Disease modifying therapies III: Novel targets

Despite significant research advances, treatment of Parkinson's disease (PD) remains confined to symptomatic therapies. Approaches aiming to halt or reverse disease progression remain an important but unmet goal. A growing understanding of disease pathogenesis and the identification of novel pathways contributing to initiation of neurodegeneration and subsequent progression has highlighted a range of potential novel targets for intervention that may influence the rate of progression of the disease process. Exploiting techniques to stratify patients according to these targets alongside using them as biomarkers to measure target engagement will likely improve patient selection and preliminary outcome measurements in clinical trials. In this review, we summarize a number of PD-related mechanisms that have recently gained interest such as neuroinflammation, lysosomal dysfunction and insulin resistance, while also exploring the potential for targeting peripheral interfaces such as the gastrointestinal tract and its ecosystem to achieve disease modification. We explore the rationale for these approaches based on preclinical studies, while also highlighting the status of relevant clinical trials as well as the promising role biomarkers may play in current and future studies

Therapeutic Strategies to Treat or Prevent Off Episodes in Adults with Parkinson's Disease

Parkinson’s disease is a chronic, neurodegenerative disease, which manifests with a mixture of motor, cognitive and behavioural symptoms. Levodopa is the most effective antiparkinsonian treatment to date, although chronic use engenders a mixture of complications in a substantial proportion of patients. Amongst these is the occurrence of episodes of worsening symptoms—‘off’ phenomena. These episodes can manifest with either motor or non-motor symptoms or a combination of these features and have been found to have profound impacts on patients’ quality of life. Although preventative measures are poorly evidenced, avoiding excessive total daily levodopa intake in selected populations that are deemed to be of a higher risk for developing these episodes warrants further exploration. Methods to improve levodopa bioavailability and delivery to the brain are currently available and are of value in addressing these episodes once they have become established. These include modifications to levodopa formulations as well as the use of complimentary agents that improve levodopa bioavailability. The deployment of device-assisted approaches is a further dimension that can be considered in addressing these debilitating episodes. This review summarises the clinical manifestations of ‘off’ phenomena and the current approaches to treat them. Although we briefly discuss clinical advances on the horizon, the predominant focus is on existing, established treatments

Revisiting the assessment of tremor: clinical review

Tremor, an involuntary, rhythmic, and oscillatory movement of a body part, is a frequent presenting symptom to general practice and by far the most common movement disorder presentation, impacting up to 15% of such cases.1 A common initial pattern is symmetric upper-limb involvement during posture and action. Although patients are often worried about Parkinson’s disease (PD), PD tremor usually has easily recognisable features.2 This concern tends to lead to frequent referrals for specialist input despite an alternative diagnosis being more likely in a majority of cases. Essential tremor (ET) is the most common diagnosis given to patients with this presentation, which is estimated to affect 0.4–6.0% of the general population.3 This may be an overestimate as the rubric of ET and the relationship between clinical features and underlying pathophysiology is uncertain. These aspects also potentially contribute to variable diagnostic and treatment outcomes.4 A recent Movement Disorder Society consensus on phenotyping charts a course towards more precise classification.5 This will not only be useful for research but also help in clarifying common clinical syndromes seen in everyday practice. This article outlines an approach to upper-limb tremor presentations in adult patients, developing a previously proposed three cardinal question method for neck pain6 while highlighting salient aspects of the consensus statement that could potentially aid in clinical stratification of cases

Progress towards therapies for disease modification in Parkinson's disease

The development of interventions to slow or halt the progression of Parkinson's disease remains a priority for patients and researchers alike. To date, no agents have been shown to have unequivocal evidence of disease-modifying effects in Parkinson's disease. The absence of disease-modifying treatments might relate not only to inadequate approaches for the selection of therapeutic candidates but also to insufficient attention to detail in clinical trial design. Better understanding of Parkinson's disease pathogenesis associated with advances in laboratory models, the use of objective biomarkers of disease progression and target engagement, and a focus on agents known to be safe for human use, alongside the use of precision medicine approaches, should together greatly increase the likelihood for successful identification of disease-modifying treatments for Parkinson's disease

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

A practical guide to troubleshooting pallidal deep brain stimulation issues in patients with dystonia

