Biomarcadores sanguíneos en la enfermedad de Alzheimer / Blood biomarkers in Alzheimer's disease

Introducción: El diagnóstico precoz de la enfermedad de Alzheimer mediante la utilización de biomarcadores podría facilitar la instauración y monitorización de intervenciones terapéuticas tempranas con potencial capacidad para modificar significativamente el curso de la enfermedad.DesarrolloLos biomarcadores clásicos de líquido cefalorraquídeo y de neuroimagen estructural y funcional aprobados tienen una aplicación clínica limitada, dado su carácter invasivo o su elevado coste. La identificación de biomarcadores más accesibles y menos costosos, como los sanguíneos, facilitaría su aplicación en la práctica clínica. Se presenta una revisión bibliográfica de los principales biomarcadores bioquímicos sanguíneos con potencial utilidad para el diagnóstico de la enfermedad de Alzheimer.ConclusionesLos biomarcadores sanguíneos son coste y tiempo efectivos con respecto a los marcadores de líquido cefalorraquídeo. Sin embargo, la aplicabilidad inmediata de los biomarcadores bioquímicos sanguíneos en la práctica clínica es poco esperable. Las principales limitaciones estriban en la dificultad para la medición y estandarización de los umbrales entre los diferentes laboratorios y en los fallos de replicación de resultados. Entre todas las moléculas estudiadas, los biomarcadores de apoptosis y neurodegeneración, al igual que los paneles de biomarcadores obtenidos mediante aproximaciones ómicas —como la metabolómica de forma aislada o combinada— ofrecen los resultados más prometedores. (AU)

Introduction: The early diagnosis of Alzheimer's disease (AD) via the use of biomarkers could facilitate the implementation and monitoring of early therapeutic interventions with the potential capacity to significantly modify the course of the disease.DevelopmentClassic cerebrospinal fluid biomarkers and approved structural and functional neuroimaging have a limited clinical application given their invasive nature and/or high cost. The identification of more accessible and less costly biomarkers, such as blood biomarkers, would facilitate application in clinical practice. We present a literature review of the main blood biochemical biomarkers with potential use for diagnosing Alzheimer's disease.ConclusionsBlood biomarkers are cost and time effective with regard to cerebrospinal fluid biomarkers. However, the immediate applicability of blood biochemical biomarkers in clinical practice is not very likely. The main limitations come from the difficulties in measuring and standardising thresholds between different laboratories and in failures to replicate results. Among all the molecules studied, apoptosis and neurodegeneration biomarkers and the biomarker panels obtained through omics approaches, such as isolated or combined metabolomics, offer the most promising results. (AU)

Blood biomarkers in Alzheimer's disease.

INTRODUCTION: Early diagnosis of Alzheimer disease (AD) through the use of biomarkers could assist in the implementation and monitoring of early therapeutic interventions, and has the potential to significantly modify the course of the disease. DEVELOPMENT: The classic cerebrospinal fluid and approved structural and functional neuroimaging biomarkers are of limited clinical application given their invasive nature and/or high cost. The identification of more accessible and less costly biomarkers, such as blood biomarkers, would increase their use in clinical practice. We review the available published evidence on the main blood biochemical biomarkers potentially useful for diagnosing AD. CONCLUSIONS: Blood biomarkers are more cost- and time-effective than CSF biomarkers. However, immediate applicability in clinical practice is relatively unlikely. The main limitations come from the difficulty of measuring and standardising thresholds between different laboratories and the failure to replicate results. Of all the molecules studied, apoptosis and neurodegeneration biomarkers and the biomarker panels obtained through "omics" approaches, such as isolated or combined metabolomics, offer the most promising results.

Epigenetic changes in headache.

INTRODUCTION: Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target. METHODS: We performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA. RESULTS: A total of 15 English-language publications related to the above terms were obtained. CONCLUSION: There is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets.

