Objective: We aimed to assess the association between phosphodiesterase 4 (PDE4) expression and sleep disturbances in vivo using combined multimodal magnetic resonance imaging (MRI) and PET molecular imaging with [¹¹C]rolipram in Parkinson’s disease (PD).

Background: Sleep disturbances are very common in patients with PD. Animal and genome-wide association studies have suggested a link between cAMP/PKA signalling, PDE4 expression (an enzyme which hydrolyses cAMP) and daytime sleepiness.

Methods: 12 PD patients and 5 healthy controls underwent clinical and imaging assessments. Sleep disturbances were assessed with the Parkinson’s disease sleep scale (PDSS), Epworth Sleepiness Scale (ESS) a measure of excessive daytime sleepiness (EDS), UPDRS-I single items for sleep and fatigue, and non-motor symptom scale (NMSS) domain 2 sleep/fatigue. MIAKAT^TM was used to generate parametric images of [¹¹C]rolipram volume of distribution (V_T) with the Logan plot. FMRIB’s diffusion toolbox (FDT) was used to perform probabilistic tractography on each subjects’ diffusion data to functionally parcellate the striatum according to cortico-striatal projections to generate connectivity maps for limbic, cognitive and sensorimotor subdivisions of the striatum.

Results: PD patients with EDS had significantly increased V_T values compared to those without EDS. Higher ESS scores, indicating greater EDS, correlated with higher PDE4 V_T in cortical regions involved in the limbic loop [amygdala (r=0.670), hippocampus (r=0.813), orbitofrontal (r=0.685), cingulate (r=0.663) and temporal cortex (r=0.809)], striatum (0.713), thalamus (r=0.660), hypothalamus (r=0.819) and accumbens (r=0.738). Furthermore, higher EDS was associated with specific increases in PDE4 within limbic portions of the striatum (connectivity based analysis, (r=0.788).

Conclusions: Our findings indicate converging evidence for an association between daytime sleepiness and elevated PDE4 in cortical and subcortical limbic regions, implicating PDE4 in the pathophysiology of sleep disturbances in PD. 

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-phosphodiesterase-4-in-sleep-disturbances-in-parkinsons-disease/