Comprehensive Physiology Wiley Online Library

Dysautonomia in Parkinson Disease

Full Article on Wiley Online Library



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.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


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.
References
 1. Abbott RD , Petrovitch H , White LR , Masaki KH , Tanner CM , Curb JD , Grandinetti A , Blanchette PL , Popper JS , Ross GW . Frequency of bowel movements and the future risk of Parkinson's disease. Neurology 57: 456‐462, 2001.
 2. Amino T , Orimo S , Takahashi A , Uchihara T , Mizusawa H . Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Path 15: 29‐34, 2005.
 3. Annerino DM , Arshad S , Taylor GM , Adler CH , Beach TG , Greene JG . Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol 124: 665‐680, 2012.
 4. Araki H , Tanaka C , Fujiwara H , Nakamura M , Ohmura I . Pressor effect of L‐threo‐3,4‐dihydroxyphenylserine in rats. J Pharm Pharmacol 33: 772‐777, 1981.
 5. Araki I , Kitahara M , Oida T , Kuno S . Voiding dysfunction and Parkinson's disease: Urodynamic abnormalities and urinary symptoms. J Urol 164: 1640‐1643, 2000.
 6. Aranda B , Cramer P . Effects of apomorphine and L‐dopa on the parkinsonian bladder. Neurourol Urodyn 12: 203‐209, 1993.
 7. Beach TG , Adler CH , Sue LI , Vedders L , Lue L , White Iii CL , Akiyama H , Caviness JN , Shill HA , Sabbagh MN , Walker DG . Multi‐organ distribution of phosphorylated alpha‐synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119: 689‐702, 2010.
 8. Benarroch EE , Schmeichel AM , Sandroni P , Low PA , Parisi JE . Involvement of vagal autonomic nuclei in multiple system atrophy and Lewy body disease. Neurology 66: 378‐383, 2006.
 9. Berendse HW , Booij J , Francot CM , Bergmans PL , Hijman R , Stoof JC , Wolters EC . Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell. Ann Neurol 50: 34‐41, 2001.
 10. Berendse HW , Ponsen MM . Detection of preclinical Parkinson's disease along the olfactory trac(t). J Neural Transm Suppl 321‐325, 2006.
 11. Biaggioni I , Robertson RM . Hypertension in orthostatic hypotension and autonomic dysfunction. Cardiol Clin 20: 291‐301, vii, 2002.
 12. Birkmayer W , Birkmayer G , Lechner H , Riederer P . DL‐3,4‐threo‐DOPS in Parkinson's disease: Effects on orthostatic hypotension and dizziness. J Neural Transm 58: 305‐313, 1983.
 13. Blok BF . Central pathways controlling micturition and urinary continence. Urology 59: 13‐17, 2002.
 14. Braak H , de Vos RA , Bohl J , Del Tredici K . Gastric alpha‐synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease‐related brain pathology. Neurosci Lett 396: 67‐72, 2006.
 15. Braak H , Ghebremedhin E , Rub U , Bratzke H , Del Tredici K . Stages in the development of Parkinson's disease‐related pathology. Cell Tissue Res 318: 121‐134, 2004.
 16. Braak H , Rub U , Gai WP , Del Tredici K . Idiopathic Parkinson's disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110: 517‐536, 2003.
 17. Bronner G , Royter V , Korczyn AD , Giladi N . Sexual dysfunction in Parkinson's disease. J Sex Marital Ther 30: 95‐105, 2004.
 18. Burke WJ , Kumar VB , Pandey N , Panneton WM , Gan Q , Franko MW , O'Dell M , Li SW , Pan Y , Chung HD , Galvin JE . Aggregation of alpha‐synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathol 115: 193‐203, 2008.
 19. Cannon WB. Bodily Changes in Pain, Hunger, Fear and Rage. New York: D. Appleton & Co., 1929.
 20. Cannon WB . A law of denervation. Am J Med Sci 198: 737‐750, 1939.
 21. Cannon WB. The Wisdom of the Body. New York: W.W. Norton, 1939.
 22. Cannon WB , Lissak K . Evidence for adrenaline in adrenergic neurones. Am J Physiol 125: 765‐777, 1939.
 23. Cannon WB , Newton HF , Bright EM , Menkin V , Moore RM . Some aspects of the physiology of animals surviving complete exclusion of sympathetic nerve impulses. Am J Physiol 89: 84‐107, 1929.
 24. Carmichael SW , Wilson RJ , Brimijoin WS , Melton LJ, III , Okazaki H , Yaksh TL , Ahlskog JE , Stoddard SL , Tyce GM . Decreased catecholamines in the adrenal medulla of patients with parkinsonism. N Engl J Med 318: 254, 1988.
 25. Caudle WM , Colebrooke RE , Emson PC , Miller GW . Altered vesicular dopamine storage in Parkinson's disease: A premature demise. Trends Neurosci 31: 303‐308, 2008.
 26. Caudle WM , Richardson JR , Wang MZ , Taylor TN , Guillot TS , McCormack AL , Colebrooke RE , Di Monte DA , Emson PC , Miller GW . Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J Neurosci 27: 8138‐8148, 2007.
 27. Cersosimo MG , Raina GB , Pecci C , Pellene A , Calandra CR , Gutierrez C , Micheli FE , Benarroch EE . Gastrointestinal manifestations in Parkinson's disease: Prevalence and occurrence before motor symptoms. J Neurol 260: 1332‐1338, 2013.
 28. Christmas TJ , Kempster PA , Chapple CR , Frankel JP , Lees AJ , Stern GM , Milroy EJ . Role of subcutaneous apomorphine in parkinsonian voiding dysfunction. Lancet 2: 1451‐1453, 1988.
 29. Dabby R , Djaldetti R , Shahmurov M , Treves TA , Gabai B , Melamed E , Sadeh M , Avinoach I . Skin biopsy for assessment of autonomic denervation in Parkinson's disease. J Neural Transm 113: 1169‐1176, 2006.
 30. Del Tredici K , Braak H . Lewy pathology and neurodegeneration in premotor Parkinson's disease. Movement Dis 27: 597‐607, 2012.
 31. Del Tredici K , Hawkes CH , Ghebremedhin E , Braak H . Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease. Acta Neuropathol 119: 703‐713, 2010.
 32. Den Hartog Jager W , Bethlem J . The distribution of Lewy bodies in the central and autonomic nervous system in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 23: 283‐290, 1960.
 33. Dickson DW , Liu W , Hardy J , Farrer M , Mehta N , Uitti R , Mark M , Zimmerman T , Golbe L , Sage J , Sima A , D'Amato C , Albin R , Gilman S , Yen SH . Widespread alterations of alpha‐synuclein in multiple system atrophy. Am J Pathol 155: 1241‐1251, 1999.
