Utility of Huntington's Disease Assessments by Disease Stage: Floor/Ceiling Effects.

Introduction: An understanding of the clinimetric properties of clinical assessments, including their constraints, is critical to sound clinical study and trial design. Utilizing data from Enroll-HD-a global, prospective HD observational study and clinical research platform-we examined several well-established HD clinical assessments across all stages of disease for evidence of instrument constraints, specifically floor/ceiling effects, to inform selection of appropriate instruments for use in future studies/trials and identify gaps in instrument utility over the life-course of the disease. Material and Methods: Analyzing publicly available data from 6,614 HD gene-expansion carriers (HDGECs), we grouped participants into deciles based on baseline CAP score, which ranged from 26 to 229. We used descriptive statistics to characterize data distribution for 25 outcome measures (encompassing motor, function, cognition, and psychiatric/behavioral domains) in each CAP decile. A skewness statistic threshold of ±2 was defined a priori to indicate floor/ceiling effects. Results: We found evidence of floor/ceiling effects in the early premanifest stages of disease for most motor and function assessments (e.g., TMS, TFC) and select cognitive tasks (MMSE, Trail Making tests). Other cognitive assessments, and the HADS-SIS scales, performed well ubiquitously, with no evidence of floor/ceiling effects at any disease stage. Floor/ceiling effects were evident at every disease stage for certain assessments, including PBA-s measures. Ceiling effects were apparent for DCL from onset stages onwards, as expected. Discussion: Developing instruments sensitive to subtle differences in performance at the earlier stages of the disease spectrum, particularly in motor and function domains, is warranted.

PET Molecular Imaging of Phosphodiesterase 10A: An Early Biomarker of Huntington's Disease Progression.

BACKGROUND: Changes in phosphodiesterase 10A enzyme levels may be a suitable biomarker of disease progression in Huntington's disease. OBJECTIVES: To evaluate phosphodiesterase 10A PET imaging as a biomarker of HD progression using the radioligand, [18 F]MNI-659. METHODS: The cross-sectional study (NCT02061722) included 45 Huntington's disease gene-expansion carriers stratified into four disease stages (early and late premanifest and Huntington's disease stages 1 and 2) and 45 age- and sex-matched healthy controls. The primary analysis compared striatal and pallidal phosphodiesterase 10A availability between Huntington's disease gene-expansion carriers and healthy controls as assessed by [18 F]MNI-659 binding. We assessed changes in phosphodiesterase 10A expression using several PET methodologies and compared with previously proposed measures of Huntington's disease progression (PET imaging of D2/3 receptors and anatomical volume loss on MRI). The longitudinal follow-up study (NCT02956148) continued evaluation of phosphodiesterase 10A availability in 35 Huntington's disease gene-expansion carriers at a mean of 18 months from baseline of the cross-sectional study. RESULTS: Primary analyses revealed that phosphodiesterase 10A availability in caudate, putamen, and globus pallidus was significantly lower in Huntington's disease gene-expansion carriers versus healthy controls across all stages. Striatal and pallidal phosphodiesterase 10A availability progressively declined in the premanifest stages and appeared to plateau between stages 1 and 2. The percentage decline of phosphodiesterase 10A availability measured cross-sectionally between Huntington's disease gene-expansion carriers and healthy controls was greater than that demonstrated by D2/3 receptor availability or volumetric changes. Annualized rates of phosphodiesterase 10A change showed a statistically significant decline between the cross-sectional study and follow-up. CONCLUSIONS: [18 F]MNI-659 PET imaging is a biologically plausible biomarker of Huntington's disease progression that is more sensitive than the dopamine-receptor and volumetric methods currently used. © 2020 International Parkinson and Movement Disorder Society.

Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D2/3 receptors and sub-cortical volumes in the human basal ganglia: A PET study with 18F-MNI-659 and 11C-raclopride with correction for partial volume effect.

