The motor prodromes of parkinson's disease: from bedside observation to large-scale application

There is sufficient evidence that the pathological process that causes Parkinson's disease begins years before the clinical diagnosis is made. Over the last 15 years, there has been much interest in the existence of a prodrome in some patients, with a particular focus on non-motor symptoms such as reduced sense of smell, REM-sleep disorder, depression, and constipation. Given that the diagnostic criteria for Parkinson's disease depends on the presence of bradykinesia, it is somewhat surprising that there has been much less research into the possibility of subtle motor dysfunction as a pre-diagnostic pointer. This review will focus on early motor features and provide some advice on how to detect and measure them

Identifying Subjects At Risk of Parkinson’s Disease in the Community: PREDICT-PD

There has been great interest in a definable prodromal period of Parkinson’s disease (PD), which is thought to be characterised by non-motor manifestations. In preparatory work, an extensive review of early non-motor features and risk factors was undertaken to develop a preliminary algorithm to identify subjects at increased risk of PD. A website was configured and keyboard-tapping test developed to aid in risk-stratifying subjects for future PD. This thesis first documents the validation of the keyboard-tapping test in PD patients and healthy controls, before its use alongside objective smell testing and a questionnaire formulated to assess early non-motor features and risk factors, all of which were delivered via the internet. The thesis describes the recruitment at baseline of over 1,300 healthy older people and annual follow-up assessments with the questionnaire, smell test and tapping test, which comprise the preliminary screening algorithm. Each year those estimated to be at higher risk were compared to lower risk subjects in terms of intermediate markers (smell loss, sleep disturbance and finger tapping speed) and differences between extremes of risk have been observed, consistent with the notion that higher risk subjects possess early features of PD. Selected higher and lower risk subjects were further investigated to determine whether there were differences in the frequency of genes associated with PD (GBA and LRRK2), and a proportion of subjects have been scanned using transcranial sonography and 123I-FP-CIT SPECT to determine whether there were imaging differences between extremes of risk. The thesis concludes by demonstrating that higher risk subjects were more likely to be diagnosed with PD during follow-up over 3 years and proposes further lines of enquiry that can be followed, building on the work undertaken to-date

Cognitive impairment in REM-sleep behaviour disorder and individuals at risk of Parkinson's disease

Background: Mild cognitive impairment (MCI) is commonly present at the time of Parkinson's Disease (PD) diagnosis, but its prevalence amongst individuals at increased risk of PD is unclear. Methods: Cognition was assessed using the Montreal Cognitive Assessment (MoCA) in 208 participants in the PREDICT-PD study, and 25 participants with REM-sleep behaviour disorder (RBD). Prevalence of MCI level I was determined in all participants, and level II MCI in the RBD sub-group. Results: Total MoCA scores were worse in the higher risk than the lower risk group defined as those below the 15th percentile of risk (p = 0.009), and in the RBD group compared to all healthy participants (p < 0.001). The prevalence of MCI level I was 12.8% in the lower-risk, 21.9% in the higher-risk (within the highest 15th percentile) and 64% in RBD participants; 66% of RBD participants had MCI level II with multi-domain MCI, but particularly attention and memory deficits. Conclusions: Cognitive impairment is increased in different groups at higher risk of PD, particularly in the subgroup formally diagnosed with RBD

Motor Dysfunction as a Prodrome of Parkinson's Disease

BACKGROUND: Recognition of motor signs in the prodromal stage could lead to best identify populations at risk for developing Parkinson's disease (PD). OBJECTIVE: This study identified motor symptoms and signs in individuals suspected of having PD but who did not have a progressive reduction in the speed and amplitude of finger tapping or other physical signs indicative of bradykinesia. METHODS: 146 patients, who had symptoms or signs suggestive of PD, were serially evaluated by a movement disorder specialist, using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III and video recordings. If the patients 'converted' to PD during follow-up, they were categorized as cases and compared with those who did not meet PD criteria during follow-up (non-cases). RESULTS: The 82 cases were more likely to have action dystonia or postural/action/rest tremor of a limb (OR 2.8; 95% CI 1.10-7.09; p = 0.02), a reduced blink rate at rest (OR 2.32; 95% CI 1.18-4.55; p = 0.01), anxiety (OR 8.91; 95% CI 2.55-31.1; p <  0.001), depression (OR 7.03; 95% CI 2.86-17.2; p <  0.001), or a frozen shoulder (OR 3.14; 95% CI 1.58-6.21) than the 64 'non-cases'. A reduction of the fast blink rate was common in patients who met the criteria for PD (p <  0.001). CONCLUSIONS: This study emphasizes that motor dysfunction is a component of the clinical prodrome seen in some patients with PD

