National Institute of Neurological Disorders and Stroke

Parkinson's disease is the second most common neurodegenerative disease and its prevalence has been projected to double over the next 30 years. An accurate diagnosis of Parkinson's disease remains challenging and the characterisation of the earliest stages of the disease is ongoing. Recent developments over the past 5 years include the validation of clinical diagnostic criteria, the introduction and testing of research criteria for prodromal Parkinson's disease, and the identification of genetic subtypes and a growing number of genetic variants associated with risk of Parkinson's disease. Substantial progress has been made in the development of diagnostic biomarkers, and genetic and imaging tests are already part of routine protocols in clinical practice, while novel tissue and fluid markers are under investigation. Parkinson's disease is evolving from a clinical to a biomarker-supported diagnostic entity, for which earlier identification is possible, different subtypes with diverse prognosis are recognised, and novel disease-modifying treatments are in development.

Challenges in the diagnosis of Parkinson's disease

Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting >1% of the population ≥65 years of age and with a prevalence set to double by 2030. In addition to the defining motor symptoms of PD, multiple non-motor symptoms occur; among them, cognitive impairment is common and can potentially occur at any disease stage. Cognitive decline is usually slow and insidious, but rapid in some cases. Recently, the focus has been on the early cognitive changes, where executive and visuospatial impairments are typical and can be accompanied by memory impairment, increasing the risk for early progression to dementia. Other risk factors for early progression to dementia include visual hallucinations, older age and biomarker changes such as cortical atrophy, as well as Alzheimer-type changes on functional imaging and in cerebrospinal fluid, and slowing and frequency variation on EEG. However, the mechanisms underlying cognitive decline in PD remain largely unclear. Cortical involvement of Lewy body and Alzheimer-type pathologies are key features, but multiple mechanisms are likely involved. Cholinesterase inhibition is the only high-level evidence-based treatment available, but other pharmacological and non-pharmacological strategies are being tested. Challenges include the identification of disease-modifying therapies as well as finding biomarkers to better predict cognitive decline and identify patients at high risk for early and rapid cognitive impairment. Cognitive impairment is common in patients with Parkinson disease and ranges in severity. This Primer reviews the epidemiology, pathophysiology, diagnosis and treatment of cognitive impairment in Parkinson disease and describes the effects on patient quality of life and the future outlook for the field.

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Parkinson disease-associated cognitive impairment.

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.

Progress towards therapies for disease modification in Parkinson's disease.

Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson’s disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson’s disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop PD.

The Emerging Role of the Lysosome in Parkinson's Disease.

Background The majority of current pharmacological treatments for Parkinson's disease (PD) were approved for clinical use in the second half of the last century and they only provide symptomatic relief. Derivatives of these therapies continue to be explored in clinical trials, together with potentially disease modifying therapies that can slow, stop or reverse the condition. Objective To provide an overview of the pharmacological therapies- both symptomatic and disease modifying- currently being clinically evaluated for PD, with the goal of creating greater awareness and opportunities for collaboration amongst commercial and academic researchers as well as between the research and patient communities. Methods We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov database and performed a breakdown analysis of studies that were active as of January 21, 2020. Results We identified 145 registered and ongoing clinical trials for therapeutics targeting PD, of which 51 were Phase 1 (35% of the total number of trials), 66 were Phase 2 (46% ), and 28 were Phase 3 (19% ). There were 57 trials (39% ) focused on long-term disease modifying therapies, with the remaining 88 trials (61% ) focused on therapies for symptomatic relief. A total of 50 (34% ) trials were testing repurposed therapies. Conclusion There is a broad pipeline of both symptomatic and disease modifying therapies currently being tested in clinical trials for PD.

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2020.

In an effort to provide timely clinical input for people with Parkinson's disease (PD) in the face of increasing demand and resource limitation in our UK based service, we introduced remote management in place of clinic appointment, including the use of the Parkinson's KinetiGraph (PKG™), a wrist-worn device that provides a continuous measure of movement. We evaluated our reporting methods and findings, the nature of unmet need we identified, our treatment recommendations and the degree of their implementation in our patients whose feedback guided our service developments. Our evaluation highlighted opportunities and challenges associated with incorporating digital data into care traditionally delivered via in-person contact.

Introducing the Parkinson's KinetiGraph into Routine Parkinson's Disease Care: A 3-Year Single Centre Experience.

Objective To evaluate the utility of the Parkinson’s Kinetigraph (PKG™) in the remote management of Parkinson’s disease (PD). Background There is a movement in Parkinson’s care from a clinic-based model1 to P4 medicine, meaning medicine that is predictive, preventive, personalised and participatory.2 The development of wearable technology provides an opportunity to monitor patients remotely, and deliver targeted care. The PKG™ is a wrist-worn device that objectively measures Parkinson’s symptoms. Aim To evaluate the utility of the PKG™ in managing PD patients remotely, and the perception of service users. Method PKG™ data were collated in real time. Patient acceptability data were collated via a patient questionnaire (n=61). Results Between July 2015 and January 2018, 216 PKGs were performed. A variety of symptoms were identified, including different types of ‘OFF’ times (wearing off (25%), delayed on (6%) no drug response (8%)) and non-motor complications (fragmented sleep (33%) and daytime somnolence (21%)), with subsequent treatment recommendations being made. Patient acceptability of the PKG™ was high, 81% of patients being satisfied not having to travel for clinic appointments. Conclusions The PKG™ facilitated remote treatment recommendations. Remote management was acceptable to patients. Future evaluations will evaluate patient outcome. References . van der Eijk M, Nijhuis FAP, Faber MJ, Bloem BR. Moving from physician-centered care towards patient-centered care for Parkinson’s disease patients. Parkinsonism Relat Disord [Internet]. Elsevier; 1 November 2013;19(11):923–7. Available from: https://www.sciencedirect.com/science/article/pii/S1353802013001697?_rdoc=1&_fmt=high&_origin=gateway&_docanchor=&md5=b8429449ccfc9c30159a5f9aeaa92ffb [cited 2018 February 6] . P4 medicine: how systems medicine will transform the healthcare sector and society. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204402/pdf/nihms532619.pdf [cited 2018 April 6]

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Thea Dominey

Papers

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2020.

Introducing the Parkinson's KinetiGraph into Routine Parkinson's Disease Care: A 3-Year Single Centre Experience.

WED 131 Evaluating the clinical utility of the parkinson’s kinetigraph (PKG)