Amyloid processing in COVID-19-associated neurological syndromes.

SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1ß, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPß (p = 0.03) as well as amyloid ß (Aß) 40 (p = 5.2 × 10-8 ), Aß42 (p = 3.5 × 10-7 ), and Aß42/Aß40 ratio (p = 0.005) compared to controls. Patients with COVID-19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPß. Conversely, GFAp was significantly reduced in COVID-19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPß. COVID-19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPß. A sensitivity analysis of COVID-19-associated GBS revealed a non-significant trend toward greater impairment of amyloid processing in COVID-19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID-19-associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.

Combining biomarkers for prognostic modelling of Parkinson's disease.

BACKGROUND: Patients with Parkinson's disease (PD) have variable rates of progression. More accurate prediction of progression could improve selection for clinical trials. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be further improved by blood biomarkers. OBJECTIVE: To determine if blood biomarkers (serum neurofilament light (NfL) and genetic status (glucocerebrosidase, GBA and apolipoprotein E (APOE))) are useful in addition to clinical measures for prognostic modelling in PD. METHODS: We evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients' genetic (GBA and APOE) status. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model, and explored how blood biomarkers compared with clinical variables in distinguishing prognostic phenotypes . RESULTS: 291 patients were assessed in this study. Baseline serum NfL was associated with baseline cognitive status. Nfl predicted a shorter time to dementia, postural instability and death (dementia-HR 2.64; postural instability-HR 1.32; mortality-HR 1.89) whereas APOEe4 status was associated with progression to dementia (dementia-HR 3.12, 95% CI 1.63 to 6.00). NfL levels and genetic variables predicted unfavourable progression to a similar extent as clinical predictors. The combination of clinical, NfL and genetic data produced a stronger prediction of unfavourable outcomes compared with age and gender (area under the curve: 0.74-age/gender vs 0.84-ALL p=0.0103). CONCLUSIONS: Clinical trials of disease-modifying therapies might usefully stratify patients using clinical, genetic and NfL status at the time of recruitment.

The Impact of Type 2 Diabetes in Parkinson's Disease.

BACKGROUND: Type 2 diabetes (T2DM) is an established risk factor for developing Parkinson's disease (PD), but its effect on disease progression is not well understood. OBJECTIVE: The aim of this study was to investigate the influence of T2DM on aspects of disease progression in PD. METHODS: We analyzed data from the Tracking Parkinson's study to examine the effects of comorbid T2DM on PD progression and quality of life by comparing symptom severity scores assessing a range of motor and nonmotor symptoms. RESULTS: We identified 167 (8.7%) patients with PD and T2DM (PD + T2DM) and 1763 (91.3%) patients with PD without T2DM (PD). After controlling for confounders, patients with T2DM had more severe motor symptoms, as assessed by Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (25.8 [0.9] vs. 22.5 [0.3] P = 0.002), and nonmotor symptoms, as assessed by Non-Motor Symptoms Scale total (38.4 [2.5] vs. 31.8 [0.7] P < 0.001), and were significantly more likely to report loss of independence (odds ratio, 2.08; 95% confidence interval [CI]: 1.34-3.25; P = 0.001) and depression (odds ratio, 1.62; CI: 1.10-2.39; P = 0.015). Furthermore, over time, patients with T2DM had significantly faster motor symptom progression (P = 0.012), developed worse mood symptoms (P = 0.041), and were more likely to develop substantial gait impairment (hazard ratio, 1.55; CI: 1.07-2.23; P = 0.020) and mild cognitive impairment (hazard ratio, 1.7; CI: 1.24-2.51; P = 0.002) compared with the PD group. CONCLUSIONS: In the largest study to date, T2DM is associated with faster disease progression in Parkinson's, highlighting an interaction between these two diseases. Because it is a potentially modifiable metabolic state, with multiple peripheral and central targets for intervention, it may represent a target for alleviating parkinsonian symptoms and slowing progression to disability and dementia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diabetes medications and risk of Parkinson's disease: a cohort study of patients with diabetes.

