Relación entre las alteraciones estructurales y el deterioro cognitivo en pacientes con Esclerosis Múltiple

Setzenes Jornades de Foment de la Investigació (Any 2011)Las causas del deterioro cognitivo en los pacientes de Esclerosis Múltiple (EM) son todavía desconocidas, así como la relación entre dicho deterioro y el daño cerebral observado con distintas técnicas de adquisición y análisis de neuroimagen. Objetivos Observar la distribución de la atrofia en sustancia gris y blanca en pacientes de EM con Deterioro Cognitivo (DC) y Sin Deterioro Cognitivo (SDC), así como su relación con variables clínicas y cognitivas Pacientes y métodos Se reclutaron para el estudio a 22 participantes control (edad= 32,22 +6,24) y a 75 pacientes diagnosticados de EM (edad= 40,06 +10,01). Todos los participantes fueron valorados con la Batería Neuropsicológica Breve (BNB) especifica para valorar deterioro cognitivo en EM. Los pacientes fueron seleccionados en dos grupos: 1) DC: los que presentaban al menos 1 test de la batería por debajo de 2 DT (n=41); 2) SDC: rendimiento normal en pruebas neuropsicológicas (n=34). Posteriormente se adquirieron los datos morfométricos de todos los participantes en una Resonancia Magnética Siemens Avanto 1.5 T. Se obtuvieron parámetros de volumen en sustancia blanca y gris utilizando el programa de análisis Diffeomorphic Anatomical Registrations Through Exponentiated Lie Algebra (DARTEL). Resultados Los pacientes con DC muestran un menor rendimiento cognitivo en todas las pruebas neuropsicológicas. Estos pacientes también muestran más atrofia en distintas zonas corticales y subcorticales tanto en sustancia blanca como en sustancia gris respecto al grupo control y respecto al grupo de pacientes SDC. Finalmente, se observa una relación entre el rendimiento neuropsicológico en distintas pruebas cognitivas y la atrofia en sustancia gris en el grupo de pacientes con DC. Conclusiones: Se observa en pacientes de EM con DC un mayor grado de atrofia así como una consistente relación entre la atrofia en sustancia gris y rendimiento en pruebas neuropsicológicas

Cambios estructurales y funcionales del hipocampo en pacientes con esclerosis múltiple y su relación con procesos de memoria

Introducción. Una de las alteraciones cognitivas más prevalentes en los pacientes con esclerosis múltiple son los proble- mas de codificación de la información (tanto verbal como visual), proceso relacionado con el hipocampo. Objetivo. Estudiar la relación entre los procesos de aprendizaje y retención de la información a largo plazo con el volumen hipocampal y la conectividad funcional (CF) en pacientes con esclerosis múltiple comparados con un grupo control. Sujetos y métodos. Ambos grupos fueron evaluados con la batería neuropsicológica breve, que incluye pruebas de me- moria verbal y visual. Se realizó el estudio de volumetría de la sustancia gris mediante la técnica de morfometría basada en el vóxel y un estudio de CF de vóxel de semilla centrado en la zona de interés (hipocampo). Se realizaron análisis de asociación entre rendimiento en memoria y cambios volumétricos y de CF. Resultados. Los resultados mostraron atrofia en la sustancia gris en el hipocampo izquierdo y una menor CF entre el hipo- campo izquierdo y el troncoencéfalo, el cerebelo, el giro fusiforme y el giro temporal superior en los pacientes respecto al grupo control. En el grupo de pacientes se observa una correlación positiva entre la sustancia gris en ambos hipocampos y el rendimiento en memoria verbal, así como una correlación positiva entre el rendimiento en memoria visual y la CF entre el hipocampo izquierdo y diversas regiones temporales. Conclusiones. Los resultados muestran una relación entre el rendimiento de memoria verbal y visual, y cambios estructu- rales y funcionales en el hipocampo en pacientes con esclerosis múltiple.Introduction. One of the most prevalent cognitive deficits in multiple sclerosis (MS) patients relates to (both verbal and visual) information encoding, a process related the hippocampus. Aim. To assess the relationship between information learning and long-term retention processes and hippocampal volume and functional connectivity (FC) in MS patients. Subjects and methods. MS patients and a control group of healthy volunteers were assessed using the brief neuro- psychological battery, which includes tests of verbal and visual memory. Gray matter volume was assessed through the voxel based morphometry technique, and a study of seed-based FC focused on the region of interest (hippocampus) was also conducted. Results. Results revealed that, as compared to the control group, MS patients display gray matter atrophy at the left hippocampus gray matter and smaller FC between left hippocampus and brainstem, cerebellum, fusiform gyrus and superior temporal gyrus. Association analyses were performed between memory tests performance and both volumetric and FC changes. Results showed a positive correlation between gray matter hippocampal (bilateral) volume and verbal memory performance of the MS group. Further, in MS patients, a positive correlation between visual memory performance and FC between the left hippocampus and several temporal regions was also found. Conclusions. The results of the present study reveal a relationship between structural and functional changes in the hippocampus of MS patients and their performance on verbal and visual memory tests.Subvención concedida por la Universitat Jaume I (P1.1B2014-05)

