Dilan Athauda

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

BACKGROUND Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinsons disease. We investigated whether these effects would be apparent in a clinical trial. METHODS In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinsons disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25-75 years, had idiopathic Parkinsons disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. FINDINGS Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. INTERPRETATION Exenatide had positive effects on practically defined off-medication motor scores in Parkinsons disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinsons disease, and effects on everyday symptoms should be examined in longer-term trials. FUNDING Michael J Fox Foundation for Parkinsons Research.

Is Exenatide a Treatment for Parkinson’s Disease?

There is growing interest in the use of glucagon-like peptide-1 agonists as treatments for Parkinsons disease following the recent publication of the results of the Exenatide-PD trial. In this randomized, double-blind, placebo controlled trial, patients with moderate stage Parkinsons disease treated with once-weekly subcutaneous injections of exenatide 2 mg (Bydureon) for 48 weeks, had a 3.5-point advantage over the placebo group in the Movement Disorders Society Unified Parkinsons Disease Rating Scale (MDS-UPDRS) motor subscale (Part 3) in the practically defined OFF medication state, 12 weeks after cessation of the trial drug. In this article, we discuss some of the important issues of relevance to this trial, with regards to trial design, patient selection, choice of outcome measure and also place into context the implications these results have for patients with Parkinsons disease and the wider research community.

Technologies Assessing Limb Bradykinesia in Parkinson’s Disease

Background: The MDS-UPDRS (Movement Disorders Society – Unified Parkinson’s Disease Rating Scale) is the most widely used scale for rating impairment in PD. Subscores measuring bradykinesia have low reliability that can be subject to rater variability. Novel technological tools can be used to overcome such issues. Objective: To systematically explore and describe the available technologies for measuring limb bradykinesia in PD that were published between 2006 and 2016. Methods: A systematic literature search using PubMed (MEDLINE), IEEE Xplore, Web of Science, Scopus and Engineering Village (Compendex and Inspec) databases was performed to identify relevant technologies published until 18 October 2016. Results: 47 technologies assessing bradykinesia in PD were identified, 17 of which offered home and clinic-based assessment whilst 30 provided clinic-based assessment only. Of the eligible studies, 7 were validated in a PD patient population only, whilst 40 were tested in both PD and healthy control groups. 19 of the 47 technologies assessed bradykinesia only, whereas 28 assessed other parkinsonian features as well. 33 technologies have been described in additional PD-related studies, whereas 14 are not known to have been tested beyond the pilot phase. Conclusion: Technology based tools offer advantages including objective motor assessment and home monitoring of symptoms, and can be used to assess response to intervention in clinical trials or routine care. This review provides an up-to-date repository and synthesis of the current literature regarding technology used for assessing limb bradykinesia in PD. The review also discusses the current trends with regards to technology and discusses future directions in development.

GBA-Associated Parkinson's Disease: Progression in a Deep Brain Stimulation Cohort

BACKGROUND Recent evidence suggests that glucosidase beta acid (GBA) mutations predispose Parkinsons disease (PD) patients to a greater burden of cognitive impairment and non-motor symptoms. This emerging knowledge has not yet been considered in patients who have undergone deep brain stimulation (DBS); a surgery that is generally contraindicated in those with cognitive deficits. OBJECTIVE To explore the long-term phenotypic progression of GBA-associated PD, in a DBS cohort. METHODS Thirty-four PD patients who had undergone DBS surgery between 2002 and 2011 were included in this study; 17 patients with GBA mutations were matched to 17 non-carriers. Clinical evaluation involved the administration of four assessments: The Mattis Dementia Rating Scale was used to assess cognitive function; non-motor symptoms were assessed using the Non-Motor Symptom Assessment Scale for PD; quality of life was measured using the Parkinsons Disease Questionnaire; and motor symptoms were evaluated using part III of the Movement Disorders Society Unified Parkinsons Disease Rating Scale, in on-medication/on-stimulation conditions. Levodopa equivalent doses (LED) and DBS settings were compared with clinical outcomes. RESULTS At a mean follow-up of 7.5 years after DBS, cognitive impairment was more prevalent (70% vs 19%) and more severe in GBA mutation carriers compared to non-carriers (60% vs 6% were severely impaired). Non-motor symptoms were also more severe and quality of life more impaired in GBA-associated PD. Motor symptoms, LED, and stimulation settings were not significantly different between groups at follow-up. CONCLUSIONS GBA status appears to be an important predictor for non-motor symptom disease progression, after deep brain stimulation surgery.