The elevated risk of Parkinson's disease in patients with diabetes might be mitigated depending on the type of drugs prescribed to treat diabetes. Population data for risk of Parkinson's disease in users of the newer types of drugs used in diabetes are scarce. We compared the risk of Parkinson's disease in patients with diabetes exposed to thiazolidinediones (glitazones), glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, with the risk of Parkinson's disease of users of any other oral glucose lowering drugs. A population-based, longitudinal, cohort study was conducted using historic primary care data from The Health Improvement Network. Patients with a diagnosis of diabetes and a minimum of two prescriptions for diabetes medications between January 2006 and January 2019 were included in our study. The primary outcome was the first recording of a diagnosis of Parkinson's disease after the index date, identified from clinical records. We compared the risk of Parkinson's disease in individuals treated with glitazones or DPP4 inhibitors and/or GLP-1 receptor agonists to individuals treated with other antidiabetic agents using a Cox regression with inverse probability of treatment weighting based on propensity scores. Results were analysed separately for insulin users. Among 100 288 patients [mean age 62.8 years (standard deviation 12.6)], 329 (0.3%) were diagnosed with Parkinson's disease during the median follow-up of 3.33 years. The incidence of Parkinson's disease was 8 per 10 000 person-years in 21 175 patients using glitazones, 5 per 10 000 person-years in 36 897 patients using DPP4 inhibitors and 4 per 10 000 person-years in 10 684 using GLP-1 mimetics, 6861 of whom were prescribed GTZ and/or DPP4 inhibitors prior to using GLP-1 mimetics. Compared with the incidence of Parkinson's disease in the comparison group (10 per 10 000 person-years), adjusted results showed no evidence of any association between the use of glitazones and Parkinson's disease [incidence rate ratio (IRR) 1.17; 95% confidence interval (CI) 0.76-1.63; P = 0.467], but there was strong evidence of an inverse association between use of DPP4 inhibitors and GLP-1 mimetics and the onset of Parkinson's disease (IRR 0.64; 95% CI 0.43-0.88; P < 0.01 and IRR 0.38; 95% CI 0.17-0.60; P < 0.01, respectively). Results for insulin users were in the same direction, but the overall size of this group was small. The incidence of Parkinson's disease in patients diagnosed with diabetes varies substantially depending on the treatment for diabetes received. The use of DPP4 inhibitors and/or GLP-1 mimetics is associated with a lower rate of Parkinson's disease compared to the use of other oral antidiabetic drugs.

Short Versus Conventional Pulse-Width Deep Brain Stimulation in Parkinson's Disease: A Randomized Crossover Comparison.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective therapy for selected Parkinson's disease patients with motor fluctuations, but can adversely affect speech and axial symptoms. The use of short pulse width (PW) has been shown to expand the therapeutic window acutely, but its utility in reducing side effects in chronic STN-DBS patients has not been evaluated. OBJECTIVE: To compare the effect of short PW settings using 30-µs with conventional 60-µs settings on stimulation-induced dysarthria in Parkinson's disease patients with previously implanted STN-DBS systems. METHODS: In this single-center, double-blind, randomized crossover trial, we assigned 16 Parkinson's disease patients who had been on STN-DBS for a mean of 6.5 years and exhibited moderate dysarthria to 30-µs or 60-µs settings for 4 weeks followed by the alternative PW setting for a further 4 weeks. The primary outcome was difference in dysarthric speech measured by the Sentence Intelligibility Test between study baseline and the 2 PW conditions. Secondary outcomes included motor, nonmotor, and quality of life measures. RESULTS: There was no difference in the Sentence Intelligibility Test scores between baseline and the 2 treatment conditions (P = 0.25). There were also no differences noted in motor, nonmotor, or quality of life scores. The 30-µs settings were well tolerated, and adverse event rates were similar to those at conventional PW settings. Post hoc analysis indicated that patients with dysarthria and a shorter duration of DBS may be improved by short PW stimulation. CONCLUSIONS: Short PW settings using 30 µs did not alter dysarthric speech in chronic STN-DBS patients. A future study should evaluate whether patients with shorter duration of DBS may be helped by short PW settings. © 2019 International Parkinson and Movement Disorder Society.

