Imaging of the Autonomic Nervous System: Focus on Cardiac Sympathetic Innervation

David S. Goldstein

doi:10.1055/s-2004-817726

Seminars in Neurology, Inhaltsverzeichnis

Semin Neurol 2003; 23(4): 423-434
DOI: 10.1055/s-2004-817726

Imaging of the Autonomic Nervous System: Focus on Cardiac Sympathetic Innervation

David S. Goldstein

Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Abstract

ABSTRACT

Symptoms or signs of abnormal autonomic nervous system function occur commonly in several neurological disorders. Clinical evaluations have depended on physiological, pharmacological, and neurochemical approaches. Recently, imaging of sympathetic noradrenergic innervation has been introduced and applied especially in the heart. Most studies have used the radiolabeled sympathomimetic amine, ¹²³I-metaiodobenzylguanidine. Decreased uptake or increased “washout” of ¹²³I-metaiodobenzylguanidine-derived radioactivity is associated with worse prognosis or more severe disease in hypertension, congestive heart failure, arrhythmias, and diabetes mellitus. This pattern may reflect a high rate of postganglionic sympathetic nerve traffic to the heart. Many recent studies have agreed on the remarkable finding that all patients with Parkinson's disease and orthostatic hypotension have a loss of cardiac sympathetic innervation, whereas all patients with multiple system atrophy, often difficult to distinguish clinically from Parkinson's disease, have intact cardiac sympathetic innervation. Because Parkinson's disease entails a postganglionic sympathetic noradrenergic lesion, the disease appears to be not only a movement disorder, with dopamine loss in the nigrostriatal system of the brain, but also a dysautonomia, with noradrenaline loss in the sympathetic nervous system of the heart. As new ligands are developed, one may predict further discoveries of involvement of components of the autonomic nervous system in neurological diseases.

KEYWORDS

Sympathetic - multiple system atrophy - Parkinson's disease - autonomic failure - norepinephrine - dysautonomia