High frequency deep brain stimulation (DBS) of the internal portion of the globus pallidus has, in the last two decades, become a mainstream therapy for the management of medically-refractory dystonia syndromes. Such increasing uptake places an onus on movement disorder physicians to become familiar with this treatment modality, in particular optimal patient selection for the procedure and how to troubleshoot problems relating to sub-optimal efficacy and therapy-related side effects. Deep brain stimulation for dystonic conditions presents some unique challenges. For example, the frequent lack of immediate change in clinical status following stimulation alterations means that programming often relies on personal experience and local practice rather than real-time indicators of efficacy. Further, dystonia is a highly heterogeneous disorder, making the development of unifying guidelines and programming algorithms for DBS in this population difficult. Consequently, physicians may feel less confident in managing DBS for dystonia as compared to other indications e.g. Parkinson's disease. In this review, we integrate our years of personal experience of the programming of DBS systems for dystonia with a critical appraisal of the literature to produce a practical guide for troubleshooting common issues encountered in patients with dystonia treated with DBS, in the hope of improving the care for these patients

Long-term success of low-frequency subthalamic nucleus stimulation for Parkinson's disease depends on tremor severity and symptom duration

Patients with Parkinson's disease can develop axial symptoms, including speech, gait and balance difficulties. Chronic high-frequency (>100 Hz) deep brain stimulation can contribute to these impairments while low-frequency stimulation (<100 Hz) may improve symptoms but only in some individuals. Factors predicting which patients benefit from low-frequency stimulation in the long term remain unclear. This study aims to confirm that low-frequency stimulation improves axial symptoms, and to go further to also explore which factors predict the durability of its effects. We recruited patients who developed axial motor symptoms while using high-frequency stimulation and objectively assessed the short-term impact of low-frequency stimulation on axial symptoms, other aspects of motor function and quality of life. A retrospective chart review was then conducted on a larger cohort to identify which patient characteristics were associated with not only the need to trial low-frequency stimulation, but also those which predicted its sustained use. Among 20 prospective patients, low-frequency stimulation objectively improved mean motor and axial symptom severity and quality of life in the short term. Among a retrospective cohort of 168 patients, those with less severe tremor and those in whom axial symptoms had emerged sooner after subthalamic nucleus deep brain stimulation were more likely to be switched to and remain on long-term low-frequency stimulation. These data suggest that low-frequency stimulation results in objective mean improvements in overall motor function and axial symptoms among a group of patients, while individual patient characteristics can predict sustained long-term benefits. Longer follow-up in the context of a larger, controlled, double-blinded study would be required to provide definitive evidence of the role of low-frequency deep brain stimulation

Frequency and outcomes of gastrostomy insertion in a longitudinal cohort study of atypical parkinsonism

\ua9 2024 The Authors. European Journal of Neurology published by John Wiley &amp; Sons Ltd on behalf of European Academy of Neurology.Background: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) show a high prevalence and rapid progression of dysphagia, which is associated with reduced survival. Despite this, the evidence base for gastrostomy is poor, and the optimal frequency and outcomes of this intervention are not known. We aimed to characterise the prevalence and outcomes of gastrostomy in patients with these three atypical parkinsonian disorders. Method: We analysed data from the natural history and longitudinal cohorts of the PROSPECT-M-UK study with up to 60 months of follow-up from baseline. Survival post-gastrostomy was analysed using Kaplan–Meier survival curves. Results: In a total of 339 patients (mean age at symptom onset 63.3 years, mean symptom duration at baseline 4.6 years), dysphagia was present in &gt;50% across all disease groups at baseline and showed rapid progression during follow-up. Gastrostomy was recorded as recommended in 44 (13%) and performed in 21 (6.2%; MSA 7, PSP 11, CBS 3) of the total study population. Median survival post-gastrostomy was 24 months compared with 12 months where gastrostomy was recommended but not done (p = 0.008). However, this was not significant when correcting for age and duration of symptoms at the time of procedure or recommendation. Conclusions: Gastrostomy was performed relatively infrequently in this cohort despite the high prevalence of dysphagia. Survival post-gastrostomy was longer than previously reported, but further data on other outcomes and clinician and patient perspectives would help to guide use of this intervention in MSA, PSP and CBS

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

IntroductionParkinson’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 analysisThis 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 disseminationThis 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 numbersNCT04232969, ISRCTN14552789.</jats:sec