Post hoc analysis of the Exenatide-PD trial-Factors that predict response.

Exenatide, a glucagon-like peptide-1 agonist and a licensed treatment for Type 2 diabetes significantly reduced deterioration in motor symptoms in patients with Parkinson's disease in a randomized, placebo-controlled trial. In addition, there were trends favouring the exenatide group in assessments of nonmotor symptoms, cognition, and quality of life. The aim of this exploratory post hoc analysis was to generate new hypotheses regarding (a) whether candidate baseline factors might predict the magnitude of response to exenatide; and (b) whether the beneficial effects of exenatide reported for the overall population are consistent in various subgroups of patients. Univariate and multivariate analyses were conducted to determine possible predictors of motor response to exenatide in this cohort. Potential treatment by subgroup interactions for changes in; motor severity, nonmotor symptoms, cognition, and quality of life after 48-weeks treatment with exenatide were evaluated among post hoc subgroups defined by age, motor phenotype, disease duration, disease severity, body mass index (BMI), and insulin resistance. In the subgroup analyses, exenatide once-weekly was associated with broadly improved outcome measures assessing motor severity, nonmotor symptoms, cognition, and quality of life across all subgroups, however, tremor-dominant phenotype and lower Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part-2 scores predicted greatest motor response to exenatide and there was an indication that patients with older age of onset and disease duration over 10 years responded less well. While patients with a range of demographic and clinical factors can potentially benefit from exenatide once-weekly, these data support an emphasis towards recruiting patients at earlier disease in future planned clinical trials of gluacagon-like peptide-1 (GLP-1) receptor agonists in Parkinson's disease (PD).

Proximity extension assay testing reveals novel diagnostic biomarkers of atypical parkinsonian syndromes.

OBJECTIVE: The high degree of clinical overlap between atypical parkinsonian syndromes (APS) and Parkinson's disease (PD) makes diagnosis challenging. We aimed to identify novel diagnostic protein biomarkers of APS using multiplex proximity extension assay (PEA) testing. METHODS: Cerebrospinal fluid (CSF) samples from two independent cohorts, each consisting of APS and PD cases, and controls, were analysed for neurofilament light chain (NF-L) and Olink Neurology and Inflammation PEA biomarker panels. Whole-cohort comparisons of biomarker concentrations were made between APS (n=114), PD (n=37) and control (n=34) groups using logistic regression analyses that included gender, age and disease duration as covariates. RESULTS: APS versus controls analyses revealed 11 CSF markers with significantly different levels in cases and controls (p<0.002). Four of these markers also reached significance (p<0.05) in APS versus PD analyses. Disease-specific analyses revealed lower group levels of FGF-5, FGF-19 and SPOCK1 in multiple system atrophy compared with progressive supranuclear palsy and corticobasal syndrome. Receiver operating characteristic curve analyses suggested that the diagnostic accuracy of NF-L was superior to the significant PEA biomarkers in distinguishing APS, PD and controls. The biological processes regulated by the significant proteins include cell differentiation and immune cell migration. Delta and notch-like epidermal growth factor-related receptor (DNER) had the strongest effect size in APS versus controls and APS versus PD analyses. DNER is highly expressed in substantia nigra and is an activator of the NOTCH1 pathway which has been implicated in the aetiology of other neurodegenerative disorders including Alzheimer's disease. CONCLUSIONS: PEA testing has identified potential novel diagnostic biomarkers of APS.

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 Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials. FUNDING: Michael J Fox Foundation for Parkinson's Research.

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells.

The aberrant misfolding and subsequent conversion of monomeric protein into amyloid aggregates characterises many neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. These aggregates are highly heterogeneous in structure, generally of low abundance and typically smaller than the diffraction limit of light (≈250 nm). To overcome the challenges these characteristics pose to the study of endogenous aggregates formed in cells, we have developed a method to characterise them at the nanometre scale without the need for a conjugated fluorophore. Using a combination of DNA PAINT and an amyloid-specific aptamer, we demonstrate that this technique is able to detect and super-resolve a range of aggregated species, including those formed by α-synuclein and amyloid-ß. Additionally, this method enables endogenous protein aggregates within cells to be characterised. We found that neuronal cells derived from patients with Parkinson's disease contain a larger number of protein aggregates than those from healthy controls.

