Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies.

Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies. We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. Unified Parkinson's Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies.

Longitudinal Changes in Parkinson's Disease Symptoms with and Without Rapid Eye Movement Sleep Behavior Disorder: The Oxford Discovery Cohort Study.

BACKGROUND: Parkinson's disease (PD) comorbid with rapid eye movement sleep behavior disorder (RBD) may show more severe motor and nonmotor symptoms, suggesting a distinct PD subtype. OBJECTIVE: The aim of this study was to investigate the impact of RBD on the longitudinal change of motor and nonmotor symptoms in patients with PD. METHODS: Patients with early PD (diagnosed within 3.5 years) recruited from 2010 to 2019 were followed every 18 months in the Oxford Parkinson's Disease Centre Discovery cohort. At each visit, we used standard questionnaires and measurements to assess demographic features and motor and nonmotor symptoms (including RBD, daytime sleepiness, mood, autonomic symptoms, cognition, and olfaction). Data were analyzed with linear mixed effects and Cox regression models. Possible RBD (pRBD) was longitudinally determined according to RBD Screening Questionnaire scores. RESULTS: A total of 923 patients were recruited (mean age: 67.1 ± 9.59 years; 35.9% female), and 788 had follow-up assessment(s) (mean: 4.8 ± 1.98 years, range: 1.3-8.3). Among them, 33.3% were identified as pRBD (PD + pRBD). Patients with PD + pRBD had more severe baseline symptoms and showed faster progression on Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts I and III, Purdue Pegboard test, and Beck Depression Inventory scores. Moreover, PD + pRBD was associated with an increased level of risk for mild cognitive impairment (hazard ratio [HR] = 1.36, 95% confidence interval [CI]: 1.01-1.83), freezing of gait (HR = 1.42, 95% CI: 1.10-1.86), and frequent falling (HR = 1.62, 95% CI: 1.02-2.60). CONCLUSIONS: Patients with PD + pRBD progress faster on motor, mood, and cognitive symptoms, confirming a more aggressive PD subtype that can be identified at baseline and has major clinical implications. © 2021 International Parkinson and Movement Disorder Society.