Hippocampal dysfunction is associated with memory impairment in multiple sclerosis: A volumetric and functional connectivity study

BACKGROUND: Previous studies have suggested a relationship between neuroanatomical and neurofunctional hippocampal alterations and episodic memory impairments in multiple sclerosis (MS) patients OBJECTIVE: We examined hippocampus volume and functional connectivity (FC) changes in MS patients with different episodic memory capabilities. METHODS: hippocampal subfield volume and FC changes were compared in two subgroups of MS patients with and without episodic memory impairment (MSi and MSp, respectively) and healthy controls. A discriminant function (DF) analysis was used to identify which of these neuroanatomical and neurofunctional parameters were the most relevant components of the mnemonic profiles of HC, MSp and MSi. RESULTS: MSi showed reduced volume in several hippocampal subfields compared to MSp and HC. Ordinal gradation (MSi>MSp>HC) was also observed for FC between the posterior hippocampus and several cortical areas. DF-based analyses revealed that reduced right fimbria volume and enhanced FC at the right posterior hippocampus were the main neural signatures of the episodic memory impairments observed in the MSi group. CONCLUSIONS: Before any sign of episodic memory alterations (MSp), FC increased on several pathways that connect the hippocampus with cortical areas. These changes further increased when the several hippocampal volumes reduced and memory deficits appeared (MSi).This study was sponsored by grants P1-1B2014-15 awarded by Universitat Jaume I and PSI2015-67285-R awarded by MINECO to Dr. Cristina For

Increased regional gray matter atrophy and enhanced functional connectivy in male multiple sclerosis patients

Evidence suggests that sex/gender is an important factor for understanding multiple sclerosis (MS) and that some of its neuropathological consequences might manifest earlier in males. In the present study, we assessed gray matter (GM) volume and functional connectivity (FC) in a sample of female and male MS patients (MSp) and female and male healthy controls (HCs). As compared to female MSp, male MSp showed decreased GM volume in the bilateral frontal areas and increased FC between different brain regions. Because both sets of changes correlated significantly and no differences in cognitive performance were observed, we suggest that the FC increase observed in male MSp acts as a compensatory mechanism for their more extensive GM loss and that it promotes a functional convergence between male- and female-MSp.This research has been supported by grant P1-1B2014-15 provided to Cristina Forn by the Universitat Jaume I

Information-processing speed is the primary deficit underlying the poor performance of multiple sclerosis patients in the Paced Auditory Serial Addition Test (PASAT)

