Table 1.

Clinical studies that examined diurnal and/or circadian rhythms of motor and non-motor functions in PD

Study Author / Date	Study population	Study methods	Main findings of the study
Fluctuations of motor symptoms
Van Hilten et al. / 1991 17	9 PD patients 10 controls	Actigraphy (6 days)	The indices of diurnal motor activity decreased with the progressive worsening of hypokinesia and rigidity.
Van Hilten et al. / 1993 18	15 PD patients with and without dyskinesias 10 ontrols	Actigraphy (5 days)	Patients with response fluctuations showed a large intra- and interindividual variability of diurnal motor activity measures. The nocturnal motor activity measures in the patients with response fluctuations indicated a severely disturbed sleep when compared with the two control groups.
Van Hilten et al. / 1993 20	68 PD patients 68 controls	Actigraphy	Mildly or moderately affected PD patients had a similar diurnal pattern to healthy controls, with a late morning peak; however, mean levels of motor activity were lower. The most severely affected patients showed an overall flattened diurnal pattern.
Van Hilten et al. / 1994 19	89 PD patients 83 controls	Actigraphy (6 nights)	Patients with PD havdan elevated nocturnal activity level and an increased proportion of time with movement. The mean duration of nocturnal immobility periods was similar for both groups.
Bonuccelli et al. / 2000 21	52 PD patients: 19 de novo 20 stable 13 wearing-off	Mean motor scores and pharmacokinetic data, evaluated for a period of 3 hours after each levodopa dose	In de novo patients, no diurnal changes in motor score were observed. A progressive daytime worsening was visible in stable and wearing-off patients. No significant correlation between motor scores and 3-O-methyldopa plasma levels was observed.
Whitehead et al. / 2008 16	50 PD patients with and without hallucinations Controls	Actigraphy (5 days)	PD patients demonstrated reduced amplitude of activity and increased intradaily variability compared to healthy older adults. Hallucinators showed lower interdaily stability significantly greater activity during “night-time” and significantly reduced relative amplitude of activity compared to non- hallucinators, independently of clinical factors including motor fluctuations.
Nyholm et al. / 2010 23	8 PD patients	4-hour levodopa profiles tested at daytime and before bedtime	The circadian rhythm and body position had an important effect on gastric emptying and absorption rate of levodopa.
Fluctuations of cardiovascular functions
Devos et al. / 2003 30	30 PD patients with variable degree of PD severity Controls	Continuous hear rate recording	The diurnal low frequency power (LF) and the ratio of LF/high frequency (HF) power were decreased in PD patients with more advanced disease. Results suggestive of an evolutive HRV decrease with disease severity but not with ON- drug-motor activity.
Ejaz et al. / 2006 29	13 PD patients	24-hour ambulatory blood pressure monitoring	Presence of reversal of BP and HR circadian rhythm (93%), postprandial hypotension (100%) and nocturnal hypertension (100%).
Niwa et al. / 2011 31	37 PD patients 30 controls	Actigraphy (7 days) 24-hour ambulatory ECG recording	PD patients had lower activity levels when out of bed and higher activity levels when in bed. The circadian rest-activity rhythm in PD decreased with disease severity. The total HR frequency component and low frequency/high frequency ratio were low in PD patients.
Oh et al. / 2014 28	225 de novo PD patients (36 with co- existent RLS)	24-hour ambulatory blood pressure monitoring	Supine blood pressure, orthostatic decline in blood pressure, nighttime blood pressure were significantly higher in the PD+RLS group than in the group without RLS.
Fluctuations of sleep-wake cycles
Lees et al. / 1988 40	220 PD patients	Nation-wide survey in UK	215 patients reported experiencing disabilities at night or on waking. The average duration of sleep was 6.5–7 h. Approximately 8% of patients reported less than 5 h sleep per night. Just over half the patients reported nocturnal problems to their physicians.
Tandberg et al. / 1998 41	245 PD patients 100 patients with diabetes mellitus 100 healthy controls	Community-based survey	Two thirds of the patients with PD reported sleep disorders. About a third of the patients with PD rated their overall nighttime problem as moderate to severe. The most common sleep disorders reported by the patients with PD were frequent awakening (sleep fragmentation) and early awakening.
Rye et al. / 2000 49	27 PD patients	Multiple Sleep Latency Test	Pathological sleepiness was common (40 of 134 nap opportunities). Degree of pathological sleepiness did not correlate with metrics of overnight sleep.
Fabbrini et al. / 2002 45	25 de novo PD patients 50 PD patients on dopaminergic therapy 25 controls	Epworth Sleepiness Scale Pittsburg Sleep Quality Index	ESS and PSQI scores were not statistically different between de novo PD patients and controls, whereas they were significantly higher in treated PD.
Abbott et al. / 2005 43	3078 participants in the Honolulu-Asia Aging Study	Sleep questionnaire	There was more than a threefold excess in the risk of PD in men with excessive daytime sleepiness versus men without excessive daytime sleepiness.
Fluctuations of sensory functions
Struck et al. / 2010 24	23 PD patients Controls	Contrast sensitivity (CS) assessments at 2- hour intervals	CS in PD was significantly worse at 3 or more spatial frequencies at all times except at 8:30 am. Analysis of CS in PD patients, with and without circadian changes in motor symptoms, revealed no significant difference between the groups.
Fluctuations of body temperature
Suzuki et al. / 2007 37	30 PD patients with and without depression	48-hour assessment of rectal temperature	PD patients with depression showed lower amplitudes of core body temperature and higher minimum rectal temperature relative to those of patients without depression.