we observed that a higher adherence to an active lifestyle (high versus low PA score beta = 0.76 95%CI 0.15,1.36; p trend = 0.011) and a high LTPA (Q4 versus Q1 beta = 0.63; 95%CI -0.01,1.26; p trend = 0.030) were associated with more favorable changes in cognitive function over time among APOE epsilon 4 non-carriers with statistically significant interactions in both cases (p for interaction = 0.042 for PA score, and p = 0.039 for LTPA). Conclusion: The results of the present study suggest that an active lifestyle is associated with a better status of cognitive function over time only among APOE epsilon 4 non-carriers.
  • Autores: Loera-Valencia, R. (Autor de correspondencia); Ismail, M. A. M.; Goikolea, J.; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN: 0893-7648 Vol.58 N° 12 2021 págs. 6063 - 6076
    Resumen
    Alterations in cholesterol metabolism in the brain have a major role in the physiology of Alzheimer's disease (AD). Oxysterols are cholesterol metabolites with multiple implications in memory functions and in neurodegeneration. Previous studies have shown detrimental effects of cholesterol metabolites in neurons, but its effect in glial cells is unknown. We used a high-fat/high-cholesterol diet in mice to study the effects of hypercholesterolemia over the alarmin S100A8 cascade in the hippocampus. Using CYP27Tg, a transgenic mouse model, we show that the hypercholesterolemia influence on the brain is mediated by the excess of 27-hydroxycholesterol (27-OH), a cholesterol metabolite. We also employed an acute model of 27-OH intraventricular injection in the brain to study RAGE and S100A8 response. We used primary cultures of neurons and astrocytes to study the effect of high levels of 27-OH over the S100A8 alarmin cascade. We report that a high-fat/high-cholesterol diet leads to an increase in S100A8 production in the brain. In CYP27Tg, we report an increase of S100A8 and its receptor RAGE in the hippocampus under elevated 27-OH in the brain. Using siRNA, we found that 27-OH upregulation of RAGE in astrocytes and neurons is mediated by the nuclear receptor RXR gamma. Silencing RXR gamma in neurons prevented 27-OH-mediated upregulation of RAGE. These results show that S100A8 alarmin and RAGE respond to high levels of 27-OH in the brain in both neurons and astrocytes through RXR gamma. Our study supports the notion that 27-OH mediates detrimental effects of hypercholesterolemia to the brain via alarmin signaling.
  • Autores: Solas Zubiaurre, Maite; Van Dam, D.; Janssens, J.; et al.
    Revista: NEUROCHEMISTRY INTERNATIONAL
    ISSN: 0197-0186 Vol.150 2021 págs. 105185
    Resumen
    Even though the involvement of serotonin (5-hydroxytryptamine; 5-HT) and its receptors in Alzheimer's disease (AD) is widely accepted, data on the expression and the role of 5-HT7 receptors in AD is relatively limited. Therefore, the objective of the present work was to study the expression of serotonergic 5-HT7 receptors in postmortem samples of AD brains and correlate it with neurotransmitter levels, cognition and behavior. The study population consisted of clinically well-characterized and neuropathologically confirmed AD patients (n = 42) and age-matched control subjects (n = 18). Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and high-performance liquid chromatography were performed on Brodmann area (BA) 7, BA10, BA22, BA24, hippocampus, amygdala, thalamus and cerebellum to measure mRNA levels of 5-HT7 receptors (HTR7), as well as the concentrations of various monoamine neurotransmitters and their metabolites. Decreased levels of HTR7 mRNA were observed in BA10. A significant association was observed between HTR7 levels in BA10 and BEHAVE-AD cluster B (hallucinations) (rs(28) = 0.444, P < 0.05). In addition, a negative correlation was observed between HTR7 levels in BA10 and both MHPG concentrations in this brain region (rs(45) = -0.311; P < 0.05), and DOPAC levels in the amygdala (rs(42) = -0.311; P < 0.05). Quite surprisingly, no association was found between HTR7 levels and cognitive status. Altogether, this study supports the notion of the involvement of 5-HT7 receptors in psychotic symptoms in AD, suggesting the interest of testing antagonist acting at this receptor to specifically treat psychotic symptoms in this illness.
  • Autores: Guevara-Hoyer, K.; Jiménez Huete, Adolfo; Vasconcelos, J.; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.11 N° 1 2021 págs. 12211
    Resumen
    The broad and heterogeneous clinical spectrum that characterizes common variable immunodeficiency (CVID) is associated with quite different disease course and prognosis, highlighting the need to develop tools that predict complications. We developed a multianalyte VISUAL score (variable immunodeficiency score upfront analytical link) aimed to predict severity using individual CVID patient data at baseline of a cohort of 50 CVID patients from two different centers in Portugal and Spain. We retrospectively applied VISUAL to the CVID clinical severity scores proposed by Ameratunga and Grimbacher after 15 years follow-up of our cohort. VISUAL score at CVID diagnosis showed adequate performance for predicting infectious and non-infectious severe complications (Cluster B). Compared to switched memory B lymphocyte phenotype alone, VISUAL provided a more accurate identification of clinically meaningful outcome, with significantly higher sensitivity (85% vs 55%, p=0.01), and negative predictive value (77% vs 58%) and AUC of the ROC curves (0.72 vs 0.64), with optimal cut-off level of 10. For every increase of 1 point in the VISUAL scale, the odds of being in the higher risk category (Cluster B) increased in 1.3 (p=0.005) for Ameratunga's severity score and 1.26 (p=0.004) for Grimbacher's severity score. At diagnosis of CVID, VISUAL score >= 10 showed 8.94-fold higher odds of severe prognosis than below this threshold. Kaplan-Meier estimates for the VISUAL >= 10 points showed significantly earlier progression to Cluster B than those with VISUAL<10 (p=0.0002). This prognostic laboratory score might allow close monitoring and more aggressive treatment in patients with scores<greater than or equal to>10 on a personalized basis approach. Further studies are needed to prospectively validate VISUAL score.
  • Autores: Sola Sevilla, Noemí; Ricobaraza Abarquero, Ana; Hernández Alcoceba, Rubén; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.22 N° 6 2021 págs. 3107
    Resumen
    Sirtuin 2 (SIRT2) has been associated to aging and age-related pathologies. Specifically, an age-dependent accumulation of isoform 3 of SIRT2 in the CNS has been demonstrated; however, no study has addressed the behavioral or molecular consequences that this could have on aging. In the present study, we have designed an adeno-associated virus vector (AAV-CAG-Sirt2.3-eGFP) for the overexpression of SIRT2.3 in the hippocampus of 2 month-old SAMR1 and SAMP8 mice. Our results show that the specific overexpression of this isoform does not induce significant behavioral or molecular effects at short or long term in the control strain. Only a tendency towards a worsening in the performance in acquisition phase of the Morris Water Maze was found in SAMP8 mice, together with a significant increase in the pro-inflammatory cytokine Il-1 beta. These results suggest that the age-related increase of SIRT2.3 found in the brain is not responsible for induction or prevention of senescence. Nevertheless, in combination with other risk factors, it could contribute to the progression of age-related processes. Understanding the specific role of SIRT2 on aging and the underlying molecular mechanisms is essential to design new and more successful therapies for the treatment of age-related diseases.
  • Autores: Belloch Perez, Francisco de Borja; Beltrán de Miguel, Elena; Venzala Bascoy, Elisabet; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN: 0924-977X Vol.44 2021 págs. 51 - 65
    Resumen
    Circadian rhythms disturbance is widely observable in patients with major depression (MD) and is also associated with depression vulnerability. Of them, disturbed melatonin secretion rhythm is particularly relevant to MD and is strongly phase-locked to core body temperature (CBT) rhythm. Here we aim to study the specific role of each melatonin receptor (MT1 and MT2) subtype in melatonin regulation of circadian CBT and its possible relationship with depressive-like behaviors. MT1-/-, MT2-/- and WT (C57BL/6) mice were used. Anhedonia, using the sucrose intake test, circadian CBT, environmental place preference (EPP) conditioning and vulnerability to chronic social defeat stress (CSDS) procedure were studied. Moreover, the antidepressant effects of reboxetine (15 mg/kg/day, i.p.) for three weeks or ketamine (15 mg/kg i.p. every four days, 4 doses in total) were studied. Further, exposure to ultra-mild stress induced by individual housing for several weeks was also studied in these mice. MT2-/- mice showed anhedonia and lower CBT compared to WT and MT1-/-. In addition, while reward exposure raised nocturnal CBT in WT this increase did not take place in MT2-/- mice. Further, MT2-/- mice showed an enhanced vulnerability to stress-induced anhedonia and social avoidance as well as an impaired acquisition of novelty seeking behavior. Both reboxetine and ketamine reverted anhedonia and induced a clear anti-helpless behavior in the tail suspension test (TST). Reboxetine raised CBT in mice and reverted ultra-mild stress-induced anhedonia. Our findings show a primary role for MT2 receptors in the regulation of circadian CBT as well as anhedonia and suggest that these receptors could be involved in depressive disorders associated to disturbed melatonin function. (C) 2021 Elsevier B.V. and ECNP. All rights reserved.
  • Autores: Cuadrado Tejedor, María del Mar (Autor de correspondencia); Pérez González, Marta; Alfaro-Ruiz, R.; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1661-6596 Vol.22 N° 21 2021 págs. 11950
    Resumen
    Despite the well-accepted role of the two main neuropathological markers (beta-amyloid and tau) in the progression of Alzheimer's disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice.
  • Autores: Frederiksen, K. S. (Autor de correspondencia); Nielsen, T. R. ; Appollonio, I. ; et al.
