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Resumen: Objetivo: El propósito de este estudio es investigar la evidencia científica sobre el efecto del ejercicio físico respecto al estado cognitivo y conductual como medida preventiva y terapéutica no farmacológica en la enfermedad de Alzheimer (EA). Diseño: Revisión sistemática Fuentes de datos: Pubmed, Science Direct, Medline y Scopus, con las palabras clave: Alzheimer, Exercise, Neuroimaging, MRI, PET y Physical Activity. Selección de artículos: Se incluyeron aquellos estudios en los que se evaluaba el efecto del ejercicio físico en la evolución de la EA y que además contenían pruebas de imagen (resonancia magnética nuclear o tomografía por emisión de positrones) con marcador Pittsburg Compound B (PiB) analizando la atrofia cerebral o el aumento del depósito de beta-Amiloide respectivamente. Se excluyeron aquellos estudios en otros tipos de demencia que no fueran la EA, los que no incluían pruebas de neuroimagen, los casos únicos y aquellos de lengua no inglesa. Para la extracción de datos se utilizó la escala de calidad PRISMA para la lectura crítica de los estudios. Los investigadores evaluaron de forma independiente los artículos y las discrepancias se resolvieron por consenso. Resultados: Se identificaron 75 artículos, de los cuales 23 fueron finalmente incluidos en la revisión. Concusiones: La mayoría de los estudios incluidos no permiten conocer la repercusión del ejercicio físico a nivel cognitivo y sobre los cambios estructurales y funcionales cerebrales en pacientes con riesgo de desarrollar la EA o en pacientes que ya presentan la enfermedad. Sin poder descartase un posible efecto beneficioso, son necesarios más estudios con un mejor diseño y rigor metodológico que permitan un mejor conocimiento de esta asociación. Abstract: Objective: The objective of this review is to analyze through a the scientific evidence about the effects of physical activity in patients with Alzheimer's disease (AD) as a preventive and non-pharmacological treatment. Design: Systematic review. Data sources: We have identified articles from Pubmed, Science Direct, Medline and Scopus databases, with the keywords Alzheimer, Exercise, Neuroimaging, MRI, PET y Physical Activity. Selected articles: We included those studies that evaluated the effects of physical activity on Alzheimer's disease and those which also included magnetic resonance imaging or positron emission tomography with Pittsburg Compound B marker (PiB) analyzing brain atrophy or increase of the beta-amyloid deposit respectively. We excluded studies including other types of dementia, different of AD. We also excluded articles which not included neuroimaging tests, single cases or non-English language articles. Data extraction: The PRISMA quality scale was used for the critical lecture of the studies. The researchers independently assessed the articles and the discrepancies were resolved by consensus. Results: We identified 75 articles, of which 23 were finally included in the review. Conclusions: Most of the studies included do not allow us to know the impact of physical exercise on cognition and the cerebral structural-functional changes in patients at risk of developing AD or in patients who already have the disease. Without being able to rule out a possible beneficial effect, more studies are needed with a better design and methodological rigor that allows a better known about this association.

Minor deficits and behavioural sequelae in children at risk for disability may restrict and condition mid- and/or longterm school performance. We assessed 95 3-year-old children subdivided into three groups: risk children with support to parents (G1); risk children with standard treatment (G2); and peers with no risk (G3), in order to analyse developmental and behavioural differences. Children underwent neurological, developmental and behavioural assessments. Comparisons between G1 and G2 children showed significant differences in the number of minor neurological sequelae. The developmental level for the three groups was within normal limits, but risk groups obtained lower scores. Although no important behaviour problems were found, there were differences in attention problems between G2 and G3. Parents' anxiety levels for the three groups were not significant, though inter-group differences were detected. Parents' support programme may have had a positive influence on their children's interaction and adaptation. [ABSTRACT FROM AUTHOR]

