Parkinson's disease (PD) is characterized by the gradual onset of motor symptoms such as
bradykinesia, rigidity, tremor, gait difficulties and postural instability, as well as
non-motor symptoms such as cognitive impairment and autonomic dysfunction among others.
Neurogenic orthostatic hypotension (nOH) is the main clinical manifestation of
cardiovascular autonomic dysfunction. The arterial baroreflex allows for beat-to-beat
regulation of the blood pressure and heart rate via differential modulation of its
cardiovagal (parasympathetic) and noradrenergic (sympathetic) efferent limbs. Several
mechanisms may contribute to nOH in PD including baroreflex-cardiovagal and
baroreflex-sympathetic noradrenergic failure. The prevalence of nOH in PD increases with
age and disease duration; however, several studies have documented that nOH may appear
early in the course of PD and reported prevalence of nOH in PD ranges from 30% to 65%.
The presence of nOH in PD is associated with poor outcomes related to cardiovascular
events, increased morbidity and mortality, more rapid disease progression, cognitive
impairment, and falls.
Levodopa is a precursor of dopamine and is the treatment of choice to treat the motor
symptoms of PD; however, the effect of levodopa on cardiovascular autonomic function in
PD is poorly understood. Orthostatic hypotension has been documented as a potential side
effect of levodopa in different studies. As a result, clinicians may be reluctant to
prescribe levodopa in patients with PD with nOH (PD+OH), which leads to suboptimal
management of motor symptoms. On the other hand, several studies failed to show any clear
relationship between levodopa and orthostatic hypotension in patients with PD. Important
limitations of prior studies include the lack of detailed investigation of baroreflex
cardiovagal and sympathetic noradrenergic functions and the fact that the same patients
were not tested on and off levodopa.
The investigators propose to investigate the effects of levodopa on cardiovascular
autonomic function in patients with PD+OH and PD without nOH (PD-OH) by performing
standardized autonomic testing in the same patients on and off levodopa.
Clinical assessment: We will perform a medical history and physical examination before
the testing procedures (baseline visit). The baseline visit will be performed on
levodopa. The scales and assessments will include the Composite Autonomic Symptoms Score
31 (COMPASS 31), the Movement Disorder Society-Sponsored Revision of the Unified
Parkinson's Disease Rating Scale (MDS-UPDRS) part I, II, III, and Hoehn and Yahr stage.
The clinical assessment and scales are part of the standard of care in PD. Orthostatic
vital signs will active standing will be also performed the two days of autonomic
testing.
Participants will undergo a baseline visit. During the baseline visit, investigators will
perform a medical history and physical examination and complete the following scales:
Composite Autonomic Symptoms Score 31 (COMPASS 31), the Movement Disorder
Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)
part I, II, III, and Hoehn and Yahr. Participants will undergo autonomic testing on two
separate days. The first autonomic testing will occur within 4 weeks of the baseline
visit. The two autonomic tests will occur within a 2-week timeframe. To avoid any
confounding of treatment effects and period effects, the order of testing (on versus off
levodopa) will be randomized so testing on the first day will be on-levodopa for half of
the participants and off-levodopa for the other participants. Autonomic testing will
include assessment of heart rate and blood pressures responses during the Valsalva
maneuver and a 10-minute tilt table test.