Changes in the Brain Extracellular Matrix Composition in schizophrenia: A Pathophysiological Dysregulation and a Potential Therapeutic Target.

The brain extracellular matrix (ECM) is involved in crucial processes of neural support, neuronal and synaptic plasticity, extrasynaptic transmission, and neurotransmission. ECM is a tridimensional fibrillary meshwork composed of macromolecules that determine its bioactivity and give it unique characteristics. The characterization of the brain ECM is critical to understand its dynamic in SZ. Thus, a comparative study was developed with 71 patients with schizophrenia (SZ) and 70 healthy controls. Plasma of participants was analysed by label-free liquid chromatography-tandem mass spectrometry, and the results were validated using the classical western blot method. Lastly, immunostaining of post-mortem human brain tissue was performed to analyse the distribution of the brain ECM proteins by confocal microscopy. The analysis identified four proteins: fibronectin, lumican, nidogen-1, and secreted protein acidic and rich in cysteine (SPARC) as components of the brain ECM. Statistical significance was found for fibronectin (P = 0.0166), SPARC (P = 0.0003), lumican (P = 0.0012), and nidogen-1 (P < 0.0001) that were decreased in the SZ group. Fluorescence imaging of prefrontal cortex (PFC) sections revealed a lower expression of ECM proteins in SZ. Our study proposes a pathophysiological dysregulation of proteins of the brain ECM, whose abnormal composition leads to a progressive neuronal impairment and consequently to neurodegenerative processes due to lack of neurophysiological support and dysregulation of neuronal homeostasis. Moreover, the brain ECM and its components are potential pharmacological targets to develop new therapeutic approaches to treat SZ.

Perfil proteómico y metabólico de pacientes crónicos con esquizofrenia tras un programa de actividad física: estudio piloto / Proteomic and metabolic profiling of chronic patients with schizophrenia induced by a physical activity program: Pilot study

Introducción: La esquizofrenia es una enfermedad crónica que suele ir acompañada de trastornos metabólicos como la diabetes, la obesidad y problemas cardiovasculares asociados muchas veces a estilos de vida poco saludables, así como a problemas neuroendocrinos ocasionados por la propia enfermedad. Los cambios en el estilo de vida, como la práctica de ejercicio físico regular, tienen un efecto positivo sobre los trastornos metabólicos y la salud mental. Sin embargo, se desconocen los cambios moleculares y su consecuente repercusión en los pacientes diagnosticados con esquizofrenia. Con este estudio se pretenden analizar los cambios moleculares inducidos por el ejercicio físico en pacientes crónicos con esquizofrenia.MétodosVeintiún pacientes con esquizofrenia crónica fueron sometidos a un programa de entrenamiento aeróbico diario durante 6 meses. El grupo de pacientes se dividió en 2 subgrupos: un subgrupo que completó en su totalidad el programa de entrenamiento (12 pacientes) y un segundo subgrupo que abandonó el programa el primer día (9 pacientes). Se analizaron los datos bioquímicos y clínicos de cada paciente y se estudió el perfil proteómico del plasma mediante ESI-LC-MS/MS de tipo shotgun.ResultadosEl análisis proteómico reconoció 21.165 proteínas y péptidos diferentes en el plasma de los pacientes. Concretamente, 4.657 proteínas sufrieron variaciones significativas, de las cuales fueron identificadas 1.812 proteínas relacionadas con las vías metabólicas y de regulación biológica. Tras el análisis de los parámetros clínicos en estos pacientes, se encontraron diferencias significativas en el peso, el IMC, el perímetro abdominal, la presión arterial diastólica y los niveles de colesterol HDL. La puntuación en la Escala de Autoevaluación de Anhedonia fue el cambio más significativo, siendo más elevada en el subgrupo que abandonó el programa de entrenamiento en comparación con el subgrupo activo. (AU)

