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Dysautonomia in Parkinson Disease

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Abstract

Dysautonomias are conditions in which altered function of one or more components of the autonomic nervous system (ANS) adversely affects health. This review updates knowledge about dysautonomia in Parkinson disease (PD). Most PD patients have symptoms or signs of dysautonomia; occasionally, the abnormalities dominate the clinical picture. Components of the ANS include the sympathetic noradrenergic system (SNS), the parasympathetic nervous system (PNS), the sympathetic cholinergic system (SCS), the sympathetic adrenomedullary system (SAS), and the enteric nervous system (ENS). Dysfunction of each component system produces characteristic manifestations. In PD, it is cardiovascular dysautonomia that is best understood scientifically, mainly because of the variety of clinical laboratory tools available to assess functions of catecholamine systems. Most of this review focuses on this aspect of autonomic involvement in PD. PD features cardiac sympathetic denervation, which can precede the movement disorder. Loss of cardiac SNS innervation occurs independently of the loss of striatal dopaminergic innervation underlying the motor signs of PD and is associated with other nonmotor manifestations, including anosmia, REM behavior disorder, orthostatic hypotension (OH), and dementia. Autonomic dysfunction in PD is important not only in clinical management and in providing potential biomarkers but also for understanding disease mechanisms (e.g., autotoxicity exerted by catecholamine metabolites). Since Lewy bodies and Lewy neurites containing alpha‐synuclein constitute neuropathologic hallmarks of the disease, and catecholamine depletion in the striatum and heart are characteristic neurochemical features, a key goal of future research is to understand better the link between alpha‐synucleinopathy and loss of catecholamine neurons in PD. © 2014 American Physiological Society. Compr Physiol 4:805‐826, 2014.

