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Background: NKX2-1-related disorders have a prevalence of 1:500,000 and are therefore considered a rare condition according to the European Commission's definition. The European Reference Network of Rare Neurological Disorders is developing the first clinical practice guideline on the management of this condition, with the support of the Andalusian Health Technology Assessment Area, Endo-ERN, ERN-Lung and Imegen, within the framework of the ERNs Guidelines programme (DG SANTE/2018/B3/030). Within the scope of this programme, it becomes necessary to explore the patient perspective in order to include it in the ongoing clinical practice guideline and accompanying patient information booklet., Methods and Analysis: This study will use qualitative methods to explore the values, preferences and information needs of patient with NKX2-1-related disorders and their caregivers. Participants will come from a variety of countries throughout Europe. One focus group and four semi-structured interviews will be conducted. Pairs will analyse the data using Grounded Theory. The Andalusian Regional Ministry of Health's Ethics Coordinating Committee for Biomedical Research (Sevilla, Andalucía, Spain) has approved this study protocol (29/03/2022)., Discussion: This is the first study to explore the values, preferences, and information needs of patients with NKX2-1-related disorders. The proposed study's findings will contribute to the generation of useful knowledge that will provide guidance to improve the care given to patients with the studied condition. While this study will provide valuable insights into the perspectives of patients with NKX2-1-related disorders, the findings are unlikely to be generalizable to patients with other conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Martín-Gómez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., Competing Interests: The authors have declared that no competing interests exist.

Experiencing a syntactic structure affects how we process subsequent instances of that structure. This phenomenon, called structural priming, is observed both in language production and in language comprehension. However, while abstract syntactic structures can be primed independent of lexical overlap in sentence production, evidence for structural priming in comprehension is more elusive. In addition, when structural priming in comprehension is found, it can often be accounted for in terms of participants' explicit expectations. Participants may use the structural repetition over several sentences and build expectations, which create a priming effect. Here, we use a new experimental paradigm to investigate structural priming in sentence comprehension independent of lexical overlap and of participants' expectations. We use an outcome dependent variable instead of commonly used online measures, which allows us to more directly compare these effects with those found in sentence production studies. We test priming effects in syntactically homogeneous and heterogeneous conditions on a sentence-picture matching task that forces participants to fully parse the sentences. We observe that, while participants learn the structural regularity in the homogeneous condition, structural priming is also found in the heterogeneous condition, in which participants do not expect any particular structure. In fact, we find that a single prime is enough to trigger priming. Our results indicate that-like in sentence production-structural priming can be observed in sentence comprehension without lexical repetition and independent of participants' expectation.

Little is known about the genetic factors modulating the progression of Huntington's disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington's Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression., Competing Interests: R. de Diego-Balaguer, C. Schramm, I. Rebeix, E. Dupoux, A. Durr, A. Brice, P. Charles, L. Cleret de Langavant, K. Youssov, G. Fénelon, C. Verny, V. Damotte, JP Azulay, C. Simonin, C. Tranchant, P. Maison, A. Rialland, D. Schmitz, C. Jacquemot, B. Fontaine have nothing to disclose. A.C. Bachoud-Lévi acted as a consultant once for Teva in 2014 and reports grants from the National Reference Center for Huntington’s Disease from the Ministry of Health and from the clinical research directorate (AP-HP). C. Goizet reports grants from the European Huntington Disease Network and the Programme Hospitalier de Recherche Clinique (PHRC) during the duration of the study; personal fees came from Raptor Pharmaceutical France, Genzyme, and Actelion; grants from Genzyme, Association Française contre les myopathies (AFM), Association Strumpell-Lorrain (ASL), Connaître les Syndromes Cérébelleux (CSC), Union Nationale des Aveugles et Déficients Visuels (UNADEV), Conseil Régional d’Aquitaine (CRA), Agence Nationale pour la Recherche (ANR), Programme Hospitalier de Recherche Clinique (PHRC), Genzyme, Actelion, and Biomarin, not covering the work submitted here. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Background: Huntington's disease (HD) is one of several neurodegenerative disorders that have been associated with metabolic alterations. Changes in Insulin Growth Factor 1 (IGF-1) and/or insulin input to the brain may underlie or contribute to the progress of neurodegenerative processes. Here, we investigated the association over time between changes in plasma levels of IGF-1 and insulin and the cognitive decline in HD patients., Methods: We conducted a multicentric cohort study in 156 patients with genetically documented HD aged from 22 to 80 years. Among them, 146 patients were assessed at least twice with a follow-up of 3.5 ± 1.8 years. We assessed their cognitive decline using the Unified Huntington's Disease Rating Scale, and their IGF-1 and insulin plasmatic levels, at baseline and once a year during the follow-up. Associations were evaluated using a mixed-effect linear model., Results: In the cross-sectional analysis at baseline, higher levels of IGF-1 and insulin were associated with lower cognitive scores and thus with a higher degree of cognitive impairment. In the longitudinal analysis, the decrease of all cognitive scores, except the Stroop interference, was associated with the IGF-1 level over time but not of insulin., Conclusions: IGF-1 levels, unlike insulin, predict the decline of cognitive function in HD., Competing Interests: The authors have declared that no competing interests exist.