Introduction: Schizophrenia is a chronic illness often accompanied by metabolic disorders, diabetes, obesity and cardiovascular problems often associated with unhealthy lifestyles, as well as neuroendocrine problems caused by the disease itself. Lifestyle changes, such as regular physical exercise, have a positive effect on metabolic disorders and mental health, although the molecular changes that occur in this type of patient and how they explain the changes in their response are unknown. This study wants to analyze in a novel way the proteins and molecular pathways involved in critical plasmatic proteins in plasma to reveal the pathways involved in the implementation of physical exercise and the changes that occur among patients who participate in such programs with those who leave.MethodsTwenty-one patients with chronic schizophrenia underwent a daily, 6-month aerobic training program. We divided them into a group that completed the program (12 patients) and a second group that left the training program (9 patients). The biochemical and clinical data of each patient were analyzed and the proteomic profile of the plasma was studied using ESI-LC-MS/MS.ResultsProteomic analysis recognizes 21.165 proteins and peptides in each patient, of which we identified 1,812 proteins that varied between both groups linked to the metabolic and biological regulation pathways. After clinical analysis of each patient we found significant differences in weight, BMI, abdominal perimeter, diastolic blood pressure, and HDL cholesterol levels. The main change that vertebrates both groups is the Self-Assessment Anhedonia Scale, where we detected higher levels in the dropout group (no physical activity) compared to the active group. (AU)

Proteomic and metabolic profiling of chronic patients with schizophrenia induced by a physical activity program: Pilot study.

INTRODUCTION: Schizophrenia is a chronic illness often accompanied by metabolic disorders, diabetes, obesity and cardiovascular problems often associated with unhealthy lifestyles, as well as neuroendocrine problems caused by the disease itself. Lifestyle changes, such as regular physical exercise, have a positive effect on metabolic disorders and mental health, although the molecular changes that occur in this type of patient and how they explain the changes in their response are unknown. This study wants to analyze in a novel way the proteins and molecular pathways involved in critical plasmatic proteins in plasma to reveal the pathways involved in the implementation of physical exercise and the changes that occur among patients who participate in such programs with those who leave. METHODS: Twenty-one patients with chronic schizophrenia underwent a daily, 6-month aerobic training program. We divided them into a group that completed the program (12 patients) and a second group that left the training program (9 patients). The biochemical and clinical data of each patient were analyzed and the proteomic profile of the plasma was studied using ESI-LC-MS/MS. RESULTS: Proteomic analysis recognizes 21.165 proteins and peptides in each patient, of which we identified 1.812 proteins that varied between both groups linked to the metabolic and biological regulation pathways. After clinical analysis of each patient we found significant differences in weight, BMI, abdominal perimeter, diastolic blood pressure, and HDL cholesterol levels. The main change that vertebrates both groups is the Self-Assessment Anhedonia Scale, where we detected higher levels in the dropout group (no physical activity) compared to the active group. CONCLUSION: The benefits of physical exercise are clear in chronic patients with schizophrenia, as it substantially improves their BMI, as well as their clinical and biochemical parameters. However, our study reveals the biological and molecular pathways that affect physical exercise in schizophrenia, such as important metabolic proteins such as ApoE and ApoC, proteins involved in neuronal regulation such as tenascin and neurotrophins, neuroinflammatory regulatory pathways such as lipocalin-2 and protein 14-3-3, as well as cytoskeleton proteins of cells such as spectrins and annexines. Understanding these molecular mechanisms opens the door to future therapies in the chronicity of schizophrenia.

The Role of the Second Extracellular Loop of Norepinephrine Transporter, Neurotrophin-3 and Tropomyosin Receptor Kinase C in T Cells: A Peripheral Biomarker in the Etiology of Schizophrenia.