 34. Edwards L , Quigley EM , Hofman R , Pfeiffer RF . Gastrointestinal symptoms in Parkinson disease: 18‐month follow‐up study. Mov Disord 8: 83‐86, 1993.
 35. Ehringer H , Hornykiewicz O . Distribution of noradrenaline and dopamine (3‐hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Wien Klin Wochenschr 38: 1236–1239, 1960.
 36. Eisenhofer G , Aneman A , Friberg P , Hooper D , Fandriks L , Lonroth H , Hunyady B , Mezey E . Substantial production of dopamine in the human gastrointestinal tract. J Clin Endocrinol Metab 82: 3864‐3871, 1997.
 37. Eisenhofer G , Esler MD , Meredith IT , Dart A , Cannon RO, III , Quyyumi AA , Lambert G , Chin J , Jennings GL , Goldstein DS . Sympathetic nervous function in human heart as assessed by cardiac spillovers of dihydroxyphenylglycol and norepinephrine. Circulation 85: 1775‐1785, 1992.
 38. Eldrup E , Mogensen P , Jacobsen J , Pakkenberg H , Christensen NJ . CSF and plasma concentrations of free norepinephrine, dopamine, 3,4‐dihydroxyphenylacetic acid (DOPAC), 3,4‐dihydroxyphenylalanine (DOPA), and epinephrine in Parkinson's disease. Acta Neurol Scand 92: 116‐121, 1995.
 39. Ertekin C , Tarlaci S , Aydogdu I , Kiylioglu N , Yuceyar N , Turman AB , Secil Y , Esmeli F . Electrophysiological evaluation of pharyngeal phase of swallowing in patients with Parkinson's disease. Movement Dis 17: 942‐949, 2002.
 40. Esler M . Clinical application of noradrenaline spillover methodology: Delineation of regional human sympathetic nervous responses. Pharmacol Toxicol 73: 243‐253, 1993.
 41. Fanara P , Wong PY , Husted KH , Liu S , Liu VM , Kohlstaedt LA , Riiff T , Protasio JC , Boban D , Killion S , Killian M , Epling L , Sinclair E , Peterson J , Price RW , Cabin DE , Nussbaum RL , Bruhmann J , Brandt R , Christine CW , Aminoff MJ , Hellerstein MK . Cerebrospinal fluid‐based kinetic biomarkers of axonal transport in monitoring neurodegeneration. J Clin Inv 122: 3159‐3169, 2012.
 42. Fitzmaurice AG , Rhodes SL , Lulla A , Murphy NP , Lam HA , O'Donnell KC , Barnhill L , Casida JE , Cockburn M , Sagasti A , Stahl MC , Maidment NT , Ritz B , Bronstein JM . Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proc Natl Acad Sci U S A 110: 636‐641, 2012.
 43. Fitzmaurice H , Fowler CJ , Rickards D , Kirby RS , Quinn NP , Marsden CD , Milroy EJ , Turner‐Warwick RT . Micturition disturbance in Parkinson's disease. Br J Urol 57: 652‐656, 1985.
 44. Frank SM , Raja SN , Bulcao C , Goldstein DS . Age‐related thermoregulatory differences during core cooling in humans. Am J Physiol Regul Integr Comp Physiol 279: R349‐354, 2000.
 45. Freeman R , Landsberg L , Young J . The treatment of neurogenic orthostatic hypotension with 3,4‐DL‐threo‐dihydroxyphenylserine: A randomized, placebo‐controlled, crossover trial. Neurology 53: 2151‐2157, 1999.
 46. Freeman R , Wieling W , Axelrod FB , Benditt DG , Benarroch E , Biaggioni I , Cheshire WP , Chelimsky T , Cortelli P , Gibbons CH , Goldstein DS , Hainsworth R , Hilz MJ , Jacob G , Kaufmann H , Jordan J , Lipsitz LA , Levine BD , Low PA , Mathias C , Raj SR , Robertson D , Sandroni P , Schatz I , Schondorff R , Stewart JM , van Dijk JG . Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 21: 69‐72, 2011.
 47. Fujishiro H , Frigerio R , Burnett M , Klos KJ , Josephs KA , Delledonne A , Parisi JE , Ahlskog JE , Dickson DW . Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson's disease. Mov Disord 23: 1085‐1092, 2008.
 48. Gai WP , Geffen LB , Denoroy L , Blessing WW . Loss of C1 and C3 epinephrine‐synthesizing neurons in the medulla oblongata in Parkinson's disease. Ann Neurol 33: 357‐367, 1993.
 49. Galinier M , Senard JM , Valet P , Doazan JP , Durrieu G , Tran MA , Monstastruc JL , Bounhoure JP . Relationship between arterial blood pressure disturbances and alpha adrenoceptor density. Clin Exp Hypertens 16: 373‐389, 1994.
 50. Galvin JE . Interaction of alpha‐synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: A case for the selective vulnerability of the substantia nigra. Acta Neuropathol 112: 115‐126, 2006.
 51. Gao X , Chen H , Schwarzschild MA , Glasser DB , Logroscino G , Rimm EB , Ascherio A . Erectile function and risk of Parkinson's disease. Am J Epidemiol 166: 1446‐1450, 2007.
 52. Gaugler MN , Genc O , Bobela W , Mohanna S , Ardah MT , El‐Agnaf OM , Cantoni M , Bensadoun JC , Schneggenburger R , Knott GW , Aebischer P , Schneider BL . Nigrostriatal overabundance of alpha‐synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity. Acta Neuropathol 123: 653‐669, 2012.
 53. Gershon MD . Developmental determinants of the independence and complexity of the enteric nervous system. Trends Neurosci 33: 446‐456, 2010.
 54. Goldstein DS . The Autonomic Nervous System in Health and Disease. New York, NY: Marcel Dekker, Inc., 2001.
 55. Goldstein DS . Dysautonomia in Parkinson's disease: Neurocardiological abnormalities. Lancet Neurol 2: 669‐676, 2003.
 56. Goldstein DS. Adrenaline and the Inner World: An Introduction to Scientific Integrative Medicine. Baltimore, MD: The Johns Hopkins University Press, 2006.
 57. Goldstein DS . Orthostatic hypotension as an early finding in Parkinson disease. Clin Auton Res 16: 46‐64, 2006.
 58. Goldstein DS . Cardiac denervation in patients with Parkinson disease. Cleve Clin J Med 74(Suppl 1): S91‐94, 2007.
 59. Goldstein DS . Cardiac ectopy in chronic autonomic failure. Clin Auton Res 20: 85‐92, 2010.
 60. Goldstein DS , Cannon RO , Quyyumi A , Chang P , Duncan M , Brush JE, Jr , Eisenhofer G . Regional extraction of circulating norepinephrine, DOPA, and dihydroxyphenylglycol in humans. J Auton Nerv Sys 34: 17‐35, 1991.
