Neurocirculatory Abnormalities in Parkinson Disease With Orthostatic Hypotension

Abstract

Abstract-Patients with Parkinson disease often have orthostatic hypotension. Neurocirculatory abnormalities underlying orthostatic hypotension might reflect levodopa treatment. Sixty-six Parkinson disease patients (36 with orthostatic hypotension, 15 off and 21 on levodopa; 30 without orthostatic hypotension) had tests of reflexive cardiovagal gain (decrease in interbeat interval per unit decrease in systolic pressure during the Valsalva maneuver; orthostatic increase in heart rate per unit decrease in pressure); reflexive sympathoneural function (decrease in pressure during the Valsalva maneuver; orthostatic increment in plasma norepinephrine); and cardiac and extracardiac noradrenergic innervation (septal myocardial 6-͓ 18 F͔fluorodopamine-derived radioactivity; supine plasma norepinephrine). Severity of orthostatic hypotension did not differ between the levodopa-untreated and levodopa-treated groups with Parkinson disease and orthostatic hypotension (Ϫ52Ϯ6 ͓SEM͔ versus Ϫ49Ϯ5 mm Hg systolic). The 2 groups had similarly low reflexive cardiovagal gain (0.84Ϯ0.23 versus 1.33Ϯ0.35 ms/mm Hg during Valsalva; 0.43Ϯ0.09 versus 0.27Ϯ0.06 bpm/mm Hg during orthostasis); and had similarly attenuated reflexive sympathoneural responses (97Ϯ29 versus 71Ϯ23 pg/mL during orthostasis; Ϫ82Ϯ10 versus Ϫ73Ϯ8 mm Hg during Valsalva). In patients off levodopa, plasma norepinephrine was lower in those with (193Ϯ19 pg/mL) than without (348Ϯ46 pg/mL) orthostatic hypotension. Low values for reflexive cardiovagal gain, sympathoneural responses, and noradrenergic innervation were strongly related to orthostatic hypotension. Parkinson disease with orthostatic hypotension features reflexive cardiovagal and sympathoneural failure and cardiac and partial extracardiac sympathetic denervation, independent of levodopa treatment. Key Words: hypotension Ⅲ sympathetic nervous system Ⅲ norepinephrine Ⅲ baroreflex P rimary chronic autonomic failure syndromes have been classified clinically in 3 forms: pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson disease (PD) with autonomic failure. 1 All 3 forms feature neurogenic orthostatic hypotension (OH), supine hypertension, 2,3 and attenuation of the orthostatic increase in the plasma level of norepinephrine (NE), the sympathetic neurotransmitter. 4,5 Levodopa is a precursor of dopamine and therefore of NE. In the treatment of PD, levodopa is usually combined with an inhibitor of L-aromatic-acid-decarboxylase, such as carbidopa, which does not penetrate the blood-brain barrier. Combined levodopa/carbidopa treatment therefore augments delivery of levodopa to the brain and mitigates nausea and vomiting thought to result from occupation of dopamine receptors outside the blood-brain barrier. Combined levodopa/carbidopa treatment attenuates but does not prevent catecholamine synthesis from levodopa outside the brain. 6,7 Reflexive cardiovagal gain has been reported to be variably decreased in PD 8,9 and markedly decreased in PDϩOH. 10 Levodopa treatment of PD can affect reflexive cardiov...

Lower vascular tone and larger plasma volume in Parkinson's disease with orthostatic hypotension

“…We did not find a significant difference in basal norepinephrine levels between the groups, in contrast to other studies (14,15,39,40), although norepinephrine in our study tended to be lower in PD ϩ OH. The lack of a norepinephrine difference could be due to larger standard deviations of norepinephrine levels in our PD patients who are treated with levodopa (16). Although norepinephrine is a potent vasoconstrictor, vascular tone is regulated by a combination of several vasoconstrictors and dilators.…”

“…PD patients have a reduced baroreflex cardiovagal function, denervation of the heart, low norepinephrine levels, and no increment in norepinephrine levels during orthostatic challenges (14,39). However, baroreflex failure and cardiac sympathetic denervation contribute to but cannot fully explain OH in PD (14,16).…”

Cardiovagal Baroreflex Sensitivity in Parkinson's Disease and Multiple-System Atrophy

“…Some studies have shown BRS to be similarly low in PD and MSA. [5][6][7] while others have shown it to be significantly smaller in MSA. 8 These previous studies are subject to a few important caveats.…”

“…It is well documented that MSA-C patients (MSA of the cerebellar type) and MSA-P patients show differences in both the severity and onset of OH 9 and it is noteworthy that several studies combined these patients in their analyses. 7,8 It has also been demonstrated that BRS is lower in Parkinson's disease patients with orthostatic hypotension (PDOH) than in those without OH 5,10 and that a lower BRS is correlated with a higher score on the Hoehn and Yahr scale of severity. 8 BRS has also been shown to differ between males and females.…”

“…7 In phase IV, the cardiovagal BRS was quantified from the point at which the R-R interval began to lengthen and continued to the point of maximum elevation of the systolic blood pressure. The slope of the relationship between the R-R interval and the systolic blood pressure was used as a measure of cardiovagal BRS if the correlation coefficient exceeded 0.80.…”