Modificaciones epigenéticas en las cefaleas / Epigenetic changes in headache

Introducción: En las cefaleas parece existir una influencia multifactorial, tanto de mecanismos genéticos como ambientales, siendo interesante el estudio de la posible participación de mecanismos epigenéticos en su desarrollo, cronificación y potencial papel como diana terapéutica.MétodosHemos llevado a cabo una revisión bibliográfica, principalmente a través de la base de datos Medline/PubMed, de la implicación de los distintos mecanismos epigenéticos en las cefaleas. Para ello hemos utilizado los términos de búsqueda en inglés: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA y miRNA.ResultadosSe obtuvieron un total de 15 publicaciones en idioma inglés relacionadas con los términos anteriores.ConclusionesExisten indicios de la relación entre la epigenética y las cefaleas, siendo imprescindible, debido al reducido número de estudios, continuar con la investigación de las modificaciones epigenéticas en las cefaleas. Esto podría ayudar a comprender la fisiopatología de las cefaleas e incluso identificar biomarcadores y nuevas dianas terapéuticas más eficaces. (AU)

Introduction: Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target.MethodsWe performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA.ResultsA total of 15 English-language publications related to the above terms were obtained.ConclusionThere is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets. (AU)

Blood biomarkers in Alzheimer's disease. / Biomarcadores sanguíneos en la enfermedad de Alzheimer.

INTRODUCTION: The early diagnosis of Alzheimer's disease (AD) via the use of biomarkers could facilitate the implementation and monitoring of early therapeutic interventions with the potential capacity to significantly modify the course of the disease. DEVELOPMENT: Classic cerebrospinal fluid biomarkers and approved structural and functional neuroimaging have a limited clinical application given their invasive nature and/or high cost. The identification of more accessible and less costly biomarkers, such as blood biomarkers, would facilitate application in clinical practice. We present a literature review of the main blood biochemical biomarkers with potential use for diagnosing Alzheimer's disease. CONCLUSIONS: Blood biomarkers are cost and time effective with regard to cerebrospinal fluid biomarkers. However, the immediate applicability of blood biochemical biomarkers in clinical practice is not very likely. The main limitations come from the difficulties in measuring and standardising thresholds between different laboratories and in failures to replicate results. Among all the molecules studied, apoptosis and neurodegeneration biomarkers and the biomarker panels obtained through omics approaches, such as isolated or combined metabolomics, offer the most promising results.

Estudio comparativo de los niveles plasmáticos de homocisteína, vitamina B12 y ácido fólico en pacientes epilépticos frente a controles / Comparative case-control study of homocysteine, vitamin B12, and folic acid levels in patients with epilepsy

Introducción: El aumento de homocisteína en sangre constituye un conocido factor de riesgo cardiovascular. Los pacientes epilépticos en tratamiento crónico con fármacos antiepilépticos pueden presentar niveles más elevados de homocisteína y, en consecuencia, un potencial aumento del riesgo cardiovascular. Material y métodos: Estudio observacional de casos y controles para la comparación de los niveles plasmáticos de homocisteína, ácido fólico y vitamina B12. Resultados: Se reclutó a un total de 88 sujetos, 52 de ellos epilépticos y 36 controles. Se observó una tendencia a niveles de homocisteína más elevados (p=0,084) en los pacientes epilépticos y unos valores de ácido fólico más bajos (p<0,05). Conclusiones: Por su potencial efecto como factor de riesgo cardiovascular, es importante prestar atención a los niveles de homocisteína en los pacientes epilépticos en tratamiento crónico con fármacos antiepilépticos y en caso de encontrar niveles elevados sugerimos la instauración de tratamiento específico (AU)

Introduction: Increased blood homocysteine levels are a known cardiovascular risk factor. Epileptic patients on long-term treatment with antiepileptic drugs may present higher homocysteine levels and, consequently, a potential increase in cardiovascular risk. Material and methods: We conducted an observational case-control study to compare plasma levels of homocysteine, folic acid, and vitamin B12. Results: Our study included a total of 88 subjects: 52 patients with epilepsy and 36 controls. Epileptic patients showed higher homocysteine levels (P=.084) and lower levels of folic acid (P<.05). Conclusion: Homocysteine levels should be monitored in epileptic patients on long-term treatment with antiepileptic drugs. We suggest starting specific treatment in patients with high homocysteine levels (AU)

Modificaciones epigenéticas en neurología: alteraciones en la metilación del ADN en la esclerosis múltiple / Epigenetic changes in neurology: DNA methylation in multiple sclerosis