    Revista: INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY
    ISSN: 0885-6230 Vol.36 N° 2 2021 págs. 324 - 333
    Resumen
    Objectives Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. Methods An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. Results The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. Conclusions The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.
  • Autores: Pérez González, Marta; Badesso, Sara; Lorenzo Ramos, María Elena; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.22 N° 17 2021 págs. 9120
    Resumen
    Understanding the mechanisms involved in cognitive resilience in Alzheimer's disease (AD) represents a promising strategy to identify novel treatments for dementia in AD. Previous findings from our group revealed that the study of aged-Tg2576 cognitive resilient individuals is a suitable tool for this purpose. In the present study, we performed a transcriptomic analysis using the prefrontal cortex of demented and resilient Tg2576 transgenic AD mice. We have been able to hypothesize that pathways involved in inflammation, amyloid degradation, memory function, and neurotransmission may be playing a role on cognitive resilience in AD. Intriguingly, the results obtained in this study are suggestive of a reduction of the influx of peripheral immune cells into the brain on cognitive resilient subjects. Indeed, CD4 mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience. For further validation of this result, we analyzed CD4 expression in human AD samples, including temporal cortex and peripheral blood mononuclear cells (PBMC). Interestingly, we have found a negative correlation between CD4 mRNA levels in the periphery and the score in the Mini-Mental State Exam of AD patients. These findings highlight the importance of understanding the role of the immune system on the development of neurodegenerative diseases and points out to the infiltration of CD4(+) cells in the brain as a key player of cognitive dysfunction in AD.
  • Autores: Gulfo, J.; Pérez de San Román, J.; Ledda, A.; et al.
    Revista: PLOS ONE
    ISSN: 1932-6203 Vol.16 N° 2 2021 págs. e0246930
    Resumen
    Corticosteroid-binding globulin (CBG) is the specific carrier of circulating glucocorticoids, but evidence suggests that it also plays an active role in modulating tissue glucocorticoid activity. CBG polymorphisms affecting its expression or affinity for glucocorticoids are associated with chronic pain, chronic fatigue, headaches, depression, hypotension, and obesity with an altered hypothalamic pituitary adrenal axis. CBG has been localized in hippocampus of humans and rodents, a brain area where glucocorticoids have an important regulatory role. However, the specific CBG function in the hippocampus is yet to be established. The aim of this study was to investigate the effect of the absence of CBG on hippocampal glucocorticoid levels and determine whether pathways regulated by glucocorticoids would be altered. We used cbg(-/-) mice, which display low total-corticosterone and high free-corticosterone blood levels at the nadir of corticosterone secretion (morning) and at rest to evaluate the hippocampus for total- and free-corticosterone levels; 11 beta-hydroxysteroid dehydrogenase expression and activity; the expression of key proteins involved in glucocorticoid activity and insulin signaling; microtubule-associated protein tau phosphorylation, and neuronal and synaptic function markers. Our results revealed that at the nadir of corticosterone secretion in the resting state the cbg(-/-) mouse hippocampus exhibited slightly elevated levels of free-corticosterone, diminished FK506 binding protein 5 expression, increased corticosterone downstream effectors and altered MAPK and PI3K pathway with increased pY216-GSK3 beta and phosphorylated tau. Taken together, these results indicate that CBG deficiency triggers metabolic imbalance which could lead to damage and long-term neurological pathologies.
  • Autores: Pereira Sánchez, Víctor (Autor de correspondencia); Franco, A. R.; de Castro Manglano, María Pilar; et al.
    Revista: FRONTIERS IN PSYCHIATRY
    ISSN: 1664-0640 Vol.12 2021 págs. 759696
    Resumen
    Neuroimaging research seeks to identify biomarkers to improve the diagnosis, prognosis, and treatment of attention-deficit/hyperactivity disorder (ADHD), although clinical translation of findings remains distant. Resting-state functional magnetic resonance imaging (R-fMRI) is increasingly being used to characterize functional connectivity in the brain. Despite mixed results to date and multiple methodological challenges, dominant hypotheses implicate hyperconnectivity across brain networks in patients with ADHD, which could be the target of pharmacological treatments. We describe the experience and results of the Clinica Universidad de Navarra (Spain) Metilfenidato (CUNMET) pilot study. CUNMET tested the feasibility of identifying R-fMRI markers of clinical response in children with ADHD undergoing naturalistical pharmacological treatments. We analyzed cross-sectional data from 56 patients with ADHD (18 treated with methylphenidate, 18 treated with lisdexamfetamine, and 20 treatment-naive patients). Standard preprocessing and statistical analyses with attention to control for head motion and correction for multiple comparisons were performed. The only results that survived correction were noted in contrasts of children who responded clinically to lisdexamfetamine after long-term treatment vs. treatment-naive patients. In these children, we observed stronger negative correlations (anticorrelations) across nodes in six brain networks, which is consistent with higher across-network functional segregation in patients treated with lisdexamfetamine, i.e., less inter-network interference than in treatment-naive patients. We also note the lessons learned, which could help those pursuing clinically relevant multidisciplinary research in ADHD en route to eventual personalized medicine. To advance reproducible open science, our report is accompanied with links providing access to our data and analytic scripts.
  • Autores: Janeiro Arenas, Manuel Humberto; García Ardanaz, Carlos; Sola Sevilla, Noemí; et al.
    Revista: ADVANCES IN LABORATORY MEDICINE / AVANCES EN MEDICINA DE LABORATORIO
    ISSN: 2628-491X Vol.2 N° 1 2021 págs. 39 - 50
    Resumen
    Objetivos: La enfermedad de Alzheimer (EA) es una enfermedad neurodegenerativa. La EA es la principal causa de demencia en el mundo, siendo el envejecimiento el principal factor de riesgo. Los criterios diagnósticos para la enfermedad de Alzheimer suelen basarse en datos clínicos. No obstante, es necesario establecer una definición biológica de la enfermedad de Alzheimer basada en biomarcadores que reflejen la neuropatología subyacente. Contenido: El objetivo de esta revisión es presentar los resultados obtenidos en la medición de biomarcadores nuevos y ya conocidos en los fluidos biológicos o en neuroimágenes. Resumen: Actualmente se emplean tres biomarcadores para el diagnóstico de la enfermedad de Alzheimer_Aß42, t-Tau y p-Tau. El uso diagnóstico de biomarcadores en el líquido cefalorraquídeo (LCR) presenta algunas limitaciones debido a que la obtención invasiva mediante punción lumbar puede provocar efectos secundarios. La práctica más común en los centros clínicos es la medición en plasma o suero, ya que es mínimamenteinvasiva y, en consecuencia, se puede obtener y procesar con mayor facilidad. Las dos principales proteínas implicadas en el proceso patológico, Aß y Tau, se pueden visualizar empleando técnicas de neuroimagen como la PET. ¿ Perspectivas: Dado que está ampliamente aceptado que la enfermedad de Alzheimer comienza décadas antes de que se ¿ diagnostiquen los primeros síntomas clínicos, la detección de alteraciones biológicas previa a la aparición de la sintomatología clínica permitiría su diagnóstico precoz o incluso abriría la puerta a nuevas opciones terapéuticas.
  • Autores: Martinez-Poles, J. (Autor de correspondencia); Toledano, R.; Jiménez Huete, Adolfo; et al.
    Revista: CLIN NEURORADIOL
    ISSN: 1869-1439 Vol.31 N° 3 2021 págs. 575 - 579
    Resumen
    Purpose We hypothesized that epilepsy associated with temporal pole encephaloceles (ETPE) could be the consequence and an unrecognized manifestation of idiopathic intracranial hypertension (IIH). To test this hypothesis in patients with ETPEs we evaluated: 1) the frequency of two radiological signs of IIH and 2) whether these patients develop over time clinical manifestations suggestive of elevated intracranial pressure (ICP). Methods Case-control study comparing two cardinal radiological signs of IIH pituitary gland height (PGH) and the diameter of the two optic nerve sheaths (ONS) between 29 patients with ETPEs (TPE group) and 29 patients with focal epilepsy of other etiologies (control group), adjusted by age, sex, body mass index ( BMI), age at epilepsy onset and epilepsy duration. Analysis was performed using conventional and ordinal logistic regression. The measurements in both groups were compared with validated radiological criteria of IIH. Results Of the patients 17 (63%) in the TPE group had all three measurements over the cut-off values for IIH, while no patients in the control group had all three findings. The TPE group patients had lower PGH (3.2 +/- 1.0mm vs. 4.9 +/- 1.3mm, p< 0.001) and larger diameter of ONS than controls (p< 0.001), being similar to validated data of IIH. No patient with TPE had clinical manifestations of elevated ICP (mean follow-up 15.1 +/- 11.7 years). Conclusion Patients with ETPEs frequently had radiological signs of IIH while not developing typical manifestations of elevated ICP over time. In this way, ETPEs could be an unrecognized manifestation of IIH, and temporal lobe seizures the only clinical expression of this epilepsy syndrome.
  • Autores: Cortés Erice, María; Fernández, R.; Cuesta, M.; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN: 0924-977X Vol.53 N° Supplement 1 2021 págs. S271 - S272
  • Autores: García Ardanaz, Carlos; Ramírez Gil, María Javier; Smerdou Picazo, Cristian; et al.
    Revista: GLIA
    ISSN: 0894-1491 Vol.69 2021 págs. E232 - E233
  • Autores: Aledo-Serrano, A.; Gil-Nagel, A.; Martínez-Vicente, L.; et al.
    Revista: EPILEPSIA
    ISSN: 0013-9580 Vol.62 N° Suppl. 3 2021 págs. 167
  • Autores: Aledo-Serrano, A. (Autor de correspondencia); Mingorance, A.; Jiménez Huete, Adolfo; et al.