Phosphodiesterase 10A enzyme (PDE10A) is an important striatal target that has been shown to be affected in patients with neurodegenerative disorders, particularly Huntington´s disease (HD). PDE10A is expressed on striatal neurones in basal ganglia where other known molecular targets are enriched such as dopamine D2/3 receptors (D2/3 R). The aim of this study was to examine the availability of PDE10A enzyme in relation with age and gender and to compare those changes with those related to D2/3 R and volumes in different regions of the basal ganglia. As a secondary objective we examined the relative distribution of D2/3 R and PDE10A enzyme in the striatum and globus pallidus. Forty control subjects (20F/20M; age: 44±11y, age range 27-69) from an ongoing positron emission tomography (PET) study in HD gene expansion carriers were included. Subjects were examined with PET using the high-resolution research tomograph (HRRT) and with 3T magnetic resonance imaging (MRI). The PDE10A radioligand 18F-MNI-659 and D2/3 R radioligand 11C-raclopride were used. The outcome measure was the binding potential (BPND) estimated with the two-tissue compartment model (18F-MNI-659) and the simplified reference tissue model (11C-raclopride) using the cerebellum as reference region. The PET data were corrected for partial volume effects. In the striatum, PDE10A availability showed a significant age-related decline that was larger compared to the age-related decline of D2/3 R availability and to the age-related decline of volumes measured with MRI. In the globus pallidus, a less pronounced decline of PDE10A availability was observed, whereas D2/3 R availability and volumes seemed to be rather stable with aging. The distribution of the PDE10A enzyme was different from the distribution of D2/3 R, with higher availability in the globus pallidus. These results indicate that aging is associated with a considerable physiological reduction of the availability of PDE10A enzyme in the striatum. Moreover as result of the analysis, in the striatum for both the molecular targets, we observed a gender effect with higher BPND the female group.

Data Analytics from Enroll-HD, a Global Clinical Research Platform for Huntington's Disease.

BACKGROUND: The study of complex neurodegenerative diseases is moving away from hypothesis-driven biological methods toward large scale multimodal approaches, requiring standardized collaborative efforts. Enroll-HD exemplifies such an integrated clinical research platform, designed and implemented to meet the research and clinical needs of Huntington's disease (HD). The aim of this study was to describe the unique organization of Enroll-HD and report baseline data analyses of its core study. METHODS: The Enroll-HD platform incorporates electronic data capture, biosampling, and a longitudinal observational study spanning four continents (ClinicalTrials.gov Identifier: NCT01574053). The primary study population includes HD gene expansion carriers (HDGECs; CAG expansion ≥36), subdivided into manifest/premanifest HD. The control population consists of genotype-negative first-degree relatives and family controls not genetically related. The study includes 10 core clinical assessments covering motor, cognitive, and behavioral domains. RESULTS: This data set comprises 1,534 participants (HDGEC = 1,071; controls = 463). Participant retention was high; 42 participants prematurely withdrew from the study. Mean ± standard deviation SD CAG repeat size was 43.5 ± 3.5 for HDGECs and 19.8 ± 3.4 for controls. Motor and behavioral assessments identified numerical differences between controls and HDGECs (manifest > premanifest > controls). Functional and independence assessments were generally similar for the premanifest and control groups with overlap in range of scores obtained. For the majority of cognitive tests, there were large differences between participants with manifest HD and all other groups. CONCLUSIONS: These first data from the Enroll-HD clinical research platform demonstrate the maturity and potential of the platform in collecting high-quality, clinically relevant data. Future data sets will be substantially larger as the platform expands longitudinally and regionally.

Long-term effects of rasagiline and the natural history of treated Parkinson's disease.

BACKGROUND: The Attenuation of Disease progression with Azilect GIven Once-daily (ADAGIO) delayed-start study demonstrated a benefit of early-start treatment with rasagiline 1 mg/day versus delayed-start treatment in PD. This follow-up study aimed to assess whether these benefits persist and the clinical progression rate during long-term naturalistic treatment. METHODS: The ADAGIO Follow-Up study was initiated approximately 26 months after completion of the ADAGIO study. Patients were followed for 3 years and were treated in an open-label manner with rasagiline 1 mg/day and any other PD treatment that was deemed appropriate. Changes from follow-up baseline to study end in UPDRS scores, and the emergence of clinical milestones (including unsteady gait and/or balance impairment, falls, freezing of gait, and cognitive decline) were assessed. RESULTS: The study enrolled 683 patients (58% of the full ADAGIO cohort and 72% of ADAGIO completers). At baseline, mean time from diagnosis was 46.9 months and UPDRS total score was 25.6 units. There were no significant differences in UPDRS total or subscale scores or time to any milestone between patients who were in the original ADAGIO early-start group versus those in the delayed-start group. At study end, patients (total cohort) had worsened by a mean ± standard deviation of 6.0 ± 11.6 UPDRS total units, 3.3 ± 8.6 UPDRS motor units and 2.0 ± 4.0 UPDRS activities of daily living (ADL) units. Overall, 43.6% of patients had onset of unsteady gait/balance impairment, 35.7% had fallen, 26.2% had freezing of gait, and 33.1% had cognitive decline. CONCLUSIONS: The ADAGIO Follow-Up study failed to demonstrate long-term benefits of early-start rasagiline treatment in the prior ADAGIO study. Clinically important milestones occurred in a substantial proportion of patients. © 2016 International Parkinson and Movement Disorder Society.

Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial.

BACKGROUND: Multiple system atrophy is a complex neurodegenerative disorder for which no effective treatment exists. We aimed to assess the effect of rasagiline on symptoms and progression of the parkinsonian variant of multiple system atrophy. METHODS: We did this randomised, double-blind, placebo-controlled trial between Dec 15, 2009, and Oct 20, 2011, at 40 academic sites specialised in the care of patients with multiple systemic atrophy across 12 countries. Eligible participants aged 30 years or older with possible or probable parkinsonian variant multiple system atrophy were randomly assigned (1:1), via computer-generated block randomisation (block size of four), to receive either rasagiline 1 mg per day or placebo. Randomisation was stratified by study centre. The investigators, study funder, and personnel involved in patient assessment, monitoring, analysis and data management were masked to group assignment. The primary endpoint was change from baseline to study end in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (parts I and II). Analysis was by modified intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00977665. FINDINGS: We randomly assigned 174 participants to the rasagiline group (n=84) or the placebo group (n=90); 21 (25%) patients in the rasagiline group and 15 (17%) in the placebo group withdrew from the study early. At week 48, patients in the rasagiline group had progressed by an adjusted mean of 7·2 (SE 1·2) total UMSARS units versus 7·8 (1·1) units in those in the placebo group. This treatment difference of -0·60 (95% CI -3·68 to 2·47; p=0·70) was not significant. 68 (81%) patients in the rasagiline group and 67 (74%) patients in the placebo group reported adverse events, and we recorded serious adverse events in 29 (35%) versus 23 (26%) patients. The most common adverse events in the rasagiline group were dizziness (n=10 [12%]), peripheral oedema (n=9 [11%]), urinary tract infections (n=9 [11%]), and orthostatic hypotension (n=8 [10%]). INTERPRETATION: In this population of patients with the parkinsonian variant of multiple system atrophy, treatment with rasagiline 1 mg per day did not show a significant benefit as assessed by UMSARS. The study confirms the sensitivity of clinical outcomes for multiple system atrophy to detect clinically significant decline, even in individuals with early disease. FUNDING: Teva Pharmaceutical Industries and H Lundbeck A/S.

A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes.