Thalamic‐Caudal Zona Incerta Deep Brain Stimulation for Refractory Orthostatic Tremor: A Report of 3 Cases

Orthostatic tremor (OT) is a rare, disabling movement disorder characterized by the development of a high‐frequency tremor of the lower limbs and feelings of unsteadiness upon standing, which compel the patient to sit down or walk. Medical therapy is often unsatisfactory. Previous reports suggest that deep brain stimulation of the ventral intermediate nucleus of the thalamus may improve clinical outcomes. The authors report 3 patients who had intractable orthostatic tremor treated with bilateral deep brain stimulation of the ventral intermediate nucleus of the thalamus‐caudal zona incerta, resulting in improved and sustained clinical improvements in symptoms, although there were no apparent changes in the underlying tremor frequency or onset.

The BRadykinesia Akinesia INcoordination (BRAIN) tap test: capturing the sequence effect

Background The BRAIN tap test is an online keyboard tapping task that has been previously validated to assess upper limb motor function in Parkinson’s disease (PD). Objectives To develop a new parameter which detects a sequence effect and to reliably distinguish between PD patients ‘on’ and ‘off’ medication. Alongside, we sought to validate a mobile version of the test for use on smartphones and tablet devices. Methods BRAIN test scores in 61 patients with PD and 93 healthy controls were compared. A range of established parameters captured speed and accuracy of alternate taps. The new VS (Velocity Score) recorded the inter-tap speed. Decrement in the VS was used as a marker for the sequence effect. In the validation phase, 19 PD patients and 19 controls were tested using multiple types of hardware platforms including smart devices. Results Quantified slopes from the VS demonstrated bradykinesia (sequence effect) in PD patients (slope cut-off −0.002) with sensitivity of 58% and specificity of 81% (discovery phase of the study) and sensitivity of 65% and specificity of 88% (validation phase). All BRAIN test parameters differentiated between ‘on’ medication and ‘off’ medication states in PD. Most BRAIN tap test parameters had high test-retest reliability values (ICC>0.75). Differentiation between PD patients and controls was possible on all hardware versions of the test. Conclusion The BRAIN tap test is a simple, user-friendly and free-to-use tool for assessment of upper limb motor dysfunction in PD, which now includes a measure of bradykinesia.

Glucagon like peptides (GLP‐1) perspectives in synucleinopathies treatment

There is great interest in repurposing drugs (i.e. evaluating the potential of drugs known to be safe in humans with an existing licensed indication) to examine additional possible therapeutic effects in other conditions. This type of approach is being widely embraced in the search for disease-modifying drugs in Parkinson’s disease (PD). Agents that have been used as cancer treatments (Nilotinib), anti-hypertensives (Isradipine), health food supplements (Inosine), as well as a number of diabetes drugs (including Pioglitazone and Exenatide) have been proposed as potential disease-modifying drugs and have successfully secured funding for clinical trials to formally assess their value. In this paper, we will focus on how and why drugs influencing the GLP-1 receptor have become of increasing interest in PD and potentially other alpha synucleinopathies.

Glucagon-like Peptides (GLP-1) Perspectives in Synucleinopathies Treatment: GLP-1 & Synucleinopathies

There is great interest in repurposing drugs (i.e. evaluating the potential of drugs known to be safe in humans with an existing licensed indication) to examine additional possible therapeutic effects in other conditions. This type of approach is being widely embraced in the search for disease-modifying drugs in Parkinson’s disease (PD). Agents that have been used as cancer treatments (Nilotinib), anti-hypertensives (Isradipine), health food supplements (Inosine), as well as a number of diabetes drugs (including Pioglitazone and Exenatide) have been proposed as potential disease-modifying drugs and have successfully secured funding for clinical trials to formally assess their value. In this paper, we will focus on how and why drugs influencing the GLP-1 receptor have become of increasing interest in PD and potentially other alpha synucleinopathies.