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REFERENCES

1 Goldstein D, Eisenhofer G, Robertson D, Straus R, Esler M. Dysautonomias: clinical disorders of the autonomic nervous system. Ann Intern Med . 2002; 137 753-763
2 Goldstein D S. The Autonomic Nervous System in Health and Disease. New York: Marcel Dekker, Inc 2001
3 Pacak K, Palkovits M, Yadid G, Kvetnansky R, Kopin I J, Goldstein D S. Heterogeneous neurochemical responses to different stressors: a test of Selye's doctrine of nonspecificity. Am J Physiol . 1998; 275 R1247-R1255
4 Young J B, Rosa R M, Landsberg L. Dissociation of sympathetic nervous system and adrenal medullary responses. Am J Physiol . 1984; 247 E35-E40
5 Oliver G, Schafer E A. On the physiological action of extract of the suprarenal capsules. J Physiol . 1895; 17 ix-xiv
6 Abel J J, Crawford A C. On the blood-pressure-raising constituent of the suprarenal capsule. Bull Johns Hopkins Hosp . 1897; 8 151-157
7 Abel J J. On a simple method of preparing epinephrin and its compounds. Bull Johns Hopkins Hosp . 1902; 13 29-36
8 Takamine J. The isolation of the active principle of the suprarenal gland. J Physiol . 1901; 27 30P-39P
9 Goldstein D S, Tack C. Non-invasive detection of sympathetic neurocirculatory failure. Clin Auton Res . 2000; 10 285-291
10 Bootsma M, Swenne C A, Van Bolhuis H H, Chang P C, Cats V M, Bruschke A V. Heart rate and heart rate variability as indexes of sympathovagal balance. Am J Physiol . 1994; 266 H1565-H1571
11 Grassi G, Esler M. How to assess sympathetic activity in humans. J Hypertens . 1999; 17 719-734
12 Hagbarth K E, Burke D. Microneurography in man. Acta Neurol (Napoli) . 1977; 32 30-34
13 Wallin B G, Elam M. Microneurography and autonomic dysfunction. In: Low PA, ed. Clinical Autonomic Disorders Boston: Little, Brown 1993: 243-252
14 Dale H H. The action of certain esters and ethers of choline, and their relation to muscarine. J Pharmacol Exp Ther . 1914; 6 147-190
15 Loewi O, Navratil E. Uber humorale Ubertragbarkeit der Herzenvenwirkung. X. Mitteilung. Uber das Schicksal des Vagusstoffs. Pflugers Arch . 1926; 214 678-688
16 Ahlquist R P. A study of adrenotropic receptors. Am J Physiol . 1948; 153 586-600
17 Polinsky R J, Kopin I J, Ebert M H, Weise V. Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology . 1981; 31 1-7
18 Bianchetti M G, Minder I, Beretta-Piccoli C, Meier A, Weidmann P. Effects of tyramine on blood pressure and plasma catecholamines in normal and hypertensive subjects. Klin Wochenschr . 1982; 60 465-470
19 Shannon J R, Flattem N L, Jordan J. et al . Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med . 2000; 342 541-549
20 Jordan J, Shannon J R, Black B K. et al . N(N)-nicotinic blockade as an acute human model of autonomic failure. Hypertension . 1998; 31 1178-1184
21 Goldstein D S, Grossman E, Listwak S, Folio C J. Sympathetic reactivity during a yohimbine challenge test in essential hypertension. Hypertension . 1991; 18(Suppl. III) 40-48
22 Charney D S, Heninger G R, Redmond Jr E D. Yohimbine induced anxiety and increased noradrenergic function in humans: effects of diazepam and clonidine. Life Sci . 1983; 33 19-29
23 Senard J M, Rascol O, Durrieu G. et al . Effects of yohimbine on plasma catecholamine levels in orthostatic hypotension related to Parkinson disease or multiple system atrophy. Clin Neuropharmacol . 1993; 16 70-76
24 Biaggioni I, Robertson R M, Robertson D. Manipulation of norepinephrine metabolism with yohimbine in the treatment of autonomic failure. J Clin Pharmacol . 1994; 34 418-423
25 Goldstein D S, Keiser H R. Pressor and depressor responses after cholinergic blockade in humans. Am Heart J . 1984; 107(5 Pt 1) 974-979
26 Bristow J D, Honour J, Pickering G W, Sleight P, Smyth H S. Diminished baroreflex sensitivity in high blood pressure. Circulation . 1969; 39 48-54
27 Cannon W B, de la Paz D. Emotional stimulation of adrenal gland secretion. Am J Physiol . 1911; 28 64-70
28 Cannon W B. The emergency function of the adrenal medulla in pain and in the major emotions. Am J Physiol . 1914; 33 356-372