Introduction: Older patients are more likely to have cognitive dysfunction, and a great proportion of patients undergone surgical procedures are older adults. Postoperative cognitive dysfunction (POCD) has been shown as a consistent complication after major surgical procedures such as heart surgery., Aim: To determine the presence of long-term POCD in ≥65-year-old patients undergoing coronary artery bypass grafting and aortic valve replacement, and to establish related risk factors., Methods: We prospectively and sequentially included 44 patients with coronary disease and aortic stenosis scheduled for heart surgery. Follow-up of all patients was standardized and a neurocognitive evaluation were performed preoperatively and at 1, 6 and 12 months after surgery., Results: Patients experienced a significantly postoperative cognitive dysfunction (33.5%, 63.4% and 38.9% at 1, 6 and 12 months, respectively) from baseline (20.5%). Patient-associated aspects such as age (p<0.01), history of smoking (p<0.01), arterial hypertension (p=0.022), diabetes mellitus (p=0.024), heart failure (p=0.036) and preoperative cognitive dysfunction (p<0.01), and surgery-associated aspects such as EuroSCORE (p<0.01) and operation time (p<0.01) were identified as related risk factors., Conclusions: Older patients who underwent heart surgery had long-term POCD. Both patient- and surgery-related risk factors were established as related risk factors. These findings suggest that the prevalence of cognitive dysfunction after cardiac surgery in older patients could be related to a possible progression to dementia. In addition, many of the risk factors identified may be modifiable but in practice, these patients are not attended to for their possible cognitive impairment., (Copyright © 2020 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Older patients managed with intensive antidiabetic therapy are more likely to be harmed. Our study's primary endpoint was to analyze the safety and efficacy of linagliptin in combination with basal insulin versus basal-bolus insulin in patients with 75 years of age or older hospitalized in medicine and surgery departments in real-world clinical practice., Methods: We retrospectively enrolled non-critically patients ≥75 years with type 2 diabetes admitted to medicine and non-cardiac surgery departments with admission glycated hemoglobin <8%, admission blood glucose <240 mg/dL, and without at-home injectable therapies managed with our hospital's antihyperglycemic protocol (basal-bolus or linagliptin-basal regimens) between January 2016 and December 2018. To match each patient who started on the basal-bolus regimen with a patient who started on the linagliptin-basal regimen, a propensity matching analysis was used., Results: Postmatching, 198 patients were included in each group. There were no significant differences in mean daily blood glucose levels after admission (P=0.203); patients with mean blood glucose 100-140mg/dL (P=0.134), 140-180mg/dL (P=0.109), or >200mg/dL (P=0.299); and number and day of treatment failure (P=0.159 and P=0.175, respectively). The total insulin dose and the number of daily injections were significantly lower in the linagliptin-basal group (both, P<0.001). Patients on the basal-bolus insulin regimen had more total hypoglycemic events than patients on the linagliptin-basal insulin regimen (P<0.001)., Conclusions: The linagliptin-basal insulin regimen was an effective alternative with fewer hypoglycemic events and daily insulin injections than intensive basal-bolus insulin in very old patients with type 2 diabetes with mild-to-moderate hyperglycemia treated at home without injectable therapies.

Background: Identifying patients at high risk of cardiovascular disease in primary prevention is a challenging task. This study aimed at detecting subclinical atherosclerosis burden in non-diabetic hypertensive patients in a primary care centre., Methods: Clinical, anthropometric and analytical data were collected from patients with hypertension who were free from clinical vascular disease and diabetes. The cardiovascular risk was assessed using the SCORE system. Subclinical atherosclerosis burden was assessed by carotid ultrasonography (intima-medial thickness [IMT] and plaque) and measurement of the ankle-brachial index (ABI)., Results: Out of 140 patients, 59 (42%) have carotid plaque, 32 (23%) have IMT higher than 75% and 12 (9%) have an ABI < 0.9. Total atherosclerosis burden was present in 91 (65%) of the subjects. Consequently, 59 (42%) patients were re-classified into the very high-risk category. In multivariate analyses, smoking, creatinine levels and duration of hypertension were associated with atherosclerosis burden. In contrast, only smoking and age were associated with the presence of carotid plaque. Almost 90% of patients were treated with hypotensive drugs, half of them combined several drugs and 60% were well-controlled. Only 30% received statins in monotherapy and only less than 20% had an LDL cholesterol < 100 mg/dL., Conclusions: In non-diabetic hypertensive patients managed at a primary care centre, 4 out of 10 had subclinical atherosclerosis burden and were re-classified into the very high- risk category. There was clear undertreatment with lipid-lowering drugs of most LDL cholesterol inappropriate levels, according to current clinical guidelines., (© 2023. The Author(s).)

Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder (MDD), with more than 300 million people diagnosed and worsened by the COVID-19 pandemic. Accumulating evidence for neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular-, cellular-, and behavioral-specific levels. The purpose of the current work was to evaluate the proliferating role of GAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus. We studied their hippocampal proliferating actions using the proliferating cell nuclear antigen (PCNA) on neuroblasts or stem cells and the expression of the brain-derived neurothrophic factor (BDNF). Moreover, we studied the formation of Y1R-GALR2 heteroreceptor complexes and analyzed morphological changes in hippocampal neuronal cells. Finally, the functional outcome of the NPY and GAL interaction on the ventral hippocampus was evaluated in the forced swimming test. We demonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotes neuroblasts proliferation in the dentate gyrus of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by the increased formation of Y1R-GALR2 heteroreceptor complexes, which may mediate the neurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF action was found necessary for the antidepressant-like effects after GALR2 and the Y1R agonists intranasal administration. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R-GALR2 heterocomplexes in the ventral hippocampus for the novel therapy of MDD or depressive-affecting diseases., (© 2023 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Dysregulation of hippocampal neurogenesis is linked to several neurodegenereative diseases, where boosting hippocampal neurogenesis in these patients emerges as a potential therapeutic approach. Accumulating evidence for a neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular-, cellular-, and behavioral-specific levels. The purpose of the current work was to evaluate the role of the NPY and GAL interaction in the neurogenic actions on the dorsal hippocampus. We studied the Y1R agonist and GAL effects on: hippocampal cell proliferation through the proliferating cell nuclear antigen (PCNA), the expression of neuroprotective and anti-apoptotic factors, and the survival of neurons and neurite outgrowth on hippocampal neuronal cells. The functional outcome was evaluated in the object-in-place task. We demonstrated that the Y1R agonist and GAL promote cell proliferation and the induction of neuroprotective factors. These effects were mediated by the interaction of NPYY1 (Y1R) and GAL2 (GALR2) receptors, which mediate the increased survival and neurites' outgrowth observed on neuronal hippocampal cells. These cellular effects are linked to the improved spatial-memory effects after the Y1R agonist and GAL co-injection at 24 h in the object-in-place task. Our results suggest the development of heterobivalent agonist pharmacophores, targeting Y1R-GALR2 heterocomplexes, therefore acting on the neuronal precursor cells of the DG in the dorsal hippocampus for the novel therapy of neurodegenerative cognitive-affecting diseases.

Objectives: To analyze by means of a systematic review the general knowledge about strokes of the Spanish population., Materials and Methods: A systematic review is performed following PRISMA guidelines and with data from PubMed, Scopus and EMBASE. All studies carried out in Spain, centred around the knowledge of strokes are compiled (terminology, pathophysiology, signs and symptoms, risk factors, treatment, and willingness to make use of the Emergency Services). From the 4,627 articles collected, 21 were ultimately included in this review., Results: In Spain, the term stroke is less known than others such as embolism or cerebrovascular accident. Loss of strength is the most widely recognized symptom, whereas arterial hypertension is the most widely identified risk factor. The least known symptom and risk factor are visual impairment and diabetes mellitus, respectively. When faced with a suspected stroke, the attitude of most respondents is adequate as they decide to go to the hospital or call the Emergency Services. However, in rural areas or in cases in which the symptoms suddenly stop, a greater number of participants choose to go to their family physician. The main sources of information of the participants are their family members and their doctors., Conclusions: General knowledge about strokes is scarce among the general population. Nonetheless, the attitude of most of the participants is adequate as they choose to contact specialized Emergency Services.

Background: There is little evidence on the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in older patients with heart failure. This work analyzed the clinical efficacy and safety of empagliflozin continuation in very old patients with type 2 diabetes hospitalized for acute decompensated heart failure., Methods: We conducted a real-world observational study between September 2015 and June 2021. Patients ≥80 years were grouped by antihyperglycemic regimen: (1) continuation of preadmission empagliflozin combined with basal insulin regimen and (2) conventional basal-bolus insulin regimen. A propensity score matching analysis matched patients in both groups in a 1:1 manner. The primary outcome was differences in clinical efficacy measured by the visual analogue scale dyspnea score, NT-proBNP levels, diuretic response, and cumulative urine output. Safety endpoints such as adverse events, worsening heart failure, discontinuation of empagliflozin, length of hospital stay, and in-hospital deaths were also analyzed., Results: After propensity score matching, 79 patients were included in each group. At discharge, the N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were lower in the empagliflozin continuation group than in the insulin group (1699 ± 522 vs. 2303 ± 598 pg/ml, p = 0.021). Both the diuretic response and cumulative urine output were greater in patients treated with empagliflozin than in patients with basal-bolus insulin during the hospitalization (at discharge: -0.14 ± -0.06 vs. -0.24 ± -0.10, p = 0.044; and 16,100 ± 1510 vs. 13,900 ± 1220 ml, p = 0.037, respectively). No differences were observed in safety outcomes., Conclusions: In very old patients with type 2 diabetes hospitalized for acute heart failure, continuing preadmission empagliflozin reduced NT-proBNP levels and increased diuretic response and urine output compared to a basal-bolus insulin regimen. The empagliflozin regimen also showed a good safety profile., (© 2021 The American Geriatrics Society.)

