Review
Cardiovascular dysautonomia in Parkinson disease: From pathophysiology to pathogenesis

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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 mm Hg or diastolic blood pressure of at least 10 mm Hg 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.

Introduction

Alterations in autonomic functions, known as dysautonomias, adversely affect health. Before considering cardiovascular manifestations of dysautonomia in PD it is important to recognize that the autonomic nervous system has multiple components (Fig. 1), which seem to be involved differentially in PD.

Langley coined the term autonomic nervous system (ANS) and recognized three components, the sympathetic nervous system (SNS), parasympathetic nervous system (another phrased he introduced, PNS), and enteric nervous system (ENS). The sympathetic nervous system is composed of two subsystems based on their main chemical messengers norepinephrine (NE), epinephrine (also known as adrenaline) and acetylcholine. The sympathetic noradrenergic system (SNaS) is the SNS component responsible for reflexive constriction of blood vessels and stimulation of the heart. The sympathetic cholinergic (SChS) system mediates sweating. The parasympathetic nervous system is responsible for a constellation of phenomena including respiratory sinus arrhythmia, gastrointestinal and urinary bladder tone, salivation, lacrimation, and pupillary constriction in response to light. Parasympathetic cholinergic failure therefore results in dry mouth and eyes, constipation, urinary retention, and photophobia. The sympathetic adrenomedullary system (SAS) uses the hormone epinephrine as the chemical effector. Epinephrine is one of the three main hormones regulating serum glucose, the others being insulin and glucagon. It is difficult if not impossible clinically to distinguish parasympathetic cholinergic denervation, enteric denervation, and disruption of reflexive modulation of autonomic outflows as determinants of symptoms such as constipation, abdominal bloating, and esophageal reflux.

At least three pathophysiologic mechanisms underlie the cardiovascular autonomic abnormalities attending PD. The first is loss of cardiac sympathetic noradrenergic nerves. As discussed below, cardiac sympathetic denervation occurs virtually universally in PD, in a manner that seems surprisingly independent of the movement disorder in individual patients. The second is extra-cardiac noradrenergic denervation. For unknown reasons, loss of extra-cardiac noradrenergic innervation in PD is less extensive than is loss of cardiac innervation. The third determinant is arterial baroreflex failure. Severely decreased function of both the parasympathetic and sympathetic components of the arterial baroreflex is characteristic in PD + OH.

These three determinants together result in orthostatic hypotension (OH). Conversely, OH is a key manifestation of cardiovascular dysautonomia in PD.

Section snippets

More than a movement disorder, more than a brain disease

The discovery about 15 years ago of neuroimaging evidence for cardiac sympathetic denervation in PD (Goldstein et al., 1997) was a watershed for scientific and clinical understanding of the disease (Fig. 2). Until then, although it had been well known that PD patients often have symptoms or signs of autonomic failure, pathophysiologic bases for these complaints had been mysterious. The findings from cardiac sympathetic neuroimaging indicated that at least one mechanism of dysautonomia in PD is

PD + OH: a distinctive pathophysiologic entity?

About 30–40% of PD patients have OH (Goldstein, 2003, Velseboer et al., 2011). The prevalence of OH varies substantially across studies, probably reflecting differences in referral patterns in different centers. If one relies on symptoms to diagnose PD + OH, then OH is quite infrequent, because patients with OH can have surprisingly low blood pressure and not notice symptoms.

Which autonomic function tests for cardiovascular dysautonomia are sensitive and which specific in PD?

There are several clinical laboratory tests available for evaluating involvement of different components of the autonomic nervous system in PD. Some are approved and widely used, while others are considered research tools. This section discusses tests that seem most relevant to cardiovascular dysautonomia in PD.

In our view the most important single test in this evaluation is beat-to-beat hemodynamics associated with performance of the Valsalva maneuver (Fig. 3). The combination of a progressive

Progression and timing of partial cardiac denervation in PD No OH

Although patients with PD + OH invariably have loss of cardiac sympathetic nerves diffusely in the left ventricular myocardium, PD patients without OH (PD No OH) can have normal innervation or have denervation that is heterogeneous within the left ventricular myocardium. The apical or inferolateral wall is denervated, while the anterobasal septal innervation is still intact. The 18F-dopamine scans in Fig. 5 exemplify this phenomenon (Li et al., 2002). Over the course of relatively few years, the

Impaired vesicular uptake of intraneuronal catecholamines in Lewy body diseases

Mechanisms of striatal and cardiac catecholaminergic denervation in Lewy body diseases such as PD have been poorly understood. A recent study examined the uptake, loss, and intra-neuronal vesicular sequestration of catecholamines, by assessing myocardial 6-[18F]dopamine-(18F-DA)-derived radioactivity and arterial plasma 18F-dihydroxyphenylacetic acid (18F-DOPAC) in PD with or without OH, pure autonomic failure (a Lewy body disease without parkinsonism), multiple system atrophy (a non-Lewy body

Summary

Cardiac and extra-cardiac noradrenergic denervation and baroreflex failure characterize and probably produce OH in PD. These abnormalities occur independently of striatal dopamine depletion. Cardiovascular autonomic variables may provide biomarkers of pre-motor PD in some patients. Understanding mechanisms of cardiac sympathetic dysfunction and denervation in PD may also help elucidate bases of central catecholaminergic lesions in a variety of neurodegenerative diseases. In particular, Lewy

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