"Ten euros now" temporal discounting in Huntington disease.

BACKGROUND: When making decisions, one often faces a trade-off between immediate and long-term rewards. In these situations, people may prefer immediate over later rewards, even if immediate rewards are smaller than later ones; a phenomenon known as temporal discounting. In this study, we, for the first time, assessed temporal discounting in three populations: participants with manifest Huntington disease (HD), participants with premanifest HD, and control participants. METHODS: Using the temporal discounting task, we invited participants to choose between small immediate amount of money vs. delayed, but larger amount of money (e.g., "Which do you prefer: you get 10 euros right now or 50 euros in a month?"). We also measured inhibition in order to test if it impacts discounting performance. RESULTS: Analysis demonstrated higher temporal discounting (i.e., a preference for the immediate rewards) in participants with manifest HD compared to those with premanifest HD or control participants, but no significant differences were observed in participants with premanifest HD and control participants. Analysis also demonstrated significant correlations between temporal discounting and scores on an inhibition test in participants with manifest HD, but not in those with premanifest HD or in control participants. DISCUSSION: We suggest that, when making decisions, patients with manifest HD may have difficulties with suppressing the temptation of smaller, but immediate, rewards.

Design and application of a customizable relational DataBase to assess clinicopathological correlations and concomitant pathology in neurodegenerative diseases.

The diagnosis of neurodegenerative diseases is made complex by the heterogenous phenotype of the patients and the regular occurrence of concomitant pathology. Studying clinicopathological correlations in autopsy series is a central approach to improve pathological prediction in clinical practice. However, such method requires a wealth of information, and the use of standard spreadsheet software is hardly suitable. To overcome this constraint, we designed a customizable and freely available neuropathology form with 456 data entry fields driven by an open-source DataBase Management Systems (DBMS) using Structured Query Language (SQL). This approach allowed us to optimize the compilation of clinical and pathological data from our brain collection (264 autopsied patients, 22,885 data points). Information was then easily retrieved using general and specific queries, facilitating the analysis of demographics, clinicopathological correlations, and incidental and concomitant proteinopathies. Tau, amyloid-ß and α-synuclein incidental pathology was observed in respectively 78.1%, 42.8%, and 10.7% of all the patients. These proportions increased with age, reaching 100% for Tau pathology after 80. Concomitant proteinopathy was observed in 46.4% of the patients diagnosed with neurodegenerative diseases and prion disease. We observed a particularly high rate of co-pathology in patients with Dementia with Lewy bodies (81.3% of associated Tau and amyloid-ß pathology) and Creutzfeldt-Jakob disease (68.4% of associated Tau pathology). Finally, we used specific queries to identify old cases that could meet newly defined neuropathological criteria and revised the diagnosis of a 90-year-old patient to LATE Stage 2. Increasing our understanding of clinicopathological correlations in neurodegenerative diseases is crucial given the implications in clinical diagnosis, biomarker identification and targeted therapies assessment. The precise characterization of clinical and pathological data of autopsy series remains a central approach but the large amount of generated data should encourage a more systematic use of DBMS.

Cyclosporine A does not prevent second-eye involvement in Leber's hereditary optic neuropathy.

BACKRGROUND: Evaluation of the efficacy of oral cyclosporine A as a prophylactic agent in preventing second-eye involvement in Leber's hereditary optic neuropathy (LHON) in a prospective, open-label, non-randomized, multicenter pilot study. Only LHON patients aged 18 years or more, with confirmed primary mitochondrial DNA mutations and strictly unilateral optic neuropathy occurring within 6 months prior to enrolment, were included in the study. All these patients, receiving treatment with oral cyclosporine (Neoral®, Novartis) at 2.5 mg/kg/day, were examined at three-month intervals for a year. The primary endpoint was the best corrected visual acuity in the unaffected eye; the secondary endpoints were the best corrected visual acuity in the first eye affected, the mean visual field defect on automated perimetry, the thickness of the perifoveal retinal ganglion cell inner plexiform layer, and the thickness of the peripapillary retinal nerve fiber layer in both eyes. RESULTS: Among the 24 patients referred to our institution with genetically confirmed LHON, between July 2011 and April 2014, only five patients, four males and one female, fulfilled the inclusion criteria. Age at enrolment ranged from 19 to 42 years (mean: 27.2 years; median: 26 years), four patients harbored the m.11778G > A pathogenic variant, and one the m.14484 T > C pathogenic variant. The time-interval between the onset of symptoms and inclusion in the study ranged from 7 to 17 weeks (mean: 11.8 weeks; median: 9 weeks). Despite treatment with oral cyclosporine A, all patients eventually experienced bilateral eye involvement, occurring within 11-65 weeks after the initiation of treatment. Over the study time period, the average best corrected visual acuity worsened in the first eye affected; by the end of the study, both eyes were equally affected. CONCLUSIONS: Oral cyclosporine, at 2.5 mg/kg/day, did not prevent second-eye involvement in patients with strictly unilateral Leber's hereditary optic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02176733 . Registrated June 25, 2014.

