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Background Recent reviews of available drug trials and case reports conclude that the guidelines for the treatment of Huntington's disease (HD) symptoms are scarce. Aims We wanted to better understand the use of neuroleptics and related drugs (NL-R) in HD by observing their use in clinical practice and their impact on disease progression. Methods/techniques We explored and compared the profile and evolution of patients treated by NL-R in the cohort of the Huntington French Speaking Group Cohort. This cohort comparative study included 760 patients with available CAG repeats and medication information, followed for 22.4 (±23.3) months between 2002 and 2010. Results/outcome 63% of patients were treated by a NL-R at least once during the follow up. The main NL-R used by the clinicians were (before and after 2006, respectively): olanzapine (38.8 vs 34.5%, NS), risperidone (15.2 vs 16.0%, NS), tiapride (9.4 vs 8.5%, NS) and tetrabenazine (0.8 vs 18.9%, p<0.001). Profiles differed by chorea (p<0.05), UHDRS Functional Assessment Scale (FAS), Total Functional Capacity (TFC) (p<0.05) and Independence Scale (IS) (p<0.01), with patients taking olanzapine being less disabled on the functional scales. Conversely, tiapride was provided to the most advanced patients. The risperidone group displayed the lowest chorea score (8.4±5.4). During treatment, effectiveness adjusted for baseline profile was statistically different between NL-R. Changes in clinical evolution differed for TFC and FAS (p<0.05) and for body mass index (BMI) (p<0.001). Patients under tiapride displayed the slower functional decline and patients with tetrabenazine were the only one where BMI decreased (3.4±5.7%/year). Conclusion In our cohort study of 760 HD patients, the four main NL-R used in HD (olanzapine, risperidone, tiapride and tetrabenazine) seem to have different effectiveness on the progression of the disease. [ABSTRACT FROM PUBLISHER]

Background Phenotypic expression is variable in Huntington's disease (HD). Mutation in the IT15/HD1 gene statistically predicts for the age at onset (AAO), but on an individual basis, repeat length accounts for about 60% of its variance supporting the fact that 40% of the remaining variance is due to additional genetic and/or environmental factors. Association of AAO with polymorphisms located in different genes (ex: ADORA2A) has been previously reported. In contrast, whether environmental factors are also able to influence AAO remain unknown. Caffeine is a non-selective antagonist of A2A receptors, selectively localised on striatal medium spiny neurons expressing enkephalin and dopaminergic D2 receptors, known to be the most vulnerable ones in HD. Interestingly, modulation of A2A receptors influence the pathophysiological outcome in experimental models of HD. Aims To determine the impact of caffeine on the AAO (primary endpoint) and the rates of functional, motor and cognitive decline (secondary endpoints) in HD patients. Methods 58 HD patients were included from eight sites over a 6 month period. Information about caffeine consumption was collected with a validated self-questionnaire. All patients were evaluated using the Unified Huntington's Disease Rating Scale. Factors influencing AAO were examined using a stepwise regression analysis. After adjustment of CAG repeat length, subjects were categorised into three group and we compared the mean of AAO between low end high consumers. Results We found a significant correlation between AAO and caffeine intake (r2=0.041; p=0.016): the highest caffeine intake was associated with the earlier AAO. Also, we demonstrated that caffeine influenced AAO with an advanced AAO of 6.9 years in high consumers compared with low consumers. However, we failed to demonstrate a relation between caffeine intake and the rate of functional, motor and cognitive decline. Conclusion Our findings suggest that caffeine could be the first environmental modifier of AAO in HD. It could have an important therapeutic impact as the modulation of A2A receptors may represent new strategies for treating HD. [ABSTRACT FROM PUBLISHER]

Background The FOXO longevity pathway and β-catenin pathway are major signalling systems that may regulate cell survival. Whether GSK3/β-catenin may interact with longevity signalling to regulate diseased neuron survival and whether this may translate into the modification of human neurodegenerative disease remain unknown. Aims We aimed to test the role of FOXO neighbours such as β-catenin on the effects of expanded polyQs/mutant huntingtin. Methods We used complementary approaches based on a model of neuronal dysfunction induced by expanded polyQ expression, a cellular model of HD pathogenesis based on full length huntingtin expression and genotype analysis using DNA samples from HD patients. Results In , we observed that neuroprotection by the sirtuin sir-2.1 requires the DAF-16/FOXO partner BAR-1/β-catenin and the DAF-16 target ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. In mutant htt striatal cells from HdhQ111 knock-in mice, β-catenin, FOXO3a, SIRT1 and UCP2 promote cell survival, with a cooperation of β-catenin and SIRT1. In Huntington's disease (HD) patients, a single nucleotide polymorphism in GSK-3β, a major repressor of β-catenin activity, modulates the age at onset of motor symptoms as observed in the French and European cohorts. In these cohorts, GSK-3β may also act in synergy with TCERG1 (also named CA150). TCERG1 is an evolutionary conserved gene known as a neuroprotective factor in models of HD and daf-16/FOXO interactor in nematodes, and is confirmed to modify HD onset age. Conclusion These data reveal a role for β-catenin on HD neuron survival and they identify GSK-3β as a modifier of age at onset of motor symptoms in HD. [ABSTRACT FROM PUBLISHER]