A need for new therapeutic approaches are necessary for dementia conditions and memory deficits of different origins, such as Alzheimer's disease. There is complex pathophysiological mechanisms involved, affecting adult hippocampal neurogenesis, in which neuropeptides and its neurogenesis regulation seem to participate. Neuropeptide Y(NPY) Y1 receptor (Y1R) and galanin (GAL) receptor 2 (GALR2) interact in brain regions responsible for learning and memory processes, emphasizing the hippocampus. Moreover, a significant challenge for treatments involving peptide drugs is bypassing the blood-brain barrier. The current study assesses the sustained memory performance induced by GALR2 and NPYY1R agonists intranasal coadministration and their neurochemical hippocampal correlates. Memory retrieval was conducted in the object-in-place task together with in situ proximity ligation assay (PLA) to manifest the formation of GALR2/Y1R heteroreceptor complexes and their dynamics under the different treatments. We evaluated cell proliferation through a 5-Bromo-2'-deoxyuridine (BrdU) expression study within the dentate gyrus of the dorsal hippocampus. The GalR2 agonist M1145 was demonstrated to act with the Y1R agonist to improve memory retrieval at 24 hours in the object-in-place task. Our data show that the intranasal administration is a feasible technique for directly delivering Galanin or Neuropeptide Y compounds into CNS. Moreover, we observed the ability of the co-agonist treatment to enhance the cell proliferation in the DG of the dorsal hippocampus through 5- Bromo-2'-deoxyuridine (BrdU) expression analysis at 24 hours. The understanding of the cellular mechanisms was achieved by analyzing the GALR2/Y1R heteroreceptor complexes upon agonist coactivation of their two types of receptor protomers in Doublecortin-expressing neuroblasts. Our results may provide the basis for developing heterobivalent agonist pharmacophores, targeting GALR2-Y1R heterocomplexes. It involves especially the neuronal precursor cells of the dentate gyrus in the dorsal hippocampus for the novel treatment of neurodegenerative pathologies as in the Alzheimer's disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Borroto-Escuela, Fores, Pita, Barbancho, Zamorano‐Gonzalez, Casares, Fuxe and Narváez.)

A need for new antidepressants is necessary since traditional antidepressants have several flaws. Neuropeptide Y(NPY) Y1 receptor (NPYY1R) and galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the hippocampus. The current study assesses the antidepressant effects induced by GALR2 and NPYY1R coactivation, together with the evaluation of cell proliferation through 5-Bromo-2'-deoxyuridine expression within the dentate gyrus of the ventral hippocampus (vDG). We employed in situ proximity ligation assay to manifest GALR2/NPYY1R heteroreceptor complexes. Additionally, the expression pattern of GALR2 and the activation of the extracellular-regulated kinases (ERK) pathway after GALR2 and NPYY1R costimulation in cell cultures were examined. GALR2 and NPYY1R coactivation resulted in sustained antidepressant behaviors in the FST after 24 h, linked to increased cell proliferation in the vDG. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was observed in vDG, on doublecortin-expressing neuroblasts. Recruitment of the GALR2 expression to the plasma membrane was observed upon the coactivation of GALR2 and NPYY1R in cell cultures, presumably associated to the enhanced effects on the activation of ERK pathway. GALR2 may promote the GALR2/NPYY1R heteroreceptor complexes formation in the ventral hippocampus. It may induce a transformation of cell proliferation toward a neuronal lineage by enhancement of ERK pathway. Thus, it may give the mechanism for the antidepressant behavior observed. These results may provide the basis for the development of heterobivalent agonist pharmacophores, targeting GALR2/NPYY1R heteromers, especially in the neuronal precursor cells of the dentate gyrus in the ventral hippocampus for the novel treatment of depression., (© 2020 Wiley Periodicals LLC.)