    Revista: EPILEPSIA
    ISSN: 0013-9580 Vol.61 N° 6 2020 págs. 1312 - 1314
  • Autores: Delgado, C.; Parees, I.; Jiménez Huete, Adolfo; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.35 N° 10 2020 págs. 1723 - 1724
  • Autores: Díaz Perdigón, Teresa; Belloch Perez, Francisco de Borja; Ricobaraza Abarquero, Ana; et al.
    Revista: NEUROPSYCHOPHARMACOLOGY
    ISSN: 1740-634X Vol.45 N° 2 2020 págs. 347-357
    Resumen
    The senescence-accelerated mouse prone-8 (SAMP8) model has been considered as a good model for aged-related cognitive decline and Alzheimer's disease (AD). Since epigenetic alterations represent a crucial mechanism during aging, in the present study we tested whether the inhibition of the histone deacetylase sirtuin 2 (SIRT2) could ameliorate the age-dependent cognitive impairments and associated neuropathology shown by SAMP8 mice. To this end, the potent SIRT2-selective inhibitor, 33i (5 mg/kg i. p. 8 weeks) was administered to 5-month-old (early treatment) and 8-month-old (late treatment) SAMP8 and aged matched control, senescence-accelerated mouse resistant-1 (SAMR1) mice. 33i administration to 5-month-old SAMP8 mice improved spatial learning and memory impairments shown by this strain in the Morris water maze. SAMP8 showed hyperphosphorylation of tau protein and decrease levels of SIRT1 in the hippocampus, which were not altered by 33i treatment. However, this treatment upregulated the glutamate receptor subunits GluN2A, GluN2B, and GluA1 in both SAMR1 and SAMP8. Moreover, early SIRT2 inhibition prevented neuroinflammation evidenced by reduced levels of GFAP, IL-1 beta, Il-6, and Tnf-alpha, providing a plausible explanation for the improvement of cognitive deficits shown by 33i-treated SAMP8 mice. When 33i was administered to 8-month-old SAMP8 with a severe established pathology, increases in GluN2A, GluN2B, and GluA1 were observed; however, it was not able to reverse the
  • Autores: Estévez-Santé, S.; Jiménez Huete, Adolfo (Autor de correspondencia)
    Revista: JOURNAL OF NEURORADIOLOGY
    ISSN: 0150-9861 Vol.47 N° 2 2020 págs. 161 - 165
    Resumen
    Introduction: Hippocampal volumetry can discriminate normal subjects from patients with amnestic mild cognitive impairment (MCI) or Alzheimer disease (AD). We have analyzed the effects of different methods of hippocampal volume (HV) adjustment on the diagnostic accuracy of this technique. Methods: Cross-sectional analysis of 148 subjects of the ADNI database (48 normal, 66 MCI, 34 AD). Brain volumes were calculated from 3T MRI scans with gm extractor, a fully automated script based on FSL. A series of logistic regression models was obtained using 9 volumes of reference and 3 methods of adjustment (normalization, covariance, bilinear regression). Diagnostic accuracy was evaluated with the receiver operating characteristic curve method. External validity was assessed with 10-fold cross-validation. Results: The models with the highest area under the curve (AUC) were those including the HV normalized by total intracranial volume (TIV). The differences with bilinear regression and the covariance method adjusted by TIV were minor and not statistically significant. The lowest AUCs corresponded to the models based on raw (unadjusted) HVs. The results were qualitatively similar in two clinical settings (normal versus MCI, and normal versus AD), but the differences were higher in the normal versus MCI context. Conclusion: The accuracy of hippocampal volumetry for the differential diagnosis between normal subjects and patients with MCI or AD was maximized by normalizing the HV by the TIV. Our results do not exclude the potential superiority of non-linear models.
  • Autores: Gil Iturbe, Eva; Solas Zubiaurre, Maite; Cuadrado Tejedor, María del Mar; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN: 0893-7648 Vol.57 N° 2 2020 págs. 798 - 805
    Resumen
    The brain depends on glucose as a source of energy. This implies the presence of glucose transporters, being GLUT1 and GLUT3 the most relevant. Expression of GLUT12 is found in mouse and human brain at low levels. We previously demonstrated GLUT12 upregulation in the frontal cortex of aged subjects that was even higher in aged Alzheimer's disease (AD) patients. However, the cause and the mechanism through which this increase occurs are still unknown. Here, we aimed to investigate whether the upregulation of GLUT12 in AD is related with aging or A beta deposition in comparison with GLUT1, GLUT3, and GLUT4. In the frontal cortex of two amyloidogenic mouse models (Tg2576 and APP/PS1) GLUT12 levels were increased. Contrary, expression of GLUT1 and GLUT3 were decreased, while GLUT4 did not change. In aged mice and the senescence-accelerated model SAMP8, GLUT12 and GLUT4 were upregulated in comparison with young animals. GLUT1 and GLUT3 did not show significant changes with age. The effect of beta-amyloid (A beta) deposition was also evaluated in A beta peptide i.c.v. injected mice. In the hippocampus, GLUT12 expression increased whereas GLUT4 was not modified. Consistent with the results in the amyloidogenic models, GLUT3 and GLUT1 were downregulated. In summary, A beta increases GLUT12 protein expression in the brain pointing out a central role of the transporter in AD pathology and opening new perspectives for the treatment of this neurodegenerative disease.
  • Autores: Lachen-Montes, M. ; Mendizuri, N. ; Ausin, K. ; et al.
    Revista: JOURNAL OF PROTEOME RESEARCH
    ISSN: 1535-3893 Vol.19 N° 12 2020 págs. 4826 - 4843
    Resumen
    The Human Proteome Project (HPP) consortium aims to functionally characterize the dark proteome. On the basis of the relevance of olfaction in early neurodegeneration, we have analyzed the dark proteome using data mining in public resources and omics data sets derived from the human olfactory system. Multiple dark proteins localize at synaptic terminals and may be involved in amyloidopathies such as Alzheimer's disease (AD). We have characterized the dark PITH domain-containing protein 1 (PITHD1) in olfactory metabolism using bioinformatics, proteomics, in vitro and in vivo studies, and neuropathology. PITHD1(-/-) mice exhibit olfactory bulb (OB) proteome changes related to synaptic transmission, cognition, and memory. OB PITHD1 expression increases with age in wild-type (WT) mice and decreases in Tg2576 AD mice at late stages. The analysis across 6 neurological disorders reveals that olfactory tract (OT) PITHDI is specifically upregulated in human AD. Stimulation of olfactory neuroepithelial (ON) cells with PITHD1 alters the ON phosphoproteome, modifies the proliferation rate, and induces a pro-inflammatory phenotype. This workflow applied by the Spanish C-HPP and Human Brain Proteome Project (HBPP) teams across the ON-OB-OT axis can be adapted as a guidance to decipher functional features of dark proteins. Data are available via ProteomeXchange with identifiers PXD018784 and PXD021634.
  • Autores: Aledo-Serrano, A. (Autor de correspondencia); García-Morales, I.; Toledano, R.; et al.
    Revista: EPILEPSY AND BEHAVIOR
    ISSN: 1525-5050 Vol.111 2020 págs. 107266
    Resumen
    Objective: This study aimed to evaluate the access to advanced diagnostic tests in patients with epilepsy and intellectual disability, with special focus on genetics. Methods: Patients with epilepsy and intellectual disability evaluated between 2016 and 2018 at the Epilepsy Unit of two hospitals in Madrid. Spain were included. The main inclusion criterion was an undetermined etiological diagnosis after clinical assessment, neuroimaging, and electroencephalogram (EEG). Results: Two hundred and five patients with epilepsy and intellectual disability were evaluated, with 124 fulfilling the inclusion criteria (mean age: 33.9 years). Regarding the etiological workup, advanced neuroimaging, prolonged video-EEG, and any type of genetic test had been performed in 58%, 41%, and 40%, respectively. An etiological diagnosis was reached in 18.5%. The workup was considered incomplete in 67%. Variables that showed the strongest association with an incomplete diagnostic workup in the multivariate analysis were current age and seizure freedom. Conclusions: Despite the multiple implications of modern diagnostic techniques, especially genetic testing, there is a large proportion of patients with epilepsy and intellectual disability who do not have access to them. Older age and seizure freedom seem to be associated with the highest diagnostic gap.
  • Autores: Pérez González, Marta; Mendioroz, M.; Badesso, Sara; et al.
    Revista: PROGRESS IN NEUROBIOLOGY
    ISSN: 0301-0082 Vol.191 2020 págs. 101818
    Resumen
    Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer's disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to identify genes that might promote cognitive resilience and hence, this study first set out to identify cognitively resilient individuals in the aged-Tg2576 mouse model. A transcriptomic analysis of these mice identified PLA2G4E as a gene that might confer resistance to dementia. Indeed, a significant decrease in PLA2G4E is evident in the brain of late-stage AD patients, whereas no such changes are observed in early stage patients with AD neuropathological lesions but no signs of dementia. We demonstrated that adeno-associated viral vector-mediated overexpression of PLA2G4E in hippocampal neurons completely restored cognitive deficits in elderly APP/PS1 mice, without affecting the amyloid or tau pathology. These PLA2G4E overexpressing APP/ PS1 mice developed significantly more dendritic spines than sham-injected mice, coinciding with the cognitive improvement observed. Hence, these results support the idea that a loss of PLA2G4E might play a key role in the onset of dementia in AD, highlighting the potential of PLA2G4E overexpression as a novel therapeutic strategy to manage AD and other disorders that course with memory deficits.
  • Autores: Masmudi-Martin, M. ; Navarro-Lobato, I. ; Lopez-Aranda, M. F.; et al.