The neurobiology of schizophrenia is multifactorial, comprising the dysregulation of several biochemical pathways and molecules. This research proposes a peripheral biomarker for schizophrenia that involves the second extracellular loop of norepinephrine transporter (NEText), the tropomyosin receptor kinase C (TrkC), and the neurotrophin-3 (NT-3) in T cells. The study of NEText, NT-3, and TrkC was performed in T cells and plasma extracted from peripheral blood of 54 patients with schizophrenia and 54 healthy controls. Levels of NT-3, TrkC, and NET were significantly lower in plasma and T cells of patients compared to healthy controls. Co-immunoprecipitation (co-IPs) showed protein interactions with Co-IP NEText-NT-3 and Co-IP NEText-TrkC. Computational modelling of protein-peptide docking by CABS-dock provided a medium-high accuracy model for NT-3-NEText (4.6935 Å) and TrkC-NEText (2.1365 Å). In summary, immunocomplexes reached statistical relevance in the T cells of the control group contrary to the results obtained with schizophrenia. The reduced expression of NT-3, TrkC, and NET, and the lack of molecular complexes in T cells of patients with schizophrenia may lead to a peripheral dysregulation of intracellular signaling pathways and an abnormal reuptake of norepinephrine (NE) by NET. This peripheral molecular biomarker underlying schizophrenia reinforces the role of neurotrophins, and noradrenergic and immune systems in the pathophysiology of schizophrenia.

Validación del RUDAS como instrumento de cribado de población con demencia en atención primaria / Validation of RUDAS: A screening tool for dementia in Primary Health Care settings

Objetivo: Validar la escala Rowland Dementia Assessment Scale (RUDAS) como instrumento de cribado de deterioro cognitivo y demencia en atención primaria (AP). Es un test breve, válido para población con bajo nivel educativo formal y fácilmente traducible en entornos multiculturales. Diseño: Se realizó un estudio epidemiológico descriptivo, de corte transversal, con seguimiento a los 5años. Emplazamiento: Centro de salud de atención primaria de O Grove, que atiende a una población de 10.650 habitantes en Pontevedra. Participantes: Ciento cincuenta personas aleatoriamente seleccionadas, con una edad media de 76,35±7,12años, bajo nivel educativo, origen predominantemente rural y semirrural y nivel socioeconómico bajo. Intervención: Se analizó la viabilidad, la aceptabilidad, la validez y la fiabilidad de la escala. Mediciones principales: RUDAS, Mini Mental State Examination, Clinical Dementia Rating, Índice de Katz, Índice de Barthel, Índice de Lawton y Escala de Depresión Geriátrica de Yesavage. Resultados: El test fue bien acogido por los pacientes y rápido de aplicar (7,58±2,10min). El área bajo la curva COR para el diagnóstico de demencia fue 0,983 (IC95%: 0,97-1,00). Para un punto de corte óptimo de 22,5 presentó una sensibilidad del 89,3% y una especificidad del 100%. El área bajo la curva COR para discriminar personas con DCL de personas con demencia fue 0,965 (IC95%: 0,91-1,00). Conclusiones: El RUDAS ha demostrado ser un instrumento viable y eficiente para cribar demencias en AP, libre de influencias educativas y socioculturales. Es especialmente sensible para discriminar población con deterioro cognitivo leve de población con demencia.(AU)

Objective: To validate Rowland Dementia Assessment Scale (RUDAS), as an instrument for the screening of people with dementia and cognitive impairment in Primary Health Care (PHC). RUDAS is a brief cognitive test, appropriate for people with minimum completed level of education and easily adaptable to multicultural contexts. For these reason it could be a good instrument for dementia screening in PHC. Design: Cross-sectional descriptive epidemiological study with a five-year follow up. Location: O Grove PHC centre, Galicia, Spain (covering a population of 10,650 individuals). Outcome measures: RUDAS; Mini Mental State Examination; Clinical Dementia Rating; Katz, Barthel and Lawton Indexes; MMSE and Yesavage Geriatric Depression Scale. Participants: A total of 150 older adults (mean age 76.35±7.12years) randomly selected, from a low sociocultural and economical background and mainly rural and semirural origin. Intervention: RUDAS viability in PHC was checked, and its psychometric properties assessed: reliability, sensitivity, specificity, positive and negative predictive values. Results: RUDAS application was brief (7.58±2.10min) and well accepted. RUDAS area under receiver operating characteristic (ROC) curve for the detection of dementia was 0.983 (95% confidence interval (CI): 0.97-1.00) for an optimal cut-off point of 22.5, with sensitivity of 89.3%, and a specificity of 100%. Area under ROC curve for discriminating dementia from mild cognitive impairment was 0.965 (95%CI: 0.91-1.00). Conclusions: RUDAS test is fit for dementia screening in PHC and it is especially sensitive to discriminate PWD from people with MCI.(AU)

