Efficacy of andrographolide in not active progressive multiple sclerosis: a prospective exploratory double-blind, parallel-group, randomized, placebo-controlled trial.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune mediated disease and the progressive phase appears to have significant neurodegenerative mechanisms. The classification of the course of progressive MS (PMS) has been re-organized into categories of active vs. not active inflammatory disease and the presence vs. absence of gradual disease progression. Clinical trial experience to date in PMS with anti-inflammatory medications has shown limited effect. Andrographolide is a new class of anti-inflammatory agent, that has been proposed as a potential drug for autoimmune disorders, including MS. In the present trial, we perform an exploratory pilot study on the efficacy and safety of andrographolide (AP) compared to placebo in not active PMS. METHODS: A pilot clinical trial using 140 mg oral AP or placebo twice daily for 24 months in patients with not active primary or secondary progressive MS was conducted. The primary efficacy endpoint was the mean percentage brain volume change (mPBVC). Secondary efficacy endpoints included 3-month confirmed disability progression (3-CDP) and mean EDSS change. RESULTS: Forty-four patients were randomized: 23 were assigned to the AP group, and 21 were assigned to the placebo group. The median baseline EDSS of both groups was 6.0. Annualized mPBVC was - 0.679% for the AP group and - 1.069% for the placebo group (mean difference: -0.39; 95% CI [- 0.836-0.055], p = 0.08, relative reduction: 36.5%). In the AP group, 30% had 3-CDP compared to 41% in the placebo group (HR: 0.596; 95% CI [0.200-1.777], p = 0.06). The mean EDSS change was - 0.025 in the AP group and + 0.352 in the placebo group (mean difference: 0.63, p = 0.042). Adverse events related to AP were mild rash and dysgeusia. CONCLUSIONS: AP was well tolerated and showed a potential effect in reducing brain atrophy and disability progression, that need to be further evaluated in a larger clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT02273635 retrospectively registered on October 24th, 2014.

Autism spectrum disorder: Clinical diagnosis and ADOS Test. / Trastorno del espectro autista: Diagnóstico clínico y test ADOS.

INTRODUCTION: Autism Spectrum Disorder (ASD) is a neurobiological disorder of high prevalence, whose clinical diagnosis is a constant challenge. OBJECTIVES: To describe the clinical profile in a co hort of children with ASD from referral to the specialist to a diagnostic test. PATIENTS AND METHOD: Descriptive study from the first symptoms perceived by the mother to the diagnostic confirmation of a series of 50 consecutive cases, which were clinically diagnosed with ASD between 2012 and 2016. Children aged between 3 to 10 years at the time of the ADOS-G test and language of at least one word were included. The children were evaluated neuropsychologically (functionality, intellectuality and ADOS test). We compared the median age to the neurological diagnosis, according to the autistic symptomatology and cognitive level. RESULTS: The ADOS test corroborated an ASD in 44 children (88%), 93.1% were males. The average age at clinical diagnosis and ADOS test was 48.2 ± 19.3 and 62.6 ± 23.3 months. The neurological consultation in 72% of cases was parental/educator initiative due to symptoms such as social interaction disorder and language delay. The autistic symptomato logy was mild, moderate and severe in 34.1, 47.7 and 18.2% respectively. In five of 27 children who were neuropsychologically evaluated cognitive deficits were detected. The median age at diagnosis was significantly lower in children with severe autism symptoms vs the ones with mild-moderate symptoms (p-value 0.024). CONCLUSION: Autistic symptoms determine the early consultation; the refore, it is necessary to guide the general and educational population as well as health professionals regarding these symptoms.

Regional brain atrophy is related to social cognition impairment in multiple sclerosis.

