The dilemma between milestones of progression versus clinical scales in Parkinson's disease.

There are significant challenges in accurately documenting the progression of Parkinson's disease (PD). The disease course is highly heterogeneous, there are no validated biomarkers, and we are reliant on repeated clinical measures to assess disease state over time. Yet, the ability to chart disease progression accurately is vital in both observational and interventional study designs, where reliable measures are critical to determine whether an outcome has been met. In this chapter, we first discuss the natural history of PD, including the spectrum of clinical presentation and expected developments through the course of the disease. We then explore in detail the current strategies for measuring disease progression, which can be broadly divided into: (i) the use of quantitative clinical scales; and (ii) determination of the onset time of key milestones. We discuss the strengths and limitations of these approaches for use in clinical trials, with a particular focus on disease modification trials. The selection of outcome measures for a particular study will depend on multiple factors, but trial duration is an important determinant. Milestones are reached over a course of years rather than months, and hence clinical scales with sensitivity to change are needed for short-term studies. However, milestones represent important markers of disease stage which are not confounded by symptomatic therapies and are of critical relevance to the patient. Prolonged but low intensity follow-up beyond a limited period of treatment with a putative disease-modifying agent may allow milestones to be incorporated into evaluation of efficacy in a practical and cost-effective way.

Huntington's disease: diagnosis and management.

Huntington's disease (HD) is an inherited neurodegenerative disease characterised by neuropsychiatric symptoms, a movement disorder (most commonly choreiform) and progressive cognitive impairment. The diagnosis is usually confirmed through identification of an increased CAG repeat length in the huntingtin gene in a patient with clinical features of the condition. Though diagnosis is usually straightforward, unusual presentations can occur, and it can be difficult to know when someone has transitioned from being an asymptomatic carrier into the disease state. This has become increasingly important recently, with several putative disease-modifying therapies entering trials. A growing number of conditions can mimic HD, including rare genetic causes, which must be considered in the event of a negative HD genetic test. Patients are best managed in specialist multidisciplinary clinics, including when considering genetic testing. Current treatments are symptomatic, and largely directed at the chorea and neurobehavioural problems, although supporting trial evidence for these is often limited.

The Gastrointestinal Dysfunction Scale for Parkinson's Disease.

BACKGROUND: Gastrointestinal dysfunction is an important feature of Parkinson's disease (PD), and there is increasing evidence that it may play a key role in the disease process. However, its assessment is limited by different tools and underlying differences in diagnostic criteria for gastrointestinal dysfunction. To date, there is no psychometric instrument for quantitative evaluation of gastrointestinal symptoms specifically designed for use in PD. OBJECTIVE: The objective of this study was to develop a self-report questionnaire-based instrument, the Gastrointestinal Dysfunction Scale for Parkinson's Disease, and to evaluate its psychometric properties. METHODS: We performed a literature review and conducted 3 focus groups to develop the Gastrointestinal Dysfunction Scale for Parkinson's Disease. Three hundred and sixteen patients with PD and 55 controls completed the Gastrointestinal Dysfunction Scale for Parkinson's Disease, the Non-Motor Symptom Scale, the Hospital Anxiety and Depression Scale, and a stool diary adapted from the Bristol Stool Chart. RESULTS: The Gastrointestinal Dysfunction Scale for Parkinson's Disease demonstrated good internal consistency (Cronbach's α = 0.82) and test-retest stability (0.79 < ICCs > 0.94). Correlation analyses supported good convergent and divergent validity. Receiver operating characteristic analysis demonstrated that a cutoff score of ≥9 on the Gastrointestinal Dysfunction Scale for Parkinson's Disease Constipation subscale discriminates between PD patients with and without constipation. CONCLUSIONS: The Gastrointestinal Dysfunction Scale for Parkinson's Disease is a novel disease-specific self-report tool to quantitatively assess the presence and severity of gastrointestinal dysfunction features in patients with PD, with strong reliability and validity. Further longitudinal studies are needed to demonstrate its utility in tracking gastrointestinal dysfunction in PD clinical cohorts. © 2021 International Parkinson and Movement Disorder Society.

Azathioprine immunosuppression and disease modification in Parkinson's disease (AZA-PD): a randomised double-blind placebo-controlled phase II trial protocol.

INTRODUCTION: The immune system is implicated in the aetiology and progression of Parkinson's disease (PD). Inflammation and immune activation occur both in the brain and in the periphery, and a proinflammatory cytokine profile is associated with more rapid clinical progression. Furthermore, the risk of developing PD is related to genetic variation in immune-related genes and reduced by the use of immunosuppressant medication. We are therefore conducting a 'proof of concept' trial of azathioprine, an immunosuppressant medication, to investigate whether suppressing the peripheral immune system has a disease-modifying effect in PD. METHODS AND ANALYSIS: AZA-PD is a phase II randomised placebo-controlled double-blind trial in early PD. Sixty participants, with clinical markers indicating an elevated risk of disease progression and no inflammatory or immune comorbidity, will be treated (azathioprine:placebo, 1:1) for 12 months, with a further 6-month follow-up. The primary outcome is the change in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale gait/axial score in the OFF state over the 12-month treatment period. Exploratory outcomes include additional measures of motor and cognitive function, non-motor symptoms and quality of life. In addition, peripheral and central immune markers will be investigated through analysis of blood, cerebrospinal fluid and PK-11195 positron emission tomography imaging. ETHICS AND DISSEMINATION: The study was approved by the London-Westminster research ethics committee (reference 19/LO/1705) and has been accepted by the Medicines and Healthcare products Regulatory Agency (MHRA) for a clinical trials authorisation (reference CTA 12854/0248/001-0001). In addition, approval has been granted from the Administration of Radioactive Substances Advisory Committee. The results of this trial will be disseminated through publication in scientific journals and presentation at national and international conferences, and a lay summary will be available on our website. TRIAL REGISTRATION NUMBERS: ISRCTN14616801 and EudraCT- 2018-003089-14.

The clinical heterogeneity of Parkinson's disease and its therapeutic implications.

Although Parkinson's disease (PD) is primarily a movement disorder, there are a range of associated nonmotor symptoms, including cognitive impairment, depression and sleep disturbance. These can occur throughout the disease course, even predating the motor syndrome. However, both motor and nonmotor symptoms are variable between individual patients. Rate of disease progression is also heterogenous: although 50% have reached key milestones of either postural instability or dementia within 4 years from diagnosis, almost a quarter have a good prognosis at 10 years. In this review we discuss how a range of different factors including clinical features, pathology and genetics, have been used to describe the heterogeneity of PD. We explore the value of longitudinal studies of incident PD cohorts, based on our own experience in Cambridgeshire, to define differences in rates of disease progression and predictors of outcome, including how such studies have informed the development of prognostic models which can be used at an individual patient level. Finally, we discuss the benefits of better understanding the basis of heterogeneity of PD in terms of implications for the development and trialling of more targeted therapies for different subgroups of patients, including regenerative approaches.