 61. Goldstein DS , Eisenhofer G , Stull R , Folio CJ , Keiser HR , Kopin IJ . Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J Clin Invest 81: 213‐220, 1988.
 62. Goldstein DS , Eldadah BA , Holmes C , Pechnik S , Moak J , Saleem A , Sharabi Y . Neurocirculatory abnormalities in Parkinson disease with orthostatic hypotension: Independence from levodopa treatment. Hypertension 46: 1333‐1339, 2005.
 63. Goldstein DS , Feuerstein G , Izzo JL, Jr , Kopin IJ , Keiser HR . Validity and reliability of liquid chromatography with electrochemical detection for measuring plasma levels of norepinephrine and epinephrine in man. Life Sci 28: 467‐475, 1981.
 64. Goldstein DS , Holmes C , Bentho O , Sato T , Moak J , Sharabi Y , Imrich R , Conant S , Eldadah BA . Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy. Parkinsonism Relat Disord 14: 600‐607, 2008.
 65. Goldstein DS , Holmes C , Cannon RO, III , Eisenhofer G , Kopin IJ . Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336: 696‐702, 1997.
 66. Goldstein DS , Holmes C , Dendi R , Bruce S , Li S‐T . Orthostatic hypotension from sympathetic denervation in Parkinson's disease. Neurology 58: 1247‐1255, 2002.
 67. Goldstein DS , Holmes C , Dendi R , Li ST , Brentzel S , Vernino S . Pandysautonomia associated with impaired ganglionic neurotransmission and circulating antibody to the neuronal nicotinic receptor. Clin Auton Res 12: 281‐285, 2002.
 68. Goldstein DS , Holmes C , Frank SM , Naqibuddin M , Dendi R , Snader S , Calkins H . Sympathoadrenal imbalance before neurocardiogenic syncope. Am J Cardiol 91: 53‐58, 2003.
 69. Goldstein DS , Holmes C , Kopin IJ , Sharabi Y . Intra‐neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases. J Clin Inv 121: 3320‐3330, 2011.
 70. Goldstein DS , Holmes C , Li ST , Bruce S , Metman LV , Cannon RO, 3rd . Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 133: 338‐347, 2000.
 71. Goldstein DS , Holmes C , Sato T , Bernson M , Mizrahi N , Imrich R , Carmona G , Sharabi Y , Vortmeyer AO . Central dopamine deficiency in pure autonomic failure. Clin Auton Res 18: 58‐65, 2008.
 72. Goldstein DS , Holmes C , Sewell L , Park MY , Sharabi Y . Sympathetic noradrenergic before striatal dopaminergic denervation: Relevance to Braak staging of synucleinopathy. Clin Auton Res 22: 57‐61, 2012.
 73. Goldstein DS , Holmes C , Sewell L , Pechnik S , Kopin IJ . Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine pro‐drug L‐DOPS. J Clin Pharmacol 2010 (in press).
 74. Goldstein DS , Holmes C , Sharabi Y . Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson's disease and other synucleinopathies. Brain 135: 1900‐1913, 2012.
 75. Goldstein DS , Holmes C , Sharabi Y , Brentzel S , Eisenhofer G . Plasma levels of catechols and metanephrines in neurogenic orthostatic hypotension. Neurology 60: 1327‐1332, 2003.
 76. Goldstein DS , Holmes CS , Dendi R , Bruce SR , Li ST . Orthostatic hypotension from sympathetic denervation in Parkinson's disease. Neurology 58: 1247‐1255, 2002.
 77. Goldstein DS , Li ST , Kopin IJ . Sympathetic neurocirculatory failure in Parkinson disease: Evidence for an etiologic role of alpha‐synuclein. Ann Intern Med 135: 1010‐1011, 2001.
 78. Goldstein DS , Orimo S . Cardiac sympathetic neuroimaging: Summary of the First International Symposium. Clin Auton Res 19: 133‐136, 2009.
 79. Goldstein DS , Sewell L , Holmes C . Association of anosmia with autonomic failure in Parkinson disease. Neurology 74: 245‐251, 2009.
 80. Goldstein DS , Sharabi Y , Karp BI , Bentho O , Saleem A , Pacak K , Eisenhofer G . Cardiac sympathetic denervation preceding motor signs in Parkinson disease. Clin Auton Res 17: 118‐121, 2007.
 81. Goldstein DS , Sullivan P , Cooney A , Jinsmaa Y , Sullivan R , Gross DJ , Holmes C , Kopin IJ , Sharabi Y . Vesicular uptake blockade generates the toxic dopamine metabolite 3,4‐dihydroxyphenylacetaldehyde in PC12 Cells: Relevance to the pathogenesis of Parkinson disease. J Neurochem 123: 932‐943, 2012.
 82. Goldstein DS , Sullivan P , Holmes C , Miller GW , Alter S , Strong R , Mash DC , Kopin IJ , Goldstein D . Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson disease. J Neurochem 126: 591‐603, 2013.
 83. Grossman E , Messerli FH . Drug‐induced hypertension: An unappreciated cause of secondary hypertension. Am J Med 125: 14‐22, 2012.
 84. Haensch CA , Lerch H , Jorg J , Isenmann S . Cardiac denervation occurs independent of orthostatic hypotension and impaired heart rate variability in Parkinson's disease. Parkinsonism Relat Disord 15: 134‐137, 2009.
 85. Hague K , Lento P , Morgello S , Caro S , Kaufmann H . The distribution of Lewy bodies in pure autonomic failure: Autopsy findings and review of the literature. Acta Neuropathol 94: 192‐196, 1997.
 86. Halliday GM , Li YW , Blumbergs PC , Joh TH , Cotton RG , Howe PR , Blessing WW , Geffen LB . Neuropathology of immunohistochemically identified brainstem neurons in Parkinson's disease. Ann Neurol 27: 373‐385, 1990.
 87. Hasegawa Y , Okamoto S . Parkinson's disease with syncope as a chief complaint induced by prominent postprandial hypotension. Rinsho Shinkeigaku 32: 1017‐1021, 1992.
 88. Hoehn MM . Levodopa‐induced postural hypotension. Treatment with fludrocortisone. Arch Neurol 32: 50‐51, 1975.
 89. Hoeldtke RD , Cilmi KM , Mattis‐Graves K . DL‐Threo‐3,4‐dihydroxyphenylserine does not exert a pressor effect in orthostatic hypotension. Clin Pharmacol Ther 36: 302‐306, 1984.