29 Cannon W B. The interrelation of emotions as suggested by recent physiological researches. Am J Psychol . 1914; 25 256-282
30 Cannon W B, Rapport D. Further observations on the denervated heart in relation to adrenal secretion. Am J Physiol . 1921; 58 308-337
31 Goldstein D S, Feuerstein G, Izzo Jr L J, Kopin I J, Keiser H R. Validity and reliability of liquid chromatography with electrochemical detection for measuring plasma levels of norepinephrine and epinephrine in man. Life Sci . 1981; 28 467-475
32 Holmes C, Eisenhofer G, Goldstein D S. Improved assay for plasma dihydroxyphenylacetic acid and other catechols using high-performance liquid chromatography with electrochemical detection. J Chromatogr B Biomed Appl . 1994; 653 131-138
33 Eisenhofer G, Goldstein D S, Stull R. et al . Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. Clin Chem . 1986; 32 2030-2033
34 Kuwahara T, Hamada M, Hiwada K. Direct evidence of impaired cardiac sympathetic innervation in essential hypertensive patients with left ventricular hypertrophy. J Nucl Med . 1998; 39 1486-1491
35 Sakata K, Shirotani M, Yoshida H, Kurata C. Cardiac sympathetic nervous system in early essential hypertension assessed by 123I-MIBG. J Nucl Med . 1999; 40 6-11
36 Watanabe K, Sekiya M, Tsuruoka T. et al . Relationship between insulin resistance and cardiac sympathetic nervous function in essential hypertension. J Hypertens . 1999; 17 1161-1168
37 Ohya Y, Sasaki M, Fujishima S. et al . Myocardial imaging with 123I-metaiodobenzylguanidine in essential hypertension and renovascular hypertension. Clin Exp Hypertens . 2001; 23 293-304
38 Takahashi N, Nakagawa M, Saikawa T. et al . Effect of essential hypertension on cardiac autonomic function in type 2 diabetic patients. J Am Coll Cardiol . 2001; 38 232-237
39 Simula S, Vanninen E, Viitanen L. et al . Cardiac adrenergic innervation is affected in asymptomatic subjects with very early stage of coronary artery disease. J Nucl Med . 2002; 43 1-7
40 Agostini D, Lecluse E, Belin A. et al . Impact of exercise rehabilitation on cardiac neuronal function in heart failure: an iodine-123 metaiodobenzylguanidine scintigraphy study. Eur J Nucl Med . 1998; 25 235-241
41 Kurata C, Shouda S, Mikami T. et al . Metaiodobenzylguanidine and heart rate variability in heart failure. Jpn Circ J . 1998; 62 770-772
42 Atsumi H, Takeishi Y, Fujiwara S, Tomoike H. Cardiac sympathetic nervous disintegrity is related to exercise intolerance in patients with chronic heart failure. Nucl Med Commun . 1998; 19 451-456
43 Merlet P, Pouillart F, Dubois-Rande J L. et al . Sympathetic nerve alterations assessed with 123I-MIBG in the failing human heart. J Nucl Med . 1999; 40 224-231
44 Sakamaki F, Satoh T, Nagaya N. et al . Correlation between severity of pulmonary arterial hypertension and 123I-metaiodobenzylguanidine left ventricular imaging. J Nucl Med . 2000; 41 1127-1133
45 de Milliano A P, van Eck-Smit L B, van Zwieten A P, de Groot C A, Tijssen J G, Lie K I. Relationship between cardiac metaiodobenzylguanidine uptake and hemodynamic, functional and neurohormonal parameters in patients with heart failure. Eur J Heart Fail . 2001; 3 693-697
46 de Milliano A P, Tijssen J G, van Eck-Smit L B, Lie K I. Cardiac 123 I-MIBG imaging and clinical variables in risk stratification in patients with heart failure treated with beta blockers. Nucl Med Commun . 2002; 23 513-519
47 Takahashi N, Ishida Y, Maeno M. et al . Noninvasive identification of left ventricular involvements in arrhythmogenic right ventricular dysplasia: comparison of 123I-MIBG, 201TlCl, magnetic resonance imaging and ultrafast computed tomography. Ann Nucl Med . 1997; 11 233-241
48 Yukinaka M, Nomura M, Ito S, Nakaya Y. Mismatch between myocardial accumulation of 123I-MIBG and 99mTc-MIBI and late ventricular potentials in patients after myocardial infarction: association with the development of ventricular arrhythmias. Am Heart J . 1998; 136 859-867
49 Nomura M, Nada T, Endo J. et al . Brugada syndrome associated with an autonomic disorder. Heart . 1998; 80 194-196
