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

doi:10.1016/j.parkreldis.2019.02.027

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

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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 [ 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 language	English
Journal	Parkinsonism and Related Disorders
Early online date	22 Feb 2019
DOIs	https://doi.org/10.1016/j.parkreldis.2019.02.027
Publication status	E-pub ahead of print - 22 Feb 2019

Keywords

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

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10.1016/j.parkreldis.2019.02.027

The role of phosphodiesterase_WILSON_Accepted18February2019Publishedonline22February2019_GREEN AAM (CC BY-NC-ND)Accepted author manuscript, 298 KBLicence: CC BY-NC-ND

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@article{fc2f4b47d5e7418ab8dc60d866c23343,

title = "The role of phosphodiesterase 4 in excessive daytime sleepiness in Parkinson's disease",

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{\textquoteright} 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. ",

keywords = "Diffusion tensor imaging, Excessive daytime sleepiness, Parkinson's disease, Phosphodiesterase 4, Positron emission tomography, Rolipram",

author = "Heather Wilson and Gennaro Pagano and Flavia Niccolini and Nils Muhlert and Mehta, {Mitul A.} and Graham Searle and Gunn, {Roger N.} and Rabiner, {Eugenii A.} and Thomas Foltynie and Marios Politis",

year = "2019",

month = feb,

day = "22",

doi = "10.1016/j.parkreldis.2019.02.027",

language = "English",

journal = "Parkinsonism and Related Disorders",

issn = "1353-8020",

publisher = "Elsevier",

}

TY - JOUR

T1 - The role of phosphodiesterase 4 in excessive daytime sleepiness in Parkinson's disease

AU - Wilson, Heather

AU - Pagano, Gennaro

AU - Niccolini, Flavia

AU - Muhlert, Nils

AU - Mehta, Mitul A.

AU - Searle, Graham

AU - Gunn, Roger N.

AU - Rabiner, Eugenii A.

AU - Foltynie, Thomas

AU - Politis, Marios

PY - 2019/2/22

Y1 - 2019/2/22

N2 - 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.

AB - 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.

KW - Diffusion tensor imaging

KW - Excessive daytime sleepiness

KW - Parkinson's disease

KW - Phosphodiesterase 4

KW - Positron emission tomography

KW - Rolipram

UR - http://www.scopus.com/inward/record.url?scp=85062017909&partnerID=8YFLogxK

U2 - 10.1016/j.parkreldis.2019.02.027

DO - 10.1016/j.parkreldis.2019.02.027

M3 - Article

AN - SCOPUS:85062017909

SN - 1353-8020

JO - Parkinsonism and Related Disorders

JF - Parkinsonism and Related Disorders

ER -

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

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