Effectiveness and safety of safinamide in routine clinical practice in a Belgian Parkinson's disease population: an open-label, levodopa add-on study.

BACKGROUND: Safinamide is a recent multimodal antiparkinsonian drug that inhibits monoamine oxidase B and modulates the glutamatergic system with positive effects on motor and nonmotor symptoms of Parkinson's disease (PD). This post-hoc analysis of the European SYNAPSES study provides first-time data on the use of safinamide in routine clinical practice in Belgium. OBJECTIVE: To describe the efficacy and safety of safinamide in Belgian PD patients in real-life conditions. METHODS: Post-hoc analysis of the Belgian cohort from the European SYNAPSES trial, which was an observational, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months. Analyses were performed in the overall population and according to different criteria such as the age limit (> 75 years), presence or absence of relevant comorbidities, presence or absence of psychiatric conditions such as depression and anxiety, patients on levodopa monotherapy or levodopa in combination with other treatments, patients on rasagiline before inclusion or not. RESULTS: Of the 172 patients included, 29.2% were > 75 years, 58.9% had relevant comorbidities and 32.7% had psychiatric conditions. Almost all the patients reported motor (98.8%) or non-motor (86.3%) symptoms. During the study, 36.3% of patients reported drug-related reactions. The adverse drug reactions were those already described in the patients' information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroups of patients. Almost 35% of the patients demonstrated a clinically significant improvement in the UPDRS and 50% of the patients with wearing-off at baseline, did not report wearing-off anymore after one year of treatment. Patients under levodopa monotherapy compared to patients receiving levodopa combined with other antiparkinsonian treatments benefit more from safinamide treatment. Patients switched from rasagiline to safinamide seemed also to benefit more from safinamide treatment. CONCLUSION: The study confirms the excellent safety and efficacy profile of safinamide, particularly in more vulnerable groups of patients such as the elderly and patients with significant comorbidities or psychiatric conditions such as depression or anxiety.

Association Between Motor Symptoms and Brain Metabolism in Early Huntington Disease.

Importance: Brain hypometabolism is associated with the clinical consequences of the degenerative process, but little is known about regional hypermetabolism, sometimes observed in the brain of patients with clinically manifest Huntington disease (HD). Studying the role of regional hypermetabolism is needed to better understand its interaction with the motor symptoms of the disease. Objective: To investigate the association between brain hypometabolism and hypermetabolism with motor scores of patients with early HD. Design, Setting, and Participants: This study started in 2001, and analysis was completed in 2016. Sixty symptomatic patients with HD and 15 healthy age-matched control individuals underwent positron emission tomography to measure cerebral metabolism in this cross-sectional study. They also underwent the Unified Huntington's Disease Rating Scale motor test, and 2 subscores were extracted: (1) a hyperkinetic score, combining dystonia and chorea, and (2) a hypokinetic score, combining bradykinesia and rigidity. Main Outcomes and Measures: Statistical parametric mapping software (SPM5) was used to identify all hypo- and hypermetabolic regions in patients with HD relative to control individuals. Correlation analyses (P < .001, uncorrected) between motor subscores and brain metabolic values were performed for regions with significant hypometabolism and hypermetabolism. Results: Among 60 patients with HD, 22 were women (36.7%), and the mean (SD) age was 44.6 (7.6) years. Of the 15 control individuals, 7 were women (46.7%), and the mean (SD) age was 42.2 (7.3) years. In statistical parametric mapping, striatal hypometabolism was significantly correlated with the severity of all motor scores. Hypermetabolism was negatively correlated only with hypokinetic scores in the cuneus (z score = 3.95, P < .001), the lingual gyrus (z score = 4.31, P < .001), and the crus I/II of the cerebellum (z score = 3.77, P < .001), a region connected to associative cortical areas. More severe motor scores were associated with higher metabolic values in the inferior parietal lobule, anterior cingulate, inferior temporal lobule, the dentate nucleus, and the cerebellar lobules IV/V, VI, and VIII bilaterally corresponding to the motor regions of the cerebellum (z score = 3.96 and 3.42 in right and left sides, respectively; P < .001). Conclusions and Relevance: Striatal hypometabolism is associated with clinical disease severity. Conversely, hypermetabolism is likely compensatory in regions where it is associated with decreasing motor scores. Hypermetabolism might be detrimental in other structures in which it is associated with more severe motor symptoms. In the cerebellum, both compensatory and detrimental contributions seem to occur. This study helps to better understand the motor clinical relevance of hypermetabolic brain regions in HD.

The use of enteral access for continuous delivery of levodopa-carbidopa in patients with advanced Parkinson's disease.