Potential Protective Link Between Type I Diabetes and Parkinson's Disease Risk and Progression

BACKGROUND: Epidemiological studies suggested an association between Parkinson's disease (PD) and type 2 diabetes, but less is known about type 1 diabetes (T1D) and PD. OBJECTIVE: This study sought to explore the association between T1D and PD. METHODS: We used Mendelian randomization, linkage disequilibrium score regression, and multi-tissue transcriptome-wide analysis to examine the association between PD and T1D. RESULTS: Mendelian randomization showed a potentially protective role of T1D for PD risk (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94-0.99; P = 0.039), as well as motor (OR, 0.94; 95% CI, 0.88-0.99; P = 0.044) and cognitive progression (OR, 1.50; 95% CI, 1.08-2.09; P = 0.015). We further found a negative genetic correlation between T1D and PD (rg = -0.17; P = 0.016), and we identified eight genes in cross-tissue transcriptome-wide analysis that were associated with both traits. CONCLUSIONS: Our results suggest a potential genetic link between T1D and PD risk and progression. Larger comprehensive epidemiological and genetic studies are required to validate our findings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Challenges of Incorporating Digital Health Technology Outcomes in a Clinical Trial: Experiences from PD STAT

\ua9 2022 - The authors. Published by IOS Press.Digital health technologies (DHTs) have great potential for use as clinical trial outcomes; however, practical issues need to be addressed in order to maximise their benefit. We describe our experience of incorporating two DHTs as secondary/exploratory outcome measures in PD STAT, a randomised clinical trial of simvastatin in people with Parkinson\u27s disease. We found much higher rates of missing data in the DHTs than the traditional outcome measures, in particular due to technical and software difficulties. We discuss methods to address these obstacles in terms of protocol design, workforce training and data management

Challenges of Incorporating Digital Health Technology Outcomes in a Clinical Trial: Experiences from PD STAT.

Digital health technologies (DHTs) have great potential for use as clinical trial outcomes; however, practical issues need to be addressed in order to maximise their benefit. We describe our experience of incorporating two DHTs as secondary/exploratory outcome measures in PD STAT, a randomised clinical trial of simvastatin in people with Parkinson's disease. We found much higher rates of missing data in the DHTs than the traditional outcome measures, in particular due to technical and software difficulties. We discuss methods to address these obstacles in terms of protocol design, workforce training and data management

The Emergence and Progression of Motor Dysfunction in Individuals at Risk of Parkinson's Disease

BACKGROUNDL: PREDICT-PD is a United Kingdom population-based study aiming to stratify individuals for future Parkinson's disease (PD) using a risk algorithm. METHODS: A randomly selected, representative sample of participants in PREDICT-PD were examined using several motor assessments, including the motor section of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III, at baseline (2012) and after an average of 6 years of follow-up. We checked for new PD diagnoses in participants seen at baseline and examined the association between risk scores and incident sub-threshold parkinsonism, motor decline (increasing ≥5 points in MDS-UPDRS-III) and single motor domains in the MDS-UPDRS-III. We replicated analyses in two independent datasets (Bruneck and Parkinson's Progression Markers Initiative [PPMI]). RESULTS: After 6 years of follow-up, the PREDICT-PD higher-risk group (n = 33) had a greater motor decline compared with the lower-risk group (n = 95) (30% vs. 12.5%, P = 0.031). Two participants (both considered higher risk at baseline) were given a diagnosis of PD during follow-up, with motor signs emerging between 2 and 5 years before diagnosis. A meta-analysis of data from PREDICT-PD, Bruneck, and PPMI showed an association between PD risk estimates and incident sub-threshold parkinsonism (odds ratio [OR], 2.01 [95% confidence interval (CI), 1.55–2.61]), as well as new onset bradykinesia (OR, 1.69 [95% CI, 1.33–2.16]) and action tremor (OR, 1.61 [95% CI, 1.30–1.98]). CONCLUSIONS: Risk estimates using the PREDICT-PD algorithm were associated with the occurrence of sub-threshold parkinsonism, including bradykinesia and action tremor. The algorithm could also identify individuals whose motor examination experience a decline over time