[Validation of RUDAS: A screening tool for dementia in Primary Health Care settings]. / Validación del RUDAS como instrumento de cribado de población con demencia en atención primaria.

OBJECTIVE: To validate Rowland Dementia Assessment Scale (RUDAS), as an instrument for the screening of people with dementia and cognitive impairment in Primary Health Care (PHC). RUDAS is a brief cognitive test, appropriate for people with minimum completed level of education and easily adaptable to multicultural contexts. For these reason it could be a good instrument for dementia screening in PHC. DESIGN: Cross-sectional descriptive epidemiological study with a five-year follow up. LOCATION: O Grove PHC centre, Galicia, Spain (covering a population of 10,650 individuals). OUTCOME MEASURES: RUDAS; Mini Mental State Examination; Clinical Dementia Rating; Katz, Barthel and Lawton Indexes; MMSE and Yesavage Geriatric Depression Scale. PARTICIPANTS: A total of 150 older adults (mean age 76.35±7.12years) randomly selected, from a low sociocultural and economical background and mainly rural and semirural origin. INTERVENTION: RUDAS viability in PHC was checked, and its psychometric properties assessed: reliability, sensitivity, specificity, positive and negative predictive values. RESULTS: RUDAS application was brief (7.58±2.10min) and well accepted. RUDAS area under receiver operating characteristic (ROC) curve for the detection of dementia was 0.983 (95% confidence interval (CI): 0.97-1.00) for an optimal cut-off point of 22.5, with sensitivity of 89.3%, and a specificity of 100%. Area under ROC curve for discriminating dementia from mild cognitive impairment was 0.965 (95%CI: 0.91-1.00). CONCLUSIONS: RUDAS test is fit for dementia screening in PHC and it is especially sensitive to discriminate PWD from people with MCI.

Plasma ß-III tubulin, neurofilament light chain and glial fibrillary acidic protein are associated with neurodegeneration and progression in schizophrenia.

Schizophrenia is a progressive disorder characterized by multiple psychotic relapses. After every relapse, patients may not fully recover, and this may lead to a progressive loss of functionality. Pharmacological treatment represents a key factor to minimize the biological, psychological and psychosocial impact of the disorder. The number of relapses and the duration of psychotic episodes induce a potential neuronal damage and subsequently, neurodegenerative processes. Thus, a comparative study was performed, including forty healthy controls and forty-two SZ patients divided into first-episode psychosis (FEP) and chronic SZ (CSZ) subgroups, where the CSZ sub group was subdivided by antipsychotic treatment. In order to measure the potential neuronal damage, plasma levels of ß-III tubulin, neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) were performed. The results revealed that the levels of these proteins were increased in the SZ group compared to the control group (P < 0.05). Moreover, multiple comparison analysis showed highly significant levels of ß-III tubulin (P = 0.0002), Nf-L (P = 0.0403) and GFAP (P < 0.015) in the subgroup of CSZ clozapine-treated. In conclusion, ß-III tubulin, Nf-L and GFAP proteins may be potential biomarkers of neurodegeneration and progression in SZ.

Brainwaves Oscillations as a Potential Biomarker for Major Depression Disorder Risk.