BACKGROUND: Continuous delivery to the jejunum of levodopa-carbidopa is a promising therapy in patients with advanced Parkinson's disease, as it reduces motor fluctuation. Percutaneous endoscopic gastrostomy and jejunal tube (PEG-J) placement is a suitable option for this. However, studies focused in PEG-J management are lacking. OBJECTIVES: We report our experience regarding this technique, including technical success, adverse events and outcomes, in patients with advanced Parkinson's disease. METHODS: Twenty-seven advanced Parkinson's disease patients (17 men, median age: 64 years, median disease duration: 11 years) were included in a retrospective study from June 2007 to April 2015. The median follow-up period was 48 months (1-96). RESULTS: No adverse events were noted during and after nasojejunal tube insertion (to assess treatment efficacy). After a good therapeutic response, a PEG-J was placed successfully in all patients. The PEG tube was inserted according to Ponsky's method. The jejunal extension was inserted during the same procedure in all patients. Twelve patients (44%) experienced severe adverse events related to the PEG-J insertion, which occurred after a median follow-up of 15.5 months. Endoscopy was the main treatment modality. Patients who experienced severe adverse events had a higher comorbidity score (p = 0.011) but were not older (p = 0.941) than patients who did not. CONCLUSIONS: While all patients responded well to levodopa-carbidopa regarding neurological outcomes, gastro-intestinal severe adverse events were frequent and related to comorbidities. Endoscopic treatment is the cornerstone for management of PEG-J related events. In conclusion, clinicians and endoscopists, as well as patients, should be fully informed of procedure-related adverse events and patients should be followed in centres experienced in their management.

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.

Longitudinal study of informed consent in innovative therapy research: experience and provisional recommendations from a multicenter trial of intracerebral grafting.

BACKGROUND: There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders. METHODS: We performed a longitudinal study of the consent of Huntington's disease patients during the Multicenter Fetal Cell Intracerebral Grafting Trial in Huntington's Disease (MIG-HD) in France and Belgium. Patients and their proxies completed a consent questionnaire at inclusion, before signing the consent form and after one year of follow-up, before randomization and transplantation. The questionnaire explored understanding of the protocol, satisfaction with the information delivered, reasons for participating in the trial and expectations regarding the transplant. Forty-six Huntington's disease patients and 27 proxies completed the questionnaire at inclusion, and 27 Huntington's disease patients and 16 proxies one year later. RESULTS: The comprehension score was high and similar for Huntington's disease patients and proxies at inclusion (72.6% vs 77.8%; P > 0.1) but only decreased in HD patients after one year. The information satisfaction score was high (73.5% vs 66.5%; P > 0.1) and correlated with understanding in both patients and proxies. The motivation and expectation profiles were similar in patients and proxies and remained unchanged after one year. CONCLUSIONS: Cognitively impaired patients with Huntington's disease were capable of consenting to participation in this trial. This consent procedure has presumably strengthened their understanding and should be proposed before signing the consent form in future gene or cell therapy trials for neurodegenerative disorders. Because of the potential cognitive decline, proxies should be designated as provisional surrogate decision-makers, even in competent patients.

Epidemiology of major depression in Belgian parkinsonian patients.

BACKGROUND: Epidemiological data concerning the prevalence of major depression in PD patients in Belgium is very scarce. METHODS: A total of 1086 patients with idiopathic Parkinsons disease were included in the analysis. The neurological evaluation of the patients was made by the Hoehn and Yahr Staging of Parkinsons disease, the Unified Parkinson Disease Rating Scale (UPDRS), and the Schwab and England Activities of Daily Living. The psychiatric evaluation was based on the Mini-International Neuropsychiatric Interview (MINI) and the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS: Based on the MINI questionnaire, the overall proportion of PD patients presenting a current major depressive episode was 15.6%. Interestingly, 30% of all patients included had a history of mood disorder and 46% received either an anxiolytic, an antidepressant or an atypical neuroleptic or a combination of them. The characterisation of the profile of depressed parkinsonian patients shows very few patient's parameters (demographics or motor symptoms) to be associated with a higher risk for major depression. CONCLUSIONS: The PARKIDEP survey confirms a high prevalence of major depression in PD patients in Belgium. A careful follow up of PD patients with a poor functionality, a history of mood disorder or with a complaint of depression or anxiety during the "off" state would help towards a better treatment of the Parkinson's disease associated depression and should improve the quality of life of PD patients.

Language processing within the striatum: evidence from a PET correlation study in Huntington's disease.

The role of sub-cortical structures in language processing, and more specifically of the striatum, remains controversial. In line with psycholinguistic models stating that language processing implies both the recovery of lexical information and the application of combinatorial rules, the striatum has been claimed to be involved either in the former component or in the latter. The present study reconciles these conflicting views by showing the striatum's involvement in both language processes, depending on distinct striatal sub-regions. Using PET scanning in a model of striatal disorders, namely Huntington's disease (HD), we correlated metabolic data of 31 early stage HD patients regarding different striatal sub-regions with behavioural scores on three rule/lexicon tasks drawn from word morphology, syntax and from a non-linguistic domain, namely arithmetic. Behavioural results reflected impairment on both processing aspects, while deficits predominated on rule application. Both correlated with the left striatum but involved distinct striatal sub-regions. We suggest that the left striatum encompasses linguistic and arithmetic circuits, which differ with respect to their anatomical and functional specification, comprising ventrally located regions dedicated to rule computations and more dorsal portions pertaining to lexical devices.