 90. Hoeldtke RD , Horvath GG , Bryner KD , Hobbs GR . Treatment of orthostatic hypotension with midodrine and octreotide. J Clin Endocrinol Metab 83: 339‐343, 1998.
 91. Hoeldtke RD , Israel BC . Treatment of orthostatic hypotension with octreotide. J Clin Endocrinol Metab 68: 1051‐1059, 1989.
 92. Hoeldtke RD , Streeten DH . Treatment of orthostatic hypotension with erythropoietin. N Engl J Med 329: 611‐615, 1993.
 93. Horimoto Y , Matsumoto M , Akatsu H , Ikari H , Kojima K , Yamamoto T , Otsuka Y , Ojika K , Ueda R , Kosaka K . Autonomic dysfunctions in dementia with Lewy bodies. J Neurol 250: 530‐533, 2003.
 94. Hussain IF , Brady CM , Swinn MJ , Mathias CJ , Fowler CJ . Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychatry 71: 371‐374, 2001.
 95. Imrich R , Eldadah BA , Bentho O , Pechnik S , Sharabi Y , Holmes C , Goldstein DS . Attenuated pre‐ejection period response to tyramine in patients with cardiac sympathetic denervation. Ann N Y Acad Sci 1148: 486‐489, 2008.
 96. Imrich R , Eldadah BA , Bentho O , Pechnik S , Sharabi Y , Holmes C , Grossman E , Goldstein DS . Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension. Parkinsonism Relat Disord 15: 122‐127, 2009.
 97. Iwasaki Y , Yokokawa Y , Aiba I , Yoshida M . Autopsy findings in a case of dementia with Lewy bodies with marked autonomic failure and repetitive cardiopulmonary arrest. Rinsho Shinkeigaku 45: 596‐599, 2005.
 98. Jain S , Goldstein DS . Cardiovascular dysautonomia in Parkinson disease: From pathophysiology to pathogenesis. Neuobiol Dis 46: 572‐580, 2012.
 99. Jain S , Goldstein DS . What ARE Parkinson disease? Non‐motor features transform conception of the shaking palsy. Neurobiol Dis 46: 505‐507, 2012.
 100. Jamnadas‐Khoda J , Koshy S , Mathias CJ , Muthane UB , Ragothaman M , Dodaballapur SK . Are current recommendations to diagnose orthostatic hypotension in Parkinson's disease satisfactory? Movement Dis 24: 1747‐1751, 2009.
 101. Jellinger KA . Neuropathological spectrum of synucleinopathies. Mov Disord 18(Suppl 6): S2‐12, 2003.
 102. Jordan J , Biaggioni I . Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension. J Clin Hypertens 4: 139‐145, 2002.
 103. Kashihara K , Ohno M , Kawada S , Okumura Y . Reduced cardiac uptake and enhanced washout of 123I‐MIBG in pure autonomic failure occurs conjointly with Parkinson's disease and dementia with Lewy bodies. J Nucl Med 47: 1099‐1101, 2006.
 104. Kato S , Oda M , Hayashi H , Shimizu T , Hayashi M , Kawata A , Tanabe H . Decrease of medullary catecholaminergic neurons in multiple system atrophy and Parkinson's disease and their preservation in amyotrophic lateral sclerosis. J Neurol Sci 132: 216‐221, 1995.
 105. Kaufmann H . Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Clin Auton Res 6: 125‐126, 1996.
 106. Kaufmann H . The discovery of the pressor effect of DOPS and its blunting by decarboxylase inhibitors. J Neural Transm Suppl 477‐484, 2006.
 107. Kaufmann H , Brannan T , Krakoff L , Yahr MD , Mandeli J . Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha‐adrenergic agonist (midodrine). Neurology 38: 951‐956, 1988.
 108. Kaufmann H , Goldstein DS . Pure autonomic failure: A restricted Lewy body synucleinopathy or early Parkinson disease? Neurology 74: 536‐537, 2010.
 109. Kaufmann H , Hague K , Perl D . Accumulation of alpha‐synuclein in autonomic nerves in pure autonomic failure. Neurology 56: 980‐981, 2001.
 110. Kaufmann H , Nahm K , Purohit D , Wolfe D . Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 63: 1093‐1095, 2004.
 111. Kaufmann H , Oribe E , Yahr MD . Treatment of orthostatic hypotension with L‐threo‐3,4‐dihydroxyphenylserine. In: Narabayashi H , Mizuno Y , editors. Norepinephrine Deficiency and Its Treatment with L‐threo‐DOPS in Parkinson's Disease and Related Disorders. Pearl River, NY: The Parthenon Publishing Group, 1993, pp. 97‐104.
 112. Kaufmann H , Saadia D , Voustianiouk A , Goldstein DS , Holmes C , Yahr MD , Nardin R , Freeman R . Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation 108: 724‐728, 2003.
 113. Kim JS , Oh YS , Lee KS , Kim YI , Yang DW , Goldstein DS . Association of cognitive dysfunction with neurocirculatory abnormalities in early Parkinson disease. Neurology 79: 1323‐1331, 2012.
 114. Kish SJ , Shannak K , Hornykiewicz O . Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. N Engl J Med 318: 876‐880, 1988.
 115. Knowles CH , Lindberg G , Panza E , De Giorgio R . New perspectives in the diagnosis and management of enteric neuropathies. Nat Rev Gastroenterol Hepatol 10: 206‐218, 2013.
 116. Kobayashi S , Tateno M , Morii H , Utsumi K , Saito T . Decreased cardiac MIBG uptake, its correlation with clinical symptoms in dementia with Lewy bodies. Psychiatry Res 174: 76‐80, 2009.
 117. Lake CR , Ziegler MG , Kopin IJ . Use of plasma norepinephrine for evaluation of sympathetic neuronal function in man. Life Sci 18: 1315‐1325, 1976.
 118. Langley JN . The autonomic nervous system. Brain 26: 1‐26, 1903.
 119. Langley JN . The Autonomic Nervous System. Cambridge, England: W. Heffer and Sons, Ltd., 1921.
 120. Lebouvier T , Neunlist M , Bruley des Varannes S , Coron E , Drouard A , N'Guyen JM , Chaumette T , Tasselli M , Paillusson S , Flamand M , Galmiche JP , Damier P , Derkinderen P . Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms. PloS One 5: e12728, 2010.
 121. Lee PH , Yeo SH , Kim HJ , Youm HY . Correlation between cardiac 123I‐MIBG and odor identification in patients with Parkinson's disease and multiple system atrophy. Mov Disord 21: 1975‐1977, 2006.
 122. Levinson PD , Goldstein DS , Munson PJ , Gill JR, Jr , Keiser HR . Endocrine, renal, and hemodynamic responses to graded dopamine infusions in normal men. J Clin Endocrinol Metab 60: 821‐826, 1985.