The retest effect-improvement of performance on second exposure to a task-may impede the detection of cognitive decline in clinical trials for neurodegenerative diseases. We assessed the impact of the retest effect in Huntington's disease trials, and investigated its possible neutralization. We enrolled 54 patients in the Multicentric Intracerebral Grafting in Huntington's Disease (MIG-HD) trial and 39 in the placebo arm of the Riluzole trial in Huntington's Disease (RIL-HD). All were assessed with the Unified Huntington's Disease Rating Scale (UHDRS) plus additional cognitive tasks at baseline (A1), shortly after baseline (A2) and one year later (A3). We used paired t-tests to analyze the retest effect between A1 and A2. For each task of the MIG-HD study, we used a stepwise algorithm to design models predictive of patient performance at A3, which we applied to the RIL-HD trial for external validation. We observed a retest effect in most cognitive tasks. A decline in performance at one year was detected in 3 of the 15 cognitive tasks with A1 as the baseline, and 9 of the 15 cognitive tasks with A2 as the baseline. We also included the retest effect in performance modeling and showed that it facilitated performance prediction one year later for 14 of the 15 cognitive tasks. The retest effect may mask cognitive decline in patients with neurodegenerative diseases. The dual baseline can improve clinical trial design, and better prediction should homogenize patient groups, resulting in smaller numbers of participants being required.

Background: There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders., Methods: We performed a longitudinal study of the consent of Huntington's disease patients during the Multicenter Fetal Cell Intracerebral Grafting Trial in Huntington's Disease (MIG-HD) in France and Belgium. Patients and their proxies completed a consent questionnaire at inclusion, before signing the consent form and after one year of follow-up, before randomization and transplantation. The questionnaire explored understanding of the protocol, satisfaction with the information delivered, reasons for participating in the trial and expectations regarding the transplant. Forty-six Huntington's disease patients and 27 proxies completed the questionnaire at inclusion, and 27 Huntington's disease patients and 16 proxies one year later., Results: The comprehension score was high and similar for Huntington's disease patients and proxies at inclusion (72.6% vs 77.8%; P > 0.1) but only decreased in HD patients after one year. The information satisfaction score was high (73.5% vs 66.5%; P > 0.1) and correlated with understanding in both patients and proxies. The motivation and expectation profiles were similar in patients and proxies and remained unchanged after one year., Conclusions: Cognitively impaired patients with Huntington's disease were capable of consenting to participation in this trial. This consent procedure has presumably strengthened their understanding and should be proposed before signing the consent form in future gene or cell therapy trials for neurodegenerative disorders. Because of the potential cognitive decline, proxies should be designated as provisional surrogate decision-makers, even in competent patients.