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Figure 1. Figure 1. Components of the Autonomic Nervous System (ANS). These include the enteric nervous system (ENS), parasympathetic nervous system (PNS), sympathetic noradrenergic system (SNS), sympathetic adrenergic system (SAS), and sympathetic cholinergic system (SCS). Langley defined the ANS in terms of the ENS, PNS, and sympathetic nervous system. Cannon considered the sympathetic nervous system and adrenal medulla to function as a unit, maintaining homeostasis in emergencies. Acetylcholine (ACh) is the neurotransmitter of the PNS and SCS, norepinephrine (NE) the neurotransmitter of the SNS, and epinephrine (EPI, adrenaline) is the main hormone secreted by the adrenal medulla in humans. The ENS seems to involve several neurotransmitters.
Figure 2. Figure 2. Cardiac Sympathetic Innervation in Synucleinopathies. Shown are individual data points for interventricular septal myocardial 18F‐DA‐derived radioactivity in groups with pure autonomic failure (PAF), Parkinson disease with orthostatic hypotension (PD+OH), PD without OH (PD No OH), multiple system atrophy (MSA), and control subjects. Horizontal dashed line indicates two standard deviations below the normal mean. Note that all PD+OH patients and about ½ of PD No OH patients have low 18F‐DA‐derived radioactivity.
Figure 3. Figure 3. Progression of Cardiac Denervation in a PD Patient. The patient had partial loss of myocardial 18F‐DA‐derived radioactivity upon initial evaluation, with normal anterobasal septal radioactivity. Loss of 18F‐DA‐derived radioactivity progressed rapidly thereafter.
Figure 4. Figure 4. Cardiac SNS lesion before motor onset of PD. The patient had neuroimaging evidence for cardiac sympathetic denervation more than 4 years before the onset of motor symptoms that led to a diagnosis of PD.
Figure 5. Figure 5. Cardiac denervation before Lewy body dementia in a patient with pure autonomic failure. This patient with neurogenic OH, baroreflex failure, neurochemical evidence of diffuse SNS denervation, and absent myocardial 18F‐DA‐derived radioactivity initially had normal striatal 18F‐DOPA‐derived radioactivity. Over years there was a loss of putamen radioactivity and development of Lewy body dementia.
Figure 6. Figure 6. Cardiac denervation long after motor onset of PD. This patient already had established PD when first evaluated. Myocardial 18F‐DA‐derived radioactivity was normal initially and for several years thereafter. Eventually, there was a loss of radioactivity in the left ventricular free wall, followed by loss of septal radioactivity.
Figure 7. Figure 7. Independent cardiac and striatal lesions. In two PD patients approximately matched in terms of severity of loss of putamen 18F‐DOPA‐derived radioactivity, one had normal cardiac innervation as assessed by 18F‐DA‐derived radioactivity and the other markedly decreased innervation. Images from a patient with pure autonomic failure (PAF) are included for comparison.
Figure 8. Figure 8. Myocardial NE depletion and decreased vesicular uptake in PD. Mean (± SEM) values for postmortem NE concentrations in the left ventricular apical myocardial are decreased by 96% in PD patients compared to control subjects. In contrast, DHPG:NE ratios are increased in PD to about 12 times that of controls. These findings indicate drastic myocardial NE depletion in PD and a shift from vesicular uptake to oxidative deamination of NE in residual SNS nerves.
Figure 9. Figure 9. Overview of intraneuronal synthesis and metabolism of norepinephrine in sympathetic nerves. Most of the irreversible loss of norepinephrine (NE) from the neurons is due to passive leakage from vesicles into the cytosol, followed by enzymatic deamination catalyzed by monoamine oxidase (MAO). Cytosolic NE is taken up into the vesicles via the type 2 vesicular monoamine transporter (VMAT). After exocytotic release of NE, there is efficient reuptake into the cytosol via the cell membrane NE transporter (NET). NE is synthesized in vesicles by dopamine‐beta‐hydroxylase (DBH) acting on dopamine (DA) taken up from the cytosol. DA is synthesized via L‐aromatic‐amino‐acid decarboxylase (LAAAD) acting on 3,4‐dihydroxyphenylalanine (DOPA) produced from tyrosine (TYR) by tyrosine hydroxylase (TH). The action of MAO on cytosolic DA produces the catecholaldehyde, 3,4‐dihydroxyphenylacetaldehyde (DOPAL) and on NE produces the catecholaldehyde, 3,4‐dihydroxyphenylglycolaldehyde (DOPEGAL). DOPEGAL is detoxified mainly by aldehyde/aldose reductase (AR), to form the glycol, 3,4‐dihydroxyphenylglycol (DHPG), and DOPAL is detoxified mainly by aldehyde dehydrogenase (ALDH) to form the acid, 3,4‐dihydroxyphenylacetic acid (DOPAC).
Figure 10. Figure 10. Decreased Immunoreactive TH in PD. The upper panels show immunoreactive TH in arrector pili muscle and the bottom panels in epicardial nerve in PD. Images in upper panels were kindly provided by R. Freeman, C. Gibbons, and N. Wang; images in lower panels are adapted, with permission, from (30). Note similar pattern of decreased and fragmented immunoreactive TH in the PD patients.
Figure 11. Figure 11. Blood pressure and heart rate responses to the Valsalva maneuver. In PD+OH and other conditions associated with baroreflex‐sympathoneural failure, baroreflex areas (highlighted in aqua) in Phases II and IV are increased.
Figure 12. Figure 12. Some alpha‐synucleinopathies. Lewy body diseases include Parkinson disease (PD), PD with dementia (PD+D), Lewy body dementia (LBD), PD with orthostatic hypotension (PD+OH), and pure autonomic failure (PAF). In multiple system atrophy (MSA), alpha‐synuclein deposits are found glial cytoplasmic inclusions, so that MSA is a non‐Lewy body form of alpha‐synucleinopathy.
Figure 13. Figure 13. Synucleinopathy etiologic in the SNS lesion attending PD. In both PARK1 (A53T mutation of the gene encoding alpha‐synuclein) and in PARK4 (triplication of the normal alpha‐synuclein gene), there is profoundly decreased cardiac 18F‐DA‐derived radioactivity, as in sporadic PD.


Figure 1. Components of the Autonomic Nervous System (ANS). These include the enteric nervous system (ENS), parasympathetic nervous system (PNS), sympathetic noradrenergic system (SNS), sympathetic adrenergic system (SAS), and sympathetic cholinergic system (SCS). Langley defined the ANS in terms of the ENS, PNS, and sympathetic nervous system. Cannon considered the sympathetic nervous system and adrenal medulla to function as a unit, maintaining homeostasis in emergencies. Acetylcholine (ACh) is the neurotransmitter of the PNS and SCS, norepinephrine (NE) the neurotransmitter of the SNS, and epinephrine (EPI, adrenaline) is the main hormone secreted by the adrenal medulla in humans. The ENS seems to involve several neurotransmitters.


Figure 2. Cardiac Sympathetic Innervation in Synucleinopathies. Shown are individual data points for interventricular septal myocardial 18F‐DA‐derived radioactivity in groups with pure autonomic failure (PAF), Parkinson disease with orthostatic hypotension (PD+OH), PD without OH (PD No OH), multiple system atrophy (MSA), and control subjects. Horizontal dashed line indicates two standard deviations below the normal mean. Note that all PD+OH patients and about ½ of PD No OH patients have low 18F‐DA‐derived radioactivity.


Figure 3. Progression of Cardiac Denervation in a PD Patient. The patient had partial loss of myocardial 18F‐DA‐derived radioactivity upon initial evaluation, with normal anterobasal septal radioactivity. Loss of 18F‐DA‐derived radioactivity progressed rapidly thereafter.