BACKGROUND: The ADAGIO study investigated whether rasagiline has disease-modifying effects in Parkinson's disease. Rasagiline 1 mg per day, but not 2 mg per day, was shown to be efficacious in the primary analysis. Here, we report additional secondary and post-hoc analyses of the ADAGIO study. METHODS: ADAGIO was a placebo-controlled, double-blind, multicentre, delayed-start study, in which 1176 patients with untreated early Parkinson's disease were randomly assigned to receive rasagiline 1 mg or 2 mg per day for 72 weeks (early-start groups) or placebo for 36 weeks followed by rasagiline 1 mg or 2 mg per day for 36 weeks (delayed-start groups). We assessed the need for additional antiparkinsonian therapy and changes in non-motor experiences of daily living and fatigue scales (prespecified outcomes) and changes in unified Parkinson's disease rating scale (UPDRS) scores and subscores in placebo and active groups (post-hoc outcomes). The ADAGIO study is registered with ClinicalTrials.gov, number NCT00256204. FINDINGS: The need for additional antiparkinsonian therapy was reduced with rasagiline 1 mg (25 of 288 [9%] patients) and 2 mg (26 of 293 [9%]) versus placebo (108 of 593 [18%]; odds ratio for 1 mg rasagiline vs placebo 0·41, 95% CI 0·25-0·65, p=0·0002; 2 mg rasagiline vs placebo 0·41, 0·26-0·64, p=0·0001). At week 36, both doses significantly improved UPDRS motor subscores compared with placebo (1 mg rasagiline mean difference -1·88 [SE 0·35]; 2 mg rasagiline -2·18 [0·35]; both p<0·0001) and activities of daily living subscores (ADL; 1 mg rasagiline -0·86 [0·18]; 2 mg rasagiline -0·88 [0·18]; both p<0·0001), and 1 mg rasagiline significantly improved UPDRS mentation subscore (-0·22 [0·08]; p=0·004). At week 72, the only significant difference between early-start and delayed-start groups was for ADL subscore with the 1 mg dose (-0·62 [0·29]; p=0·035). When assessed for the effect on non-motor symptoms at week 36, both doses showed benefits on the Parkinson fatigue scale versus placebo (1 mg rasagiline mean difference -0·14 [SE 0·05], p=0·0032; 2 mg rasagiline -0·19 [0·05], p<0·0001), and the 1 mg dose showed benefits on the scale for non-motor experiences of daily living compared with placebo (mean difference -0·33 [0·17]; p=0·049). The rate of progression of total UPDRS score for patients in the placebo group was 4·3 points [SE 0·3] over 36 weeks, with extrapolation to about 6 units per year. In the placebo group, patients with the lowest quartile of baseline UPDRS scores (≤14; n=160) progressed more slowly than did those with highest scores (>25·5; n=145; mean difference -3·46 [SE 0·77]; p<0·0001). INTERPRETATION: These findings show that rasagiline delayed the need for symptomatic antiparkinsonian drugs and emphasise the contribution of the UPDRS ADL in the response of the rasagiline 1 mg per day early-start versus delayed-start group. The rate of UPDRS deterioration was less than was anticipated from previous studies and correlated with baseline severity. Understanding of the pattern of UPDRS deterioration is essential to assess disease modification. FUNDING: Teva Pharmaceutical Industries and H Lundbeck A/S.

Long-term efficacy of rasagiline in early Parkinson's disease.

This study was designed to follow the long-term efficacy, safety, and tolerability of rasagiline for Parkinson's disease (PD) with data collected from all patients who had ever taken rasagiline during the 12-month TEMPO monotherapy trial (N = 398) and subsequent open-label extension. Patients were followed for up to 6.5 years with a mean of 3.5 +/- 2.1 years. After 12 months, additional PD medications were added as required. Of patients remaining in the trial at 2 years, 46% were maintained on rasagiline monotherapy. The majority of patients received a dopamine agonist prior to levodopa as the first additional dopaminergic agent. Analysis using a Kaplan-Meier method indicated that by 5.4 years only 25% of patients progressed to Hoehn & Yahr stage III. Rasagiline was well tolerated, with 11.3% of patients (45/398) withdrawing because of an adverse event. Rasagiline therapy for PD was effective, well tolerated, and safe in this long-term trial.

Long-term outcome of early versus delayed rasagiline treatment in early Parkinson's disease.

The purpose of this study to compare the long-term clinical outcome of early versus delayed rasagiline treatment in early Parkinson's disease (PD). Subjects (N = 404) were randomly assigned to initial treatment with rasagiline (early-start group) or placebo for 6 months followed by rasagiline (delayed-start group) in the TEMPO study. Subjects who chose to participate in an open-label extension (N = 306) continued to receive rasagiline as well as other PD medications as needed. Average (+/-SD) duration in the study was 3.6 +/- 2.1 years; 177 subjects received rasagiline for > or =5.0 years. Over the entire 6.5-year follow-up period, the adjusted mean difference in change from baseline in total UPDRS scores was 2.5 units (SE 1.1; P = 0.021) or 16% (SE 5.7; P = 0.006) in favor of the early-start versus delayed-start rasagiline group. Although the interaction between treatment and time was significant, values for the early-start group were better than the delayed-start group across all time points. Significantly less worsening (percent change) in total UPDRS scores was observed in the early-start group at the time points 0.5, 1.5, 2.0, 3.0, 4.5, 5.0, and 5.5 years (P < 0.05). Compared to delayed start, early initiation of rasagiline provided long-term clinical benefit, even in the face of treatment with other dopaminergic agents. This might reflect enduring benefits due to neuroprotection or effects on compensatory mechanisms in early PD.