1. The role of phosphodiesterase 4 in excessive daytime sleepiness in Parkinson's disease
- Author
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Graham E. Searle, Eugenii A. Rabiner, Flavia Niccolini, Thomas Foltynie, Heather Wilson, Mitul A. Mehta, Gennaro Pagano, Roger N. Gunn, Nils Muhlert, and Marios Politis
- Subjects
Male ,0301 basic medicine ,Parkinson's disease ,1702 Cognitive Sciences ,Hippocampus ,Excessive daytime sleepiness ,Striatum ,Severity of Illness Index ,0302 clinical medicine ,Medicine ,Gray Matter ,Epworth Sleepiness Scale ,Parkinson Disease ,Middle Aged ,Pathophysiology ,Diffusion tensor imaging ,Neurology ,Hypothalamus ,Female ,medicine.symptom ,Rolipram ,medicine.drug ,Positron emission tomography ,medicine.medical_specialty ,Clinical Neurology ,Disorders of Excessive Somnolence ,03 medical and health sciences ,Internal medicine ,Humans ,Aged ,Phosphodiesterase 4 ,Neurology & Neurosurgery ,business.industry ,1103 Clinical Sciences ,medicine.disease ,Corpus Striatum ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,030104 developmental biology ,Endocrinology ,Neurology (clinical) ,Geriatrics and Gerontology ,Sleep ,business ,030217 neurology & neurosurgery - 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 [ 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.
- Published
- 2020