Glial fibrillary acidic protein antibody-positive meningoencephalomyelitis.

Glial fibrillary acidic protein antibody-positive meningoencephalomyelitis is a newly described, possibly under-recognised, severe inflammatory condition of the nervous system. The clinical presentation is variable but most commonly is a combination of meningitis, encephalitis and myelitis; other manifestations may include seizures, psychiatric symptoms and tremor. There is a significant association with malignancies, often occult, and with other autoimmune conditions. Although the disease responds well to corticosteroids acutely, it typically relapses when these are tapered, and so patients need long-term immunosuppression. We report a young man presenting with subacute meningoencephalitis and subsequent myelitis, and discuss the typical presentation and management of this severe but treatable condition.

Clinically silent idiopathic Parkinson's disease unmasked by valproate use: a brief report.

Valproate is an important but uncommon cause of drug induced parkinsonism in the elderly. The development of symptoms after valproate onset is unpredictable, and severity of symptoms is unrelated to plasma levels. However, though the majority of cases improve after drug cessation, parkinsonian symptoms can persist and should prompt investigation into underlying degenerative parkinsonism, as valproate can unmask idiopathic Parkinson's disease in susceptible individuals. This case describes a patient on chronic valproate therapy developing a severely disabling akinetic-rigid syndrome, only partially reversed on stopping valproate. We hypothesise that an increase in valproate dosage unmasked clinically silent Parkinson's disease. The patient made an excellent recovery following cessation of valproate and commencement of dopaminergic therapy.

Clinical outcomes after MRI connectivity-guided radiofrequency thalamotomy for tremor.

OBJECTIVE: Radiofrequency thalamotomy (RF-T) is an established treatment for refractory tremor. It is unclear whether connectivity-guided targeting strategies could further augment outcomes. The aim of this study was to evaluate the efficacy and safety of MRI connectivity-guided RF-T in severe tremor. METHODS: Twenty-one consecutive patients with severe tremor (14 with essential tremor [ET], 7 with Parkinson's disease [PD]) underwent unilateral RF-T at a single institution between 2017 and 2020. Connectivity-derived thalamic segmentation was used to guide targeting. Changes in the Fahn-Tolosa-Marin Rating Scale (FTMRS) were recorded in treated and nontreated hands as well as procedure-related side effects. RESULTS: Twenty-three thalamotomies were performed (with 2 patients receiving a repeated intervention). The mean postoperative assessment time point was 14.1 months. Treated-hand tremor scores improved by 63.8%, whereas nontreated-hand scores deteriorated by 10.1% (p < 0.01). Total FTMRS scores were significantly better at follow-up compared with baseline (mean 34.7 vs 51.7, p = 0.016). Baseline treated-hand tremor severity (rho = 0.786, p < 0.01) and total FTMRS score (rho = 0.64, p < 0.01) best correlated with tremor improvement. The most reported side effect was mild gait ataxia (n = 11 patients). CONCLUSIONS: RF-T guided by connectivity-derived segmentation is a safe and effective option for severe tremor in both PD and ET.

Prediction of mechanistic subtypes of Parkinson's using patient-derived stem cell models.