50 Schafers M, Wichter T, Lerch H. et al . Cardiac 123I-MIBG uptake in idiopathic ventricular tachycardia and fibrillation. J Nucl Med . 1999; 40 1-5
51 Okishige K, Sasano T, Yano K, Azegami K, Suzuki K, Itoh K. Serious arrhythmias in patients with apical hypertrophic cardiomyopathy. Intern Med . 2001; 40 396-402
52 Wichter T, Matheja P, Eckardt L. et al . Cardiac autonomic dysfunction in Brugada syndrome. Circulation . 2002; 105 702-706
53 Nagaoka H, Iizuka T, Kubota S. et al . Depressed contractile response to exercise in diabetic patients in the absence of cardiovascular disease: relationship to adrenergic cardiac dysinnervation. Nucl Med Commun . 1997; 18 761-770
54 Ziegler D, Weise F, Langen K J. et al . Effect of glycaemic control on myocardial sympathetic innervation assessed by [123I]metaiodobenzylguanidine scintigraphy: a 4-year prospective study in IDDM patients. Diabetologia . 1998; 41 443-451
55 Nagamachi S, Jinnouchi S, Kurose T. et al . 123I-MIBG myocardial scintigraphy in diabetic patients: relationship with 201Tl uptake and cardiac autonomic function. Ann Nucl Med . 1998; 12 323-331
56 Uehara A, Kurata C, Sugi T, Mikami T, Shouda S. Diabetic cardiac autonomic dysfunction: parasympathetic versus sympathetic. Ann Nucl Med . 1999; 13 95-100
57 Giordano A, Calcagni M L, Verrillo A. et al . Assessment of sympathetic innervation of the heart in diabetes mellitus using 123I-MIBG. Diabetes Nutr Metab . 2000; 13 350-355
58 Nagamachi S, Jinnouchi S, Kurose T. et al . Serial change in 123I-MIBG myocardial scintigraphy in non-insulin-dependent diabetes mellitus. Ann Nucl Med . 2002; 16 33-38
59 Hattori N, Rihl J, Bengel F M. et al . Cardiac autonomic dysinnervation and myocardial blood flow in long-term type 1 diabetic patients. Diabet Med . 2003; 20 375-381
60 Agostini D, Babatasi G, Manrique A. et al . Impairment of cardiac neuronal function in acute myocarditis: iodine-123-MIBG scintigraphy study. J Nucl Med . 1998; 39 1841-1844
61 Kakuchi H, Sasaki T, Ishida Y, Komamura K, Miyatake K. Clinical usefulness of 123I meta-iodobenzylguanidine imaging in predicting the effectiveness of beta blockers for patients with idiopathic dilated cardiomyopathy before and soon after treatment. Heart . 1999; 81 148-152
62 Toyama T, Aihara Y, Iwasaki T. et al . Cardiac sympathetic activity estimated by 123I-MIBG myocardial imaging in patients with dilated cardiomyopathy after beta-blocker or angiotensin-converting enzyme inhibitor therapy. J Nucl Med . 1999; 40 217-223
63 Momose M, Kobayashi H, Iguchi N. et al . Comparison of parameters of 123I-MIBG scintigraphy for predicting prognosis in patients with dilated cardiomyopathy. Nucl Med Commun . 1999; 20 529-535
64 Merlet P, Benvenuti C, Moyse D. et al . Prognostic value of MIBG imaging in idiopathic dilated cardiomyopathy. J Nucl Med . 1999; 40 917-923
65 Maunoury C, Agostini D, Acar P. et al . Impairment of cardiac neuronal function in childhood dilated cardiomyopathy: an 123I-MIBG scintigraphic study. J Nucl Med . 2000; 41 400-404
66 Naruse H, Arii T, Kondo T. et al . Relation between myocardial response to dobutamine stress and sympathetic nerve activation in patients with idiopathic dilated cardiomyopathy: a comparison of 123I-MIBG scintigraphic and echocardiographic data. Ann Nucl Med . 2000; 14 427-432
67 Matsui T, Tsutamoto T, Kinoshita M. Relationship between cardiac 123I-metaiodobenzylguanidine imaging and the transcardiac gradient of neurohumoral factors in patients with dilated cardiomyopathy. Jpn Circ J . 2001; 65 1041-1046
68 Shimizu M, Ino H, Yamaguchi M. et al . Heterogeneity of cardiac sympathetic nerve activity and systolic dysfunction in patients with hypertrophic cardiomyopathy. J Nucl Med . 2002; 43 15-20
69 Matsui T, Tsutamoto T, Maeda K, Kusukawa J, Kinoshita M. Prognostic value of repeated 123I-metaiodobenzylguanidine imaging in patients with dilated cardiomyopathy with congestive heart failure before and after optimized treatments-comparison with neurohumoral factors. Circ J . 2002; 66 537-543
