The role of phosphodiesterase 4 in excessive daytime sleepiness in Parkinson's disease

Heather Wilson, Gennaro Pagano, Flavia Niccolini, Nils Muhlert, Mitul A. Mehta, Graham Searle, Roger N. Gunn, Eugenii A. Rabiner, Thomas Foltynie, Marios Politis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
138 Downloads (Pure)


Introduction: Preclinical studies suggest a link between cAMP/PKA signalling, phosphodiesterase 4 (PDE4) expression and excessive daytime sleepiness (EDS). Here, we investigated in vivo the association between PDE4 expression and EDS in Parkinson's disease (PD) patients using [ 11 C]rolipram PET and MR imaging. Methods: Eighteen participants, 12 PD and 6 healthy controls, underwent one [ 11 C]rolipram PET and a multi-modal MRI scan. Probabilistic tractography was performed on subjects’ diffusion data to functionally parcellate the striatum according with projections to limbic cortical areas. The severity of EDS was assessed using the Epworth Sleepiness Scale (ESS). To assess PDE4 expression in PD patients with EDS, the PD cohort was divided according to the presence (n = 5) or absence (n = 7) of EDS, defined using validated cut-off of score ≥10 on the ESS as score ≥10 on the ESS. Results: PD patients with EDS showed significantly increased [ 11 C]rolipram volume of distribution (V T ) in the caudate (P = 0.029), hypothalamus (P = 0.013), hippocampus (P = 0.036) and limbic striatum (P = 0.030) compared to patients without EDS. Furthermore, higher ESS scores correlated with increased [ 11 C]rolipram V T in the caudate (r = 0.77; P = 0.003), hypothalamus (r = 0.84; P = 0.001), hippocampus (r = 0.81; P = 0.001) and limbic subdivisions of the striatum (r = 0.80; P = 0.003). Conclusion: Our findings translate into humans preclinical data indicating that EDS is associated with elevated PDE4 in regions regulating sleep. The severity of EDS in PD was associated with elevated PDE4 expression; thus, suggesting a role of PDE4 in the pathophysiology of EDS in PD.

Original languageEnglish
JournalParkinsonism and Related Disorders
Early online date22 Feb 2019
Publication statusE-pub ahead of print - 22 Feb 2019


  • Diffusion tensor imaging
  • Excessive daytime sleepiness
  • Parkinson's disease
  • Phosphodiesterase 4
  • Positron emission tomography
  • Rolipram


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