Early Strokes Are Associated with More Global Cognitive Deficits in Adults with Sickle Cell Disease

This study sought to link neurocognitive profiles in sickle cell disease (SCD) patients with clinical characteristics. We conducted a prospective cohort study of adults with SCD who underwent comprehensive neuropsychological assessment at the UMGGR clinic at Henri Mondor Hospital, Créteil (France). A cluster analysis was performed based on neuropsychological testing scores. The association between clusters and clinical profiles was assessed. Between 2017 and 2021, 79 patients with a mean age of 36 [range 19–65] years were included. On principal component analysis, a 5-factor model presented the best fit (Bartlett’s sphericity test [χ2 (171) = 1345; p < 0.001]), explaining 72% of the variance. The factors represent distinct cognitive domains and anatomical regions. On hierarchical classification, three clusters emerged. Cluster 1 (n = 24) presented deficits in all five factors compared to Cluster 3 (n = 33). Cluster 2 (n = 22) had deficits in all factors, but to a lesser extent than Cluster 1. MoCA scores mirrored the severity of these cognitive deficits. Age, genotype and stroke prevalence did not differ significantly between clusters. However, the time of first stroke occurrence differed significantly between Cluster 1 and 2–3: 78% of strokes occurred during childhood, whereas 80% and 83% occurred during adulthood in Clusters 2 and 3, respectively. Educational attainment was also reduced in Cluster 1. SCD patients with childhood stroke seem to be at increased risk of a global cognitive deficit profile. In addition to existing methods of primary and secondary stroke prevention, early neurorehabilitation should be prioritized in order to reduce the long-term cognitive morbidity of SCD

Les troubles attentionnels dans la maladie de Huntington

La maladie de Huntington (MH) est une maladie génétique rare, neurodégénérative, qui entraîne une triade de symptômes : des troubles moteurs, intellectuels et psychiatriques. Le striatum, structure d entrée des ganglions de la base, est atteint de façon inaugurale, même chez des patients asymptomatiques porteurs du gène muté. Si nous connaissons de mieux en mieux la maladie et ses mécanismes, à l heure actuelle il n existe aucun traitement curatif efficace. L enjeu pour l instant est donc de trouver des marqueurs phénotypiques du démarrage de la dégénérescence afin de proposer au plus vite une prise en charge adaptée. Les troubles attentionnels apparaissent très tôt et pourraient constituer un bon marqueur comportemental. Ce travail de thèse avait pour but de détailler ces troubles attentionnels et le décours temporel de leur évolution dans cette pathologie en référence au modèle systémique dynamique de Posner et Petersen. Ce modèle postule l existence de trois réseaux attentionnels : (1) un réseau d alerte qui mobilise toutes les ressources énergétiques de l individu afin de le rendre apte à réagir à la survenue de nouveaux stimuli, (2) un réseau d orientation de l attention vers une stimulation interne ou externe et (3) le réseau exécutif dévolu à la gestion et à la résolution de conflits. On peut mobiliser son attention de façon volontaire endogène - en fonction des buts internes ou de façon automatique exogène - attirée par un stimulus soudain.Quatre expériences comportementales et une étude anatomo-clinique ont permis de montrer que les patients MH étaient altérés dans les trois réseaux et que l atteinte suivait le décours temporel de la maladie. Précocement, les patients présentaient des troubles du contrôle exécutif comme l a montré la plupart des études. Dans les stades débutants, l orientation de l attention était également touchée, à la fois dans sa composante endogène et sa composante exogène, dans le temps et dans l espace. Ce qui n avait jamais été montré jusqu à présent, c était l altération de l orientation temporelle de l attention chez ces patients. En outre, leur déficit dans l orientation visuo-spatiale de l attention décrivait un profil étonnant, similaire à celui des patients négligents. Les patients MH montraient des difficultés à orienter leur attention dans l hémi-espace droit, décrivant une pseudo-négligence. Les corrélations anatomo-cliniques entre une tâche de barrage, le test de Zazzo, et l activité métabolique du cerveau au repos montraient que la tête du noyau caudé gauche et le putamen droit étaient impliqués dans ce phénomène de pseudo-négligence. Enfin, nous avons montré que l alerte était atteinte dans les stades avancés, ce qui n avait jamais été fait auparavant. Cette atteinte contribuait à l aggravation de la perturbation des autres réseaux.Ce profil exhaustif permet de proposer le phénomène de pseudo-négligence et l atteinte de l orientation temporelle comme marqueurs phénotypiques de la maladie. L atteinte tardive de l alerte permet quant à elle de proposer très tôt un outil de réhabilitation attentionnelle, basé sur cette composante longtemps préservée.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Orienting of spatial attention in Huntington's Disease.