Purpose: Huntington's disease is a rare condition. Patients are commonly treated with antipsychotics and tetrabenazine. The evidence of their effect on disease progression is limited and no comparative study between these drugs has been conducted. We therefore compared the effectiveness of antipsychotics on disease progression., Methods: 956 patients from the Huntington French Speaking Group were followed for up to 8 years between 2002 and 2010. The effectiveness of treatments was assessed using Unified Huntington's Disease Rating Scale (UHDRS) scores and then compared using a mixed model adjusted on a multiple propensity score., Results: 63% of patients were treated with antipsychotics during the survey period. The most commonly prescribed medications were dibenzodiazepines (38%), risperidone (13%), tetrabenazine (12%) and benzamides (12%). There was no difference between treatments on the motor and behavioural declines observed, after taking the patient profiles at the start of the drug prescription into account. In contrast, the functional decline was lower in the dibenzodiazepine group than the other antipsychotic groups (Total Functional Capacity: 0.41 ± 0.17 units per year vs. risperidone and 0.54 ± 0.19 vs. tetrabenazine, both p<0.05). Benzamides were less effective than other antipsychotics on cognitive evolution (Stroop interference, Stroop color and Literal fluency: p<0.05)., Conclusions: Antipsychotics are widely used to treat patients with Huntington's disease. Although differences in motor or behavioural profiles between patients according to the antipsychotics used were small, there were differences in drug effectiveness on the evolution of functional and cognitive scores.

Patients with Huntington's disease (HD) are often described as unaware of their motor symptoms, their behavioral disorders or their cognitive deficits, including memory. Nevertheless, because patients with Parkinson's disease (PD) remain aware of their memory deficits despite striatal dysfunction, we hypothesize that early stage HD patients in whom degeneration predominates in the striatum can accurately judge their own memory disorders whereas more advanced patients cannot. In order to test our hypothesis, we compared subjective questionnaires of memory deficits (in HD patients and in their proxies) and objective measures of memory dysfunction in patients. Forty-six patients with manifest HD attending the out-patient department of the French National Reference Center for HD and thirty-three proxies were enrolled. We found that HD patients at an early stage of the disease (Stage 1) were more accurate than their proxies at evaluating their own memory deficits, independently from their depression level. The proxies were more influenced by patients' functional decline rather than by patients' memory deficits. Patients with moderate disease (Stage 2) misestimated their memory deficits compared to their proxies, whose judgment was nonetheless influenced by the severity of both functional decline and depression. Contrasting subjective memory ratings from the patients and their objective memory performance, we demonstrate that although HD patients are often reported to be unaware of their neurological, cognitive and behavioral symptoms, it is not the case for memory deficits at an early stage. Loss of awareness of memory deficits in HD is associated with the severity of the disease in terms of CAG repeats, functional decline, motor dysfunction and cognitive impairment, including memory deficits and executive dysfunction.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess Depression, Anxiety and Apathy in prHD and early HD individuals.

Communicative pointing is a human specific gesture which allows sharing information about a visual item with another person. It sets up a three-way relationship between a subject who points, an addressee and an object. Yet psychophysical and neuroimaging studies have focused on non-communicative pointing, which implies a two-way relationship between a subject and an object without the involvement of an addressee, and makes such gesture comparable to touching or grasping. Thus, experimental data on the communicating function of pointing remain scarce. Here, we examine whether the communicative value of pointing modifies both its behavioral and neural correlates by comparing pointing with or without communication. We found that when healthy participants pointed repeatedly at the same object, the communicative interaction with an addressee induced a spatial reshaping of both the pointing trajectories and the endpoint variability. Our finding supports the hypothesis that a change in reference frame occurs when pointing conveys a communicative intention. In addition, measurement of regional cerebral blood flow using H(2)O(15) PET-scan showed that pointing when communicating with an addressee activated the right posterior superior temporal sulcus and the right medial prefrontal cortex, in contrast to pointing without communication. Such a right hemisphere network suggests that the communicative value of pointing is related to processes involved in taking another person's perspective. This study brings to light the need for future studies on communicative pointing and its neural correlates by unraveling the three-way relationship between subject, object and an addressee.

