A composite clinical motor score as a comprehensive and sensitive outcome measure for Parkinson's disease.

BACKGROUND: An unmet need remains for sensitive outcome measures in neuroprotective trials. The study aims to determine whether a composite clinical motor score, combining the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III motor examination score, Purdue Pegboard Test, and Timed Up and Go, provides greater sensitivity in detecting motor change in early disease than the MDS-UPDRS III alone. METHODS: The Oxford Discovery longitudinal cohort study involves individuals with isolated rapid eye movement sleep behaviour disorder (iRBD) (n=272, confirmed polysomnographically, median follow-up: 1.6 years), idiopathic Parkinson's disease (PD) (n=909, median follow-up: 3.5 years, baseline: <3.5 years disease duration) and controls (n=316, age-matched and sex-matched, without a first-degree family history of PD). Motor and non-motor assessments were performed at each in-person visit. RESULTS: Compared with the MDS-UPDRS III, the composite clinical motor score demonstrated a wider score distribution in iRBD and controls, lower coefficient of variation (37% vs 67%), and higher correlation coefficients with self-reported measures of motor severity (0.65 vs 0.61) and overall health status (-0.40 vs -0.33). Greater score range in mild to moderate PD, higher magnitude of longitudinal change in iRBD and longitudinal score linearity suggest better sensitivity in detecting subtle motor change. The composite clinical motor score was more accurate than the MDS-UPDRS III in predicting clinical outcomes, requiring 64% fewer participants with PD and 51% fewer participants with iRBD in sample size estimations for a hypothetical 18-month placebo-controlled clinical trial. CONCLUSION: The composite clinical motor score may offer greater consistency and sensitivity in detecting change than the MDS-UPDRS III.

Genetics of validated Parkinson's disease subtypes in the Oxford Discovery and Tracking Parkinson's cohorts.

OBJECTIVES: To explore the genetics of four Parkinson's disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. METHODS: We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer's disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype. RESULTS: A severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no individual variants met genome wide significance (<5×10e-8) although four variants require further follow-up, meeting a threshold of <1×10e-6. CONCLUSIONS: We have found that four previously defined PD subtypes have different genetic determinants which will help to inform future studies looking at underlying disease mechanisms and pathogenesis in these different subtypes of disease.

Spectrum of impulse control behaviours in Parkinson's disease: pathophysiology and management.

Impulse control behaviours (ICBs) are a range of behaviours linked by their reward-based, repetitive natures. They can be precipitated in Parkinson's disease (PD) by dopamine replacement therapy, often with detrimental consequences for patients and caregivers. While now a well-recognised non-motor feature of treated PD, much remains unknown about the influence of risk factors, pathophysiological mechanisms, vulnerability factors for specific types of behaviour and the optimal management strategies. Imaging studies have identified structural and functional changes in striatal and prefrontal brain regions, among others. Gene association studies indicate a role for genetic predisposition to PD-ICB. Clinical observational studies have identified potential modifiable and non-modifiable risk factors. Psychological studies shed light on the neurocognitive domains implicated in PD-ICBs and identify psychosocial determinants that may perpetuate the cycle of impulsive and harm-avoidance behaviours. Based on these results, a range of pharmacological and non-pharmacological management strategies have been trialled in PD-ICBs with varying success. The purpose of this review is to update clinicians on the evidence around the pathophysiology of PD-ICB. We aim to translate our findings into an interpretable biopsychosocial model that can be applied to the clinical assessment and management of individual cases of PD-ICB.