BACKGROUND: Multiple sclerosis exhibits specific neuropathological phenomena driving to both global and regional brain atrophy. At the clinical level, the disease is related to functional decline in cognitive domains as the working memory, processing speed, and verbal fluency. However, the compromise of social-cognitive abilities has concentrated some interest in recent years despite the available evidence suggesting the risk of disorganization in social life. Recent studies have used the MiniSEA test to assess the compromise of social cognition and have found relevant relationships with memory and executive functions, as well as with the level of global and regional brain atrophy. OBJECTIVE: The present article aimed to identify structural changes related to socio-cognitive performance in a sample of patients with relapsing-remitting multiple sclerosis. METHODS: 68 relapsing-remitting multiple sclerosis Chilean patients and 50 healthy control subjects underwent MRI scans and neuropsychological evaluation including social-cognition tasks. Total brain, white matter, and gray matter volumes were estimated. Also, voxel-based morphometry was applied to evaluate regional structural changes. RESULTS: Patients exhibited lower scores in all neuropsychological tests. Social cognition exhibited a significant decrease in this group mostly related to the declining social perception. Normalized brain volume and white matter volume were significantly decreased when compared to healthy subjects. The regional brain atrophy analysis showed that changes in the insular cortex and medial frontal cortices are significantly related to the variability of social-cognitive performance among patients. CONCLUSIONS: In the present study, social cognition was only correlated with the deterioration of verbal fluency, despite the fact that previous studies have reported its link with memory and executive functions. The identification of specific structural correlates supports the comprehension of this phenomenon as an independent source of cognitive disability in these patients.

Social cognition in Multiple Sclerosis is associated to changes in brain connectivity: A resting-state fMRI study.

BACKGROUND: Multiple Sclerosis produces changes in the functional connectivity of the brain. Resting-State fMRI is a useful tool for the study of functional changes in the human brain, and its metrics can be related to clinical findings involved in clinical decline. Social cognition has focused increasing interest because patients are exposed to experiencing social disorganization during the progression of the disease. fMRI has proved to be a useful tool for studying brain connectivity and its relation with social cognition both in resting-state and during socio-cognitive tasks. OBJECTIVE: to identify functional changes during rest in Relapsing-Remitting Multiple Sclerosis patients and look for a correlation with social cognition. METHODS: 45 patients with Relapsing-Remitting Multiple Sclerosis and 47 control subjects were recruited to perform a neuropsychological evaluation of the social cognition performance and to acquire resting-state fMRI. RESULTS: Patients exhibited lower performance in social cognition tasks, mostly related to face emotion recognition. Decreased functional connectivity in patients is seen concerning the right anterior insula, middle frontal, and occipital regions while increased connectivity is mostly related to the occipital and visual areas. The connectivity of the fusiform cortex and the amygdala is related to the performance in emotion recognition and Theory of Mind tasks respectively. CONCLUSION: Social cognition compromise was found in this sample. Functional connectivity changes during rest were detected and correlated with social cognition changes in patients.

Frontoparietal connectivity correlates with working memory performance in multiple sclerosis.

Working Memory (WM) impairment is the most common cognitive deficit of patients with Multiple Sclerosis (MS). However, evidence of its neurobiological mechanisms is scarce. Here we recorded electroencephalographic activity of twenty patients with relapsing-remitting MS and minimal cognitive deficit, and 20 healthy control (HC) subjects while they solved a WM task. In spite of similar performance, the HC group demonstrated both a correlation between temporoparietal theta activity and memory load, and a correlation between medial frontal theta activity and successful memory performances. MS patients did not show theses correlations leading significant differences between groups. Moreover, cortical connectivity analyses using granger causality and phase-amplitude coupling between theta and gamma revealed that HC group, but not MS group, presented a load-modulated progression of the frontal-to-parietal connectivity. This connectivity correlated with working memory capacity in MS groups. This early alterations in the oscillatory dynamics underlaying working memory could be useful for plan therapeutic interventions.

Corpus callosum atrophy and post-surgical seizures in temporal lobe epilepsy associated with hippocampal sclerosis.