Major depressive disorder (MDD) is a multidimensional disorder that is characterized by the presence of alterations in mood, cognitive capacity, sensorimotor, and homeostatic functions. Given that about half of the patients diagnosed with MDD do not respond to the various current treatments, new techniques are being sought to predict not only the course of the disease but also the characteristics that differentiate responders from non-responders. Using the electroencephalogram, a noninvasive and inexpensive tool, most studies have proposed that patients with MDD have some lateralization in brain electrical activity, with alterations in alpha and theta rhythms being observed, which would be related to dysfunctions in emotional capacity such as the absence or presence of responses to the different existing treatments. These alterations help in the identification of subjects at high risk of suffering from depression, in the differentiation into responders and nonresponders to various therapies (pharmacological, electroconvulsive therapy, and so on), as well as to establish in which period of the disease the treatment will be more effective. Although the data are still inconclusive and more research is needed, these alpha and theta neurophysiological markers could support future clinical practice when it comes to establishing an early diagnosis and treating state disorders more successfully and accurately of mood disorders.

Proteomics in Schizophrenia: A Gateway to Discover Potential Biomarkers of Psychoneuroimmune Pathways.

Schizophrenia is a severe and disabling psychiatric disorder with a complex and multifactorial etiology. The lack of consensus regarding the multifaceted dysfunction of this ailment has increased the need to explore new research lines. This research makes use of proteomics data to discover possible analytes associated with psychoneuroimmune signaling pathways in schizophrenia. Thus, we analyze plasma of 45 patients [10 patients with first-episode schizophrenia (FES) and 35 patients with chronic schizophrenia] and 43 healthy subjects by label-free liquid chromatography-tandem mass spectrometry. The analysis revealed a significant reduction in the levels of glia maturation factor beta (GMF-ß), the brain-derived neurotrophic factor (BDNF), and the 115-kDa isoform of the Rab3 GTPase-activating protein catalytic subunit (RAB3GAP1) in patients with schizophrenia as compared to healthy volunteers. In conclusion, GMF-ß, BDNF, and 115-kDa isoform of RAB3GAP1 showed significantly reduced levels in plasma of patients with schizophrenia, thus making them potential biomarkers in schizophrenia.

Guía de práctica clínica sobre la depresión mayor en la infancia y adolescencia: actualización / Clinical practice guide on major depression in childhood and adolescence: update

Objetivos: Mejorar la atención sanitaria prestada a los niños y adolescentes con depresión en el ámbito de la atención primaria y especializada. Ofrecer recomendaciones al profesional sanitario para la atención de estos pacientes. Desarrollar indicadores de evaluación de la calidad asistencial. Ayudar a los pacientes y a sus familiares a la toma de decisiones informada y a la mejora de la comunicación entre los pacientes y los profesionales. No se abordan otros servicios, como los sociales, educacionales o de tiempo libre. Aspectos contemplados Las áreas clínicas que contempla la guía son: - Criterios diagnósticos y caracterización de la depresión infanto-juvenil. - Factores de riesgo y de protección. - Evaluación. - Perspectivas de pacientes y familiares. - Cribado en atención primaria. - Opciones de tratamiento de la depresión: - Tratamiento psicológico (modalidades, numero de sesiones, duración). - Manejo farmacológico (indicación, dosis, duración, cese, efectos secundarios, toxicidad y ausencia de respuesta a la medicación). - Tratamiento combinado. - Prevención de recaídas/recurrencia. - Estrategias para la depresión que no responde al tratamiento. - Tratamiento de la depresión mayor con síntomas psicóticos. - Otras alternativas terapéuticas: ejercicio físico, intervenciones online y terapias alternativas. - El consentimiento informado desde el punto de vista legal en España. - Algoritmo terapéutico: criterios de derivación y manejo según gravedad. Aspectos no abordados en la GPC 1) Los trastornos distímico, bipolar, ni el adaptativo. 2) La prevención primaria de la depresión en la infancia y adolescencia. 3) La prevención de la conducta suicida, debido a que este aspecto se recoge en la GPC de Prevención y Tratamiento de la Conducta Suicida del Programa de GPC en el SNS, en su apartado especifico sobre infancia y adolescencia.