Introduction: Older patients are more likely to have cognitive dysfunction, and a great proportion of patients undergone surgical procedures are older adults. Postoperative cognitive dysfunction (POCD) has been shown as a consistent complication after major surgical procedures such as heart surgery., Aim: To determine the presence of long-term POCD in ≥65-year-old patients undergoing coronary artery bypass grafting and aortic valve replacement, and to establish related risk factors., Methods: We prospectively and sequentially included 44 patients with coronary disease and aortic stenosis scheduled for heart surgery. Follow-up of all patients was standardized and a neurocognitive evaluation were performed preoperatively and at 1, 6 and 12 months after surgery., Results: Patients experienced a significantly postoperative cognitive dysfunction (33.5%, 63.4% and 38.9% at 1, 6 and 12 months, respectively) from baseline (20.5%). Patient-associated aspects such as age (p<0.01), history of smoking (p<0.01), arterial hypertension (p=0.022), diabetes mellitus (p=0.024), heart failure (p=0.036) and preoperative cognitive dysfunction (p<0.01), and surgery-associated aspects such as EuroSCORE (p<0.01) and operation time (p<0.01) were identified as related risk factors., Conclusions: Older patients who underwent heart surgery had long-term POCD. Both patient- and surgery-related risk factors were established as related risk factors. These findings suggest that the prevalence of cognitive dysfunction after cardiac surgery in older patients could be related to a possible progression to dementia. In addition, many of the risk factors identified may be modifiable but in practice, these patients are not attended to for their possible cognitive impairment., (Copyright © 2020 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: The objective of this review is to analyze through a the scientific evidence about the effects of physical activity in patients with Alzheimer's disease (AD) as a preventive and non-pharmacological treatment., Design: Systematic review., Data Sources: We have identified articles from Pubmed, Science Direct, Medline and Scopus databases, with the keywords Alzheimer, Exercise, Neuroimaging, MRI, PET y Physical Activity. Selected articles: We included those studies that evaluated the effects of physical activity on Alzheimer's disease and those which also included magnetic resonance imaging or positron emission tomography with Pittsburg Compound B marker (PiB) analyzing brain atrophy or increase of the beta-amyloid deposit respectively. We excluded studies including other types of dementia, different of AD. We also excluded articles which not included neuroimaging tests, single cases or non-English language articles., Data Extraction: The PRISMA quality scale was used for the critical lecture of the studies. The researchers independently assessed the articles and the discrepancies were resolved by consensus., Results: We identified 75 articles, of which 23 were finally included in the review., Conclusions: Most of the studies included do not allow us to know the impact of physical exercise on cognition and the cerebral structural-functional changes in patients at risk of developing AD or in patients who already have the disease. Without being able to rule out a possible beneficial effect, more studies are needed with a better design and methodological rigor that allows a better known about this association., (Copyright © 2018 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Although postoperative cognitive dysfunction is a relevant complication after surgery, assessment for the condition is not routine in clinical practice., Objective: The aim of this study was to compare the use of screening versus brief domain-specific cognitive tests in assessing long-term cognitive dysfunction after concomitant aortic valve replacement and coronary artery bypass grafting., Methods: In this observational prospective study, we evaluated 70 patients preoperatively and after 1, 6, and 12 months using 2 screening tests (Mini-Mental State Examination and Clock Drawing Test) and 2 brief domain-specific cognitive tests (Trail Making Test to evaluate attention and executive function, and Semantic and Phonological Tests to evaluate verbal fluency)., Results: The brief domain-specific cognitive tests detected significant postoperative worsening in performances (up to 19% on the Trail Making Test and 15.4% on verbal fluency tests at 6 months). Postoperative mild attention/executive dysfunction or inferior normal performance was detected with the maximums being seen at 6 months (44.6%, P < .001). Performances on screening tests did not significantly change during the study period., Conclusions: A brief domain-specific cognitive evaluation could be routinely implemented in perioperative care practice to detect postoperative cognitive dysfunction.

Introduction: The use of dipeptidyl peptidase-4 inhibitors in hospitalized patients is an area of active research. We aimed to compare the efficacy and the safety of the basal-bolus insulin regimen versus linagliptin-basal insulin in non-critically ill non-cardiac surgery patients in a real-world setting. Methods: We enrolled patients with type 2 diabetes hospitalized in non-cardiac surgery departments with admission glycated haemoglobin level < 8%, admission blood glucose concentration < 240 mg/dL, and no at-home injectable treatments who were treated with basal-bolus ( n  = 347) or linagliptin-basal ( n  = 190) regimens between January 2016 and December 2017. To match patients on the two regimens, a propensity matching analysis was performed. Results: After matching, 120 patients were included in each group. No differences were noted in mean blood glucose concentration after admission ( p  = .162), number of patients with a mean blood glucose 100-140 mg/dL ( p  = .163) and > 200 mg/dL ( p  = .199), and treatment failures ( p  = .395). Total daily insulin and number of daily insulin injections were lower in the linagliptin-basal group (both p  < .001). Patients on linagliptin-basal insulin had fewer hypoglycaemic events (blood glucose < 70 mg/dL) ( p  < .001). Conclusion: For type 2 diabetes surgery patients with mild to moderate hyperglycaemia without pre-hospitalization injectable therapies, linagliptin-basal insulin was an effective, safe alternative with fewer hypoglycaemic events in real-world practice. Key messages Treatment with basal-bolus insulin regimens is the standard of care for non-critically ill hospitalized patients with type 2 diabetes. A differentiated treatment protocol that takes into account glycaemic control and clinical factors should be implemented in the hospital setting. Linagliptin-basal insulin is an effective, safe alternative with fewer hypoglycaemic events during the hospitalization of non-critically ill non-cardiac surgery patients with T2D in real-world practice.