 123. Lewin RJ , Dillard GV , Porter RW . Extrapyramidal inhibition of the urinary bladder. Brain Res 4: 301‐307, 1967.
 124. Li ST , Dendi R , Holmes C , Goldstein DS . Progressive loss of cardiac sympathetic innervation in Parkinson's disease. Ann Neurol 52: 220‐223, 2002.
 125. Loew F , Gauthey L , Koerffy A , Herrmann FR , Estade M , Michel JP , Vallotton MB . Postprandial hypotension and orthostatic blood pressure responses in elderly Parkinson's disease patients. J Hypertens 13: 1291‐1297, 1995.
 126. Lokhandwala MF , Hegde SS . Cardiovascular pharmacology of dopamine receptor agonists. In: Amenta F , editor. Peripheral Dopamine Pathophysiology. Boca Raton, FL: CRC Press, Inc., 1990, pp. 63‐77.
 127. Lotharius J , Brundin P . Pathogenesis of Parkinson's diease: Dopamine, vesicles, and [alpha]‐synuclein. Nat Rev Neurosci 3: 932‐942, 2002.
 128. Magerkurth C , Schnitzer R , Braune S . Symptoms of autonomic failure in Parkinson's disease: Prevalence and impact on daily life. Clin Auton Res 15: 76‐82, 2005.
 129. Marion MH , Qurashi M , Marshall G , Foster O . Is REM sleep behaviour disorder (RBD) a risk factor of dementia in idiopathic Parkinson's disease? J Neurol 255: 192‐196, 2008.
 130. Matsui H , Udaka F , Oda M , Kubori T , Nishinaka K , Kameyama M . Metaiodobenzylguanidine (MIBG) scintigraphy at various parts of the body in Parkinson's disease and multiple system atrophy. Auton Neurosci 119: 56‐60, 2005.
 131. Matsui H , Udaka F , Oda M , Tamura A , Kubori T , Nishinaka K , Kameyama M . Metaiodobenzylguanidine (MIBG) uptake in Parkinson's disease also decreases at thyroid. Ann Nucl Med 19: 225‐229, 2005.
 132. Mazza A , Ravenni R , Antonini A , Casiglia E , Rubello D , Pauletto P . Arterial hypertension, a tricky side of Parkinson's disease: Physiopathology and therapeutic features. Neurol Sci 34: 621‐627, 2013.
 133. McKeith IG , Galasko D , Kosaka K , Perry EK , Dickson DW , Hansen LA , Salmon DP , Lowe J , Mirra SS , Byrne EJ , Lennox G , Quinn NP , Edwardson JA , Ince PG , Bergeron C , Burns A , Miller BL , Lovestone S , Collerton D , Jansen EN , Ballard C , de Vos RA , Wilcock GK , Jellinger KA , Perry RH . Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 47: 1113‐1124, 1996.
 134. Meredith IT , Eisenhofer G , Lambert GW , Jennings GL , Thompson J , Esler MD . Plasma norepinephrine responses to head‐up tilt are misleading in autonomic failure. Hypertension 19: 628‐633, 1992.
 135. Mosharov EV , Larsen KE , Kanter E , Phillips KA , Wilson K , Schmitz Y , Krantz DE , Kobayashi K , Edwards RH , Sulzer D . Interplay between cytosolic dopamine, calcium, and alpha‐synuclein causes selective death of substantia nigra neurons. Neuron 62: 218‐229, 2009.
 136. Mosharov EV , Staal RG , Bove J , Prou D , Hananiya A , Markov D , Poulsen N , Larsen KE , Moore CM , Troyer MD , Edwards RH , Przedborski S , Sulzer D . Alpha‐synuclein overexpression increases cytosolic catecholamine concentration. J Neurosci 26: 9304‐9311, 2006.
 137. Niimi Y , Ieda T , Hirayama M , Koike Y , Sobue G , Hasegawa Y , Takahashi A . Clinical and physiological characteristics of autonomic failure with Parkinson's disease. Clin Auton Res 9: 139‐144, 1999.
 138. Nozaki S , Kang J , Miyai I , Matsumura T . Postprandial hypotension in Parkinson's disease–the incidence and risk factor. Rinsho Shinkeigaku 33: 1135‐1139, 1993.
 139. Nylin G , Levander M . Studies on the circulation with the aid of tagged erythrocytes in a case of orthostatic hypotension (asympathicotonic hypotension). Ann Intern Med 28: 723‐746, 1948.
 140. O'Sullivan SS , Holton JL , Massey LA , Williams DR , Revesz T , Lees AJ . Parkinson's disease with Onuf's nucleus involvement mimicking multiple system atrophy. J Neurol Neurosurg Psychiatry 79: 232‐234, 2008.
 141. Oh YS , Kim JS , Chung Y‐A , You IR , Yang D‐W , Chung S‐W , Park J‐W , Kim Y‐I , Lee K‐S . Orthostatic hypotension, non‐dipping and striatal dopamine in Parkinson disease. Neurol Sci 34: 557‐560, 2013.
 142. Oka H , Morita M , Onouchi K , Yoshioka M , Mochio S , Inoue K . Cardiovascular autonomic dysfunction in dementia with Lewy bodies and Parkinson's disease. J Neurol Sci 254: 72‐77, 2007.
 143. Oka H , Toyoda C , Yogo M , Mochio S . Cardiovascular dysautonomia in de novo Parkinson's disease without orthostatic hypotension. Eur J Neurol 18: 286‐292, 2011.
 144. Oka H , Yoshioka M , Onouchi K , Morita M , Mochio S , Suzuki M , Hirai T , Ito Y , Inoue K . Characteristics of orthostatic hypotension in Parkinson's disease. Brain 130: 2425‐2432, 2007.
 145. Olichney JM , Murphy C , Hofstetter CR , Foster K , Hansen LA , Thal LJ , Katzman R . Anosmia is very common in the Lewy body variant of Alzheimer's disease. J Neurol Neurosurg Psychiatry 76: 1342‐1347, 2005.
 146. Orimo S , Kanazawa T , Nakamura A , Uchihara T , Mori F , Kakita A , Wakabayashi K , Takahashi H . Degeneration of cardiac sympathetic nerve can occur in multiple system atrophy. Acta Neuropathol (Berl) 113: 81‐86, 2007.
 147. Orimo S , Oka T , Miura H , Tsuchiya K , Mori F , Wakabayashi K , Nagao T , Yokochi M . Sympathetic cardiac denervation in Parkinson's disease and pure autonomic failure but not in multiple system atrophy. J Neurol Neurosurg Psychiatry 73: 776‐777, 2002.
