Disentangling the neurobiological bases of temporal impulsivity in Huntington's disease

BackgroundDespite its impact on daily life, impulsivity in Huntington's disease (HD) is understudied as a neuropsychiatric symptom. Our aim is to characterize temporal impulsivity in HD and to disentangle the white matter correlate associated with impulsivity.MethodsForty-seven HD individuals and 36 healthy controls were scanned and evaluated for temporal impulsivity using a delay-discounting (DD) task and complementary Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Diffusion tensor imaging was employed to characterize the structural connectivity of three limbic tracts: the uncinate fasciculus (UF), the accumbofrontal tract (NAcc-OFC), and the dorsolateral prefrontal cortex connectig the caudate nucleus (DLPFC-cn). Multiple linear regression analyses were applied to analyze the relationship between impulsive behavior and white matter microstructural integrity.ResultsOur results revealed altered structural connectivity in the DLPC-cn, the NAcc-OFC and the UF in HD individuals. At the same time, the variability in structural connectivity of these tracts was associated with the individual differences in temporal impulsivity. Specifically, increased structural connectivity in the right NAcc-OFC and reduced connectivity in the left UF were associated with higher temporal impulsivity scores.ConclusionsThe present findings highlight the importance of investigating the spectrum of temporal impulsivity in HD. As, while less prevalent than other psychiatric features, this symptom is still reported to significantly impact the quality of life of patients and caregivers. This study provides evidence that individual differences observed in temporal impulsivity may be explained by variability in limbic frontostriatal tracts, while shedding light on the role of sensitivity to reward in modulating impulsive behavior through the selection of immediate rewards. This study investigates individual differences in temporal impulsivity by using a delay discounting task and, its relationship with white matter connectivity. Our findings reveal significant alterations in the microstructure of key tracts of interest, including the right DLPF-Ccn, bilateral uncinate fasciculus and the left accumbo-frontal tract, in individuals with HD. Furthermore, we observed that variability in the structural connectivity in specific tracts is associated with individual differences in temporal impulsivity. imag

White matter cortico-striatal tracts predict apathy subtypes in Huntington's disease

Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. Forty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains. We elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract. The current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Language disintegration in spontaneous speech in Huntington’s disease: a more fine-grained analysis

Huntington’s disease (HD) is a neurodegenerative disease causing motor symptoms along with cognitive and affective problems. Recent evidence suggests that HD also affects language across core levels of linguistic organization, including at stages of the disease when standardized neuropsychological test profiles are still normal and motor symptoms do not yet reach clinical thresholds (‘pre-manifest HD’). The present study aimed to subject spontaneous speech to a more fine-grained linguistic analysis in a sample of 20 identified HD gene-carriers, 10 with pre-manifest and 10 with early manifest HD. We further explored how language performance related to non-linguistic cognitive impairment, using standardized neuropsychological measures. A distinctive pattern of linguistic impairments marked off participants with both pre-manifest and manifest HD from healthy controls and each other. Fluency patterns in premanifest HD were marked by prolongations, filled pauses, and repetitions, which shifted to a pattern marked by empty (unfilled) pauses, re-phrasings, and truncations in manifest HD. Both HD groups also significantly differed from controls and each other in how they grammatically connected clauses and used noun phrases referentially. Functional deficits in language occurred in pre-manifest HD in the absence of any non-linguistic neuropsychological impairment and did largely not correlate with standardized neuropsychological measures in manifest HD. These results further corroborate that language can act as a fine-grained clinical marker in HD, which can track disease progression from the pre-manifest stage, define critical remediation targets, and inform the role of the basal ganglia in language processing.This research was supported by the Ministerio de Economía y Competitividad (MINECO, Spanish Government), grant FFI2013-40526P, and the Generalitat de Catalunya, Grant SGR-1265, both to W.H

White matter cortico-striatal tracts predict apathy subtypes in Huntington's disease

Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. Forty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains. We elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract. The current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders

Dialogyca en el mundo real y virtual

El proyecto “Dialogyca en el mundo real y virtual” se presenta como continuación del anterior “Dialogyca: los diálogos como punto de encuentro filológico entre lenguas y culturas”, realizado durante el curso 2019-2020. La base para ambos reside en el trabajo realizado desde hace más de una década por el Grupo de estudios de Prosa hispánica Bajomedieval y Renacentista (eProMyR) del Instituto Universitario Menéndez Pidal, que ha considerado esencial, desde sus inicios, establecer sinergias entre investigación, docencia y transferencia de conocimiento. Por ello, tanto en el anterior proyecto como en este se agrupa a miembros de la comunidad universitaria de diversas categorías: profesores permanentes, profesores temporales, personal de apoyo a la investigación, investigadores en formación y estudiantes de Grado y de Máster. Todos ellos colaboran en la realización de diferentes actividades (análisis de obras, de ediciones impresas, dramatizaciones, propuestas de creación literaria, etc.) con el objetivo prioritario de establecer una red de trabajo que favorezca el aprendizaje integral de los alumnos más allá del aula, su primer acercamiento a las actividades de un grupo de investigación, así como formación en facetas clave para un posible futuro en el ámbito investigador. El género que da unidad a este proyecto es el diálogo literario, una modalidad literaria que se remonta a la Antigüedad clásica y que ha pervivido hasta nuestros días, con especial éxito en periodos y culturas como la bajomedieval y renacentista, el Siglo de Oro, la Ilustración y desde la Edad de Plata a nuestros días. Por sus características intrínsecas, se muestra especialmente orientado al didactismo, algo que percibieron muchos de los autores que se decantaron por él para expresar sus ideas o teorías sobre los más variados temas. Su versatilidad lo ha hecho idóneo para tratar materias como la aritmética, medicina, física, filosofía…, es decir, a través de estas obras se puede contemplar una perspectiva panorámica sobre la historia de la ciencia y el pensamiento. Por ello, se considera un género apropiado para que el alumno ejercite su capacidad argumentativa al mismo tiempo que se acerca al conocimiento de los fundamentos de culturas y sociedades de distintas épocas, algo indispensable para el desarrollo de una actitud crítica y a la vez respetuosa y abierta. Así, este proyecto se plantea utilizar el género del diálogo como recurso didáctico y objeto de indagación para proporcionar al alumno conocimientos esenciales del ámbito de las Humanidades, en especial, del filológico, pero también de otras disciplinas, a través de acciones dentro y fuera del aula, de forma presencial y a distancia.Depto. de Literaturas Hispánicas y BibliografíaFac. de FilologíaInstituto Universitario Menéndez PidalFALSEsubmitte

Dialogyca: formación en pensamiento analítico y conciencia crítica

El proyecto “Dialogyca: formación en pensamiento analítico y conciencia crítica” retoma una línea establecida en proyectos anteriores, “Dialogyca en el mundo real y virtual” y “Dialogyca: los diálogos como punto de encuentro filológico entre lenguas y culturas”. La base reside en el trabajo realizado desde hace más de una década por el Grupo de estudios de Prosa hispánica Bajomedieval y Renacentista (eProMyR) del Instituto Universitario Menéndez Pidal, que ha considerado esencial, desde sus inicios, establecer relaciones de confluencia entre investigación, docencia y transferencia de conocimiento. Por ello, en este proyecto se agrupa a miembros de la comunidad universitaria de diversas categorías: profesores permanentes, profesores temporales, personal de apoyo a la investigación, investigadores en formación, estudiantes de Grado y de Máster, y profesorado y estudiantes de Educación Secundaria. Todos ellos colaboran en la realización de diferentes actividades con el objetivo prioritario de establecer una red de trabajo que favorezca el aprendizaje integral de los alumnos más allá del aula, su primer acercamiento a las actividades de un grupo de investigación, la formación docente de miembros jóvenes del PDI, la transferencia a ámbitos externos a la universidad, como la enseñanza secundaria, etc. El proyecto se articula en torno al género del diálogo literario, una modalidad literaria que se remonta a la Antigüedad clásica y que ha pervivido hasta nuestros días, con especial éxito en periodos y culturas como la bajomedieval y renacentista, el Siglo de Oro, la Ilustración y desde la Edad de Plata a nuestros días. Por sus características intrínsecas, se muestra especialmente orientado al didactismo, algo que percibieron muchos de los autores que se decantaron por él para expresar sus ideas o teorías sobre los más variados temas. Por ello, se considera un género apropiado para que el alumno ejercite su capacidad argumentativa al mismo tiempo que se acerca al conocimiento de los fundamentos de culturas y sociedades de distintas épocas, algo indispensable para el desarrollo de una actitud crítica y a la vez respetuosa y abierta. En definitiva, este proyecto se plantea utilizar el género del diálogo como recurso didáctico y objeto de indagación para proporcionar al alumno conocimientos esenciales del ámbito de las Humanidades, en especial, del filológico, pero también de otras disciplinas, a través de acciones dentro y fuera del aula, de forma presencial y a distancia, y ya desde niveles formativos previos al universitario, como es la Enseñanza Secundaria.Depto. de Literaturas Hispánicas y BibliografíaInstituto Universitario Menéndez PidalFALSEsubmitte