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

Wilson, Heather, Pagano, Gennaro, Niccolini, Flavia, Muhlert, Nils ORCID: https://orcid.org/0000-0002-6414-5589, Mehta, Mitul A., Searle, Graham, Gunn, Roger N., Rabiner, Eugenii A., Foltynie, Thomas and Politis, Marios 2020. The role of phosphodiesterase 4 in excessive daytime sleepiness in Parkinson's disease. Parkinsonism & Related Disorders 77 , pp. 163-169. 10.1016/j.parkreldis.2019.02.027

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Abstract

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 [11C]rolipram PET and MR imaging. Methods Eighteen participants, 12 PD and 6 healthy controls, underwent one [11C]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 [11C]rolipram volume of distribution (VT) 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 [11C]rolipram VT 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Psychology
Publisher:	Elsevier
ISSN:	1353-8020
Date of Acceptance:	18 February 2019
Last Modified:	10 Nov 2022 11:11
URI:	https://orca.cardiff.ac.uk/id/eprint/149570

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