Anxiety is evoked by a threatening situation and display adaptive or defensive behaviors, found similarly in animals and humans. Neuropeptide Y (NPY) Y1 receptor (NPYY1R) and Galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the amygdala. In a previous study, GALR2 enhanced NPYY1R mediated anxiolytic actions on spatiotemporal parameters in the open field and elevated plus maze, involving the formation of GALR2/NPYY1R heteroreceptor complexes in the amygdala. Moreover, the inclusion of complementary ethological parameters provides a more comprehensive profile on the anxiolytic effects of a treatment. The purpose of the current study is to evaluate the anxiolytic effects and circuit activity modifications caused by coactivation of GALR2 and NPYY1R. Ethological measurements were performed in the open field, the elevated plus-maze and the light-dark box, together with immediate early gene expression analysis within the amygdala-hypothalamus-periaqueductal gray (PAG) axis, as well as in situ proximity ligation assay (PLA) to demonstrate the formation of GALR2/NPYY1R heteroreceptor complexes. GALR2 and NPYY1R coactivation resulted in anxiolytic behaviors such as increased rearing and head-dipping, reduced stretch attend postures and freezing compared to single agonist or aCSF injection. Neuronal activity indicated by cFos expression was decreased in the dorsolateral paracapsular intercalated (ITCp-dl) subregion of the amygdala, ventromedial hypothalamic (VMH) nucleus and ventrolateral part of the periaqueductal gray (vlPAG), while increased in the perifornical nucleus of the hypothalamus (PFX) following coactivation of GALR2 and NPYY1R. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was explicitly observed in ITCp-dl, following GALR2 and NPYY1R coactivation. Besides, knockdown of GALR2 was found to reduce the density of complexes in ITCp-dl. Taken together, these results open up the possibility that the increased anxiolytic activity demonstrated upon coactivation of NPYY1R and GALR2 receptor was related to actions on the ITCp-dl. GALR2-NPYY1R heteroreceptor complexes may inhibit neuronal activity, by also modifying the neuronal networks of the hypothalamus and the PAG. These results indicate that GALR2/NPYY1R interactions in medial paracapsular intercalated amygdala can provide a novel integrative mechanism in anxiolytic behavior and the basis for the development of heterobivalent agonist drugs targeting GALR2/NPYY1R heteromers, especially in the ITCp-dl of the amygdala for the treatment of anxiety.

To assess the possible function of glutamate in the interaction between the dorsomedial hypothalamic nucleus-perifornical area (DMH-PeF) and the A5 pontine region (A5), cardiovascular and respiratory changes were studied in response to electrical stimulation of the DMH-PeF (1 ms pulses, 30-50 μA given at 100 Hz for 5 s) before and after the microinjection of kynurenic acid (non-specific glutamate receptor antagonist; 50 nl, 5 nmol), MK-801 (NMDA receptor antagonist; 50 nl, 50 nmol), CNQX (non-NMDA receptor antagonist; 50 nl, 50 nmol) or MCPG (metabotropic glutamate receptor antagonist; 50 nl, 5 nmol) within the A5 region. DMH-PeF electrical stimulation elicited a pressor (p < 0.001) and tachycardic response (p < 0.001) which was accompanied by an inspiratory facilitation characterised by an increase in respiratory rate (p < 0.001) due to a decrease in expiratory time (p < 0.01). Kynurenic acid within the A5 region decreased the tachycardia (p < 0.001) and the intensity of the blood pressure response (p < 0.001) to DMH-PeF stimulation. After the microinjection of MK-801 and CNQX into the A5 region, the magnitude of the tachycardia and the pressor response were decreased (p < 0.05 and p < 0.01; p < 0.001 and p < 0.05, respectively). After MCPG microinjection into the A5 region, a decrease in the tachycardia (p < 0.001) with no changes in the pressor response was observed during DMH-PeF stimulation. The respiratory response elicited by DMH-PeF stimulation was not changed after the microinjection of kynurenic acid, MK-801, CNQX or MCPG within the A5 region. These results suggest that A5 region glutamate receptors play a role in the cardiovascular response elicited from the DMH-PeF. The possible mechanisms involved in these interactions are discussed.