 148. Orimo S , Ozawa E , Oka T , Nakade S , Tsuchiya K , Yoshimoto M , Wakabayashi K , Takahashi H . Different histopathology accounting for a decrease in myocardial MIBG uptake in PD and MSA. Neurology 57: 1140‐1141, 2001.
 149. Orimo S , Takahashi A , Uchihara T , Mori F , Kakita A , Wakabayashi K , Takahashi H . Degeneration of cardiac sympathetic nerve begins in the early disease process of Parkinson's disease. Brain Pathol 17: 24‐30, 2007.
 150. Orimo S , Uchihara T , Nakamura A , Mori F , Kakita A , Wakabayashi K , Takahashi H . Axonal alpha‐synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson's disease. Brain 131: 642‐650, 2008.
 151. Palma JA , Carmona‐Abellan MM , Barriobero N , Trevino‐Peinado C , Garcia‐Lopez M , Fernandez‐Jarne E , Luquin MR . Is cardiac function impaired in premotor Parkinson's disease? A retrospective cohort study. Mov Disord 28: 591‐596, 2013.
 152. Panneton WM , Kumar VB , Gan Q , Burke WJ , Galvin JE . The neurotoxicity of DOPAL: Behavioral and stereological evidence for its role in Parkinson disease pathogenesis. PLoS One 5: e15251, 2010.
 153. Papatsoris AG , Deliveliotis C , Singer C , Papapetropoulos S . Erectile dysfunction in Parkinson's disease. Urology 67: 447‐451, 2006.
 154. Park SS , Schulz EM , Lee D . Disruption of dopamine homeostasis underlies selective neurodegeneration mediated by alpha‐synuclein. Eur J Neurosci 26: 3104‐3112, 2007.
 155. Parkinson J. An Essay on the Shaking Palsy. London: Whittingham & Rowland, 1817.
 156. Pathak A , Senard JM . Blood pressure disorders during Parkinson's disease: Epidemiology, pathophysiology and management. Expert Rev Neurother 6: 1173‐1180, 2006.
 157. Perez‐Lloret S , Rey MV , Fabre N , Ory F , Spampinato U , Senard JM , Pavy‐Le Traon A , Montastruc JL , Rascol O . Factors related to orthostatic hypotension in Parkinson's disease. Park Rel Dis 18: 501‐505, 2012.
 158. Pilleri M , Facchini S , Gasparoli E , Biundo R , Bernardi L , Marchetti M , Formento P , Antonini A . Cognitive and MRI correlates of orthostatic hypotension in Parkinson's disease. J Neurol 260: 253‐259, 2013.
 159. Plaschke M , Trenkwalder P , Dahlheim H , Lechner C , Trenkwalder C . Twenty‐four‐hour blood pressure profile and blood pressure responses to head‐up tilt tests in Parkinson's disease and multiple system atrophy. J Hypertens 16: 1433‐1441, 1998.
 160. Polinsky RJ , Kopin IJ , Ebert MH , Weise V . Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology 31: 1‐7, 1981.
 161. Polymeropoulos MH , Lavedan C , Leroy E , Ide SE , Dehejia A , Dutra A , Pike B , Root H , Rubenstein J , Boyer R , Stenroos ES , Chandrasekharappa S , Athanassiadou A , Papapetropoulos T , Johnson WG , Lazzarini AM , Duvoisin RC , Di Iorio G , Golbe LI , Nussbaum RL . Mutation in the alpha‐synuclein gene identified in families with Parkinson's disease. Science 276: 2045‐2047, 1997.
 162. Porges SW . Cardiac vagal tone: A physiological index of stress. Neurosci Biobehav Rev 19: 225‐233, 1995.
 163. Porges SW . The polyvagal theory: New insights into adaptive reactions of the autonomic nervous system. Cleve Clin J Med 76(Suppl 2): S86‐90, 2009.
 164. Proulx M , de Courval FP , Wiseman MA , Panisset M . Salivary production in Parkinson's disease. Mov Disord 20: 204‐207, 2005.
 165. Raffel DM , Koeppe RA , Little R , Wang CN , Liu S , Junck L , Heumann M , Gilman S . PET measurement of cardiac and nigrostriatal denervation in parkinsonian syndromes. J Nucl Med 47: 1769‐1777, 2006.
 166.Rahman F, Goldstein DS. Quantitative indices of baroreflex‐sympathoneural function. Clin Auton Res (in press).
 167. Rajput AH , Rozdilsky B . Dysautonomia in Parkinsonism: A clinicopathological study. J Neurol Neurosurg Psychiatry 39: 1092‐1100, 1976.
 168. Rajput AH , Rozdilsky B , Rajput A . Accuracy of clinical diagnosis in parkinsonism–a prospective study. Can J Neurol Sci 18: 275‐278, 1991.
 169. Reis DJ , Morrison S , Ruggiero DA . The C1 area of the brainstem in tonic and reflex control of blood pressure. State of the art lecture. Hypertension 11(Suppl. I): I‐8‐I‐13, 1988.
 170. Roberts WJ , Levitt GR . Histochemical evidence for sympathetic innervation of hair receptor afferents in cat skin. J Comp Neurol 210: 204‐209, 1982.
 171. Romenets SR , Gagnon JF , Latreille V , Panniset M , Chouinard S , Montplaisir J , Postuma RB . Rapid eye movement sleep behavior disorder and subtypes of Parkinson's disease. Movement Dis 27: 996‐1003, 2012.
 172. Rose S , Jenner P , Marsden CD . The effect of carbidopa on plasma and muscle levels of L‐dopa, dopamine, and their metabolites following L‐dopa administration to rats. Mov Disord 3: 117‐125, 1988.
 173. Ross GW , Petrovitch H , Abbott RD , Tanner CM , Popper J , Masaki K , Launer L , White LR . Association of olfactory dysfunction with risk for future Parkinson's disease. Ann Neurol 63: 167‐173, 2008.
 174. Schachter S , Singer J . Cognitive, social, and physiological determinants of emotional state. Psychol Rev 69: 379‐399, 1962.
 175. Schotzinger RJ , Landis SC . Cholinergic phenotype developed by noradrenergic sympathetic neurons after innervation of a novel cholinergic target in vivo. Nature 335: 637‐639, 1988.
 176. Schrezenmaier C , Singer W , Swift NM , Sletten D , Tanabe J , Low PA . Adrenergic and vagal baroreflex sensitivity in autonomic failure. Arch Neurol 64: 381‐386, 2007.
 177. Seif C , Herzog J , van der Horst C , Schrader B , Volkmann J , Deuschl G , Juenemann KP , Braun PM . Effect of subthalamic deep brain stimulation on the function of the urinary bladder. Ann Neurol 55: 118‐120, 2004.