International audienceTo explore the functioning of spatial attention in Huntington's Disease (HD), 14 HD patients and 14 age-matched controls performed a cued response time (RT) task with peripheral cues. In Experiment 1, cues were not informative about the future target location, thus eliciting a purely exogenous orienting of attention. At short stimulus-onset asynchrony (SOA), controls showed an initial facilitation for cued locations, later replaced by a cost (inhibition of return, IOR). Patients had a larger and more persistent validity effect, with delayed IOR, resulting from a larger cost for uncued targets. This suggests an impairment of attentional disengaging from cued locations. In Experiment 2, 80% of the cues were valid, thus inducing an initially exogenous, and later endogenous, attentional shift towards the cued box. The validity effect was larger in patients than in controls, again as a result of a disproportionate cost for uncued targets. In Experiment 3, 80% of the cues were invalid, thus inviting participants to endogenously re-orient attention towards the uncued box. Patients could take advantage of invalid cues to re-orient their attention towards the uncued targets but at a longer SOA than controls, thus suggesting that endogenous orienting is preserved in HD, but slowed down by the disengage deficit. The disengage deficit correlated with several radiological and biological markers of HD, thus suggesting a causal relationship between HD and attentional impairments. Cued RT tasks are promising tools for the clinical monitoring of HD and of its potential treatments

Evidence of Educational Bias in Cognitive Screening of Adults with Sickle Cell Disease: Comparison of Available Tools and Possible Strategies for Mitigation

International audienceBackground: Cognitive impairment is a dreaded complication of sickle cell disease (SCD) that impacts quality of life, school performance and employment. In 2020, the American Society of Hematology issued a strong recommendation that clinicians supervising the care of adults with SCD conduct surveillance for cognitive impairment using simplified signaling questions (DeBaun, 2020). However, guidance on the optimal screening strategy is lacking and several available tools are biased by language and education. The Rowland Universal Dementia Assessment Scale (RUDAS) was specifically designed for cognitive screening in multicultural populations (Storey, 2004). In the general elderly population, RUDAS is less biased by education than the Montreal Cognitive Assessment (MoCA) (Naqvi, 2015). Hypothesis: In adults with SCD, performance on the RUDAS is less influenced by educational attainment when compared to the MoCA. Our primary aim was to estimate the prevalence of suspected cognitive impairment using RUDAS and MoCA in adult SCD patients. The secondary aims were to examine for the presence of educational bias and to develop mitigation strategies in case of such a bias. Methods: Study design: cross-sectional study at UMGRR clinic at Henri Mondor Hospital, Créteil (France). Inclusion criteria: out-patients ≥18 years-old; all SCD phenotypes. Exclusion criteria: inability to obtain informed consent and/or follow study instructions. Intervention: Cognitive screening was performed using the RUDAS (translated to French by Philippe Desmarais), MoCA (third alternative version) and an additional visuospatial task of copying overlapping triangles (from the French BEC96 assessment). RUDAS and MoCA scores <28 and <26, respectively, were considered suggestive of cognitive impairment per previous studies (Basic, 2009 and Nasredinne, 2005) and patients were referred for definite neuropsychological evaluation. Survey on demographics and screening for depression and anxiety using Hospital Anxiety Depression Scale (HADS) were completed by the participants. Educational attainment was scored based on the number of years of schooling for the highest completed diploma. Statistical plan: linear regression was performed to identify possible associations between RUDAS, MoCA and social determinants of health. Results: Among the first 45 consecutive adult SCD patients undergoing routine cognitive screening, the median age was 39 (range 19-67). RUDAS and MoCA scores suggestive of mild cognitive impairment were found in 33/45 (73.3%) and 29/45 (64.4%) participants, respectively. There was a strong correlation between both tests (r=0.48, p=0.001). Both RUDAS and MoCA scores increased significantly with increasing level of education (r=0.36, p=0.015 and r=0.39, p=0.007, respectively), but were not significantly influenced by the HADS score. RUDAS and MoCA test items most biased by education were visuoconstructional tasks. Tasks assessing executive functioning and language were also biased in MoCA. Substituting the 3D visuospatial task of the RUDAS by a 2D task reduced the educational bias (r=0.20, p=0.045). Adding 1 point for highest level of education £ 12 years after kindergarten did significantly mitigate the effect of education on the RUDAS but only partially for the MoCA (r=0.23, p=0.131 and r=0.30, p=0.047). Conclusions: Overall, these results suggest there is an educational bias in the neurocognitive screening of adult SCD patients using available tools such as the RUDAS and MoCA. Although RUDAS was less biased overall, visuospatial assessment remained biased. The task often considered more "culture-fair" is still subject to the impact of educational potential (Statucka, 2019). We provide different strategies to mitigate education bias when assessing with RUDAS. Thus, the RUDAS adjusted by the educational level allows to systematically identify SCD patients in need of comprehensive neurocognitive testing. Prospective validation is ongoing. Disclosures Forté: Canadian Hematology Society: Research Funding; Pfizer - Global Medical Grants: Research Funding. Soulieres:Novartis: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Kuo:Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy; Apellis: Consultancy. Bartolucci:Roche: Consultancy; Innovhem: Other; AGIOS: Consultancy; Bluebird: Consultancy; Emmaus: Consultancy; Addmedica: Research Funding; Fabre Foundation: Research Funding; Novartis: Research Funding; Bluebird: Research Funding; GBT: Consultancy; ADDMEDICA: Consultancy; HEMANEXT: Consultancy; Novartis: Consultancy

