Cardiovascular dysautonomia in Parkinson disease: from pathophysiology to pathogenesis

Abstract

Signs or symptoms of impaired autonomic regulation of circulation often attend Parkinson disease (PD). This review covers biomarkers and mechanisms of autonomic cardiovascular abnormalities in PD and related alpha-synucleinopathies. The clearest clinical laboratory correlate of dysautonomia in PD is loss of myocardial noradrenergic innervation, detected by cardiac sympathetic neuroimaging. About 30-40% of PD patients have orthostatic hypotension (OH), defined as a persistent, consistent fall in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 min of change in position from supine to standing. Neuroimaging evidence of cardiac sympathetic denervation is universal in PD with OH (PD+OH). In PD without OH about half the patients have diffuse left ventricular myocardial sympathetic denervation, a substantial minority have partial denervation confined to the inferolateral or apical walls, and a small number have normal innervation. Among patients with partial denervation the neuronal loss invariably progresses over time, and in those with normal innervation at least some loss eventually becomes evident. Thus, cardiac sympathetic denervation in PD occurs independently of the movement disorder. PD+OH also entails extra-cardiac noradrenergic denervation, but this is not as severe as in pure autonomic failure. PD+OH patients have failure of both the parasympathetic and sympathetic components of the arterial baroreflex. OH in PD therefore seems to reflect a "triple whammy" of cardiac and extra-cardiac noradrenergic denervation and baroreflex failure. In contrast, most patients with multiple system atrophy, which can resemble PD+OH clinically, do not have evidence for cardiac or extra-cardiac noradrenergic denervation. Catecholamines in the neuronal cytoplasm are potentially toxic, via spontaneous and enzyme-catalyzed oxidation. Normally cytoplasmic catecholamines are efficiently taken up into vesicles via the vesicular monoamine transporter. The recent finding of decreased vesicular uptake in Lewy body diseases therefore suggests a pathogenetic mechanism for loss of catecholaminergic neurons in the periphery and brain. Parkinson disease (PD) is one of the most common chronic neurodegenerative diseases of the elderly, and it is likely that as populations age PD will become even more prevalent and more of a public health burden. Severe depletion of dopaminergic neurons of the nigrostriatal system characterizes and likely produces the movement disorder (rest tremor, slowness of movement, rigid muscle tone, and postural instability) in PD. Over the past two decades, compelling evidence has accrued that PD also involves loss of noradrenergic neurons in the heart. This finding supports the view that loss of catecholaminergic neurons, both in the nigrostriatal system and the heart, is fundamental in PD. By the time PD manifests clinically, most of the nigrostriatal dopaminergic neurons are already lost. Identifying laboratory measures-biomarkers-of the disease process is therefore crucial for advances in treatment and prevention. Deposition of the protein, alpha-synuclein, in the form of Lewy bodies in catecholaminergic neurons is a pathologic hallmark of PD. Alpha-synucleinopathy in autonomic neurons may occur early in the pathogenetic process. The timing of cardiac noradrenergic denervation in PD is therefore a key issue. This review updates the field of autonomic cardiovascular abnormalities in PD and related disorders, with emphasis on relationships among striatal dopamine depletion, sympathetic noradrenergic denervation, and alpha-synucleinopathy.

Figure 1

Components of the autonomic nervous system (ANS). Langley taught the ANS has three components: the sympathetic nervous system (SNS), parasympathetic nervous system (PNS), and enteric nervous system (ENS). Cannon added a hormonal component, the sympathetic adrenomedullary system (SAS), in which epinephrine (EPI) is the chemical messenger. Acetylcholine (ACh) is the neurotransmitter of the sympathetic cholinergic system (SChS) and norepinephrine (NE) the neurotransmitter of the sympathetic noradrenergic system (SNoS). Cannon taught that the sympathoadrenal system is a functional unit.

Figure 2

Typical ¹³NH₃ and ¹⁸F-dopamine (¹⁸FDA) positron emission tomographic scans in a control subject, a patient with pure autonomic failure (PAF), a patient with multiple system atrophy (MSA), and a patient with Parkinson disease (PD). Note absence of discernible myocardial ¹⁸FDA-derived radioactivity in the PAF and PD patients and normal radioactivity in the MSA patient.

Figure 3

Continuous recordings of heart rate and blood pressure in a control subject and a patient with neurogenic orthostatic hypotension associated with performance of the Valsalva maneuver. Note that the patient has a progressive decrease in pressure in Phase II, no pressure overshoot in Phase IV, and blunted heart rate responses.

Figure 4

Algorithm for evaluation of orthostatic hypotension. The algorithm asks if orthostatic hypotension is persistent and consistent; if it is neurogenic; and if it is associated with post-ganglionic, sympathetic, noradrenergic denervation. Abbreviations: AAG=autoimmune autonomic ganglionopathy; BP=blood pressure; CNS=central nervous system; LBD=Lewy body dementia; MSA=multiple system atrophy; NE=norepinephrine; PAF=pure autonomic failure; PD+NOH=Parkinson disease with neurogenic orthostatic hypotension.

Figure 5

Serial ¹⁸F-dopamine scans in a patient with Parkinson disease who did not have orthostatic hypotension. Note initially normal septal radioactivity, with progressive loss of radioactivity.

Figure 6

Serial ¹⁸F-DOPA, ¹⁸F-dopamine, and ¹³NH₃ scans in a patient with pure autonomic failure. Note initially normal striatal ¹⁸F-DOPA-derived radioactivity and low myocardial ¹⁸F-dopamine-derived radioactivity, with progressive loss of striatal radioactivity.

Figure 7

Cardiac septal and free wall ¹⁸F-dopamine-derived radioactivity as a function of years of follow-up in a patient with Parkinson disease who did not have orthostatic hypotension. Note that the patient had normal radioactivity for several years.

Figure 8

Mean (±SEM) values for a vesicular uptake index in patient groups with Parkinson disease and orthostatic hypotension (PD+OH), pure autonomic failure (PAF), or multiple system atrophy (MSA) and normal control subjects. Note decreased vesicular uptake indices in the Lewy body diseases.