Altered Impulsivity Across Drug-Naïve Parkinsonism, Isolated Rapid Eye Movement Sleep Behavior Disorder, and Their High-Risk Relatives.

OBJECTIVE: To determine multidimensional impulsivity levels across different early stages of α-synucleinopathy. METHODS: This cross-sectional study investigated motor and decisional impulsivity levels using a panel of computerized tasks among drug-naïve parkinsonism patients, isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) patients and their first-degree relatives (iRBD-FDRs), and control participants. Trait impulsivity and impulse control behaviors were assessed by self-reported questionnaires. RESULTS: A total of 27 drug-naïve parkinsonism patients, 157 iRBD patients, 66 iRBD-FDRs, and 82 control participants were recruited. Parkinsonism and iRBD patients had fewer numbers of extracted beads in beads task 1 and 2 (both p < 0.001), and a higher rate of irrational choice in task 1 (p = 0.046) before making decisions, and fewer numbers of pumps of unexploded blue balloons in the balloon analog risk task (p = 0.004) than control participants, indicating a higher level of reflection impulsivity and a lower level of risk taking, respectively. iRBD patients had more no-go errors in the go/no-go task than control participants (padjusted = 0.036), suggesting a higher level of motor impulsivity. iRBD-FDRs with dream-enactment behaviors had fewer numbers of extracted beads (p = 0.047) in beads task 2 than FDRs without dream-enactment behaviors, suggesting a possible higher level of reflection impulsivity. INTERPRETATION: A complex construct of altered impulsivity with decreased risk taking, but increased reflection and motor impulsivity, has already occurred at the prodromal and early stages of α-synucleinopathy, which have implications for underlying pathophysiology and clinical management of α-synucleinopathy, especially for impulse control behaviors upon dopaminergic drug treatment. ANN NEUROL 2024;95:544-557.

Proximity extension assay testing reveals novel diagnostic biomarkers of atypical parkinsonian syndromes.

OBJECTIVE: The high degree of clinical overlap between atypical parkinsonian syndromes (APS) and Parkinson's disease (PD) makes diagnosis challenging. We aimed to identify novel diagnostic protein biomarkers of APS using multiplex proximity extension assay (PEA) testing. METHODS: Cerebrospinal fluid (CSF) samples from two independent cohorts, each consisting of APS and PD cases, and controls, were analysed for neurofilament light chain (NF-L) and Olink Neurology and Inflammation PEA biomarker panels. Whole-cohort comparisons of biomarker concentrations were made between APS (n=114), PD (n=37) and control (n=34) groups using logistic regression analyses that included gender, age and disease duration as covariates. RESULTS: APS versus controls analyses revealed 11 CSF markers with significantly different levels in cases and controls (p<0.002). Four of these markers also reached significance (p<0.05) in APS versus PD analyses. Disease-specific analyses revealed lower group levels of FGF-5, FGF-19 and SPOCK1 in multiple system atrophy compared with progressive supranuclear palsy and corticobasal syndrome. Receiver operating characteristic curve analyses suggested that the diagnostic accuracy of NF-L was superior to the significant PEA biomarkers in distinguishing APS, PD and controls. The biological processes regulated by the significant proteins include cell differentiation and immune cell migration. Delta and notch-like epidermal growth factor-related receptor (DNER) had the strongest effect size in APS versus controls and APS versus PD analyses. DNER is highly expressed in substantia nigra and is an activator of the NOTCH1 pathway which has been implicated in the aetiology of other neurodegenerative disorders including Alzheimer's disease. CONCLUSIONS: PEA testing has identified potential novel diagnostic biomarkers of APS.

REM sleep behaviour disorder is associated with worse quality of life and other non-motor features in early Parkinson's disease.

BACKGROUND: Concomitant REM sleep behaviour disorder (RBD) is commonly observed in patients with Parkinson's disease (PD). Although the brainstem structures responsible for the symptoms of RBD correspond to the premotor stages of PD, the association of RBD with motor and non-motor features in early PD remains unclear. METHODS: The study evaluated 475 patients with PD within 3.5 years of diagnosis for the presence of probable RBD (pRBD) using the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A neurologist and a trained research nurse carried out evaluation of each participant blinded to the results of the RBDSQ. Standardised rating scales for motor and non-motor features of PD, as well as health-related quality of life measures, were assessed. Multiple linear and logistic regression analyses were used to determine the relationship between pRBD and a variety of outcomes, controlling for confounding factors. RESULTS: The overall frequency of pRBD was 47.2% (95% CI 42.7% to 51.9%). None of the patients had a previous diagnosis of RBD. Patients with PD and concomitant pRBD did not differ on motor phenotype and scored comparably on the objective motor scales, but reported problems with motor aspects of daily living more frequently. Adjusted for age, sex, disease duration and smoking history, pRBD was associated with greater sleepiness (p=0.001), depression (p=0.001) and cognitive impairment (p=0.006). CONCLUSIONS: pRBD is common and under-recognised in early PD. It is associated with increased severity and frequency of non-motor features, poorer subjective motor performance and a greater impact on health-related quality of life.