Dissociation between decision-making under risk and decision-making under ambiguity in premanifest and manifest Huntington's disease.

We investigated decision-making under ambiguity (DM-UA) and decision making under risk (DM-UR) in individuals with premanifest and manifest Huntington's disease (HD). Twenty individuals with premanifest HD and 23 individuals with manifest HD, on one hand, and 39 healthy individuals divided into two control groups, on the other, undertook a modified version of the Iowa Gambling Task (IGT), an adaptation of a DM-UA task, and a modified version of the Game of Dice Task (GDT), an adaptation of a DM-UR task. Participants also filled in a questionnaire of impulsivity and responded to cognitive tests specifically designed to assess executive functions. Compared to controls, individuals with premanifest HD were unimpaired in performing executive tests as well as in decision-making tasks, except for the Stroop task. In contrast, individuals with manifest HD were impaired in both the IGT and executive tasks, but not in the GDT. No sign of impulsivity was observed in individuals with premanifest or manifest HD. Our results suggest that the progression of HD impairs DM-UA without affecting DM-UR, and indicate that decision-making abilities are preserved during the premanifest stage of HD.

A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease.

BACKGROUND: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease. METHODS: Ninety-six patients with early-stage Huntington's disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. RESULTS: At 18 months, the treatment effect was not statistically significant - least-squares mean difference, -1.5 ± 1.71 (P = 0.385) - although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. CONCLUSIONS: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society.

The neural substrates of script knowledge deficits as revealed by a PET study in Huntington's disease.

INTRODUCTION: Previous neuropsychological investigations have suggested that both the prefrontal cortex and the basal ganglia are involved in the management of script event knowledge required in planning behavior. METHODS: This study was designated to map, the correlations between resting-state brain glucose utilization as measured by FDG-PET (positron emission tomography) and scores obtained by means of a series of script generation and script sorting tasks in 8 patients with early Huntington's disease. RESULTS: These patients exhibited a selectively greater impairment for the organizational aspects of scripts compared to the semantic aspects of scripts. We showed significant negative correlations between the number of sequencing, boundary, perseverative and intrusion errors and the metabolism of several cortical regions, not only including frontal, but also posterior regions. CONCLUSION: Our findings suggest that, within the fronto-striatal system, the cortical frontal regions are more crucial in script retrieval and script sequencing than the basal ganglia.

Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation.

Hereditary spastic paraplegia refers to a genetically heterogeneous syndrome. We identified five members of a family suffering from a late-onset spastic paraplegia-like disorder, carrying the homoplasmic m.9176 T>C mutation in the mitochondrial ATP6 gene. The clinical severity of the disease observed in the family was correlated with the biochemical and assembly defects of the ATP synthase. The m.9176 T>C mutation has been previously associated to Leigh syndrome or familial bilateral striatal necrosis. Other factors such as modifying genes may be involved in the phenotypic expression of the disease. The family belongs to the mitochondrial haplogroup J, previously shown to play a role in modulating the phenotype of mitochondrial diseases and be associated with longevity. Moreover other nuclear modifying genes or environmental factors may contribute to the disease phenotype. This finding extends the genetic heterogeneity of the hereditary spastic paraplegia together with the clinical spectrum of mutations of the ATP6 gene.

Refsum's disease may mimic familial Guillain Barre syndrome.

Refsum's disease is a rare autosomal recessive disorder with clinical features including retinitis pigmentosa, anosmia, deafness, chronic sensory-motor neuropathy, ataxia and the accumulation of phytanic acid in blood plasma and body tissues. We report the occurrence of Refsum's disease in two sisters, both presenting with acute demyelinating polyneuropathy mimicking the familial Guillain Barre syndrome. Thus, when GBS is suspected, particularly in cases of familial recurrence as well as in atypical cases of acute polyneuropathy, the diagnosis of Refsum's disease should be considered, looking for other features of the disease and, if appropriate, testing plasma phytanic acid levels.