The aims of this study were to determine which cognitive domains are evaluated by the Paced Auditory Serial Addition Test (PASAT) and to identify which of them are responsible for the poorer performance displayed by multiple sclerosis (MS) patients in this task. A total of 30 healthy controls and 30 MS patients completed the PASAT task as well as the different tests contained in the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), some Wechsler Adult Intelligence Scale (WAIS-III) subtests, the Spanish version of the Chicago Multiscale Depression Inventory (CMDI), and a new PASAT-based task (ADD1) that was specifically designed for this study. Analysis of covariance and regression-based analyses were performed to identify the predictors that are most strongly associated with the PASAT scores and the between-groups differences in the performance of this task. PASAT execution was associated with scores of the Digit Backward test, Symbol Digit Modality Test (SDMT), and measures of working memory and information-processing speed. On the other hand, differences between healthy volunteers and MS patients were mainly associated with the SDMT scores. MS patients also exhibited poorer execution than controls in the ADD1 task. Our results suggest that reduced information-processing speed (and not working memory) is the primary alteration underlying the lower scores in the PASAT task (and probably other cognitive deficits) that characterize MS patients. Based on these results, we suggest that tests that capitalize the role of information-processing speed may be of special relevance in the neuropsychological assessment of this clinical population

The link between resting-state functional connectivity and cognition in MS patients

Background/Objective: The objective of this paper is to explore differences in resting-state functional connectivity between cognitively impaired and preserved multiple sclerosis (MS) patients. Methods: Sixty MS patients and 18 controls were assessed with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). A global Z score of the BRB-N was obtained and allowed us to classify MS patients as cognitively impaired and cognitively preserved (n = 30 per group). Functional connectivity was assessed by independent component analysis of resting-state networks (RSNs) related to cognition: the default mode network, left and right frontoparietal and salience network. Between-group differences were evaluated and a regression analysis was performed to describe relationships among cognitive status, functional connectivity and radiological variables. Results: Compared to cognitively preserved patients and healthy controls, cognitively impaired patients showed a lesser degree of functional connectivity in all RSNs explored. Cognitively preserved patients presented less connectivity than the control group in the left frontoparietal network. Global Z scores were positively and negatively correlated with brain parenchymal fraction and lesion volume, respectively. Conclusion: Decreased cognitive performance is accompanied by reduced resting state functional connectivity and directly related to brain damage. These results support the use of connectivity as a powerful tool to monitor and predict cognitive impairment in MS patients

Gray matter atrophy is associated with funcional connectivity reorganization during the Pasat Auditory Serial Addition Test (PASAT) execution in Multiple Sclerosis (MS)

Background and purpose: We explored the relationship between gray matter atrophy and reorganization of functional connectivity in multiple sclerosis patients during execution of the Paced Auditory Serial Addition Test (PASAT). Materials and methods: Seventeen patients and 15 healthy controls were selected for the study. Atrophy was determined using voxel-based morphometry, and atrophy-related connectivity changes were assessed using psychophysiological interaction analysis. Group differences, and correlations with PASAT performance and radiological variables were also examined. Results: Gray matter atrophy in MS patients was circumscribed to the bilateral posterior cingulate gyrus/precuneus. Compared with controls, patients showed stronger connectivity between the left posterior cingulate gyrus/precuneus, and the left middle temporal gyrus and left cerebellum. A regression analysis in controls showed a negative correlation between PASAT scores and functional connectivity between: (1) the left posterior cingulate gyrus/precuneus, and left pre/postcentral gyri and left occipital gyrus, and (2) the right posterior cingulate gyrus/precuneus, and bilateral cerebellum and left pre/postcentral gyri. Patients showed a negative correlation between brain parenchymal fraction and functional connectivity between the left posterior cingulate gyrus/precuneus and left cerebellum. Conclusion: Patients with early MS and little brain damage presented more connectivity during PASAT execution, which may be interpreted as compensatory processes that help preserve cognitive functions.This work was supported by the Brainglot project of the CONSOLIDER-INGENIO 2010 Program (grant number CSD2007-00012), a grant from MINECO (PSI2010-20168), a grant from Universitat Jaume I (P1 · 1B2011-09), and an edu- cational grant from Biogen Idec to CA

A comparison of brain activation patterns during covert and overt paced auditory serial addition test tasks