Introducción: La epigenética se define como el estudio de los mecanismos que regulan la expresión génica sin modificar la secuencia de ADN, siendo entre ellos el más conocido la metilación del ADN. La esclerosis múltiple (EM) es una enfermedad de etiología no del todo conocida, en la que se plantea que la participación de factores ambientales sobre individuos con una determinada predisposición genética, pueden resultar claves para el desarrollo de la enfermedad. Es en esta intersección entre la predisposición genética y los factores ambientales donde la metilación del ADN puede desempeñar un papel patogénico. Desarrollo: Realizamos una revisión bibliográfica de los efectos que los factores de riesgo ambiental para el desarrollo de EM pueden ejercer sobre los distintos mecanismos epigenéticos, así como la implicación que presentan dichas modificaciones en el desarrollo de la enfermedad. Conclusión: El conocimiento de las modificaciones epigenéticas involucradas en la patogenia de la EM abre una nueva vía de investigación para la identificación de potenciales biomarcadores, así como para la búsqueda de nuevas dianas terapéuticas (AU)

Introduction: Epigenetics is defined as the study of the mechanisms that regulate gene expression without altering the underlying DNA sequence. The best known is DNA methylation. Multiple Sclerosis (MS) is a disease with no entirely known etiology, in which it is stated that the involvement of environmental factors on people with a genetic predisposition, may be key to the development of the disease. It is at this intersection between genetic predisposition and environmental factors where DNA methylation may play a pathogenic role. Development: A literature review of the effects of environmental risk factors for the development of MS can have on the different epigenetic mechanisms as well as the implication that such changes have on the development of the disease. Conclusion: Knowledge of epigenetic modifications involved in the pathogenesis of MS, opens a new avenue of research for identification of potential biomarkers, as well as finding new therapeutic targets (AU)

Epigenetic changes in neurology: DNA methylation in multiple sclerosis. / Modificaciones epigenéticas en neurología: alteraciones en la metilación del ADN en la esclerosis múltiple.

INTRODUCTION: Epigenetics is defined as the study of the mechanisms that regulate gene expression without altering the underlying DNA sequence. The best known is DNA methylation. Multiple Sclerosis (MS) is a disease with no entirely known etiology, in which it is stated that the involvement of environmental factors on people with a genetic predisposition, may be key to the development of the disease. It is at this intersection between genetic predisposition and environmental factors where DNA methylation may play a pathogenic role. DEVELOPMENT: A literature review of the effects of environmental risk factors for the development of MS can have on the different epigenetic mechanisms as well as the implication that such changes have on the development of the disease. CONCLUSION: Knowledge of epigenetic modifications involved in the pathogenesis of MS, opens a new avenue of research for identification of potential biomarkers, as well as finding new therapeutic targets.

Comparative case-control study of homocysteine, vitamin B12, and folic acid levels in patients with epilepsy. / Estudio comparativo de los niveles plasmáticos de homocisteína, vitamina B12 y ácido fólico en pacientes epilépticos frente a controles.

INTRODUCTION: Increased blood homocysteine levels are a known cardiovascular risk factor. Epileptic patients on long-term treatment with antiepileptic drugs may present higher homocysteine levels and, consequently, a potential increase in cardiovascular risk. MATERIAL AND METHODS: We conducted an observational case-control study to compare plasma levels of homocysteine, folic acid, and vitamin B12. RESULTS: Our study included a total of 88 subjects: 52 patients with epilepsy and 36 controls. Epileptic patients showed higher homocysteine levels (P=.084) and lower levels of folic acid (P<.05). CONCLUSION: Homocysteine levels should be monitored in epileptic patients on long-term treatment with antiepileptic drugs. We suggest starting specific treatment in patients with high homocysteine levels.

Epigenética y epilepsia / Epigenetics and epilepsy

Introducción: La epigenética es el estudio de los cambios heredables en el ADN sin afectar a las secuencia de nucleótidos. Entre los mecanismos de regulación epigenética, los más estudiados y conocidos hasta la fecha son la metilación del ADN, la modificación de las histonas y los ARN no codificantes. Mediante estos mecanismos se regula la expresividad génica y la alteración de los mismos puede llevar al desarrollo de patologías. Desarrollo: Describimos los principales mecanismos de regulación epigenética y realizamos una revisión de la bibliografía reciente sobre los mecanismos de regulación epigenética y su implicación en distintos síndromes epilépticos. Conclusión: La identificación de los mecanismos epigenéticos implicados en la epilepsia constituye una prometedora vía de investigación para profundizar en el conocimiento de la fisiopatología y terapéutica de esta enfermedad

Introduction: Epigenetics is the study of heritable modifications in gene expression that do not change the DNA nucleotide sequence. Some of the most thoroughly studied epigenetic mechanisms at present are DNA methylation, post-transcriptional modifications of histones, and the effect of non-coding RNA molecules. Gene expression is regulated by means of these mechanisms and disruption of these molecular pathways may elicit development of diseases. Development: We describe the main epigenetic regulatory mechanisms and review the most recent literature about epigenetic mechanisms and how those mechanisms are involved in different epileptic syndromes. Conclusion: Identifying the epigenetic mechanisms involved in epilepsy is a promising line of research that will deliver more in-depth knowledge of epilepsy pathophysiology and treatments

Epigenetics and epilepsy.