Figure 4. Cardiac SNS lesion before motor onset of PD. The patient had neuroimaging evidence for cardiac sympathetic denervation more than 4 years before the onset of motor symptoms that led to a diagnosis of PD.


Figure 5. Cardiac denervation before Lewy body dementia in a patient with pure autonomic failure. This patient with neurogenic OH, baroreflex failure, neurochemical evidence of diffuse SNS denervation, and absent myocardial 18F‐DA‐derived radioactivity initially had normal striatal 18F‐DOPA‐derived radioactivity. Over years there was a loss of putamen radioactivity and development of Lewy body dementia.


Figure 6. Cardiac denervation long after motor onset of PD. This patient already had established PD when first evaluated. Myocardial 18F‐DA‐derived radioactivity was normal initially and for several years thereafter. Eventually, there was a loss of radioactivity in the left ventricular free wall, followed by loss of septal radioactivity.


Figure 7. Independent cardiac and striatal lesions. In two PD patients approximately matched in terms of severity of loss of putamen 18F‐DOPA‐derived radioactivity, one had normal cardiac innervation as assessed by 18F‐DA‐derived radioactivity and the other markedly decreased innervation. Images from a patient with pure autonomic failure (PAF) are included for comparison.


Figure 8. Myocardial NE depletion and decreased vesicular uptake in PD. Mean (± SEM) values for postmortem NE concentrations in the left ventricular apical myocardial are decreased by 96% in PD patients compared to control subjects. In contrast, DHPG:NE ratios are increased in PD to about 12 times that of controls. These findings indicate drastic myocardial NE depletion in PD and a shift from vesicular uptake to oxidative deamination of NE in residual SNS nerves.


Figure 9. Overview of intraneuronal synthesis and metabolism of norepinephrine in sympathetic nerves. Most of the irreversible loss of norepinephrine (NE) from the neurons is due to passive leakage from vesicles into the cytosol, followed by enzymatic deamination catalyzed by monoamine oxidase (MAO). Cytosolic NE is taken up into the vesicles via the type 2 vesicular monoamine transporter (VMAT). After exocytotic release of NE, there is efficient reuptake into the cytosol via the cell membrane NE transporter (NET). NE is synthesized in vesicles by dopamine‐beta‐hydroxylase (DBH) acting on dopamine (DA) taken up from the cytosol. DA is synthesized via L‐aromatic‐amino‐acid decarboxylase (LAAAD) acting on 3,4‐dihydroxyphenylalanine (DOPA) produced from tyrosine (TYR) by tyrosine hydroxylase (TH). The action of MAO on cytosolic DA produces the catecholaldehyde, 3,4‐dihydroxyphenylacetaldehyde (DOPAL) and on NE produces the catecholaldehyde, 3,4‐dihydroxyphenylglycolaldehyde (DOPEGAL). DOPEGAL is detoxified mainly by aldehyde/aldose reductase (AR), to form the glycol, 3,4‐dihydroxyphenylglycol (DHPG), and DOPAL is detoxified mainly by aldehyde dehydrogenase (ALDH) to form the acid, 3,4‐dihydroxyphenylacetic acid (DOPAC).


Figure 10. Decreased Immunoreactive TH in PD. The upper panels show immunoreactive TH in arrector pili muscle and the bottom panels in epicardial nerve in PD. Images in upper panels were kindly provided by R. Freeman, C. Gibbons, and N. Wang; images in lower panels are adapted, with permission, from (30). Note similar pattern of decreased and fragmented immunoreactive TH in the PD patients.


Figure 11. Blood pressure and heart rate responses to the Valsalva maneuver. In PD+OH and other conditions associated with baroreflex‐sympathoneural failure, baroreflex areas (highlighted in aqua) in Phases II and IV are increased.


Figure 12. Some alpha‐synucleinopathies. Lewy body diseases include Parkinson disease (PD), PD with dementia (PD+D), Lewy body dementia (LBD), PD with orthostatic hypotension (PD+OH), and pure autonomic failure (PAF). In multiple system atrophy (MSA), alpha‐synuclein deposits are found glial cytoplasmic inclusions, so that MSA is a non‐Lewy body form of alpha‐synucleinopathy.


Figure 13. Synucleinopathy etiologic in the SNS lesion attending PD. In both PARK1 (A53T mutation of the gene encoding alpha‐synuclein) and in PARK4 (triplication of the normal alpha‐synuclein gene), there is profoundly decreased cardiac 18F‐DA‐derived radioactivity, as in sporadic PD.
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David S. Goldstein. Dysautonomia in Parkinson Disease. Compr Physiol 2014, 4: 805-826. doi: 10.1002/cphy.c130026