Cognitive decline in Huntington's disease in the Digitalized Arithmetic Task (DAT)

Background Efficient cognitive tasks sensitive to longitudinal deterioration in small cohorts of Huntington’s disease (HD) patients are lacking in HD research. We thus developed and assessed the digitized arithmetic task (DAT), which combines inner language and executive functions in approximately 4 minutes. Methods We assessed the psychometric properties of DAT in three languages, across four European sites, in 77 early-stage HD patients (age: 52 ± 11 years; 27 females), and 57 controls (age: 50 ± 10, 31 females). Forty-eight HD patients and 34 controls were followed up to one year with 96 participants who underwent MRI brain imaging (HD patients = 46) at baseline and 50 participants (HD patients = 22) at one year. Linear mixed models and Pearson correlations were used to assess associations with clinical assessment. Results At baseline, HD patients were less accurate (p = 0.0002) with increased response time (p<0.0001) when compared to DAT in controls. Test-retest reliability in HD patients ranged from good to excellent for response time (range: 0.63–0.79) and from questionable to acceptable for accuracy (range: r = 0.52–0.69). Only DAT, the Mattis Dementia Rating Scale, the Symbol Digit Modalities Test, and Total Functional Capacity scores were able to detect a decline within a one-year follow-up in HD patients (all p< 0.05). In contrast with all the other cognitive tasks, DAT correlated with striatal atrophy over time (p = 0.037) but not with motor impairment. Conclusions DAT is fast, reliable, motor-free, applicable in several languages, and able to unmask cognitive decline correlated with striatal atrophy in small cohorts of HD patients. This likely makes it a useful endpoint in future trials for HD and other neurodegenerative diseases

A new approach to digitized cognitive monitoring: validity of the SelfCog in Huntington's disease

Cognitive deficits represent a hallmark of neurodegenerative diseases, but evaluating their progression is complex. Most current evaluations involve lengthy paper-and-pencil tasks which are subject to learning effects dependent on the mode of response (motor or verbal), the countries’ language or the examiners. To address these limitations, we hypothesized that applying neuroscience principles may offer a fruitful alternative. We thus developed the SelfCog, a digitized battery that tests motor, executive, visuospatial, language and memory functions in 15 min. All cognitive functions are tested according to the same paradigm, and a randomization algorithm provides a new test at each assessment with a constant level of difficulty. Here, we assessed its validity, reliability and sensitivity to detect decline in early-stage Huntington’s disease in a prospective and international multilingual study (France, the UK and Germany). Fifty-one out of 85 participants with Huntington’s disease and 40 of 52 healthy controls included at baseline were followed up for 1 year. Assessments included a comprehensive clinical assessment battery including currently standard cognitive assessments alongside the SelfCog. We estimated associations between each of the clinical assessments and SelfCog using Spearman’s correlation and proneness to retest effects and sensitivity to decline through linear mixed models. Longitudinal effect sizes were estimated for each cognitive score. Voxel-based morphometry and tract-based spatial statistics analyses were conducted to assess the consistency between performance on the SelfCog and MRI 3D-T1 and diffusion-weighted imaging in a subgroup that underwent MRI at baseline and after 12 months. The SelfCog detected the decline of patients with Huntington’s disease in a 1-year follow-up period with satisfactory psychometric properties. Huntington’s disease patients are correctly differentiated from controls. The SelfCog showed larger effect sizes than the classical cognitive assessments. Its scores were associated with grey and white matter damage at baseline and over 1 year. Given its good performance in longitudinal analyses of the Huntington’s disease cohort, it should likely become a very useful tool for measuring cognition in Huntington’s disease in the future. It highlights the value of moving the field along the neuroscience principles and eventually applying them to the evaluation of all neurodegenerative diseases