    Revista: NEUROSCIENCE
    ISSN: 0306-4522 Vol.448 2020 págs. 287 - 298
    Resumen
    The integrity of the perirhinal cortex (PRh) is essential for object recognition memory (ORM) function, and damage to this brain area in animals and humans induces irreversible ORM deficits. Here, we show that activation of area V2, a brain area interconnected with brain circuits of ventral stream and medial temporal lobe that sustain ORM, by expression of regulator of G-protein signaling 14 of 414 amino acids (RGS14(414)) restored ORM in memory-deficient PRh-lesioned rats and nonhuman primates. Furthermore, this treatment was sufficient for full recovery of ORM in rodent models of aging and Alzheimer's disease, conditions thought to affect multiple brain areas. Thus, RGS14(414)-mediated activation of area V2 has therapeutic relevance in the recovery of recognition memory, a type of memory that is primarily affected in patients or individuals with symptoms of memory dysfunction. These findings suggest that area V2 modulates the processing of memory-related information through activation of interconnected brain circuits formed by the participation of distinct brain areas. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Autores: Galiano, A.; Mengual Poza, Elisa; García de Eulate Ruiz, María Reyes; et al.
    Revista: BRAIN IMAGING AND BEHAVIOR
    ISSN: 1931-7557 Vol.14 N° 2 2020 págs. 436 - 450
    Resumen
    Aging leads to cerebral perfusion and functional connectivity changes that have been assessed using various neuroimaging techniques. In addition, a link between these two parameters has been demonstrated in healthy young adults. In this work, we employed arterial spin labeling (ASL) fMRI to measure global and voxel-wise differences in cerebral blood flow (CBF) and intrinsic connectivity contrast (ICC) in the resting state in a group of cognitively normal elderly subjects and a group of cognitively normal young subjects, in order to assess the effects of aging on CBF-ICC coupling, which had not been previously evaluated. Our results showed age-related global and regional CBF decreases in prefrontal mesial areas, lateral frontal regions, insular cortex, lateral parietal areas, precuneus and occipital regions. Subcortically, perfusion was reduced in the medial thalamus and caudate nucleus. ICC was also found reduced with age in prefrontal cortical areas and insular cortex, affecting key nodes of the default mode and salience networks. Areas of ICC and CBF decrease partially overlapped, however, the CBF reduction was more extensive and encompassed more areas. This dissociation was accompanied by a decrease in CBF-ICC coupling. These results suggest that aging leads to a disruption in the relationship between CBF and intrinsic functional connectivity that could be due to neurovascular dysregulation.
  • Autores: Delgado, R. T. (Autor de correspondencia); Garcia-Morales, I. ; Parejo-Carbonell, B. ; et al.
    Revista: EPILEPSIA
    ISSN: 0013-9580 Vol.61 N° 6 2020 págs. 1109 - 1119
    Resumen
    Objective To assess the effectiveness and tolerability of perampanel (PER) monotherapy in routine clinical practice for the treatment of focal onset and generalized tonic-clonic seizures (GTCS). Methods This multicenter, retrospective, observational study was conducted in patients aged >= 12 years treated with PER as primary monotherapy or converted to PER monotherapy by progressive reduction of background antiepileptic drugs. Outcomes included retention, responder, and seizure-free rate after 3, 6, and 12 months and tolerability throughout the follow-up. Results A total of 98 patients (mean age = 49.6 +/- 21.7 years, 51% female) with focal seizures and/or GTCS were treated with PER monotherapy for a median exposure of 14 months (range = 1-57) with a median dose of 4 mg (range = 2-10). The retention rates at 3, 6, and 12 months and last follow-up were 93.8%, 89.3%, 80.9%, and 71.4%, respectively. The retention rates according to the type of monotherapy (primary vs conversion) did not differ (log-rank P value = .57). Among the 98 patients, 61.2% patients had seizures throughout the baseline period, with a median seizure frequency of 0.6 seizures per month (range = 0.3-26). Responder rates at 3, 6, and 12 months were 79.6%, 70.1%, and 52.8%, respectively, and seizure freedom rates at the same points were 62.7%, 56.1%, and 41.5%. Regarding the 33 patients who had GTCS in the baseline period, 87.8% were seizure-free at 3 months, 78.1% at 6 months, and 55.1% at 12 months. Over the entire follow-up, PER monotherapy was generally well tolerated, and only 16% of patients discontinued PER due to adverse events (AEs). Female patients were found to be at a higher risk of psychiatric AEs (female vs male odds ratio = 2.85, 95% confidence interval = 1-8.33, P = .046). Significance PER demonstrated good effectiveness and a good safety profile when used as primary therapy or conversion to monotherapy at relatively low doses, in a clinical setting with patients with focal seizures and GTCS.
  • Autores: Alemán-Gómez, Y.; Poch, C.; Toledano, R.; et al.
    Revista: JOURNAL OF NEUROPSYCHOLOGY
    ISSN: 1748-6645 Vol.14 N° 2 2020 págs. 260 - 282
    Resumen
    Visual object naming is a complex cognitive process that engages an interconnected network of cortical regions moving from occipitotemporal to anterior-inferior temporal cortices, and extending into the inferior frontal cortex. Naming can fail for diverse reasons, and different stages of the naming multi-step process appear to be reliant upon the integrity of different neuroanatomical locations. While the neural correlates of semantic errors have been extensively studied, the neural basis of omission errors remains relatively unspecified. Although a strong line of evidence supports an association between anterior temporal lobe damage and semantic errors, there are some studies suggesting that the anterior temporal lobe could be also associated with omissions. However, support for this hypothesis comes from studies with patients in whom damage affected extensive brain regions, sometimes bilaterally. Here, we availed of a group of 12 patients with epilepsy associated with a small lesion at the tip of the left temporal pole. Using an unbiased surface-based morphometry methodology, we correlated two morphological features with errors observed during visual naming. Analyses revealed a correlation between omission errors and reduced local gyrification index in three cortical clusters: one in the left anteromedial temporal lobe region (AMTL) and two in the left anterior cingulate cortex (ACC). Our findings support the view that regions in ACC and AMTL are critical structures within a network engaged in word selection from semantics.
  • Autores: Janeiro Arenas, Manuel Humberto; Orbe Lopategui, Josune; Solas Zubiaurre, Maite; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN: 0924-977X Vol.40 2020 págs. S434 - S435
  • Autores: Cortés Erice, María; Fernandez, R. ; Cuesta, M. ; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN: 0924-977X Vol.40 2020 págs. S201 - S202
  • Autores: Ambrosio Gutierrez, Leire; Portillo Vega, María Carmen; Martín Lanas, Raquel; et al.
    Revista: MOVEMENT DISORDERS
    ISSN: 0885-3185 Vol.35 N° S1 2020 págs. S575 - S576
  • Autores: Puerta Ruiz de Azua, Elena; Tordera Baviera, Rosa María; Beltran, E.; et al.
    Revista: EUROPEAN NEUROPSYCHOPHARMACOLOGY
    ISSN: 0924-977X Vol.40 2020 págs. S46 - S47
  • Autores: Ortega-Suero, G.; Fernández Matarrubia, Marta; López-Valdés, E.; et al.
    Revista: ACS PHOTONICS
    ISSN: 2330-4022 Vol.6 N° 2 2019 págs. 171 - 173
  • Autores: Cuadrado Tejedor, María del Mar; Pérez González, Marta; Garcia-Munoz, C. ; et al.
    Revista: FRONTIERS IN AGING NEUROSCIENCE
    ISSN: 1663-4365 Vol.11 2019 págs. 149
    Resumen
    The discouraging results with therapies for Alzheimer's disease (AD) in clinical trials, highlights the urgent need to adopt new approaches. Like other complex diseases, it is becoming clear that AD therapies should focus on the simultaneous modulation of several targets implicated in the disease. Recently, using reference compounds and the first-in class CM-414, we demonstrated that the simultaneous inhibition of histone deacetylases [class I histone deacetylases (HDACs) and HDAC6] and phosphodiesterase 5 (PDE5) has a synergistic therapeutic effect in AD models. To identify the best inhibitory balance of HDAC isoforms and PDEs that provides a safe and efficient therapy to combat AD, we tested the compound CM-695 in the Tg2576 mouse model of this disease. CM-695 selectively inhibits HDAC6 over class I HDAC isoforms, which largely overcomes the toxicity associated with HDAC class 1 inhibition. Furthermore, CM-695 inhibits PDE9, which is expressed strongly in the brain and has been proposed as a therapeutic target for AD. Chronic treatment of aged Tg2576 mice with CM-695 ameliorates memory impairment and diminishes brain A beta although its therapeutic effect was no longer apparent 4 weeks after the treatment was interrupted. An increase in the presence of 78-KDa glucose regulated protein (GRP78) and heat shock protein 70 (Hsp70) chaperones may underlie the therapeutic effect of CM-695. In summary, chronic treatment with CM-695 appears to reverse the AD phenotype in a safe and effective manner. Taking into account that AD is a multifactorial disorder, the multimodal action of these compounds and the different events they affect may open new avenues to combat AD.
  • Autores: Espinosa-Jovel, C. (Autor de correspondencia); Toledano, R.; Jiménez Huete, Adolfo; et al.