Desarrollo e impacto de los sistemas informatizados de apoyo a las decisiones en el manejo clínico de la depresión: revisión sistemática / Development and impact of computerised decision support systems for clinical management of depression: a systematic review

Una de las propuestas para conseguir mejorar la práctica clínica es la incorporación de sistemas informatizados de apoyo a las decisiones (SADC) y su integración con los registros clínicos electrónicos. El objetivo de este trabajo es revisar de forma sistemática la evidencia sobre la eficacia de los SADC en el manejo de la depresión. Para ello se realizó una búsqueda bibliográfica en Medline, EMBASE y PsycInfo. La calidad de los estudios cuantitativos se evaluó mediante el método SIGN y los estudios cualitativos mediante el checklist de CASPe. Se identificaron 7 estudios (3 ensayos clínicos aleatorizados, 3 ensayos no aleatorizados y un estudio cualitativo). Los SADC evaluados incorporaron contenidos derivados de guías u otros productos basados en la evidencia. En líneas generales, los SADC mostraron un impacto positivo sobre diferentes aspectos como el cribado y diagnóstico, tratamiento, mejora de síntomas depresivos y calidad de vida y derivación de pacientes a asistencia especializada. El empleo de SADC podría optimizar la atención de la depresión en diversos escenarios mediante la provisión de recomendaciones basadas en la mejor evidencia disponible y la facilitación de la toma de decisiones de los profesionales en la práctica clínica (AU)

One of the proposals for improving clinical practice is to introduce computerised decision support systems (CDSS) and integrate these with electronic medical records. Accordingly, this study sought to systematically review evidence on the effectiveness of CDSS in the management of depression. A search was performed in Medline, EMBASE and PsycInfo, in order to do this. The quality of quantitative studies was assessed using the SIGN method, and qualitative studies using the CASPe checklist. Seven studies were identified (3 randomised clinical trials, 3 non-randomised trials, and one qualitative study). The CDSS assessed incorporated content drawn from guidelines and other evidence-based products. In general, the CDSS had a positive impact on different aspects, such as the screening and diagnosis, treatment, improvement in depressive symptoms and quality of life, and referral of patients. The use of CDSS could thus serve to optimise care of depression in various scenarios by providing recommendations based on the best evidence available and facilitating decision-making in clinical practice (AU)

Development and impact of computerised decision support systems for clinical management of depression: A systematic review.

One of the proposals for improving clinical practice is to introduce computerised decision support systems (CDSS) and integrate these with electronic medical records. Accordingly, this study sought to systematically review evidence on the effectiveness of CDSS in the management of depression. A search was performed in Medline, EMBASE and PsycInfo, in order to do this. The quality of quantitative studies was assessed using the SIGN method, and qualitative studies using the CASPe checklist. Seven studies were identified (3 randomised clinical trials, 3 non-randomised trials, and one qualitative study). The CDSS assessed incorporated content drawn from guidelines and other evidence-based products. In general, the CDSS had a positive impact on different aspects, such as the screening and diagnosis, treatment, improvement in depressive symptoms and quality of life, and referral of patients. The use of CDSS could thus serve to optimise care of depression in various scenarios by providing recommendations based on the best evidence available and facilitating decision-making in clinical practice.

Guía de práctica clínica para el tratamiento de depresión en adultos / Clinical practice guideline for the treatment of depression in adults

La guía trata de temas relacionados al tratamiento de la depresión, tocando temas como: las perspectivas y experiencias de los pacientes con depresión y sus familiares; evaluación y cribado de la depresión; los modelos de atención; tratamiento psicoterapéutico, tratamiento farmacológico; estrategias psicoterapéuticas y farmacológicas en la depresión resistente.