Excessive daytime sleepiness may be associated with caudate denervation in Parkinson disease

Excessive daytime sleepiness (EDS) is one of the earliest and most common non-motor symptoms of PD, substantially impacting on patient's quality of life. Using the Parkinson's Progression Markers Initiative database, we performed a case-control study to investigate whether dopaminergic deficit is associated with the development of EDS using dopaminergic specific single photon emission computed tomography (SPECT) molecular imaging of dopamine transporters (DAT). We enrolled 84 early de novo PD patients with EDS and 84 without EDS, who were matched for age, gender, age of diagnosis, years of education and disease duration. We assessed and compared semi-quantified [¹²³I]FP-CIT SPECT, and motor and non-motor features among these two groups, alongside exploring the clinical and imaging correlates of EDS and the predictive significance of these markers in the development of EDS. PD patients with EDS had worse non-motor (MDS-UPDRS Part-I, P < 0.001) and motor (MDS-UPRDS Part-II, P = 0.005) experiences of daily living, as well as worse autonomic (SCOPA-AUT, P < 0.0001) and cognitive (MoCA P = 0.05) function, depression (GDS, P = 0.002), and reduced caudate DAT ([¹²³I]FP-CIT, P = 0.024) compared to PD patients without EDS. Lower caudate [¹²³I]FP-CIT values correlated with higher EDS scores (r = -0.192, P = 0.013). Among patients without EDS, 47 PD patients (56%) developed EDS over a median follow-up of 36 months. Cox multivariate analysis, including all clinical and imaging data available, revealed that abnormal caudate [¹²³I]FP-CIT uptake (P = 0.030) and disease duration (P = 0.018) were predictors for the development of EDS. Although our findings indicate that dopaminergic deficits in the caudate may be associated to EDS in patients with PD, the pathophysiological causality is debateable, given that dopamine caudate denervation may covary with dopaminergic involvement at other targets and with non-dopaminergic involvement.