    Revista: EPILEPSIA OPEN
    ISSN: 2470-9239 Vol.4 N° 3 2019 págs. 487 - 492
    Resumen
    Several lines of research have linked olfactory regions with the pathophysiology of focal epilepsies. Among those regions, the piriform cortex represents the major part of the primary olfactory cortex. According to these data, we raised the hypothesis that in patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis exists an interictal dysfunction of olfactory processing that could be more significant compared to patients with extra-hippocampal focal epilepsy and healthy controls. This could be the consequence of a dysfunctional epileptogenic network that extends beyond the hippocampus and affects other structures, including the piriform cortex. To test this hypothesis, we evaluated the olfactory function with the Sniffin' Sticks test in 32 patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis, 30 patients with extra-hippocampal focal epilepsy, and 22 healthy controls. Compared to the other study groups, patients with temporal lobe epilepsy due to hippocampal sclerosis showed a basal olfactory dysfunction characterized by an impairment in odor discrimination and odor identification. We also found that high seizure frequency had a strong correlation with the evaluated olfactory tasks. Our results are consistent with neuroimaging and neuropathological data that establish a link between olfactory regions and the pathophysiology of temporal lobe epilepsy.
  • Autores: Lachen-Montes, M.; Gonzalez-Morales, A.; Palomino, M.; et al.
    Revista: FRONTIERS IN AGING NEUROSCIENCE
    ISSN: 1663-4365 Vol.11 2019
    Resumen
    The olfactory bulb (OB) is the first processing station in the olfactory pathway. Despite smell impairment, which is considered an early event in Alzheimer's disease (AD), little is known about the initial molecular disturbances that accompany the AD development at olfactory level. We have interrogated the time-dependent OB molecular landscape in Tg2576 AD mice prior to the appearance of neuropathological amyloid plaques (2-, and 6-month-old), using combinatorial omics analysis. The metabolic modulation induced by overproduction of human mutated amyloid precursor protein (APP) clearly differs between both time points. Besides the progressive perturbation of the APP interactome, functional network analysis unveiled an inverse regulation of downstream extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) routes in 2-month-old Tg2576 mice with respect to wild-type (WT) mice. In contrast, Akt and MAPK kinase 4 (SEK1)/stress-activated protein kinase (SAPK) axis were parallel activated in the OB of 6-months-old-Tg2576 mice. Furthermore, a survival kinome profiling performed during the aging process (2-, 6-, and 18-month-old) revealed that olfactory APP overexpression leads to changes in the activation dynamics of protein kinase A (PKA), and SEK1/MKK4-SAPK/JNK between 6 and 18 months of age, when memory deficits appear and AD pathology is well established in transgenic mice. Interestingly, both olfactory pathways were differentially activated in a stage-dependent manner in human sporadic AD subjects with different neuropathological grading. Taken together, our data reflect the early impact of mutated APP on the OB molecular homeostasis, highlighting the progressive modulation of specific signaling pathways during the olfactory amyloidogenic pathology.
  • Autores: Chincarini, A. (Autor de correspondencia); Peira, E.; Morbelli, S.; et al.
    Revista: NEUROIMAGE. CLINICAL
    ISSN: 2213-1582 Vol.23 2019
    Resumen
    Background: amyloid-PET reading has been classically implemented as a binary assessment, although the clinical experience has shown that the number of borderline cases is non negligible not only in epidemiological studies of asymptomatic subjects but also in naturalistic groups of symptomatic patients attending memory clinics. In this work we develop a model to compare and integrate visual reading with two independent semi-quantification methods in order to obtain a tracer-independent multi-parametric evaluation. Methods: We retrospectively enrolled three cohorts of cognitively impaired patients submitted to F-18-florbetaben (53 subjects), F-18-flutemetamol (62 subjects), F-18-florbetapir (60 subjects) PET/CT respectively, in 6 European centres belonging to the EADC. The 175 scans were visually classified as positive/negative following approved criteria and further classified with a 5-step grading as negative, mild negative, borderline, mild positive, positive by 5 independent readers, blind to clinical data. Scan quality was also visually assessed and recorded. Semi-quantification was based on two quantifiers: the standardized uptake value (SUVr) and the ELBA method. We used a sigmoid model to relate the grading with the quantifiers. We measured the readers accord and inconsistencies in the visual assessment as well as the relationship between discrepancies on the grading and semi-quantifications. Conclusion: It is possible to construct a map between different tracers and different quantification methods without resorting to ad-hoc acquired cases. We used a 5-level visual scale which, together with a mathematical model, delivered cut-offs and transition regions on tracers that are (largely) independent from the population. All fluorinated tracers appeared to have the same contrast and discrimination ability with respect to the negative-to-positive grading. We validated the integration of both visual reading and different quantifiers in a more robust framework thus bridging the gap between a binary and a user-independent continuous scale.
  • Autores: Colyn, L.; Venzala Bascoy, Elisabet; Marco Martínez, Sonia; et al.
    Revista: BEHAVIOURAL BRAIN RESEARCH
    ISSN: 0166-4328 Vol.373 2019 págs. 112079
    Resumen
    Previous studies show that chronic stress induces synaptic structural alterations in brain regions involved in emotional processing such as the prefrontal cortex (PFC) and the basolateral amygdala (BLA). Yet, these studies are based mainly in animal exposure to unpredictable stressors or to restraint stress. On the other hand, studies using the chronic social defeat stress (CSDS), a relevant model of depression based on social conflict, are lacking. Here we aim to study the acute (24 h after CSDS) and long-term (one month after CSDS) effects of CSDS on dendritic and synaptic structures in the PFC and BLA of C57BL/6 mice. Specifically, BLA and PFC dendritic spine densities as well as BLA arborisation were analysed. Subsequently, we investigate in these regions the synaptic response to a friendly (interaction with a same strain mouse) or a fearful (interaction with a dominant strain mouse) social stimulus. Spine densities of the apical dendrites from the PFC pyramidal neurons were decreased by CSDS in the long-term (one month after CSDS). In addition, CSDS increased BLA stellate neurons spine density in the short-term (24 h after CSDS) and dendritic arborisation in the long-term. Moreover, long-term CSDS mice exposed to a fearful stimulus experienced a marked social avoidance and showed a significant increase in the expression of the immature form of the brain derived neurotrophic factor (proBDNF) in the amygdala. Taken together these results suggest the existence of persistent neuronal adaptations in the PFC and BLA in socially defeated mice. Specifically, spine density retraction in the PFC and increased BLA dendritic arborisation could represent an adaptive structural change allowing rapid expression of synaptic markers in response to fearful experiences.
  • Autores: Martínez Valbuena, Iván; Valentí Azcárate, Rafael; Amat-Villegas, I.; et al.
    Revista: ANNALS OF NEUROLOGY
    ISSN: 0364-5134 Vol.86 N° 4 2019 págs. 539 - 551
    Resumen
    Objective Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and beta-amyloid (A beta) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients. Methods We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined A beta and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or A beta interact with amylin in either the pancreas or brain of these subjects. Results Cytoplasmic tau and A beta protein deposits were detected in pancreatic beta cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with A beta and tau in both the pancreas and hippocampus. Interpretation The presence of both tau and A beta inclusions in pancreatic beta cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019
  • Autores: Raygene, M (Autor de correspondencia); Liefhebber, JM; García Osta, Ana María; et al.
    Revista: MOLECULAR THERAPY - NUCLEIC ACIDS
    ISSN: 2162-2531 Vol.16 2019 págs. 26 - 37
  • Autores: Vela, S.; Sáinz Amillo, Neira; Moreno Aliaga, María Jesús; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN: 0893-7648 Vol.56 N° 3 2019 págs. 1618 - 1627
    Resumen
    A potential role of marine n-3 polyunsaturated fatty acids (-3 PUFAs) has been suggested in memory, learning, and cognitive processes. Therefore, -3 PUFAs might be a promising treatment option, albeit controversial, for Alzheimer's disease (AD). Among the different mechanisms that have been proposed as responsible for the beneficial effects of -3 PUFAs, inhibition of JNK stands as a particularly interesting candidate. In the present work, it has been studied whether the administration of two different PUFAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and a DHA-derived specialized pro-resolving lipid mediator (MaR1) is able to reverse cognitive deficits in the senescence-accelerated mouse prone 8 (SAMP8) mouse model of sporadic AD. The novel object recognition test (NORT) test showed that recognition memory was significantly impaired in SAMP8 mice, as shown by a significantly decreased discrimination index that was reversed by MaR1 and DHA. In the retention phase of the Morris water maze (MWM) task, SAMP8 mice showed memory deficit that only DHA treatment was able to reverse. pJNK levels were significantly increased in the hippocampus of SAMP8 mice compared to SAMR1 mice, and only DHA treatment was able to significantly reverse these increased pJNK levels. Similar results were found when measuring c-Jun, the main JNK substrate. Consequently to the increases in tau phosphorylation after increased pJNK, it was checked that tau phosphorylation (PHF-1) was increased in SAMP mice, and this effect was reversed after DHA treatment. Altogether, DHA could represent a new approach for the treatment of AD through JNK inhibition.
  • Autores: Álvarez-Linera Prado, J. (Autor de correspondencia); Jiménez Huete, Adolfo
    Revista: RADIOLOGIA
    ISSN: 0033-8338 Vol.61 N° 1 2019 págs. 66 - 81
    Resumen
    Dementia is a syndrome characterised by chronic, multi-domain, acquired cognitive impairment that causes significant functional limitations. MRI is the standard imaging study for these cases, since it enables detection of the atrophy patterns of the various neurodegenerative diseases (Alzheimer's disease, frontotemporal degeneration, Lewy body dementia), the vascular lesions associated with vascular dementia, and various potentially reversible diseases (for example, tumours, hydrocephaly) or diseases that require special management measures (for example, prion diseases). In certain cases other imaging methods can be used, such as CT, functional MRI, HMPAO SPECT or dopaminergic markers and FDG PET, amyloid markers or dopaminergic markers. The indications for these methods have not yet been clearly established, and therefore should be used in multidisciplinary dementia units.
  • Autores: Matrov, D.; Kaart, T. ; Lanfumey, L.; et al.