INTRODUCTION: Epigenetics is the study of heritable modifications in gene expression that do not change the DNA nucleotide sequence. Some of the most thoroughly studied epigenetic mechanisms at present are DNA methylation, post-transcriptional modifications of histones, and the effect of non-coding RNA molecules. Gene expression is regulated by means of these mechanisms and disruption of these molecular pathways may elicit development of diseases. DEVELOPMENT: We describe the main epigenetic regulatory mechanisms and review the most recent literature about epigenetic mechanisms and how those mechanisms are involved in different epileptic syndromes. CONCLUSION: Identifying the epigenetic mechanisms involved in epilepsy is a promising line of research that will deliver more in-depth knowledge of epilepsy pathophysiology and treatments.

Biomarcadores plasmáticos en la enfermedad vascular cerebral isquémica / Plasma biomarkers in ischemic cerebral vascular disease

La utilización de biomarcadores plasmáticos está siendo cada vez más aceptada en la práctica clínica. En el caso del ictus isquémico, la determinación de diferentes moléculas que participan en la cascada isquémica o en los eventos moleculares subsiguientes, podría ser de gran utilidad diagnóstica, pronóstica y terapéutica. La respuesta inflamatoria desencadenada por la isquemia desempeña un papel destacado, asociándose las citocinas proinflamatorias (interleucina [IL]-1, IL-6 o factor de necrosis tumoral alfa) a un mayor daño cerebral y las anti-inflamatorias (IL-10) a un efecto neuroprotector. Las quimiocinas (IL-8, proteína quimiotáctica de monocitos 1 [MCP-1]) y las moléculas de adhesión (molécula de adhesión intercelular, molécula de adhesión a la célula vascular, molécula de adhesión leucocitaria endotelial, Antígeno asociado a función de linfocitos 1 [LFA-1]) responsables del reclutamiento y adhesión de leucocitos, que liberan diversas proteasas en la zona afectada, también juegan un papel en el ictus isquémico.La identificación de predictores de transformación hemorrágica tras el tratamiento trombolítico es de gran relevancia, puesto que el riesgo de hemorragia todavía limita la aplicación de activador tisular del plasminógeno (t-PA) en la práctica. En este sentido, las MMP (matrix metalloproteinases ‘metaloproteinasas de la matriz’) son moléculas clave, puesto que participan en la degradación de la lámina basal, y se ha demostrado que el t-PA es capaz de activar la MMP-9 «in vivo» en modelos animales y se ha encontrado sobreexpresión de la MMP-9 en zonas de transformación hemorrágica en cerebros humanos. Otras moléculas, como la fibronectina y los inhibidores endógenos de la fibrinolisis (inhibidor de la fibrinolisis activable por trombina, inhibidor del activador del plasminógeno tipo 1) podrían servir también para predecir la transformación hemorrágica.(.. ) (AU)

Use of plasma biomarkers is gathering increasing more acceptance in the clinical practice. In the case of ischemic stroke, measurement of some molecules involved in the ischemic cascade or in the subsequent molecular events could prove to have great diagnostic, prognostic and therapeutic utility. The ischemia-related inflammatory response plays an important main role, since pro-inflammatory cytokines (IL-1, IL-6 or TNF-á) are associated with brain damage and anti-inflammatory cytokines (IL-10) seem to be associated to a neuroprotective effect. In addition, chemokines (IL-8, MCP-1) and cell adhesion molecules (ICAM-1, VCAM-1, ELAM-1, LFA-1), which are involved in leukocyte recruitment, that may release proteases in the injured area, also play a role in ischemic stroke.Identifying predictors of hemorrhagic transformation after thrombolytic therapy is also very important in the field, since risk of brain hemorrhaging still limits the use of t-PA treatments. In this sense, matrix metalloproteinases (MMPs) are key molecules involved in basal lamina degradation that are activated by t-PA “in vivo” in animal models and are over-expressed in human brain hemorrhagic areas. Moreover, other markers such as fibronectin and endogenous fibrinolysis inhibitors (TAFI, PAI-1) might be useful hemorrhagic predictors as well.Use of several of these potential plasmatic biomarkers might be incorporated into daily clinical practice in the near future in order to improve diagnosis, prognosis and therapeutic decisions in ischemic stroke(AU)

[Analysis of gait and movement of upper limbs in muscular dystrophies]. / Análisis de la marcha y del movimiento de las extremidades superiores en distrofias musculares.

