The ongoing pursuit of neuroprotective therapies in Parkinson disease

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD

Cognitive decline in Huntington's disease expansion gene carriers

BACKGROUND: In Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline over time is unknown. OBJECTIVE: The aim of this study is to quantify the progression of cognitive decline across all HD stages, from pre-motormanifest to advanced HD, and to investigate if CAG length mediates cognitive decline. METHODS: In the European REGISTRY study 2669 HD expansion gene carriers underwent annual cognitive assessment. General linear mixed models were used to model the cognitive decline for each cognitive task across all disease stages. Additionally, a model was developed to evaluate the cognitive decline based on CAG length and age rather than disease stage. RESULTS: There was significant cognitive decline on all administered tasks throughout pre-motormanifest (close to estimated disease onset) participants and the subsequent motormanifest participants from stage 1 to stage 4. Performance on the Stroop Word and Stroop Color tests additionally declined significantly across the two pre-motormanifest groups: far and close to estimated disease onset. The evaluation of cognition performance in relation to CAG length and age revealed a more rapid cognitive decline in participants with longer CAG length than participants with shorter CAG length over time. CONCLUSION: Cognitive performance already shows decline in pre-motormanifest HD gene expansion carriers and gradually worsens to late stage HD. HD gene expansion carriers with certain CAG length have their own cognitive profile, i.e., longer CAG length is associated with more rapid decline

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

A Swedish version of the 16-item Parkinson fatigue scale (PFS-16).

The PFS-16 is a 16-item fatigue scale for Parkinson's disease (PD) developed in the UK. However, documented translations and psychometric evaluations are sparse. Aim - To translate the PFS-16 into Swedish and conduct initial testing of its psychometric properties. Methods - Following translation, the PFS-16 was administered twice (2 weeks apart) to 30 people with PD (18 men; mean age/PD duration, 60/6.4 years). The PFS-16 uses five response categories (1 = strongly disagree, 5 = strongly agree), and the total score is the mean over item scores (1-5; 5 = more fatigue). An alternative, dichotomised scoring method has also been suggested (total score, 0-16; 16 = more fatigue). Scaling assumptions, floor/ceiling effects, reliability, and correlations with other variables including the generic fatigue scale Functional Assessment of Chronic Illness Therapy - Fatigue scale (FACIT-F) were tested. Results - Scaling assumptions were generally supported for the original scoring [range of mean (SD) item scores, 2.1-3.3 (1-1.4); corrected item-total correlations, ≥0.40], but not for dichotomised scoring [range of mean (SD) item scores, 0.1-0.6 (0.3-0.5); corrected item-total correlations, ≥0.16]. Reliabilities were ≥0.88. Floor effects were absent (original scoring) and >23% (dichotomised scoring); there were no ceiling effects. Correlations with other variables followed expectations (e.g. -0.88 with FACIT-F scores). Conclusions - These observations support the psychometric properties of the Swedish PFS-16, but cautions against dichotomised scoring

Levodopa-carbidopa intestinal gel (LCIG) treatment in routine care of patients with advanced Parkinsons disease: An open-label prospective observational study of effectiveness, tolerability and healthcare costs

Background: Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) can effectively manage motor and non-motor complications in advanced Parkinsons disease (PD). Healthcare costs, quality of life (QoL), effectiveness, and tolerability were assessed in routine care treatment with LCIG. Methods: The seventy-seven patients enrolled in this prospective, open-label, 3-year study in routine medical care were LCIG-naive (N = 37), or had previous LCIG treatment for amp;lt;2 (N = 22), or amp;gt;= 2 (N = 18) years. Healthcare costs were collected monthly. PD symptoms and QoL were assessed with the Unified Parkinsons Disease Rating Scale (UPDRS), 39-item Parkinsons Disease Questionnaire (PDQ-39), and EuroQoL 5-Dimension Visual Analog Scale (EQ-5D VAS); LCIG dose, safety, and tolerability were monitored. Results: Mean monthly costs per patient ( 8226 5952) were similar across cohorts, remained steady during 3-year follow-up, and increased with PD severity and QoL impairment. In LCIG-naive patients, significant improvements compared to baseline were observed on the UPDRS total score and PDQ-39 summary index score through 18 months (n = 24; UPDRS, p = 0.033; PDQ-39, p = 0.049). Symptom control was maintained during 3-year follow-up in LCIG-experienced cohorts. Small changes in mean daily LCIG dose were observed. Adverse events were common and generally related to the device, procedure, levodopa, or laboratory evaluations. Conclusions: Costs in LCIG-treated patients were stable over 3 years. LCIG treatment led to significant improvements in motor function and QoL over 18 months in LCIG-naive patients and no worsening was observed in LCIG-experienced patients over 3 years despite natural PD progression over time. The longterm safety was consistent with the established LCIG profile. (C) 2016 AbbVie Inc. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Funding Agencies|AbbVie Inc.</p