Background: Huntington's disease (HD) is a severe inherited neurodegenerative disorder characterized, in addition to neurological impairment, by weight loss suggesting endocrine disturbances. The aims of this study were to look for neuroendocrine disturbances in patients with Huntington's disease (HD) and to determine the relationship with weight loss seen in HD METHODS AND FINDING: We compared plasma levels of hormones from the five pituitary axes in 219 patients with genetically documented HD and in 71 sex- and age-matched controls. Relationships between hormone levels and disease severity, including weight-loss severity, were evaluated. Growth hormone (GH) and standard deviation score of insulin-like growth factor 1 (SDS IGF-1) were significantly higher in patients than in controls (0.25 (0.01-5.89) vs. 0.15 (0.005-4.89) ng/ml, p = 0.013 and 0.16+/-1.02 vs. 0.06+/-0.91, p = 0.039; respectively). Cortisol was higher (p = 0.002) in patients (399.14+/-160.5 nmol/L vs. 279.8+/-130.1 nmol/L), whereas no differences were found for other hormone axes. In patients, elevations in GH and IGF-1 and decreases in thyroid-stimulating hormone, free triiodothyronine and testosterone (in men) were associated with severity of impairments (Independence scale, Functional score, Total Functional Capacity, Total Motor score, Behavioral score). Only GH was independently associated with body mass index (beta = -0.26, p = 0.001)., Conclusion: Our data suggest that the thyrotropic and in men gonadotropic axes are altered in HD according to the severity of the disease. The somatotropic axis is overactive even in patients with early disease, and could be related to the weight loss seen in HD patients.

The initial process of identifying words from spoken language and the detection of more subtle regularities underlying their structure are mandatory processes for language acquisition. Little is known about the cognitive mechanisms that allow us to extract these two types of information and their specific time-course of acquisition following initial contact with a new language. We report time-related electrophysiological changes that occurred while participants learned an artificial language. These changes strongly correlated with the discovery of the structural rules embedded in the words. These changes were clearly different from those related to word learning and occurred during the first minutes of exposition. There is a functional distinction in the nature of the electrophysiological signals during acquisition: an increase in negativity (N400) in the central electrodes is related to word-learning and development of a frontal positivity (P2) is related to rule-learning. In addition, the results of an online implicit and a post-learning test indicate that, once the rules of the language have been acquired, new words following the rule are processed as words of the language. By contrast, new words violating the rule induce syntax-related electrophysiological responses when inserted online in the stream (an early frontal negativity followed by a late posterior positivity) and clear lexical effects when presented in isolation (N400 modulation). The present study provides direct evidence suggesting that the mechanisms to extract words and structural dependencies from continuous speech are functionally segregated. When these mechanisms are engaged, the electrophysiological marker associated with rule-learning appears very quickly, during the earliest phases of exposition to a new language.

Background: The brain is deemed "immunologically privileged" due to sparse professional antigen-presenting cells and lymphatic drainage, and to the blood-brain barrier. Although the actual extent of this privilege is controversial, there is general consensus about the limited need in intracerebral neural grafts for immunosuppressive regimens comparable to those used in other cases of allotransplantation. This has led over the past fifteen years to the use of either short-term or even no immunosuppression in most clinical trials with foetal neural transplant in patients with Parkinson's and Huntington's disease., Methodology/principal Findings: We report biological demonstration of alloimmunisation without signs of rejection in four grafted patients out of 13 studied during the course of a clinical trial involving fetal neural transplantation in patients with Huntington's Disease. Biological, radiological and clinical demonstration of an ongoing rejection process was observed in a fifth transplanted patient. The rejection process was, however, fully reversible under immunosuppressive treatment and graft activity recovered within six months., Conclusions/significance: There had been, up to date, no report of documented cases that could have cast a doubt on those procedures. Our results underline the need for a reconsideration of the extent of the so-called immune privilege of the brain and of the follow-up protocols of patients with intracerebral grafts. It also suggests that some of the results obtained in past studies with foetal neural transplants may have been biased by an unrecognized immune response to donor cells.