OBJECTIVE: Our aim in this retrospective study was to explore whether corpus callosum atrophy could predict the post-surgical seizure control in patients with temporal lobe epilepsy associated with Hippocampal Sclerosis (HS). METHODS: We used the Corpus Callosum Index (CCI) obtained from best mid-sagittal T2/FLAIR or T1-weighted MRI at two time-points, more than one year apart. CCI has been mainly used in Multiple Sclerosis (MS), but not in epilepsy, so we tested the validity of our results performing a proof of concept cohort, incorporating MS patients with and without epilepsy. Then, we explored this measurement in a well-characterized and long-term cohort of patients with temporal lobe epilepsy associated with HS. RESULTS: In the proof of concept cohort (MS without epilepsy n:40, and MS with epilepsy, n:15), we found a larger CCI atrophy rate in MS patients with poor epilepsy control vs. MS without epilepsy (p:0.01). Then, in HS patients (n:74), annualized CCI atrophy rate was correlated with the long-term Engel scale (Rho:0.31, p:0.007). In patients with post-surgical seizure recurrence, a larger CCI atrophy rate was found one year before any seizure relapse. Univariate analysis showed an increased risk of seizure recurrence in males, higher pre-surgical seizure frequency, necessity of invasive EEG monitoring, and higher CCI atrophy rate. Two of these variables were independent predictors in the multivariate analysis, male gender (HR:4.87, p:0.002) and CCI atrophy rate (HR:1.21, p:0.001). CONCLUSION: We demonstrated that atrophy of the corpus callosum, using the CCI, is related with poor seizure control in two different neurological disorders presenting with epilepsy, which might suggest that corpus callosum atrophy obtained in early post-surgical follow-up, could be a biomarker for predicting recurrences and guiding treatment plans.

Regional brain atrophy is related to social cognition impairment in multiple sclerosis / La atrofia cerebral regional se relaciona con el deterioro de la cognición social en sclerosis múltiple

ABSTRACT Background: Multiple sclerosis exhibits specific neuropathological phenomena driving to both global and regional brain atrophy. At the clinical level, the disease is related to functional decline in cognitive domains as the working memory, processing speed, and verbal fluency. However, the compromise of social-cognitive abilities has concentrated some interest in recent years despite the available evidence suggesting the risk of disorganization in social life. Recent studies have used the MiniSEA test to assess the compromise of social cognition and have found relevant relationships with memory and executive functions, as well as with the level of global and regional brain atrophy. Objective: The present article aimed to identify structural changes related to socio-cognitive performance in a sample of patients with relapsing-remitting multiple sclerosis. Methods: 68 relapsing-remitting multiple sclerosis Chilean patients and 50 healthy control subjects underwent MRI scans and neuropsychological evaluation including social-cognition tasks. Total brain, white matter, and gray matter volumes were estimated. Also, voxel-based morphometry was applied to evaluate regional structural changes. Results: Patients exhibited lower scores in all neuropsychological tests. Social cognition exhibited a significant decrease in this group mostly related to the declining social perception. Normalized brain volume and white matter volume were significantly decreased when compared to healthy subjects. The regional brain atrophy analysis showed that changes in the insular cortex and medial frontal cortices are significantly related to the variability of social-cognitive performance among patients. Conclusions: In the present study, social cognition was only correlated with the deterioration of verbal fluency, despite the fact that previous studies have reported its link with memory and executive functions. The identification of specific structural correlates supports the comprehension of this phenomenon as an independent source of cognitive disability in these patients.

RESUMEN Antecedentes: La esclerosis múltiple presenta fenómenos neuropatológicos específicos que conducen a la atrofia cerebral global y regional. A nivel clínico, la enfermedad está relacionada con el deterioro funcional de los dominios cognitivos como la memoria de trabajo, la velocidad de procesamiento y la fluidez verbal. Sin embargo, el compromiso de las habilidades socio-cognitivas ha concentrado cierto interés en los últimos años debido a la evidencia disponible que sugiere el riesgo de desorganización en la vida social. Estudios recientes han utilizado la prueba MiniSEA para evaluar el compromiso de la cognición social y han encontrado relaciones relevantes con la memoria y funciones ejecutiva, así como con el nivel de atrofia cerebral global y regional. Objetivo: El presente artículo tiene como objetivo identificar cambios estructurales relacionados con el rendimiento sociocognitivo en una muestra de pacientes con esclerosis múltiple recurrente-remitente. Métodos: 68 pacientes Chilenos con esclerosis múltiple recurrente-remitente y 50 sujetos de control sanos se sometieron a resonancias magnéticas y evaluación neuropsicológica, incluidas las tareas de cognición social. Se estimaron los volúmenes cerebrales totales, de materia blanca y materia gris. Además, se aplicó la morfometría basada en vóxel para evaluar los cambios estructurales regionales. Resultados: Los pacientes muestran puntuaciones más bajas en todas las pruebas neuropsicológicas. La cognición social exhibe una disminución significativa en este grupo principalmente relacionada con la disminución de la percepción social. El volumen normalizado del cerebro y el volumen de la materia blanca disminuyeron significativamente en comparación con los sujetos sanos. El análisis regional de atrofia cerebral mostró que los cambios en la corteza insular y la corteza frontal medial están significativamente relacionados con la variabilidad del rendimiento sociocognitivo entre los pacientes. Conclusiones: En el presente estudio, la cognición social sólo se correlacionó con el deterioro de la fluencia verbal, a pesar de que estudios previos han reportado su vinculación con la memoria y funciones ejecutivas. La identificación de correlatos estructurales específicos apoya la comprensión de este fenómeno como una fuente independiente de discapacidad cognitiva en estos pacientes.

