Katia Youssov

Striatal degeneration impairs language learning: evidence from Huntington's disease

Although the role of the striatum in language processing is still largely unclear, a number of recent proposals have outlined its specific contribution. Different studies report evidence converging to a picture where the striatum may be involved in those aspects of rule-application requiring non-automatized behaviour. This is the main characteristic of the earliest phases of language acquisition that require the online detection of distant dependencies and the creation of syntactic categories by means of rule learning. Learning of sequences and categorization processes in non-language domains has been known to require striatal recruitment. Thus, we hypothesized that the striatum should play a prominent role in the extraction of rules in learning a language. We studied 13 pre-symptomatic gene-carriers and 22 early stage patients of Huntingtons disease (pre-HD), both characterized by a progressive degeneration of the striatum and 21 late stage patients Huntingtons disease (18 stage II, two stage III and one stage IV) where cortical degeneration accompanies striatal degeneration. When presented with a simplified artificial language where words and rules could be extracted, early stage Huntingtons disease patients (stage I) were impaired in the learning test, demonstrating a greater impairment in rule than word learning compared to the 20 age- and education-matched controls. Huntingtons disease patients at later stages were impaired both on word and rule learning. While spared in their overall performance, gene-carriers having learned a set of abstract artificial language rules were then impaired in the transfer of those rules to similar artificial language structures. The correlation analyses among several neuropsychological tests assessing executive function showed that rule learning correlated with tests requiring working memory and attentional control, while word learning correlated with a test involving episodic memory. These learning impairments significantly correlated with the bicaudate ratio. The overall results support striatal involvement in rule extraction from speech and suggest that language acquisition requires several aspects of memory and executive functions for word and rule learning.

Association between caffeine intake and age at onset in Huntington's disease

Habitual consumption of caffeine, a non-selective adenosine receptor (AR) antagonist, has been suggested to be beneficial in Parkinsons and Alzheimers diseases. Experimental evidence support that ARs play a role in Huntingtons disease (HD) raising the hypothesis that caffeine may be a life-style modifier in HD. To determine a possible relationship between caffeine consumption and age at onset (AAO) in HD, we retrospectively assessed caffeine consumption in 80 HD patients using a dietary survey and determined relationship with AAO. Following adjustment for gender, smoking status and CAG repeat length, caffeine consumption greater than 190mg/day was significantly associated with an earlier AAO. These data support an association between habitual caffeine intake and AAO in HD patients, but further studies are warranted to understand the link between these variables.

The unified huntington's disease rating scale for advanced patients: Validation and follow-up study: Assessment of Advanced-HD Patients

The Unified Huntingtons Disease Rating Scale (UHDRS) adequately measures decline in patients at early and moderate stages of Huntingtons disease (HD). In advanced patients, floor effects hamper the evaluation, thus calling for an adjusted scale. We designed the UHDRS‐For Advanced Patients (UHDRS‐FAP), in order to improve longitudinal assessment of patients at advanced disease stage. Sixty‐nine patients with a Total Functional Capacity (TFC) ≤ 5 were recruited in France and in the Netherlands. Among them, 45 patients were followed longitudinally (mean 1.6 ± 1.2 years) with the UHDRS‐FAP; 30 were also assessed with the UHDRS. Cross‐sectional analyses evaluated psychometric properties and interrater reliability of the scale. Longitudinal analyses evaluated the sensitivity to decline compared to the UHDRS. Internal consistency was higher for motor and cognitive scores than for somatic and behavioral scores (0.84, 0.91, 0.70, and 0.49, respectively). Interrater reliability was ≥ 0.88 in all scores. The somatic score, specific to the UHDRS‐FAP, declined over time, as well as motor and cognitive performance with both scales. Although performance with the 2 scales correlated, the UHDRS‐FAP appeared more sensitive to change and was the only scale that detected decline in patients with a TFC ≤ 1. Neither scale detected a significant decline in behavioral scores. The UHDRS‐FAP is reliable and more sensitive to change than the original UHDRS for cognitive and motor domains. It offers items relevant for daily care. Behavioral scores tended to decline but this may reflect the decline in the communicative abilities of the patients.

A phase II, open-label evaluation of cysteamine tolerability in patients with Huntington's disease

Huntington’s disease (HD) is an adult-onset, autosomal dominant, progressive neurodegenerative disease, with no treatment available for preventing or slowing down the course of the disease in humans. However, in murine models, cystamine can be neuroprotective and prolongs survival. Cysteamine, the reduced form of cystamine, is currently used to treat cystinosis. Our phase IIa open-label clinical trial was carried out to evaluate the tolerability of cysteamine in patients with HD. Nine women and seven men with HD were treated for 16 weeks with increasing doses of cysteamine. The patients recruited were adults (18-65 years), with a confirmed diagnosis of HD for 1 year or longer, CAG repeats greater than 40, a score greater than 5 on the Unified Huntington’s Disease Rating Scale for the motor function, and a score greater than 7 on the total functional capacity test. Written informed consent was required from each patient, as was the assistance of a family member. The protocol of the study was approved by an Institutional Review Board (“Comit e de Protection des Personnes Ouest II” number 2008-15) in accordance with French law. After starting cysteamine at 450 mg/d during the first 4 weeks, the dose was increased by 450 mg/d every 4 weeks to a final dose of 1,800 mg/d, administered in three equal portions each day. Patients were examined by a neurologist at the beginning of the trial and at end of each 4-week period. Cysteamine tolerability was evaluated by the neurologist according to patients’ statements and clinical examination. At each visit, blood tests were carried out to evaluate the biological tolerance to cysteamine. The maximum dose of cysteamine ranged from 22 to 36 mg/kg/d. Fifteen of the 16 patients with HD completed the treatment as planned. Forty-four episodes of side effects occurred, the most frequent being asthenia, subjectively estimated by the physician based on the reduction of daily activities and resting time, and nausea (Table 1). Three patients suffered from bad breath, reported by the patient or a family member. In our study, the dose-limiting side effects were asthenia and balance disorder, as experienced by one 46-year-old patient. The patient completed the treatment at the lowest dose of 450 mg of cysteamine per day. Considering that the patient was hospitalized for the same symptoms after the end of the study, these may have been unrelated to the treatment. Biological tests showed no significant abnormality. No significant differences were found in the results of the clinical tests: the Unified Huntington’s Disease Rating Scale motor, functional, behavioral, and cognitive tests, the Mini-

Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach.

IMPORTANCE Huntington disease (HD), a prototypic monogenic disease, is caused by an expanded CAG repeat in the HTT gene exceeding 35 units. However, not all patients with an HD phenotype carry the pathological expansion in HTT, and the positive diagnosis rate is poor. OBJECTIVES To examine patients with HD phenotypes to determine the frequency of HD phenocopies with typical features of HD but without pathological CAG repeat expansions in HTT in an attempt to improve the positive diagnosis rate. DESIGN, SETTING, AND PARTICIPANTS Between January 1, 2004, and April 18, 2011, a total of 226 consecutive index patients with an HD phenotype were referred to specialized clinics of the French National Huntington Disease Reference Centre for Rare Diseases. They underwent detailed clinical examination and follow-up, as well as neuropsychological, biological, imaging, and genetic examinations. Nucleotide expansions in JPH3, ATN1, TBP, and C9ORF72 and mutations in PRNP, as well as acquired conditions commonly causing HD phenocopies, were first screened. MAIN OUTCOMES AND MEASURES The diagnostic rate of HD phenocopies and frequency of other etiologies using deep clinical phenotyping and next generation sequencing. Our goal was to improve the genetic diagnosis of HD phenocopies and to identify new HD related genes. RESULTS One hundred ninety-eight patients carried a pathological CAG repeat expansion in HTT, whereas 28 patients (12 women and 16 men) did not. Huntington disease phenocopies accounted for 12.4%, and their mean (SD) age at onset was similar to those of the HD-HTT group (47.3 [12.7] years vs 50.3 [16.4] years, P = .29). We first identified 3 patients with abnormal CTG expansions in JPH3, a fourth patient with an antiphospholipid syndrome, and a fifth patient with B12 avitaminosis. A custom-made 63-gene panel was generated based on clinical evolution and exome sequencing. It contained genes responsible for HD phenocopies and other neurodegenerative conditions, as well as candidate genes from exome sequencing in 3 index cases with imaging features of brain iron accumulation. We identified mutations in genes associated with neurodegeneration, including CACNA1A (n = 2), VPS13A (n = 1), UBQLN2 (n = 1), and VCP (n = 1). CONCLUSIONS AND RELEVANCE Huntington disease phenocopies without CAG repeat expansions in HTT are not rare, occurring in 12.4% (28 of 226) herein, and should be considered in genetic counseling. We used next-generation sequencing combined with clinical data and disease evolution to explore multiple etiologies simultaneously. Our combined clinical and genetic exploration of 28 HD phenocopies identified the underlying cause in 35.7% (10 of 28). In conclusion, the etiologies of HD phenocopies are heterogeneous, and clinical evolution should be taken into account when searching for a genetic cause. The panel of candidate genes to be examined is larger than expected but can be guided by specific imaging and clinical features. Other neurodegenerative diseases with late onset in which variant segregation cannot be verified could be productively explored with the combined approach illustrated herein.

Effectiveness of anti-psychotics and related drugs in the Huntington French-speaking group cohort.

Purpose: Huntingtons 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 Huntingtons 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 Huntingtons 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.

COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

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.

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 Huntingtons disease.

How to capitalize on the retest effect in future trials on Huntington's disease

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.

The most appropriate primary outcomes to design clinical trials on Huntington's disease: meta‐analyses of cohort studies and randomized placebo‐controlled trials

Huntingtons disease (HD) is a rare multifactorial neurodegenerative disease. Both its natural course and any placebo effect are poorly known. All are obstacles to design randomized controlled trials (RCTs). We conducted meta‐analyses of RCTs and cohorts on all parameters of the Unified Huntingtons Disease Rating Scale to determine the most appropriate outcomes and to minimize the number of patients required to design RCTs in HD. Twenty‐four RCTs were included, involving 838 patients with a mean age of 50.0 ± 2.3 years and a mean total functional capacity (TFC) score of 9.8 ± 0.6. Nineteen cohorts were included involving 1939 patients with a mean age of 48.9 ± 2.3 years and a mean TFC of 10.1 ± 0.7. Significant deterioration was observed in RCTs for all scores except behavioral score. Effect sizes were comparable between RCTs and cohorts for each test except that there was a significant difference for TFC. The weighted mean deterioration per year on the TFC scale was −0.5 (0.2) in RCTs and −0.8 (0.2) in cohorts. The lowest number of patients required per group in a RCT was for TFC (19 per group), whereas 30 patients would be required per group for the total motor score (TMS). For cognition, the verbal fluency test required the smallest number of patients: 104 per group. In conclusion, TMS and TFC are the most appropriate outcomes to design RCTs on HD likewise the verbal fluency test for cognition. Our results suggest an effect of placebo administration on the total functional capacity.