 178. Senard JM , Arias A , Berlan M , Tran MA , Rascol A , Montastruc JL . Pharmacological evidence of alpha 1‐ and alpha 2‐adrenergic supersensitivity in orthostatic hypotension due to spinal cord injury: A case report. Eur J Clin Pharmacol 41: 593‐596, 1991.
 179. Senard JM , Brefel‐Courbon C , Rascol O , Montastruc JL . Orthostatic hypotension in patients with Parkinson's disease: Pathophysiology and management. Drugs Aging 18: 495‐505, 2001.
 180. Senard JM , Rascol O , Durrieu G , Tran MA , Berlan M , Rascol A , Montastruc JL . Effects of yohimbine on plasma catecholamine levels in orthostatic hypotension related to Parkinson disease or multiple system atrophy. Clin Neuropharmacol 16: 70‐76, 1993.
 181. Senard JM , Valet P , Durrieu G , Berlan M , Tran MA , Montastruc JL , Rascol A , Montastruc P . Adrenergic supersensitivity in parkinsonians with orthostatic hypotension. Eur J Clin Invest 20: 613‐619, 1990.
 182. Shannon J , Jordan J , Costa F , Robertson RM , Biaggioni I . The hypertension of autonomic failure and its treatment. Hypertension 30: 1062‐1067, 1997.
 183. Sharabi Y , Imrich R , Holmes C , Pechnik S , Goldstein DS . Generalized and neurotransmitter‐selective noradrenergic denervation in Parkinson's disease with orthostatic hypotension. Mov Disord 23: 1725‐1732, 2008.
 184. Sharabi Y , Li ST , Dendi R , Holmes C , Goldstein DS . Neurotransmitter specificity of sympathetic denervation in Parkinson's disease. Neurology 60: 1036‐1039, 2003.
 185. Shibao C , Gamboa A , Diedrich A , Dossett C , Choi L , Farley G , Biaggioni I . Acarbose, an alpha‐glucosidase inhibitor, attenuates postprandial hypotension in autonomic failure. Hypertension 50: 54‐61, 2007.
 186. Shy GM , Drager GA . A neurological syndrome associated with orthostatic hypotension. Arch Neurol 3: 511‐527, 1960.
 187. Siddiqui MF , Rast S , Lynn MJ , Auchus AP , Pfeiffer RF . Autonomic dysfunction in Parkinson's disease: A comprehensive symptom survey. Parkinsonism Relat Disord 8: 277‐284, 2002.
 188. Siderowf A , Newberg A , Chou KL , Lloyd M , Colcher A , Hurtig HI , Stern MB , Doty RL , Mozley PD , Wintering N , Duda JE , Weintraub D , Moberg PJ . [99mTc]TRODAT‐1 SPECT imaging correlates with odor identification in early Parkinson disease. Neurology 64: 1716‐1720, 2005.
 189. Singaram C , Ashraf W , Gaumnitz EA , Torbey C , Sengupta A , Pfeiffer R , Quigley EM . Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation. Lancet 346: 861‐864, 1995.
 190. Singer C , Weiner WJ , Sanchez‐Ramos JR . Autonomic dysfunction in men with Parkinson's disease. Eur Neurol 32: 134‐140, 1992.
 191. Singleton A , Gwinn‐Hardy K , Sharabi Y , Li ST , Holmes C , Dendi R , Hardy J , Crawley A , Goldstein DS . Association between cardiac denervation and parkinsonism caused by alpha‐synuclein gene triplication. Brain 127: 768‐772, 2004.
 192. Singleton AB , Farrer M , Johnson J , Singleton A , Hague S , Kachergus J , Hulihan M , Peuralinna T , Dutra A , Nussbaum R , Lincoln S , Crawley A , Hanson M , Maraganore D , Adler C , Cookson MR , Muenter M , Baptista M , Miller D , Blancato J , Hardy J , Gwinn‐Hardy K . alpha‐Synuclein locus triplication causes Parkinson's disease. Science 302: 841, 2003.
 193. Sommer S , Aral‐Becher B , Jost W . Nondipping in Parkinson's disease. Parkinson's Dis 2011: 897586, 2011.
 194. Sowers JR , Crane PD , Beck FWJ , McClanahan M , King ME , Mohanty PK . Relationship between urinary dopamine production and natriuresis after acute intravascular volume expansion with sodium chloride in dogs. Endocrinology 115: 2085‐2090, 1984.
 195. Spillantini MG , Schmidt ML , Lee VM , Trojanowski JQ , Jakes R , Goedert M . Alpha‐synuclein in Lewy bodies. Nature 388: 839‐840, 1997.
 196. Stocchi F , Badiali D , Vacca L , D'Alba L , Bracci F , Ruggieri S , Torti M , Berardelli A , Corazziari E . Anorectal function in multiple system atrophy and Parkinson's disease. Mov Disord 15: 71‐76, 2000.
 197. Stoddard SL , Ahlskog JE , Kelly PJ , Tyce GM , van Heerden JA , Zinsmeister AR , Carmichael SW . Decreased adrenal medullary catecholamines in adrenal transplanted parkinsonian patients compared to nephrectomy patients. Exp Neurol 104: 218‐222, 1989.
 198. Stoddard SL , Tyce GM , Ahlskog JE , Zinsmeister AR , Carmichael SW . Decreased catecholamine content in parkinsonian adrenal medullae. Exp Neurol 104: 22‐27, 1989.
 199. Stubendorff K , Aarsland D , Minthon L , Londos E . The impact of autonomic dysfunction on survival in patients with dementia with Lewy bodies and Parkinson's disease with dementia. PloS One 7: e45451, 2012.
 200. Taki J , Nakajima K , Hwang EH , Matsunari I , Komai K , Yoshita M , Sakajiri K , Tonami N . Peripheral sympathetic dysfunction in patients with Parkinson's disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 27: 566‐573, 2000.
 201. Tamura N , Shimazu K , Yamamoto T , Maeda A , Hamaguchi K . Cardiovascular alpha‐, beta 1‐ and beta 2‐adrenoceptor functions in neurogenic orthostatic hypotension. Rinsho Shinkeigaku 35: 1120‐1124, 1995.
 202. Thaisetthawatkul P , Boeve BF , Benarroch EE , Sandroni P , Ferman TJ , Petersen R , Low PA . Autonomic dysfunction in dementia with Lewy bodies. Neurology 62: 1804‐1809, 2004.
 203. Tijero B , Gomez‐Esteban JC , Llorens V , Lezcano E , Gonzalez‐Fernandez MC , de Pancorbo MM , Ruiz‐Martinez J , Cembellin JC , Zarranz JJ . Cardiac sympathetic denervation precedes nigrostriatal loss in the E46K mutation of the alpha‐synuclein gene (SNCA). Clin Auton Res 20: 267‐269, 2010.