Changes in ERP (P100 and N400) and root mean square (RMS) were obtained during a silent reading task in 28 patients with chronic post-stroke aphasia in a randomized, double-blind, placebo-controlled trial of both memantine and constraint-induced aphasia therapy (CIAT). Participants received memantine/placebo alone (weeks 0-16), followed by drug treatment combined with CIAT (weeks 16-18), and then memantine/placebo alone (weeks 18-20). ERP/RMS values (week 16) decreased more in the memantine group than in the placebo group. During CIAT application (weeks 16-18), improvements in aphasia severity and ERP/RMS values were amplified by memantine and changes remained stable thereafter (weeks 18-20). Changes in ERP/RMS occurred in left and right hemispheres and correlated with gains in language performance. No changes in ERP/RMS were found in a healthy group in two separated evaluations. Our results show that aphasia recovery induced by both memantine alone and in combination with CIAT is indexed by bilateral cortical potentials., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To assess cognitive impairment after off-pump coronary-artery bypass grafting, with a particular emphasis on long-term follow-up and related risk factors., Design: Prospective study., Setting: Virgen de la Victoria University Hospital, Málaga, Spain., Participants: Participants were 36 patients undergoing off-pump coronary-artery bypass grafting., Measurements: Changes in the neuropsychological test battery administered from before to after surgery (1, 6, and 12 months). Postoperative cognitive impairment was defined by a significant decrease., Results: A significantly multidomain (attention-executive functions, P < .01; immediate and delayed memory, P < .001; and verbal fluency, P < .05) postoperative cognitive impairment was shown, being maximum at 6 months (more than 50% of patients) and still presented at 12 months (more than 30% of patients), but partially recovered. Related risk factors as smoking (P < .01), diabetes mellitus (P < .01), peripheral arteriopathy (P < .01), obesity (P < .05), lower hematocrit (P < .01), and hemoglobin (P < .05) levels and diastolic blood pressure (P < .05) were identified as predictors of cognitive impairment. Better New York Heart Association class (P < .01) and less severity of angina (P < .01) were associated with partial postoperative recovering., Conclusion: A multidomain long-term postoperative cognitive impairment and a partial neurocognitive recovering were detected after off-pump coronary-artery bypass grafting and were associated with several nonspecific surgery factors. These findings may be useful when counseling patients before surgery and suggest the importance of long-term neurocognitive evaluation., (Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Coronary disease has been associated with cognitive disorders. We studied the presence of dysexecutive mild cognitive impairment in patients scheduled for coronary surgery., Patients and Methods: The executive function of 35 patients was evaluated (Trail Making Test). They were classified into 2 groups: normal performance or cognitive impairment, and we assessed the relationship with others variables (Mann-Whitney, chi-square and multiple regression analysis)., Results: The dysexecutive cognitive impairment group (n=7; 20%) showed greater degree of angina (odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1-2.6; P=.04), 3-vessels coronary artery disease (OR 1.3, 95% CI 1.08-3.6; P=.04) and body mass index (OR 1.56, 95% CI 1.16-3.65; P=.03) and lower diastolic blood pressure (OR 1.56, 95% CI 1.2-2.98; P=.02), hemoglobin (OR 2.03, 95% CI 1.18-4.05; P=.02) and hematocrit (OR 2.45, 95% CI 1.67-3.99; P<.001); these variables proved to be significant in the test performance considered as a dependent variable (R(2)=0.62)., Conclusions: We found a significant prevalence of dysexecutive mild cognitive impairment, which was associated with cardiovascular risk factors. We recommend assessment and monitoring of cognitive performance for probable neurological complications after cardiac surgery., (Copyright © 2013 Elsevier España, S.L. All rights reserved.)

In order to assess the possible interactions between the pontine A5 region and the hypothalamic defence area (HDA), we have examined the pattern of double staining for c-Fos protein immunoreactivity (c-Fos-ir) and tyrosine hydroxylase, throughout the rostrocaudal extent of the A5 region in spontaneously breathing anaesthetized male Sprague-Dawley rats during electrical stimulation of the HDA. Activation of the HDA elicited a selective increase in c-Fos-ir with an ipsilateral predominance in catecholaminergic and non-catecholaminergic A5 somata (P < 0.001 in both cases). A second group of experiments was done to examine the importance of the A5 region in modulating the cardiorespiratory response evoked from the HDA. Cardiorespiratory changes were analysed in response to electrical stimulation of the HDA before and after ipsilateral microinjection of muscimol within the A5 region. Stimulation of the HDA evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (P < 0.001) due to a decrease in expiratory time (P < 0.01). The respiratory response was accompanied by a pressor response (P < 0.001) and tachycardia (P < 0.001). After muscimol microinjection within the A5 region, pressor and heart rate responses to HDA stimulation were reduced (P < 0.01 and P < 0.001, respectively). The respiratory response persisted unchanged. Finally, to confirm functional interactions between the HDA and the A5 region, extracellular recordings of putative A5 neurones were obtained during HDA stimulation. Seventy-five A5 cells were recorded, 35 of which were affected by the HDA (47%). These results indicate that neurones of the A5 region participate in the cardiovascular response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.

