Parkinson's disease dementia: a neural networks perspective.

In the long-term, with progression of the illness, Parkinson's disease dementia affects up to 90% of patients with Parkinson's disease. With increasing life expectancy in western countries, Parkinson's disease dementia is set to become even more prevalent in the future. However, current treatments only give modest symptomatic benefit at best. New treatments are slow in development because unlike the pathological processes underlying the motor deficits of Parkinson's disease, the neural mechanisms underlying the dementing process and its associated cognitive deficits are still poorly understood. Recent insights from neuroscience research have begun to unravel the heterogeneous involvement of several distinct neural networks underlying the cognitive deficits in Parkinson's disease dementia, and their modulation by both dopaminergic and non-dopaminergic transmitter systems in the brain. In this review we collate emerging evidence regarding these distinct brain networks to give a novel perspective on the pathological mechanisms underlying Parkinson's disease dementia, and discuss how this may offer new therapeutic opportunities

The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action

Growing evidence suggests that agonists of the glucagon-like peptide 1 (GLP-1) receptor provide neuroprotection across a range of experimental models of Parkinson's disease (PD) and, recently, a small proof-of-concept, open-label human trial of exenatide in the treatment moderate severity PD appeared to show persistent improvements in motor and cognitive function. The underlying mechanisms of action remain unclear, but as evidence for the potential use of GLP-1 agonists in treating several neurodegenerative disease mounts, and with several clinical trials of GLP-1 analogues in PD and Alzheimer's disease (AD) currently underway, here we review the molecular mechanisms underlying the neuroprotective effects of GLP-1 analogues in the laboratory and their potential therapeutic utility with particular relevance to PD and PD dementia (PDD)

Insulin resistance and Parkinson's disease: A new target for disease modification?

There is growing evidence that patients with Type 2 diabetes have an increased risk of developing Parkinson's disease and share similar dysregulated pathways suggesting common underlying pathological mechanisms. Historically insulin was thought solely to be a peripherally acting hormone responsible for glucose homeostasis and energy metabolism. However accumulating evidence indicates insulin can cross the blood-brain-barrier and influence a multitude of processes in the brain including regulating neuronal survival and growth, dopaminergic transmission, maintenance of synapses and pathways involved in cognition. In conjunction, there is growing evidence that a process analogous to peripheral insulin resistance occurs in the brains of Parkinson's disease patients, even in those without diabetes. This raises the possibility that defective insulin signalling pathways may contribute to the development of the pathological features of Parkinson's disease, and thereby suggests that the insulin signalling pathway may potentially be a novel target for disease modification. Given these growing links between PD and Type 2 diabetes it is perhaps not unsurprising that drugs used the treatment of T2DM are amongst the most promising treatments currently being prioritised for repositioning as possible novel treatments for PD and several clinical trials are under way. In this review, we will examine the underlying cellular links between insulin resistance and the pathogenesis of PD and then we will assess current and future pharmacological strategies being developed to restore neuronal insulin signalling as a potential strategy for slowing neurodegeneration in Parkinson's disease

Challenges in detecting disease modification in Parkinson's disease clinical trials.

Despite the wealth of encouraging data from numerous compounds that demonstrate "neuroprotection" in pre-clinical studies of Parkinson's disease, and despite numerous clinical trials, to date, no intervention has been demonstrated to able to modify the course of disease progression. While this "failure to translate" is likely due to numerous factors including our incomplete understanding of the pathogenic mechanisms underlying PD together with excessive reliance on data from the toxin-based animal models of PD, here we will discuss the "structural issues" pertaining to inadequate clinical trial design, selection of inappropriate endpoints and poor patient selection which are often not addressed following failed disease modification trials. Future directions to overcome these challenges such as reducing the heterogeneity of patient cohorts, identifying and utilising a pre-diagnostic population, embracing a personalised medicine approach and utilising novel trial designs may be required to ultimately fulfil the goal of conclusively demonstrating evidence of disease modification

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

Understanding DCM: ten simple rules for the clinician.

Despite almost a decade since the introduction of Dynamic Causal Modelling (DCM), there remains some confusion within the wider neuroimaging, neuroscience and clinical communities as to what DCM studies are probing, and what all the jargon means. We provide ten simple rules, and a theoretical example to gently introduce the reader to the rationale behind DCM analyses, and how one should consider neuroimaging data and experiments that use DCM. It is deliberately written as a primer or orientation for non-technical imaging neuroscientists or clinicians who have had to contend with the technical intricacies of understanding DCM

The frequency and validity of self-reported diagnosis of Parkinson's Disease in the UK elderly: MRC CFAS cohort

Background: Estimates of the incidence and prevalence of chronic diseases can be made using established cohort studies but these estimates may have lower reliability if based purely on self-reported diagnosis.Methods: The MRC Cognitive Function & Ageing Study ( MRC CFAS) has collected longitudinal data from a population-based random sample of 13004 individuals over the age of 65 years from 5 centres within the UK. Participants were asked at baseline and after a two-year follow-up whether they had received a diagnosis of Parkinson's disease. Our aim was to make estimates of the incidence and prevalence of PD using self-reporting, and then investigate the validity of self-reported diagnosis using other data sources where available, namely death certification and neuropathological examination.Results: The self-reported prevalence of Parkinson's disease ( PD) amongst these individuals increases with age from 0.7% (95% CI 0.5 - 0.9) for 65 - 75, 1.4% ( 95% CI 1.0 - 1.7) for 75 - 85, and 1.6% ( 95% CI 1.0 - 2.3) for 85+ age groups respectively. The overall incidence of self reported PD in this cohort was 200/100,000 per year ( 95% CI 144 - 278). Only 40% of the deceased individuals reporting prevalent PD and 35% of those reporting incident PD had diagnoses of PD recorded on their death certificates. Neuropathological examination of individuals reporting PD also showed typical PD changes in only 40%, with the remainder showing basal ganglia pathologies causing parkinsonism rather than true PD pathology.Conclusion: Self-reporting of PD status may be used as a screening tool to identify patients for epidemiological study, but inevitably identifies a heterogeneous group of movement disorders patients. Within this group, age, male sex, a family history of PD and reduced cigarette smoking appear to act as independent risk factors for self-reported PD

Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: The Effect of Varying Stimulation Parameters

Subthalamic Nucleus Deep Brain Stimulation (STN DBS) is a well-established and effective treatment modality for selected patients with Parkinson's disease (PD). Since its advent, systematic exploration of the effect of stimulation parameters including the stimulation intensity, frequency, and pulse width have been carried out to establish optimal therapeutic ranges. This review examines published data on these stimulation parameters in terms of efficacy of treatment and adverse effects. Altering stimulation intensity is the mainstay of titration in DBS programming via alterations in voltage or current settings, and is characterised by a lower efficacy threshold and a higher side effect threshold which define the therapeutic window. In addition, much work has been done in exploring the effects of frequency modulation, which may help patients with gait freezing and other axial symptoms. However, there is a paucity of data on the use of ultra-short pulse width settings which are now possible with technological advances. We also discuss current evidence for the use of novel programming techniques including directional and adaptive stimulation, and highlight areas for future research