Prevalence and state-dependent patterns of non-motor fluctuations in Parkinson's disease

Parkinson's disease (PD) has non-motor symptoms (NMS), many of which fluctuate with motor states. These non-motor fluctuations (NMF) can remain under-characterized, particularly in relation to age at onset. Early-onset PD (EOPD) and late-onset PD (LOPD) may exhibit distinct fluctuation patterns, potentially reflecting differences in neurochemical vulnerability. To characterize the prevalence, distribution, and state dependence of NMF in a large PD cohort using the Non-Motor Fluctuation Assessment (NoMoFA) questionnaire, and to compare NMF profiles between EOPD and LOPD. In this study 484 patients meeting MDS-PD criteria were recruited at a tertiary centre and NMS/NMF were collected using NoMoFA. Symptoms were classified as static or fluctuating, with OFF state, ON state, or mixed-state worsening. Group comparisons used chi-square tests for categorical variables and independent-sample t-tests for continuous variables and multivariate binary logistic regression was performed to identify independent predictors of NMF. A substantial proportion of NMS demonstrated fluctuation. Emotional and sensory symptoms showed the highest fluctuating burden, with OFF-state worsening predominating. Pain fluctuated in 44.5% of symptomatic patients, almost entirely during OFF. Excessive daytime sleepiness showed more ON-state worsening. EOPD exhibited significantly higher fluctuating emotional symptoms whereas LOPD showed greater prevalence of static autonomic symptoms. NMF presence was associated with significantly higher Parkinson's Disease Questionnaire-39 (PDQ-39) scores across multiple domains, particularly mobility, activities of daily living (ADL), emotional well-being, and bodily discomfort (p < 0.001). NMF are common, clinically significant, and predominantly related to the OFF state. Distinct NMF patterns in EOPD vs. LOPD suggest differing pathophysiological contributions. Female gender and dyskinesia were independent predictors of NMF after multivariate adjustment.