The Paced Auditory Serial Addition test (PASAT) is a sensitive task for evaluating cognitive impairment in patients with diffuse brain disorders, such as multiple sclerosis patients. Brain areas involved in this task have been investigated in diverse fMRI studies using different methodologies to control the subjects' responses during scanning. Here, we examined the possible differences between overt and covert responses during the PASAT task in 13 volunteers. Results showed similar activations in parietal and frontal brain areas during both versions of the task. The contrast between the two conditions (overt and covert) indicated that differences in these two methodologies were minimal. Unlike the covert condition, the overt version of the task obtained significant activations in the left superior and inferior frontal gyrus, bilateral occipital cortex, caudate nucleus and cerebellum. As expected, no significant overactivations were observed in the covert when compared with the overt condition. Discussion focuses on the lower cost of using verbal responses to monitor performance during the PASAT task, which might be generalisable to other frontal lobe tasks requiring discrete responses

Anatomical and functional differences between the Paced Auditory Serial Addition Test and the Symbol Digit Modalities Test

The Paced Auditory Serial Addition Test (PASAT) and the Symbol Digit Modalities Test (SDMT) are generally used to detect cognitive impairments in multiple sclerosis patients. Although both seem to be sensitive to the slow information-processing speed, some results suggest that they do not involve the same cognitive functions. The aim of the present study is to observe possible differences between these tasks to help understand their utility to cognitive assessment. A total of 17 participants were recruited for the study and completed a block-design version of each task. Comparisons between tasks were calculated using an analysis of variance (ANOVA; p < .05, familywise error, FWE, corrected). We observed activations in the left frontal and parietal areas during both tasks; however, the PASAT activated more frontal areas than did the SDMT. These tasks require an efficient transfer of information among large areas. Moreover, the PASAT requires more executive functions to be executed

A critical analysis of neuroimaging studies in relation to cognitive performance in multiple sclerosis patients

El estudio y comprensión del deterioro cognitivo en los pacientes de esclerosis múltiple (EM) resulta esencial para entender esta enfermedad. El uso de las técnicas de neuroimagen puede aportar datos a la comprensión de la naturaleza de dichos déficits, así como a su evolución. Durante los últimos años, se ha producido un marcado incremento de trabajos que evalúan la relación entre el deterioro cognitivo de esta población clínica y diversas variables patológicas ob- tenidas mediante técnicas de neuroimagen clásicas, así como mediante el uso de otros procedimientos de desarrollo más reciente. Los resultados de los estudios que usan técnicas de neuroimagen estructural han revelado la importancia de procesos atróficos en el deterioro cognitivo de la EM. Sin embargo, esta información debe complementarse con la aporta- da por otros procedimientos más novedosos acerca de alteraciones en la sustancia blanca y en la sustancia gris de ‘apariencia normal’. Por otra parte, los estudios que han empleado técnicas de resonancia magnética funcional han mostrado la existencia de distintos procesos de neuroplasticidad que pueden enmascarar la relación entre los índices morfológicos de daño cerebral y el rendimiento cognitivo de los pacientes con EM. Estos procesos no deben ignorarse, en tanto que pueden compensar las alteraciones cognitivas de esta población clínica. El presente trabajo de revisión intenta aportar una visión crítica e integradora de los estudios dedicados a evaluar la relación entre el deterioro cognitivo de la EM y diferentes tipos de información aportados por las técnicas de neuroimagen.Studying the cognitive impairment of multiple sclerosis (MS) patients is fundamental for a global understanding of this disease. Neuroimaging techniques might provide crucial data about the nature of this deficit and their progression. Accordingly to this idea, over the last years there has been a marked increase in the number of studies devoted to explore the possible relationship between the cognitive alterations of this clinical population and different sorts of neuropathological indexes provided by both, classical as well as by more recently developed techniques. The results of the studies using structural information provided by structural techniques, have revealed the important role of atrophic processes in the aethiology of cognitive decline in MS patients. However, this information needs to be complemented with newer indexes of neuropathological alterations in ‘apparently normal’ gray and white matter. On the other hand, functional magnetic resonance imaging studies have provided clear evidence of the existence and functional significance of neuroplastic processes that can mask the relationship between morphological markers of tissue damage and cognitive performance of MS patients. Those neuroplastic processes need to be taken into account as they might compensate the cognitive decline of this clinical population. In summary, the present review tries to provide a critic and integrative view of different studies assessing the relationship between cognitive impairment in MS patients and different kinds of information provided by neuroimaging techniques