Effect of Levodopa on Cardiovascular Autonomic Function in Parkinson's Disease

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.

Inclusion criteria

• Subjects with a diagnosis of Parkinson's disease
• For the subgroup of participants with orthostatic hypotension (OH), OH will be defined by a sustained drop in systolic blood pressure > 20 mmHg and/or a drop in diastolic blood pressure > 10 mmHg within 3 minutes from supine to standing during tilt not attributable to medications. Autonomic testing and a ratio of orthostatic heart rate change/systolic blood pressure change < 0.5 bpm/mmHg will confirm the neurogenic etiology.

Exclusion criteria

• Any medication indicated for withdrawal that would result in undue risk to the participant if discontinued or that would confound heart rate and blood pressure measures
• Cognitive impairment that limits the ability to follow instructions