    Revista: BEHAVIOURAL BRAIN RESEARCH
    ISSN: 0166-4328 Vol.356 2019 págs. 435 - 443
    Resumen
    The psychopathology of depression is highly complex and the outcome of studies on animal models is divergent. In order to find brain regions that could be metabolically distinctively active across a variety of mouse depression models and to compare the interconnectivity of brain regions of wild-type and such genetically modified mice, histochemical mapping of oxidative metabolism was performed by the measurement of cytochrome oxidase activity. We included mice with the heterozygous knockout of the vesicular glutamate transporter (VGLUT(1)(-/+)), full knockout of the cannabinoid 1 receptor (CB1(-/-)), an anti-sense knockdown of the gluco- corticoid receptor (GRi) and overexpression of the human 5-hydroxytryptamine transporter (h5-HTT). Altogether 76 mouse brains were studied to measure oxidative metabolism in one hundred brain regions, and the obtained dataset was submitted to a variety of machine learning algorithms and multidimensional scaling. Overall, the top brain regions having the largest contribution to classification into depression model were the lateroanterior hypothalamic nucleus, the anterior part of the basomedial amygdaloid nucleus, claustrum, the suprachiasmatic nucleus, the ventromedial hypothalamic nucleus, and the anterior hypothalamic area. In terms of the patterns of inter-regional relationship between wild-type and genetically modified mice there was little overall difference, while the most deviating brain regions were cortical amygdala and ventrolateral and ventral posteromedial thalamic nuclei. The GRi mice that most clearly differed from their controls exhibited deviation of connectivity for a number of brain regions, such as ventrolateral thalamic nucleus, the intermediate part of the lateral septal nucleus, the anteriodorsal part of the medial amygdaloid nucleus, the medial division of the central amygdaloid nucleus, ventral pallidum, nucleus of the vertical limb of the diagonal band, anteroventral parts of the thalamic nucleus and parts of the bed nucleus of the stria terminalis. Conclusively, the GRi mouse model was characterized by changes in the functional connectivity of the extended amygdala and stress response circuits.
  • Autores: Rabal, O. (Autor de correspondencia); Sanchez-Arias, J. A.; Cuadrado Tejedor, María del Mar; et al.
    Revista: ACS CHEMICAL NEUROSCIENCE
    ISSN: 1948-7193 Vol.10 N° 9 2019 págs. 4076 - 4101
    Resumen
    Here, we present a series of dual-target phosphodiesterase 9 (PDE9) and histone deacetylase (HDAC) inhibitors devised as pharmacological tool compounds for assessing the implications of these two targets in Alzheimer's disease (AD). These novel inhibitors were designed taking into account the key pharmacophoric features of known selective PDE9 inhibitors as well as privileged chemical structures, bearing zinc binding groups (hydroxamic acids and ortho-amino anilides) that hit HDAC targets. These substituents were selected according to rational criteria and previous knowledge from our group to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective, and class I selective) that were confirmed in biochemical screens. Their functional response in inducing acetylation of histone and tubulin and phosphorylation of cAMP response element binding (CREB) was measured as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability, was chosen for assessing in vivo efficacy of these first-in-class inhibitors, as well as studying their mode of action (MoA).
  • Autores: Rabal Gracia, María Obdulia; Sanchez-Arias, J. A.; Cuadrado Tejedor, María del Mar; et al.
    Revista: ACS CHEMICAL NEUROSCIENCE
    ISSN: 1948-7193 Vol.10 N° 3 2019 págs. 1765 - 1782
    Resumen
    In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDES) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDES and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).
  • Autores: Gil Iturbe, Eva; Solas Zubiaurre, Maite; Cuadrado Tejedor, María del Mar; et al.
    Revista: ACTA PHYSIOLOGICA
    ISSN: 1748-1708 Vol.227 N° Supl. 718 2019 págs. 83 - 84
  • Autores: Garcia, R. G. R. ; Ortega, G.; Valdes, E. L.; et al.
    Revista: EUROPEAN JOURNAL OF NEUROLOGY
    ISSN: 1351-5101 Vol.26 2019 págs. 847 - 847
  • Autores: Cortés Jiménez, Adriana; Solas Zubiaurre, Maite; Pejenaute Martínez de Lizarrondo, Álvaro; et al.
    Revista: FREE RADICAL BIOLOGY AND MEDICINE
    ISSN: 0891-5849 Vol.139 N° S1 2019 págs. S17 - S17
  • Autores: Sendino Miguel, Teresa; Mugueta Uriaque, María del Carmen; Macias Conde, Monica; et al.
    Revista: CLINICA CHIMICA ACTA
    ISSN: 0009-8981 Vol.493 N° Supl. 1 2019 págs. S414 - S415
  • Autores: Ferrero Hidalgo, Hilda; Larráyoz Roldán, Ignacio Marcos; Gil Bea, Francisco Javier; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN: 0893-7648 Vol.55 N° 12 2018 págs. 8799 - 8814
    Resumen
    Neurodegenerative diseases represent a heterogeneous group of disorders whose common characteristic is the progressive degeneration of neuronal structure and function. Although much knowledge has been accumulated on the pathophysiology of neurodegenerative diseases over the years, more efforts are needed to understand the processes that underlie these diseases and hence to propose new treatments. Adrenomedullin (AM) is a multifunctional peptide involved in vasodilation, hormone secretion, antimicrobial defense, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins that interfere with microtubule dynamics. Furthermore, AM may intervene in neuronal dysfunction through other mechanisms such as immune and inflammatory response, apoptosis, or calcium dyshomeostasis. Alterations in AM expression have been described in neurodegenerative processes such as Alzheimer's disease or vascular dementia. This review addresses the current state of knowledge on AM and its possible implication in neurodegenerative diseases.
  • Autores: Rabal Gracia, María Obdulia; Sanchez-Arias, J. A.; Cuadrado Tejedor, María del Mar; et al.
    Revista: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
    ISSN: 0223-5234 Vol.150 2018 págs. 506 - 524
    Resumen
    We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo. (C) 2018 Elsevier Masson SAS. All rights reserved.
  • Autores: de Alboniga-Chindurza, A. (Autor de correspondencia); Riva, E.; Jiménez Huete, Adolfo; et al.
    Revista: CLINICAL NEUROLOGY AND NEUROSURGERY
    ISSN: 0303-8467 Vol.173 2018 págs. 194 - 195
    Resumen
    The stiff person syndrome is a rare neurological disorder, difficult to diagnose and to treat. Paraneoplastic patients usually present amphiphysin antibodies but the association with anti-Ri antibodies is less known. We present a case report of paraneoplastic SPS, small cell carcinoma of the bladder and anti-Ri antibodies.
  • Autores: Gálvez-Ruiz, A. (Autor de correspondencia); Riva-Amarante, E.; Jiménez Huete, Adolfo; et al.
    Revista: NEURO-OPHTHALMOLOGY
    ISSN: 0165-8107 Vol.42 N° 1 2018 págs. 44 - 47
    Resumen
    Saccadic intrusions are small involuntary saccadic movements that disrupt visual fixation. Among saccadic intrusions without intersaccadic intervals, ocular flutter and opsoclonus are prominent. The saccade amplitude can occasionally be very small, which is referred to as ocular microflutter. The authors present a patient with acute-onset oscillopsia following a non-specific viral condition. An ocular microflutter was subsequently detected using video-oculography. After extensive investigation, a diagnosis of isolated idiopathic or post-viral ocular microflutter was made. The evolution of the condition was favourable, and the progressive improvement of oscillopsia occurred during the following months; however, complete resolution was not achieved. Ocular microflutter is a saccadic intrusion that is rarely described in the literature and is likely go clinically unnoticed because of its small amplitude and the rare use of video-oculography in daily practice. In patients in whom this condition is suspected, the use of video-oculography is essential for a correct diagnosis.
  • Autores: Moreno Ajona, David (Autor de correspondencia); Irimia Sieira, Pablo; Fernández Matarrubia, Marta
    Revista: HEADACHE
    ISSN: 0017-8748 Vol.58 N° 5 2018 págs. 746 - 749
    Resumen
    ObjectiveTo expand the differential diagnosis of headache and ophthalmoparesis by describing a case report in which anti-GQ1b was demonstrated to be the cause. BackgroundAnti-GQ1b antibody syndrome refers to a clinical spectrum of conditions that share common mechanisms and overlapping manifestations, including the Miller-Fisher syndrome, pharyngeal-cervical-brachial weakness, and Bickerstaff brainstem encephalitis. Rare atypical cases presenting as acute ophthalmoparesis (AO) without ataxia or areflexia have been described. Headache is a rare condition in these disorders. MethodsA 49-year-old woman with no history of headaches began experiencing an acute severe bilateral throbbing headache associated with nausea and photophobia. Five days later, she developed constant binocular horizontal diplopia. ResultsBilateral paresis of both sixth nerves was noted. Her ocular fundi, tendon reflexes, and other findings of the physical exam were normal. In addition, both a brain MRI performed with gadolinium and a lumbar puncture yielded normal results. Serum anti-GQ1b IgG was found to be positive. Her symptoms resolved completely following treatment with immunoglobulins (0.4 g/kg/day for 5 days). ConclusionsThis is the first reported case of AO related to anti-GQ1b antibodies presenting with headache as its initial symptom. The presence of anti-GQ1b antibodies should be determined in patients with headache and AO of unknown origin. Immunoglobulins could hasten the resolution of symptoms
  • Autores: Ferrero Hidalgo, Hilda; Larráyoz Roldán, Ignacio Marcos; Solas Zubiaurre, Maite; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN: 0893-7648 Vol.55 N° 12 2018 págs. 9328 - 9333
    Resumen
    Tau is a microtubule-associated protein highly expressed in neurons with a chief role in microtubule dynamics and axonal maintenance. Adrenomedullin gene (ADM) codifies for various peptides that exert broad range of actions in the body. Previous works in our groups have shown that increased ADM products are positively correlated to microtubule disruption and tau pathology in Alzheimer's disease brains. In the present study, we explore the involvement of ADM in the neuropathology of frontotemporal lobar degeneration that presents with primary tauopathy (FTLD-tau). Proteins from frontal cortices of FTLD-tau patients and age- and sex-matched non-demented controls were analyzed with antibodies against different microtubule components, including adrenomedullin, and synaptic markers. Tau pathology in frontal cortex from FTLD patients was confirmed. Levels of total III-tubulin as well as acetylated and detyrosinated tubulins, two markers of stabilized and aged microtubules, were significantly reduced and directly correlated with PSD95 and proBDNF in FTLD-tau patients when compared to non-demented controls. In contrast, no change in actin cytoskeleton was found. Interestingly, changes in microtubule elements, indicators of disturbed axonal preservation, were accompanied by decreased levels of free adrenomedullin, although no association was found. Altogether, reduced levels of adrenomedullin might not be directly linked to the microtubule pathology of FTLD-tau, but based on previous works, it is suggested that downregulation of ADM might be an adaptive attempt of neurons to mitigate microtubule disruption.