Trastorno del espectro autista: diagnóstico clínico y test ADOS / Autism spectrum disorder: clinical diagnosis and ADOS Test

INTRODUCCIÓN: El trastorno del espectro autista (TEA) es un desorden neurobiológico altamente prevalente, cuyo diagnóstico clínico es un desafío constante. OBJETIVOS: Describir el perfil clínico, en una cohorte de niños con TEA desde su derivación al especialista hasta la realización de un test diagnóstico. PACIENTES Y MÉTODO: Estudio descriptivo desde los primeros síntomas pesquisados por la madre, hasta la certificación diagnóstica de una serie de 50 niños, diagnosticados clínicamente con TEA entre 2012-2016. Se incluyeron niños de 3 a 10 años al momento del Test ADOS-G, con lenguaje de al menos una palabra. Los niños fueron evaluados neuropsicológicamente (funcionali dad, intelectualidad y test ADOS). Comparamos las medianas de edad al diagnóstico neurológico, según carga de sintomatología autista y nivel cognitivo. RESULTADOS: El test ADOS corroboró un TEA en 44 niños (88%), 93,1% eran varones. La edad promedio al diagnóstico clínico y test ADOS fue 48,2 ± 18,3 y 62,6 ± 23,3 meses. La consulta neurológica en el 72% de los casos fue motivación parental/educador por síntomas como trastorno interacción social y retraso de lenguaje. El 34,1; 47,7 y 18,2% tenían sintomatología autista leve, moderada y severa respectivamente. En 5 de 27 ni ños en los que se realizó la evaluación neuropsicológica se detectó déficit cognitivo. La mediana de edad al diagnóstico fue significativamente menor en niños con sintomatología autista grave vs leve- moderada (p 0,024). CONCLUSIÓN: La sintomatología autista determina la precocidad de consulta, por lo que es necesario orientar a la población general, educadores y personal de salud, respecto a estos síntomas.

INTRODUCTION: Autism Spectrum Disorder (ASD) is a neurobiological disorder of high prevalence, whose clinical diagnosis is a constant challenge. OBJECTIVES: To describe the clinical profile in a co hort of children with ASD from referral to the specialist to a diagnostic test. PATIENTS AND METHOD: Descriptive study from the first symptoms perceived by the mother to the diagnostic confirmation of a series of 50 consecutive cases, which were clinically diagnosed with ASD between 2012 and 2016. Children aged between 3 to 10 years at the time of the ADOS-G test and language of at least one word were included. The children were evaluated neuropsychologically (functionality, intellectuality and ADOS test). We compared the median age to the neurological diagnosis, according to the autistic symptomatology and cognitive level. RESULTS: The ADOS test corroborated an ASD in 44 children (88%), 93.1% were males. The average age at clinical diagnosis and ADOS test was 48.2 ± 19.3 and 62.6 ± 23.3 months. The neurological consultation in 72% of cases was parental/educator initiative due to symptoms such as social interaction disorder and language delay. The autistic symptomato logy was mild, moderate and severe in 34.1, 47.7 and 18.2% respectively. In five of 27 children who were neuropsychologically evaluated cognitive deficits were detected. The median age at diagnosis was significantly lower in children with severe autism symptoms vs the ones with mild-moderate symptoms (p-value 0.024). CONCLUSION: Autistic symptoms determine the early consultation; the refore, it is necessary to guide the general and educational population as well as health professionals regarding these symptoms.