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La négligence spatiale unilatérale (NSU) est une affection neurologique fréquemment observée après une lésion de l'hémisphère cérébral droit. Les patients ne vont plus être en mesure de prendre en compte les stimuli présentés dans l'hémi-espace gauche. La NSU participe à l'aggravation du handicap des patients, par la réduction des possibilités en rééducation motrice et cognitive à la phase aigue d'un accident vasculaire comme sur le long terme. L'identification des facteurs prédictifs de sa chronicité pourrait permettre une meilleure prise en charge clinique de ces patients. Nous avons étudié les altérations des connexions anatomiques observées en IRM de diffusion sous-tendant la persistance de la NSU. Nos résultats démontrent qu'en plus d'un dysfonctionnement fronto-pariétal hémisphérique droit, la persistance de ce syndrome serait associée à une déconnexion interhémisphérique. L'hémisphère gauche isolé ne serait pas en mesure de compenser les déficits des patients. La récupération devrait s'effectuer par une amélioration dans les capacités d'échange des informations entre les deux hémisphères, notamment dans les régions postérieures pariétales et occipitales. Nous nous sommes intéressés à tester cette hypothèse par le biais d'une méthode de rééducation, l'adaptation prismatique (AP). Il s'agit d'une thérapie dont les effets sur la sémiologie des patients sont remarquables. Nos résultats suggèrent que l'amélioration de la NSU pourrait s'observer par le recrutement du réseau fronto-ponto-cérébelleux. Les régions frontales gauches seraient un relais anatomique entre le cervelet droit et le réseau fronto-pariétal gaucheUnilateral spatial neglect is a frequent neurological condition after right hemisphere damage. Patients behave as if objects on their left did not exist anymore. The presence of neglect has negative prognostic value for functional recovery in the acute and chronic phases after a stroke. Finding predictors of persistent neglect would permit to adapt rehabilitation procedures. We used diffusion MRI to define the state of anatomical connections in neglect and their predictor value for neglect persistence. Our results revealed that, together with right intra-hemispheric fronto-parietal disconnections, persistence of neglect is associated with inter-hemispheric disconnection. We concluded that an isolated left hemisphere may fail to compensate neglect because it cannot take into account left-sided objects. Recovery of neglect would instead occur thanks to the sharing of visual information between the two hemispheres, notably in posterior parietal and occipital cortices. We tested this hypothesis by using prism adaptation (PA) therapy. PA is a non-invasive and convenient technique to rehabilitate neglect. We showed that patients with damaged fronto-ponto-cerebellar pathways did not benefit from PA. This finding strongly suggests that PA can ameliorate signs of neglect by improving inter-hemispheric communication through enhanced activity of these connections. Left frontal areas may constitute the anatomical link between the right cerebellum and the left fronto-parietal network. Thus, connectional anatomy can help predict both neglect recovery and the quality of its response to rehabilitation therapie

Prismatic adaptation therapy in visual neglect: the importance of connectional anatomy

International audienceThe meta-analysis conducted by Székely et al. described the lack of beneficial effect of prism adaptation in neglect patients. The authors concluded that the results did “not support the routine use of prism adaptation as a therapy for spatial neglect”. However, a possible nuance to this conclusion could be that the response (or lack thereof) of neglect patients to prism adaptation may actually depend on the connectional anatomy of their lesion. We develop this idea in our commentary, in order to offer a more balanced perspective on the implications of the findings obtained by Székely et al

Improvement of Navigation and Representation in Virtual Reality after Prism Adaptation in Neglect Patients