  • Autores: Ferrero Hidalgo, Hilda; Larrayoz, I. M.; Martisová, Eva; et al.
    Revista: MOLECULAR NEUROBIOLOGY
    ISSN: 0893-7648 Vol.55 N° 6 2018 págs. 5177 - 5183
    Resumen
    Alzheimer's disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD.
  • Autores: Zamarbide, M. (Autor de correspondencia); Gil Bea, Francisco Javier; Bannenberg, Paul; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.8 2018
    Resumen
    The risk of suffering from Alzheimer's disease (AD) is higher in individuals from AD-affected mothers. The purpose of this investigation was to study whether maternal transmission might produce AD-related alterations in progenies of mice that do not have any genotypic alteration. We used cognitively-intact mothers harbouring in heterozygosity the transgene for overexpressing the Swedish double mutant version of the human amyloid precursor protein (hA(3PPswe). The phenotype of the offspring with or without the transgene resulting from crossing young Tg2576 females with wild-type males were compared with those of the offspring resulting from crossing wild-type females with Tg2576 males. The hAOPPswe-bearing offspring from Tg2576 mothers showed an aggravated AD-like phenotype. Remarkably, cognitive, immunohistochemica I and some biochemical features displayed by Tg2576 heterozygous mice were also found in wild-type animals generated from Tg2576 females. This suggests the existence of a maternal imprinting in the wild-type offspring that confers a greater facility to launch an AD-like neurodegenerative cascade. Such progeny, lacking any mutant amyloid precursor protein, constitutes a novel model to study maternal transmission of AD and, even more important, to discover early risk markers that predispose to the development of AD.
  • Autores: Muñoz-Cobo Orosa, Irene; Erburu Calvo, Mercedes Micaela; Zwergel, C.; et al.
    Revista: PSYCHOPHARMACOLOGY
    ISSN: 0033-3158 Vol.235 N° 10 2018 págs. 2831 - 2846
    Resumen
    Rationale Antidepressant action has been linked to increased synaptic plasticity in which epigenetic mechanisms such as histone posttranslational acetylation could be involved. Interestingly, the histone deacetylases HDAC5 and SIRT2 are oppositely regulated by stress and antidepressants in mice prefrontal cortex (PFC). Besides, the neuroblastoma SH-SY5Y line is an in vitro neuronal model reliable to study drug effects with clear advantages over animals. Objectives We aimed to characterize in vitro the role of HDAC5 and SIRT2 in antidepressant regulation of neuroplasticity. Methods SH-SY5Y cultures were incubated with imipramine, fluoxetine, and reboxetine (10 mu M, 2 and 24 h) as well as the selective HDAC5 (MC3822, 5 mu M, 24 h) or SIRT2 (33i, 5 mu M, 24 h) inhibitors. The regulation of the brain-derived neurotrophic factor (BDNF), the vesicular glutamate transporter 1 (VGLUT1), the acetylated histones 3 (AcH3) and 4 (AcH4), HDAC5, and SIRT2 was studied. Comparatively, the long-term effects of these antidepressants (21 days, i.p.) in the mice (C57BL6, 8 weeks) PFC were studied. Results Antidepressants increased both in vitro and in vivo expression of BDNF, VGLUT1, AcH3, and AcH4. Moreover, imipramine and reboxetine increased the phosphorylated form of HDAC5 (P-HDAC5), mediating its cytoplasmic export. Further, SIRT2 was downregulated by all antidepressants. Finally, specific inhibition of HDAC5 and SIRT2 increased neuroplasticity markers. Conclusions This study supports the validity of the SH-SY5Y model for studying epigenetic changes linked to synaptic plasticity induced by antidepressants as well as the effect of selective HDAC inhibitors. Particularly, nucleocytoplasmic export of HDAC5 and SIRT2 downregulation mediated by antidepressants could enhance synaptic plasticity markers leading to antidepressant action.

Proyectos desde 2018

  • Título: INNOLFACT 2.0: Combinación de Inteligencia Artificial y Reposicionamiento de Fármacos en Medicina de Precisión Olfatoria
    Código de expediente: 0011-1411-2023-000094
    Investigador principal: JUAN JOSE LASARTE SAGASTIBELZA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2023 GN PROYECTOS ESTRATEGICOS DE I+D 2023-2026
    Fecha de inicio: 01-07-2023
    Fecha fin: 31-12-2025
    Importe concedido: 381.486,95€
    Otros fondos: -
  • Título: INNOLFACT 2.0: Combinación de Inteligencia Artificial y Reposicionamiento de Fármacos en Medicina de Precisión Olfatoria
    Código de expediente: 0011-1411-2023-000100
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2023 GN PROYECTOS ESTRATEGICOS DE I+D 2023-2026
    Fecha de inicio: 01-07-2023
    Fecha fin: 31-12-2025
    Importe concedido: 331.400,55€
    Otros fondos: -
  • Título: Implicación de las adipo-mioquinas en el desarrollo de obesidad sarcopénica y comorbilidades asociadas
    Código de expediente: PI22/00223
    Investigador principal: AMAIA RODRIGUEZ MURUETA-GOYENA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2022 AES Proyectos de investigación
    Fecha de inicio: 01-01-2023
    Fecha fin: 31-12-2025
    Importe concedido: 123.420,00€
    Otros fondos: Fondos FEDER
  • Título: Validación de biomarcadores epigenéticos asociados a la depresión mayor y a la resistencia al tratamiento antidepresivo.
    Código de expediente: GN2022/57
    Investigador principal: ROSA MARIA TORDERA BAVIERA, ROSA MARIA TORDERA BAVIERA.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2022 GN Proyectos de Investigación en salud
    Fecha de inicio: 22-12-2022
    Fecha fin: 21-12-2025
    Importe concedido: 79.998,87€
    Otros fondos: -
  • Título: Estudio de la comunicación IR-GLUT1 Astrocítico en la enfermedad de Alzheimer
    Código de expediente: PID2021-128737NB-I00
    Investigador principal: MAITE SOLAS ZUBIAURRE.
    Financiador: AGENCIA ESTATAL DE INVESTIGACION
    Convocatoria: FIMA 2021 MCIU AEI GENERACION CONOCIMIENTO
    Fecha de inicio: 01-09-2022
    Fecha fin: 31-08-2025
    Importe concedido: 229.900,00€
    Otros fondos: Fondos FEDER
  • Título: Marcadores séricos en pacientes con nevus melanocíticos congénitos: correlación clínico-patológica y genética. Posible modulación farmacológica.
    Código de expediente: PI21/01416
    Investigador principal: PEDRO REDONDO BELLON.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2021 AES Proyectos de investigación
    Fecha de inicio: 01-01-2022
    Fecha fin: 31-12-2024
    Importe concedido: 147.620,00€
    Otros fondos: Fondos FEDER
  • Título: Estudio sobre la interacción funcional entre amilina y sinucleína in vivo. Implicación para la neurodegeneración y nuevas terapias en La enfermedad de Parkinson
    Código de expediente: PI21/00259
    Investigador principal: MARIA ROSARIO ISABEL LUQUIN PIUDO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2021 AES Proyectos de investigación
    Fecha de inicio: 01-01-2022
    Fecha fin: 31-12-2024
    Importe concedido: 171.820,00€
    Otros fondos: Fondos FEDER
  • Título: Utilidad clínica de GDF15 y FGF21 como biomarcadores de riesgo de diabetes tipo 2. Efecto del envejecimiento.
    Código de expediente: 58/2021
    Investigador principal: JAVIER GOMEZ AMBROSI.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2021 GN Proyectos de Investigación en salud
    Fecha de inicio: 23-12-2021
    Fecha fin: 22-12-2024
    Importe concedido: 75.104,24€
    Otros fondos: Fondos FEDER
  • Título: Papel de SIRT2 microglial en la Enfermedad de Alzheimer
    Código de expediente: PID2020-119729GB-I00
    Investigador principal: ELENA PUERTA RUIZ DE AZUA.