Parkinson's disease is a common, incurable neurodegenerative disorder that is clinically heterogeneous: it is likely that different cellular mechanisms drive the pathology in different individuals. So far it has not been possible to define the cellular mechanism underlying the neurodegenerative disease in life. We generated a machine learning-based model that can simultaneously predict the presence of disease and its primary mechanistic subtype in human neurons. We used stem cell technology to derive control or patient-derived neurons, and generated different disease subtypes through chemical induction or the presence of mutation. Multidimensional fluorescent labelling of organelles was performed in healthy control neurons and in four different disease subtypes, and both the quantitative single-cell fluorescence features and the images were used to independently train a series of classifiers to build deep neural networks. Quantitative cellular profile-based classifiers achieve an accuracy of 82%, whereas image-based deep neural networks predict control and four distinct disease subtypes with an accuracy of 95%. The machine learning-trained classifiers achieve their accuracy across all subtypes, using the organellar features of the mitochondria with the additional contribution of the lysosomes, confirming the biological importance of these pathways in Parkinson's. Altogether, we show that machine learning approaches applied to patient-derived cells are highly accurate at predicting disease subtypes, providing proof of concept that this approach may enable mechanistic stratification and precision medicine approaches in the future.

Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson's disease in midbrain dopaminergic neurons.

Mutations in the SNCA gene cause autosomal dominant Parkinson's disease (PD), with loss of dopaminergic neurons in the substantia nigra, and aggregation of α-synuclein. The sequence of molecular events that proceed from an SNCA mutation during development, to end-stage pathology is unknown. Utilising human-induced pluripotent stem cells (hiPSCs), we resolved the temporal sequence of SNCA-induced pathophysiological events in order to discover early, and likely causative, events. Our small molecule-based protocol generates highly enriched midbrain dopaminergic (mDA) neurons: molecular identity was confirmed using single-cell RNA sequencing and proteomics, and functional identity was established through dopamine synthesis, and measures of electrophysiological activity. At the earliest stage of differentiation, prior to maturation to mDA neurons, we demonstrate the formation of small ß-sheet-rich oligomeric aggregates, in SNCA-mutant cultures. Aggregation persists and progresses, ultimately resulting in the accumulation of phosphorylated α-synuclein aggregates. Impaired intracellular calcium signalling, increased basal calcium, and impairments in mitochondrial calcium handling occurred early at day 34-41 post differentiation. Once midbrain identity fully developed, at day 48-62 post differentiation, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling and increased autophagy. Ultimately these multiple cellular stresses lead to abnormal excitability, altered neuronal activity, and cell death. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.

Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity.

Aggregation of alpha-synuclein (α-Syn) drives Parkinson's disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)-derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.

The Future of Incretin-Based Approaches for Neurodegenerative Diseases in Older Adults: Which to Choose? A Review of their Potential Efficacy and Suitability.

The current treatment options for neurodegenerative diseases in older adults rely mainly on providing symptomatic relief. Yet, it remains imperative to identify agents that slow or halt disease progression to avoid the most disabling features often associated with advanced disease stages. A potential overlap between the pathological processes involved in diabetes and neurodegeneration has been established, raising the question of whether incretin-based therapies for diabetes may also be useful in treating neurodegenerative diseases in older adults. Here, we review the different agents that belong to this class of drugs (GLP-1 receptor agonists, dual/triple receptor agonists, DPP-4 inhibitors) and describe the data supporting their potential role in treating neurodegenerative conditions including Parkinson's disease and Alzheimer's disease. We further discuss whether there are any distinctive properties among them, particularly in the context of safety or tolerability and CNS penetration, that might facilitate their successful repurposing as disease-modifying drugs. Proof-of-efficacy data will obviously be of the greatest importance, and this is most likely to be demonstrable in agents that reach the central nervous system and impact on neuronal GLP-1 receptors. Additionally, however, the long-term safety and tolerability (including gastrointestinal side effects and unwanted weight loss) as well as the route of administration of this class of agents may also ultimately determine success and these aspects should be considered in prioritising which approaches to subject to formal clinical trial evaluations.

Exenatide once weekly over 2 years as a potential disease-modifying treatment for Parkinson's disease: protocol for a multicentre, randomised, double blind, parallel group, placebo controlled, phase 3 trial: The 'Exenatide-PD3' study.

INTRODUCTION: Parkinson's disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure. METHODS AND ANALYSIS: This is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks.The primary outcome is the comparison of Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences. ETHICS AND DISSEMINATION: This trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format. TRIAL REGISTRATION NUMBERS: NCT04232969, ISRCTN14552789.