The lysophosphatidic acid LPA₁ receptor has recently been involved in the adaptation of the hippocampus to chronic stress. The absence of LPA₁ receptor aggravates the chronic stress-induced impairment of both hippocampal neurogenesis and apoptosis that were accompanied with hippocampus-dependent memory deficits. Apoptotic death and neurogenesis in the hippocampus are regulated by oxidative stress. In the present work, we studied the involvement of LPA₁ receptor signaling pathway in the regulation of the hippocampal redox after chronic stress. To this end, we used malpar1 knockout (KO) and wild-type mice assigned to either chronic stress (21 days of restraint, 3 h/day) or control conditions. Lipid peroxidation, the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX), as well as mitochondrial function stimulation, monitored through the activity of cytochrome c oxidase (COX), were studied in the hippocampus. Our results showed that chronic immobilization stress enhanced lipid peroxidation as well as the activity of the antioxidant enzymes studied (CAT, SOD, and GPX). This effect was only observed in absence of LPA₁ receptor. Furthermore, only malpar1 KO mice submitted to chronic stress exhibited a severe downregulation of the COX activity, suggesting the presence of mitochondrial damage. Altogether, these results suggest that malpar1 KO mice display enhanced oxidative stress in the hippocampus after chronic stress. This may be involved in the hippocampal abnormalities observed in this genotype after chronic immobilization, including memory, neurogenesis, and apoptosis.

We report the rare case of a patient, JNR, with history of mixed handedness, developmental dyslexia, dysgraphia, and attentional deficits associated with a Klippel-Trenaunay syndrome and a small subcortical frontal lesion involving the left arcuate fasciculus. In adulthood, he suffered a large right perisylvian stroke and developed atypical conduction aphasia with deficits in input and output phonological processing and poor auditory-verbal short-term memory. Lexical-semantic processing for single words was intact, but he was unable to access meaning in sentence comprehension and repetition. Reading and writing deficits worsened after the stroke and he presented a combination of developmental and acquired dysgraphia and dyslexia with mixed lexical and phonological processing deficits. This case suggest that a small lesion sustained prenatally or early in life could induce a selective rightward shift of phonology sparing the standard left hemisphere lateralisation of lexical-semantic functions.

Objective: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of both memantine and constraint-induced aphasia therapy (CIAT) on chronic poststroke aphasia followed by an open-label extension phase., Methods: Patients were randomized to memantine (20 mg/day) or placebo alone during 16 weeks, followed by combined drug treatment with CIAT (weeks 16-18), drug treatment alone (weeks 18-20), and washout (weeks 20-24), and finally, an open-label extension phase of memantine (weeks 24-48). After baseline evaluations, clinical assessments were done at two end points (weeks 16 and 18), and at weeks 20, 24, and 48. Outcome measures were changes in the Western Aphasia Battery-Aphasia Quotient and the Communicative Activity Log., Results: Twenty-eight patients were included, and 27 completed both treatment phases. The memantine group showed significantly better improvement on Western Aphasia Battery-Aphasia Quotient compared with the placebo group while the drug was taken (week 16, p = 0.002; week 18, p = 0.0001; week 20, p = 0.005) and at the washout assessment (p = 0.041). A significant increase in Communicative Activity Log was found in favor of memantine-CIAT relative to placebo-CIAT (week 18, p = 0.040). CIAT treatment led to significant improvement in both groups (p = 0.001), which was even greater under additional memantine treatment (p = 0.038). Beneficial effects of memantine were maintained in the long-term follow-up evaluation, and patients who switched to memantine from placebo experienced a benefit (p = 0.02)., Interpretation: Both memantine and CIAT alone improved aphasia severity, but best outcomes were achieved combining memantine with CIAT. Beneficial effects of memantine and CIAT persisted on long-term follow-up.

Introduction: The objective of this study is to describe the frequency and severity of behavioral and psychological symptoms (BPS) in a group of 125 patients diagnosed of Alzheimer's disease (AD) (DSM-IV-TR and NINCDSADRDA criteria)., Methods: The evaluation of the BPS was carried out using the Neuropsychiatric Inventory (NPI; Cummings et al., 1994). The sociodemographic and personal background data of the patients were gathered and the dementia stage was established with the Global Deterioration Scale (GDS Reisberg, 1982)., Results: A total of 122 patients (98%) presented BPS, with an average of five symptoms per patient. Frequency of presentation was the following: apathy (75%), irritability (66%), depression (60%), agitation (55%), anxiety (54%), aberrant motor activity (47%), delirium (38%), sleeping disorders (36%), disinhibition (29%), eating disorders (28%), hallucinations (20%) and euphoria (4%)., Conclusions: These results show the high incidence of BPS in AD patients and point to the necessity and importance of treating these disorders appropriately.