 204. Tipre DN , Goldstein DS . Cardiac and extra‐cardiac sympathetic denervation in Parkinson disease with orthostatic hypotension and in pure autonomic failure. J Nucl Med 46: 1775‐1781, 2005.
 205. Tu PH , Galvin JE , Baba M , Giasson B , Tomita T , Leight S , Nakajo S , Iwatsubo T , Trojanowski JQ , Lee VM . Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha‐synuclein. Ann Neurol 44: 415‐422, 1998.
 206. Turkka JT , Myllyla VV . Sweating dysfunction in Parkinson's disease. Eur Neurol 26: 1‐7, 1987.
 207. Ueki A , Otsuka M . Life style risks of Parkinson's disease: Association between decreased water intake and constipation. J Neurol 251(Suppl 7): vII18‐23, 2004.
 208. Ulusoy A , Bjorklund T , Buck K , Kirik D . Dysregulated dopamine storage increases the vulnerability to alpha‐synuclein in nigral neurons. Neurobiol Dis 47: 367‐377, 2012.
 209. Velseboer DC , de Haan RJ , Wieling W , Goldstein DS , de Bie RM . Prevalence of orthostatic hypotension in Parkinson's disease: A systematic review and meta‐analysis. Parkinsonism Relat Disord 2011.
 210. Visser M , Marinus J , Stiggelbout AM , Van Hilten JJ . Assessment of autonomic dysfunction in Parkinson's disease: The SCOPA‐AUT. Movement Dis 19: 1306‐1312, 2004.
 211. Vogel ER , Sandroni P , Low PA . Blood pressure recovery from Valsalva maneuver in patients with autonomic failure. Neurology 65: 1533‐1537, 2005.
 212. Volles MJ , Lansbury PT, Jr . Vesicle permeabilization by protofibrillar alpha‐synuclein is sensitive to Parkinson's disease‐linked mutations and occurs by a pore‐like mechanism. Biochemistry 41: 4595‐4602, 2002.
 213. von Euler US . A specific sympathomimetic ergone in adrenergic nerve fibres (sympathin) and its relations to adrenaline and nor‐adrenaline. Acta Physiol Scand 12: 73‐96, 1946.
 214. Wakabayashi K , Takahashi H . Neuropathology of autonomic nervous system in Parkinson's disease. Eur Neurol 38(Suppl 2): 2‐7, 1997.
 215. Wakabayashi K , Yoshimoto M , Tsuji S , Takahashi H . Alpha‐synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249: 180‐182, 1998.
 216. Wallin BG , Morlin C , Hjemdahl P . Muscle sympathetic activity and venous plasma noradrenaline concentrations during static exercise in normotensive and hypertensive subjects. Acta Physiol Scand 129: 489‐497, 1987.
 217. Wang N , Gibbons CH , Freeman R . Novel immunohistochemical techniques using discrete signal amplification systems for human cutaneous peripheral nerve fiber imaging. J Histochem Cytochem 59: 382‐390, 2011.
 218. Wenning GK , Quinn NP . Parkinsonism. Multiple system atrophy. Bailliere's clinical neurology 6: 187‐204, 1997.
 219. Wenning GK , Scherfler C , Granata R , Bosch S , Verny M , Chaudhuri KR , Jellinger K , Poewe W , Litvan I . Time course of symptomatic orthostatic hypotension and urinary incontinence in patients with postmortem confirmed parkinsonian syndromes: A clinicopathological study. J Neurol Neurosurg Psychiatry 67: 620‐623, 1999.
 220. Werner WG , DiFrancisco‐Donoghue J , Lamberg EM . Cardiovascular response to treadmill testing in Parkinson disease. J Neurol Phys Ther 30: 68‐73, 2006.
 221. Wey M , Fernandez E , Martinez PA , Sullivan P , Goldstein DS , Strong R . Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: Implications for Parkinson's disease. PLoS ONE 7: e31522, 2012.
 222. Wolfovitz E , Grossman E , Folio CJ , Keiser HR , Kopin IJ , Goldstein DS . Derivation of urinary dopamine from plasma dihydroxyphenylalanine in humans. Clin Sci 84: 549‐557, 1993.
 223. Wullner U , Schmitz‐Hubsch T , Antony G , Fimmers R , Spottke A , Oertel WH , Deuschl G , Klockgether T , Eggert K . Autonomic dysfunction in 3414 Parkinson's disease patients enrolled in the German Network on Parkinson's disease (KNP e.V.): The effect of ageing. Eur J Neurol 14: 1405‐1408, 2007.
 224. Yeh BK , McNay JL , Goldberg LI . Attenuation of dopamine renal and mesenteric vasodilation by haloperidol: Evidence for a specific dopamine receptor. J Pharmacol Exp Ther 168: 303‐309, 1969.
 225. Yoshimura N , Kuno S , Chancellor MB , De Groat WC , Seki S . Dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6‐hydroxydopamine (6‐OHDA) lesion of the nigrostriatal pathway. Br J Pharmacol 139: 1425‐1432, 2003.
 226. Zesiewicz TA , Gold M , Chari G , Hauser RA . Current issues in depression in Parkinson's disease. Am J Geriatr Psychaitry 7: 110‐118, 1999.
 227. Zesiewicz TA , Helal M , Hauser RA . Sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men with Parkinson's disease. Movement Dis 15: 305‐308, 2000.
 228. Zimlichman R , Levinson PD , Kelly G , Stull R , Keiser HR , Goldstein DS . Derivation of urinary dopamine from plasma dopa. Clin Sci 75: 515‐520, 1988.

Related Articles:

Catecholaminergic Brain Stem Regulatory Systems
Transmitters in Motor Systems
Neurogenic Control of the Vascular System: Focus on Cerebral Circulation
Brain Monoamines, Homeostasis, and Adaptive Behavior
Baroreflex Control of Systemic Arterial Pressure and Vascular Bed
Arterial Baroreflexes in Humans
Cardiovascular Adjustments to Gravitational Stress
Catecholamines in the Brain and Responses to Environmental Challenges
Concepts of Scientific Integrative Medicine Applied to the Physiology and Pathophysiology of Catecholamine Systems
Hypertension: Physiology and Pathophysiology
Loss of Integration and Resiliency with Age: A Dissipative Destruction
Human Studies
Cardiovascular System
Human Nervous System
Maintenance and Regulation in Brain of Neurotransmission, Trophic Factors, and Immune Responses

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

David S. Goldstein. Dysautonomia in Parkinson Disease. Compr Physiol 2014, 4: 805-826. doi: 10.1002/cphy.c130026