INTRODUCTION: The objective is to analyze gait and upper extremity movement in a sample of healthy individuals and patients with different muscular dystrophies and to determine the relationship of the obtained variables with the pattern of muscular involvement. SUBJECTS AND METHODS: Gait and upper limb movement was analyzed with a three-dimensional photogrammetry system. Convenience sample of 28 healthy volunteers, 40 patients with myotonic dystrophy (MD), 9 patients with facioscapulohumeral dystrophy (FSHD) and 14 patients with limb-girdle muscular dystrophy type 2A (LGMD2A). Spatio-temporal and kinematic variables were analyzed. RESULTS: Patients had lower velocity, cadence and shorter stride duration than healthy subjects. Gait and upper extremity kinematic variables suggested proximal muscular involvement in LGMD2A patients and distal muscular abnormalities in MD patients. The most characteristic finding in FSHD patients was related with dorsiflexor muscles' weakness. Some of the variables were also correlated to the patients' functional stage. CONCLUSIONS: This analysis allows the distinction of kinematic and spatio-temporal patterns of gait and upper extremity movement that correlate with muscular dystrophy's phenotype. The use of this analysis in the clinical setting to assess disease progression or the potential effects of treatments requires further studies.

Análisis de la marcha y del movimiento de las extremidades superiores en distrofias musculares / Analysis of gait and movement of upper limbs in muscular dystrophies

Introducción. El objetivo del estudio es analizar y comparar la marcha y el movimiento de las extremidades superiores en una muestra de individuos sanos y con diferentes tipos de distrofias musculares y determinar la relación entre las variables obtenidas y el patrón de afectación muscular. Pacientes y métodos. Se analizó la marcha y el movimiento de las extremidades superiores a través de un sistema de fotogrametria tridimensional a una muestra de 28 voluntarios sanos, 40 pacientes con distrofia miotónica (DM). 9 pacientes con distrofia facioescapulohumeral (DMFEH) y 14 pacientes con distrofia muscular de cinturas tipo 2A (LGM02A). Se analizaron variables espacio-temporales y cinemáticas. Resultados. Los pacientes presentaron una menor velocidad, cadencia y menor duración de la zancada que los sujetos sanos. Las variables cinemáticas se correlacionaron con una afectación muscular proximal en los pacientes con LGM02A y con anomalías en la musculatura distal en pacientes con OM. Los hallazgos más característicos en los pacientes con OMFEH se relacionaron con una debilidad de la musculatura dorsiflexora del pie. Se encontró también correlación entre la alteración de algunas variables y el estadio funcional de los pacientes. Conclusiones. Este análisis permite establecer una correlación entre las alteraciones de las variables espaciotemporales y cinemáticas de la marcha y el movimiento de los miembros superiores y el fenotipo de cada una de las distrofias musculares examinadas. La utilización de este análisis en la práctica clínica para evaluar la progresión de la enfermedad o los efectos potenciales de diferentes intervenciones requiere estudios adicionales

Introduction. The objective is to analyze gait and upper extremity movement in a sample of healthy individuals and patients with different muscular dystrophies and to determine the relationship of the obtained variables with the pattern of muscular involvement. Subjects and methods. Gait and upper limb movement was analyzed with a three-dimensional phtogrammetry system. Convenience sample of 28 healthy volunteers, 40 patients with myotonic dystrophy (MD), 9 patients with facioscapulohumeral dystrophy (FSHD) and 14 patients with limb-girdle muscular dystrophy type 2A (LGMD2A). Spatio-temporal and kinematic variables were analyzed. Results. Patients had lower velocity, cadence and shorter stride duration than healthy subjects. Gait and upper extremity kinematic variables suggested proximal muscular involvement in LGMD2A patients and distal muscular abnormalities in MD patients. The most characteristic finding in FSHD patients was related with dorsiflexor muscles' weakness. Some of the variables were also correlated to the patients' functional stage. Conclusions. This analysis allows the distinction of kinematic and spatio-temporal patterns of gait and upper extremity movement that correlate with muscular dystrophy's phenotype. The use of this analysis in the clinical setting to assess disease progression or the potential effects of treatments requires further studies