Objective: To examine the clinical and biomarker correlates of Restless legs syndrome (RLS) in Parkinson’s disease (PD).

Background: RLS is more common in PD than in the general population. This is paradoxical, as RLS has been linked to increased presynaptic dopaminergic activity, whereas PD is characterized by nigrostriatal dopamine deficiency.

Method: We used Parkinson’s Progression Markers Initiative (PPMI) data from all participants enrolled through December 2025. PPMI is a large, multicenter, longitudinal cohort with standardized clinical, imaging, and biospecimen protocols, enrolling individuals with PD within 1–2 years of diagnosis. We included 1085 participants with sporadic PD, all untreated with dopaminergic therapy at baseline (drug-naïve stage), minimizing treatment-related confounding of RLS symptoms. Biomarker measures included α-synuclein seed amplification assay (SAA) and striatal dopamine transporter binding ratios on DaTscan SPECT. Clinical assessments included olfaction, autonomic function, anxiety, depression, and daytime sleepiness.

Results: Among 1,085 individuals with sporadic PD, 64 (5.9%) had concurrent RLS. Compared with PD patients without RLS, those with RLS were older (65.8±9.1 vs 63.2±9.5 years, p=0.027), with similar sex distribution (64.1% vs 65.6% male, p=0.799). Despite older age, the PD/RLS+ group had better olfaction (UPSIT percentile:22.5±26.9 vs 14.8±19.4, p=0.028), but greater daytime sleepiness (ESS:7.0±4.5 vs 5.6±3.6, p=0.016), worse anxiety (STAI:70.6±20.0 vs 63.6±18.2, p=0.008), more depressive symptoms (GDS:3.2±2.7 vs 2.2±2.6, p=0.010), and more severe autonomic dysfunction (SCOPA-AUT:12.5±6.7 vs 10.2±6.7, p=0.012). The PD/RLS+ group also showed lower α-synuclein SAA positivity (75.4% vs 91.3%, p<0.001) and higher putaminal DaTscan binding ratio (0.86±0.44 vs 0.74±0.27, p=0.030).

Conclusion: In early PD, RLS was associated with a distinct biomarker and clinical profile. PD patients with RLS had relatively higher putaminal dopaminergic reserve, supporting a paradoxical hyperdopaminergic state despite underlying dopamine deficiency. α-synuclein aggregation was also less frequently detected by SAA in this subgroup. These novel findings suggest that RLS in early PD may define a biologically distinct phenotype with less severe nigrostriatal dopaminergic degeneration and lower detectable synucleinopathy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/biomarker-and-clinical-correlates-of-restless-legs-syndrome-rls-in-parkinsons-disease-a-paradoxical-hyperdopaminergic-state/