    Financiador: AGENCIA ESTATAL DE INVESTIGACION
    Convocatoria: 2020 AEI PROYECTOS I+D+i (incluye Generación del conocimiento y Retos investigación)
    Fecha de inicio: 01-09-2021
    Fecha fin: 31-08-2024
    Importe concedido: 157.300,00€
    Otros fondos: -
  • Título: Desarrollo de terapias nasales inmunomoduladoras en envejecimiento y neurodegeneración (INNOLFACT)
    Código de expediente: 0011-1411-2020-000049
    Investigador principal: JUAN JOSE LASARTE SAGASTIBELZA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022 FIMA 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-07-2020
    Fecha fin: 30-11-2022
    Importe concedido: 399.206,06€
    Otros fondos: -
  • Título: INNOLFACT: Implementación de Medicina de Precisión Olfatoria y Desarrollo de terapias nasales
    Código de expediente: 0011-1411-2020-000036
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-07-2020
    Fecha fin: 30-11-2022
    Importe concedido: 601.228,00€
    Otros fondos: -
  • Título: Estudio de la función de PLA2G4E en plasticidad cerebral y en la resiliencia cognitiva. Nueva estrategia para el tratamiento de la enfermedad de Alzheimer
    Código de expediente: PID2019-104921RB-I00
    Investigador principal: ANA MARIA GARCIA OSTA, MARIA DEL MAR CUADRADO TEJEDOR.
    Financiador: MINISTERIO DE CIENCIA, INNOVACIÓN Y UNIVERSIDADES
    Convocatoria: FIMA 2019 MCIU - AEI PROYECTOS DE I+D RETOS INVESTIGACION
    Fecha de inicio: 01-06-2020
    Fecha fin: 31-05-2024
    Importe concedido: 108.900,00€
    Otros fondos: Fondos FEDER
  • Título: Implicación de guanilina y uroguanilina en el desarrollo de obesidad y resistencia a la insulina.
    Código de expediente: PI19/00990
    Investigador principal: AMAIA RODRIGUEZ MURUETA-GOYENA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2022
    Importe concedido: 171.820,00€
    Otros fondos: Fondos FEDER
  • Título: Validación de los microRNAs plasmáticos como biomarcadores de la enfermedad de Alzheimer: estudio clínico, de neuroimagen y genética molecular.
    Código de expediente: 97/2018
    Investigador principal: MARTA FERNANDEZ MATARRUBIA.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2018 PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2019
    Fecha fin: 05-10-2021
    Importe concedido: 69.058,65€
    Otros fondos: Fondos FEDER
  • Título: Estudio del eje p27-Cdk2 como nueva diana terapéutica para combatir la obesidad y el Alzheimer durante el envejecimiento
    Código de expediente: 0011-1383-2019-000006
    Investigador principal: ANA MARIA GARCIA OSTA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2019
    Importe concedido: 21.808,75€
    Otros fondos: -
  • Título: Estudio del eje p27-Cdk2 como nueva diana terapéutica para combatir la obesidad y el Alzheimer durante el envejecimiento
    Código de expediente: 0011-1383-2019-00005 (PC056 ALZOBIN)
    Investigador principal: MARIA JESUS MORENO ALIAGA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 GN Centros
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2019
    Importe concedido: 49.077,94€
    Otros fondos: -
  • Título: SinPARK. Identificación de patrones de neuroinflamación específicos en la muerte neuronal dependiente de alfa-sinucleína en modelos de enfermedad de Parkinson
    Código de expediente: 0011-1383-2019-000005 PC60
    Investigador principal: MARIA SOLEDAD AYMERICH SOLER.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 GN Centros
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2019
    Importe concedido: 70.700,00€
    Otros fondos: -
  • Título: GENEURONA. Implantación del diagnóstico genómico de la epilepsia y la migraña en Navarra
    Código de expediente: 0011-1411-2018-000044
    Investigador principal: ANA MARIA GARCIA OSTA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018- GN PROY. ESTRATEGICOS DE I+D 2018-2020 2018- GN PROY. ESTRATEGICOS DE I+D 2018-2020
    Fecha de inicio: 01-04-2018
    Fecha fin: 30-11-2020
    Importe concedido: 482.739,34€
    Otros fondos: -
  • Título: Redes cerebrales de procesamiento temporal en pacientes estables con esquizofrenia frente a trastorno bipolar
    Código de expediente: PI17/00240
    Investigador principal: FELIPE ORTUÑO SANCHEZ-PEDREÑO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2017 PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-06-2022
    Importe concedido: 54.450,00€
    Otros fondos: Fondos FEDER
  • Título: Modulación de la interacción neurona-glía a través del sistema endocannabinoide como estrategia de neuroprotección para la enfermedad de Parkinson
    Código de expediente: PI17/01931
    Investigador principal: MARIA SOLEDAD AYMERICH SOLER.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2017 PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-12-2020
    Importe concedido: 99.220,00€
    Otros fondos: Fondos FEDER
  • Título: Descifrando el papel del GLUT1 astrocítico en la enfermedad de Alzheimer.
    Código de expediente: SAF2017-87619-P
    Investigador principal: MAITE SOLAS ZUBIAURRE.
    Financiador: MINISTERIO DE CIENCIA, INNOVACIÓN Y UNIVERSIDADES
    Convocatoria: 2017 MINECO EXCELENCIA
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-09-2022
    Importe concedido: 196.262,00€
    Otros fondos: Fondos FEDER
  • Título: Inhibición de Sirtuina 2: una nueva estrategia terapéutica para el tratamiento de la Enfermedad de Alzheimer.
    Código de expediente: SAF2017-87595-R
    Investigador principal: ELENA PUERTA RUIZ DE AZUA.
    Financiador: MINISTERIO DE CIENCIA, INNOVACIÓN Y UNIVERSIDADES
    Convocatoria: 2017 MINECO RETOS INVESTIGACION. PROYECTOS DE I+D+i
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-09-2021
    Importe concedido: 142.659,00€
    Otros fondos: Fondos FEDER
  • Título: Papel de HDAC5 y SIRT2 en el grado de severidad de la depresión y en la eficacia clínica de los antidepresivos en pacientes de Navarra
    Código de expediente: 81/2017
    Investigador principal: ROSA MARIA TORDERA BAVIERA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2017 GN SALUD
    Fecha de inicio: 16-12-2017
    Fecha fin: 31-12-2021
    Importe concedido: 90.000,00€
    Otros fondos: -
  • Título: Identificación de factores genéticos y epigeneticos que confieren resistencia al desarrollo de demencia
    Código de expediente: 67/2017
    Investigador principal: ANA MARIA GARCIA OSTA.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2017 PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 15-12-2017
    Fecha fin: 31-03-2021
    Importe concedido: 90.000,00€
    Otros fondos: Fondos FEDER
  • Título: Estudio de la interacción de adipoquinas y mioquinas en el desarrollo de obesidad y comorbilidades asociadas.
    Código de expediente: PI16/00221
    Investigador principal: AMAIA RODRIGUEZ MURUETA-GOYENA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2016 AES PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2017
    Fecha fin: 31-12-2019
    Importe concedido: 92.565,00€
    Otros fondos: Fondos FEDER
  • Título: Evaluación del impacto de la imagen pet de Amiloide - beta en el diagnóstico y control clínico de los pacientes con deterioro cognitivo evaluados por sospecha de enfermedad de Alzheimer (EA)
    Código de expediente: DTS15/00141
    Investigador principal: JAVIER IGNACIO ARBIZU LOSTAO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2015 AES DESARROLLO TECNOLÓGICO EN SALUD
    Fecha de inicio: 01-01-2016
    Fecha fin: 31-12-2018
    Importe concedido: 59.139,00€
    Otros fondos: -
  • Título: Nueva estrategia para el tratamiento de la EA: validación de dianas epigenéticas, desde in-vitro a un modelo murino de la enfermedad. Diseño y desarrollo de nuevas herramientas farmacológicas
    Código de expediente: PI14/01244
    Investigador principal: ANA MARIA GARCIA OSTA, MARIA DEL MAR CUADRADO TEJEDOR.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2014 - PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2015
    Fecha fin: 30-12-2018
    Importe concedido: 104.665,00€
    Otros fondos: Fondos FEDER
  • Título: Impact of astrocytic insulin receptor on cognitive deficiencies associated to neuropsychiatric disorders
    Código de expediente: 28177
    Investigador principal: MAITE SOLAS ZUBIAURRE
    Financiador: BRAIN & BEHAVIOUR RESEARCH FOUNDATION
    Convocatoria: NARSAD YOUNG INVESTIGATOR GRANT
    Fecha de inicio: 15-01-2020
    Fecha fin: 15-01-2022
    Importe concedido: 70.000,00€
    Otros fondos: -
  • Título: PLA2G4E: a new target for dementia treatment
    Investigador principal: ANA MARIA GARCIA OSTA
    Financiador: FUNDACIÓN BANCARIA LA CAIXA
    Convocatoria: FIMA 2020 - CAIXAIMPULSE
    Fecha de inicio: 01-12-2020
    Fecha fin: 30-09-2023
    Importe concedido: 70.000,00€
  • Título: Impacto del déficit de inervación glutamatérgica cortical sobre las poblaciones neuronales del rafe dorsal y el locus coeruleus en un modelo murino de depresión
    Investigador principal: ELISA MENGUAL POZA
    Financiador: UNIVERSIDAD DE NAVARRA
    Convocatoria: 2020 Convocatoria PIUNA, 2021 Convocatoria PIUNA
    Fecha de inicio: 01-09-2020
    Fecha fin: 31-08-2022
    Importe concedido: 29.320,00€
  • Título: Estudio de los mecanismos de nueroprotección mediada por el docanabinoide 2-araquidonilglicerol en un modelo animal de enfermedad de Parkinson.
    Investigador principal: MARIA SOLEDAD AYMERICH SOLER
    Financiador: FUNDACION GANGOITI
    Convocatoria: Fundación Gangoiti-2014
    Fecha de inicio: 01-01-2015
    Fecha fin: 31-12-2023
    Importe concedido: 40.000,00€