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Background Cysteamine has been demonstrated as potentially neuroprotective in numerous animal models of Huntington’s disease (HD). Methods Ninety-six early-stage HD patients were randomised to a double-blind trial to receive 600 mg delayed-release cysteamine bitartrate (DR-CB) (51) or placebo (45) twice a day for 18 months. The primary endpoint was the change from baseline in the Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor Score (TMS) at 18 months. Key secondary endpoints included other UHDRS scales: total functional capacity, independence, cognition and behaviour. Results are expressed as the least-squares mean (LSM) treatment-effect difference of DR-CB minus placebo; negative values indicating less deterioration relative to placebo. Results The mean baseline TMS (± SD) was 24.2 (10.7) (5 to 53 points). The 18 month treatment-effect (LSM ± standard error [± SE]) was not statistically significant: −1.5 (1.71) points (95% CI: −4.9; 1.9; p = 0.385); representing less mean (± SE) increase (deterioration) from baseline in DR-CB- compared with placebo-treated patients: 4.9 (1.17) versus 6.4 (1.25) points, respectively. No significant treatment-effects were observed for key secondary endpoints. DR-CB was safe and well-tolerated. Post-hoc analyses dichotomized by median baseline TMS ( Interpretation Statistical significance was not observed for the primary endpoint. However, post-hoc analysis indicated statistical significance in patients with more severe baseline motor impairment. Further studies involving a larger number of patients are warranted. Trial registration EudraCT Number: 2010–019444-39

A 46-year-old woman with a history of kidney transplant for IgA nephropathy (on tacrolimus and mycophenolate mofetil), type II diabetes and non-alcoholic steatohepatitis was admitted for gait instability. Neurological examination revealed lower limb sensory ataxia and brisk patellar reflexes. Brain/spinal MRI results were normal. Blood tests disclosed macrocytosis (but no vitamin deficiencies) and mild hepatic cytolysis. Lumbar puncture showed the absence of cells, normal protein, hypoglycorrhachia (glycorrhachia: 0.62 g/l; glycaemia: 1.65 g/l) and no oligoclonal bands. Cerebrospinal fluid cultures were negative. Assays for neurotropic viruses, paraneoplastic …

Dysexecutive symptoms such as apathy, impulsivity and distractibility have been reported on clinical ground in HD. However previous studies have assessed dysexecutive behavioural disorders using clinical interview or nonspecific questionnaires incorporating other features resulting in highly variable evaluation with poorly defined performance indices. This study aimed to assess dysexecutive behavioural abnormalities in HD, using a validated instrument, the Behavioural Dysexecutive Syndrome Inventory (BDSI). 14 patients (mean age: 55.5 years; SD 12.4; range: 34–73; mean duration: 8.7 years; SD=7; range: 2–30; mean MMSE score: 25; SD=3.4) with clinically diagnosed and genetically confirmed HD, were included. The assessment of depressive symptoms (Montgomery Asberg Depression Scale) showed a mild depression in 7 patients. The BDSI is a highly structured caregiver based interview which rates frequency and severity of 12 dysexecutive disturbances (global hypoactivity with apathy, hyperactivity, irritability-impulsivity, euphoria, perseverative behaviour; environmental dependency, social behaviour disorders). The analysis of individual performance was performed using cutoff scores at the 5% level using normative data obtained in 96 controls 1 . The prevalence of behavioural dysexecutive syndrome was high (50%; 95% CI: 24–76). The behavioural profile was characterised by the prominence of irritability (50%), hyperactivity (43%), apathy (29%), disinterest (22%) and difficulties for anticipation (14%). This study based on the BDSI revealed in HD that behavioural dysexecutive disorders are: 1 frequent with a prevalence of 50%, 2 characterised by a specific profile with the prominence of irritability and hyperactivity-distractibility, 13 whereas the hypoactivity-apathy disorders were less frequent contrary to most other degenerative disorders. 1 Godefroy et al . Ann Neurol. 2010

Background Whereas behavioural disorders, including impulsivity, are frequent and early in Huntington’s disease (HD), their physiopathology remains still poorly understood, especially by lack of validate instrument for their evaluation. Aim The aim objective of this study was to objective that impulsivity is increased in HD by a quantitative evaluation using a delay discouting paradigm, an experimental task specific of impulsive choice. Methods 19 patients with symptomatic MH and 19 healthy and matched controls from the general population were included. Patients underwent a neurological and standardised neuropsychological examination, with an additional assessment exploring behavioural disorders including the delay discounting task (DDT), performed on a computer, and scales of self-report questionnaires to measure impulsivity (Barratt Impulsiveness Scale-11) and apathy (Starkstein scale), and an hetero-report questionnaire, the Behavioural Dysexecutive Syndrome Inventory (BDSI). Results 52.3% of HD patients performances at the DDT were incoherent and could not be interpreted according to the experimental model. Evaluation by BDSI showed significantly impulsivity in HD patients (p = 0.001), as well as irritability and apathy. Statistical analysis did not reveal cognitive factor or factor related to the evolution of HD correlated with the scores at the DDT, BDSI or behavioural scales. Apparent fluctuations between impulsivity and apathy in HD patients could involve inhibitory control disturbances. Conclusion Quantitative evaluation of impulsivity by a delay discounting paradigm seems to be inappropriate in HD. The BDSI is a validate instrument relevant for the qualitative assessment of behavioural disorders in HD, and should be widely used in this pathology.

Background Phenotypic expression is variable in Huntington9s 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 Huntington9s 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.

Background Recent reviews of available drug trials and case reports conclude that the guidelines for the treatment of Huntington9s 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 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.