Prism adaptation (PA) is responsible for an expansion of sensori-motor after-effects to cognitive domains for patients with spatial neglect. One important question is whether the cognitive after-effects induced by PA may also concern higher aspects of spatial cognition, such as navigation and topographic memory, which are critical in everyday life. The aim of this study was to assess whether multiple sessions of right PA can affect navigation and topographic memory. Seven right brain-damaged (RBD) patients with chronic neglect were included. We used a virtual supermarket named VAP-S which is an original paradigm, similar to the “shopping list test” during which patients had to purchase items from a list of eight products. Furthermore, in order to assess generalization of PA effects on constructing a spatial map from virtual information, each participant was then asked to draw the map of the virtual supermarket from memory. Regarding navigation performance, significant results were obtained: session duration reduction, fewer numbers of pauses and omissions, more items purchased on the left side and more items purchased over all. A long-lasting effect was noted, up to one month after PA. The representational task performance was also significantly increased for map drawing, with a reduction of the right shift of the symmetry axis of the map, more items drawn on the left side of maps and over all, and more items correctly located on the map. Some of these effects lasted for at least 7 days. These results suggest an expansion of PA benefit to a virtual environment. Crucially, the cognitive benefits induced by PA were noted for complex spatial cognition tasks required in everyday life such as navigation and topographic memory and this improvement was maintained for up to 1 month

Disruption of Fibers from the Tau Model AcPHF6 by Naturally Occurring Aurones and Synthetic Analogues

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The specific role of the striatum in interval timing: The Huntington’s disease model

International audienceTime processing over intervals of hundreds of milliseconds to minutes, also known as interval timing, is associated with the striatum. Huntington's disease patients (HD) with striatal degeneration have impaired interval timing, but the extent and specificity of these deficits remain unclear. Are they specific to the temporal domain, or do they extend to the spatial domain too? Do they extend to both the perception and production of interval timing? Do they appear before motor symptoms in Huntington's disease (Pre-HD)? We addressed these issues by assessing both temporal abilities (in the seconds range) and spatial abilities (in the cm range) in 20 Pre-HD, 25 HD patients, and 25 healthy Controls, in discrimination, bisection and production paradigms. In addition, all participants completed a questionnaire assessing temporal and spatial disorientation in daily life, and the gene carriers (i.e., HD and Pre-HD participants) underwent structural brain MRI. Overall, HD patients were more impaired in the temporal than in the spatial domain in the behavioral tasks, and expressed a greater disorientation in the temporal domain in the daily life questionnaire. In contrast, Pre-HD participants showed no sign of a specific temporal deficit. Furthermore, MRI analyses indicated that performances in the temporal discrimination task were associated with a larger striatal grey matter volume in the striatum in gene carriers. Altogether, behavioral, brain imaging and questionnaire data support the hypothesis that the striatum is a specific component of interval timing processes. Evaluations of temporal disorientation and interval timing processing could be used as clinical tools for HD patients

Anatomical predictors of successful prism adaptation in chronic visual neglect

International audienceVisual neglect is a frequent and disabling consequence of right hemisphere damage. Previous work demonstrated a probable role of posterior callosal dysfunction in the chronic persistence of neglect signs. Prism adaptation is a non-invasive and convenient technique to rehabilitate chronic visual neglect, but it is not effective in all patients. Here we aimed to assess the hypothesis that prism adaptation improves left neglect by facilitating compensation through the contribution of the left, undamaged hemisphere. We assessed the relationship between prism adaptation effects, cortical thickness and white matter integrity in a group of 14 patients with unilateral right-hemisphere strokes and chronic visual neglect. Results showed that patients who benefitted from prism adaptation had thicker cortex in temporo-parietal, prefrontal and cingulate areas of the left, undamaged hemisphere. Additionally, these patients had a higher fractional anisotropy value in the body and genu of the corpus callosum. Results from normal controls show that these callosal regions connect temporo-parietal, sensorimotor and prefrontal areas. Finally, shorter time intervals from the stroke tended to improve patients' response to prism adaptation. We concluded that prism adaptation may improve left visual neglect by promoting the contribution of the left hemisphere to neglect compensation. These results support current hypotheses on the role of the healthy hemisphere in the compensation for stroke-induced, chronic neuropsychological deficits, and suggest that prism adaptation can foster this role by exploiting sensorimotor/prefrontal circuits, especially when applied at early stages post-stroke