Early Strokes Are Associated with More Global Cognitive Deficits in Adults with Sickle Cell Disease

This study sought to link neurocognitive profiles in sickle cell disease (SCD) patients with clinical characteristics. We conducted a prospective cohort study of adults with SCD who underwent comprehensive neuropsychological assessment at the UMGGR clinic at Henri Mondor Hospital, Créteil (France). A cluster analysis was performed based on neuropsychological testing scores. The association between clusters and clinical profiles was assessed. Between 2017 and 2021, 79 patients with a mean age of 36 [range 19–65] years were included. On principal component analysis, a 5-factor model presented the best fit (Bartlett’s sphericity test [χ2 (171) = 1345; p n = 24) presented deficits in all five factors compared to Cluster 3 (n = 33). Cluster 2 (n = 22) had deficits in all factors, but to a lesser extent than Cluster 1. MoCA scores mirrored the severity of these cognitive deficits. Age, genotype and stroke prevalence did not differ significantly between clusters. However, the time of first stroke occurrence differed significantly between Cluster 1 and 2–3: 78% of strokes occurred during childhood, whereas 80% and 83% occurred during adulthood in Clusters 2 and 3, respectively. Educational attainment was also reduced in Cluster 1. SCD patients with childhood stroke seem to be at increased risk of a global cognitive deficit profile. In addition to existing methods of primary and secondary stroke prevention, early neurorehabilitation should be prioritized in order to reduce the long-term cognitive morbidity of SCD

The postulation of intermittent land bridges as an explanation for reiterated colonization events of Madagascar by African vertebrates: An in-depth review and novel insights in honour of the late Judith Masters and Fabien Génin

International audienceMadagascar's vertebrate fauna is the result of an intricate biogeographic history not considered in the models developed to explain colonisation on other islands. For 80 years popular opinion has held that most of Madagascar's terrestrial vertebrate fauna arrived via transoceanic dispersal (i.e., by rafting or swimming), chiefly from Africa. The alternative solution of recurrent uplifts of a land bridge connected with cyclic global kinematic revolutions, proposed in 2021, was recently challenged. The 2021 paper demonstrates the strength of a comprehensive holistic approach (sedimentary, tectonic, kinematic, and palaeo-environmental studies) based on the new, largescale dataset provided by the PAMELA (Passive Margins Exploration Laboratories) research project. This episodic land bridges hypothesis was tested with divergence estimates of dispersal mechanisms of Madagascar's Angiosperm taxa. The present study includes preliminary palynological results obtained on the latest Miocene to earliest Pliocene material from DSDP Site 242. These pollen assemblages are illustrative of vegetation belts from the coastline to high relief, i.e., from mangrove up to montane forests including intermediate low altitude vegetation

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589