70 Kasama S, Toyama T, Hoshizaki H. et al . Dobutamine gated blood pool scintigraphy predicts the improvement of cardiac sympathetic nerve activity, cardiac function, and symptoms after treatment in patients with dilated cardiomyopathy. Chest . 2002; 122 542-548
71 Lanza G A. Abnormal cardiac nerve function in syndrome X. Herz . 1999; 24 97-106
72 Lanza G A, Giordano A, Pristipino C. et al . Relationship between myocardial 123I-metaiodobenzylguanidine scintigraphic uptake and heart rate variability in patients with syndrome X. Ital Heart J . 2000; 1 221-225
73 Abe Y, Sugiura T, Takehana K. et al . Clinical significance of denervated but viable myocardium in patients with recanalized acute myocardial infarction. Nucl Med Commun . 1999; 20 727-735
74 Bengel F M, Barthel P, Matsunari I, Schmidt G, Schwaiger M. Kinetics of 123I-MIBG after acute myocardial infarction and reperfusion therapy. J Nucl Med . 1999; 40 904-910
75 Ando M, Yamabe H, Sakurai K, Kawai H, Yokoyama M. Relationship between cardiac sympathetic function and baroreceptor sensitivity after acute myocardial infarction. Circ J . 2002; 66 247-252
76 Soeki T, Tamura Y, Bandou K. et al . Long-term effects of the angiotensin-converting enzyme inhibitor enalapril on chronic heart failure. Examination by 123I-MIBG imaging. Jpn Heart J . 1998; 39 743-751
77 Sakata K, Shirotani M, Yoshida H. et al . Effects of amlodipine and cilnidipine on cardiac sympathetic nervous system and neurohormonal status in essential hypertension. Hypertension . 1999; 33 1447-1452
78 Agostini D, Belin A, Amar M H. et al . Improvement of cardiac neuronal function after carvedilol treatment in dilated cardiomyopathy: a 123I-MIBG scintigraphic study. J Nucl Med . 2000; 41 845-851
79 Lotze U, Kaepplinger S, Kober A, Richartz B M, Gottschild D, Figulla H R. Recovery of the cardiac adrenergic nervous system after long-term beta-blocker therapy in idiopathic dilated cardiomyopathy: assessment by increase in myocardial 123I-metaiodobenzylguanidine uptake. J Nucl Med . 2001; 42 49-54
80 de Milliano A P, de Groot C A, Tijssen J G, van Eck-Smit L B, Van Zwieten A P, Lie K I. Beneficial effects of metoprolol on myocardial sympathetic function: evidence from a randomized, placebo-controlled study in patients with congestive heart failure. Am Heart J . 2002; 144 E3
81 Goldstein D S, Katzper M, Linares O A, Kopin I J. Kinetic model for the fate of the sympathoneural imaging agent 6[18F]fluorodopamine in the human heart: a novel means to assess cardiac sympathetic neuronal function. Naunyn Schmiedebergs Arch Pharmacol . 2002; 365 38-49
82 Shouda S, Kurata C, Mikami T, Wakabayashi Y. Effects of extrinsically elevated plasma norepinephrine concentration on myocardial 123I-MIBG kinetics in rats. J Nucl Med . 1999; 40 2088-2093
83 Senard J M, Rai S, Lapeyre-Mestre M. et al . Prevalence of orthostatic hypotension in Parkinson's disease. J Neurol Neurosurg Psychiatry . 1997; 63 584-589
84 Micieli G, Martignoni E, Cavallini A, Sandrini G, Nappi G. Postprandial and orthostatic hypotension in Parkinson's disease. Neurology . 1987; 37 386-393
85 Anonymous. Cardiovascular disorders in Parkinson disease are underrated. Fortschr Neurol Psychiatr . 1999; 67 A8-A9
86 Hillen M E, Wagner M L, Sage J I. “Subclinical” orthostatic hypotension is associated with dizziness in elderly patients with Parkinson disease. Arch Phys Med Rehabil . 1996; 77 710-712
87 Gilman S, Low P, Quinn N. et al . Consensus statement on the diagnosis of multiple system atrophy. Clin Auton Res . 1998; 8 359-362
88 Mathias C J. The classification and nomenclature of autonomic disorders-ending chaos, resolving conflict and hopefully achieving clarity. Clin Auton Res . 1995; 5 307-310
89 Goldstein D S, Polinsky R J, Garty M. et al . Patterns of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol . 1989; 26 558-563
90 Goldstein D S, Holmes C, Sharabi Y, Brentzel S, Eisenhofer G. Plasma levels of catechols and metanephrines in neurogenic orthostatic hypotension. Neurology . 2003; 60 1327-1332
91 Polinsky R J. Neuropharmacological investigation of autonomic failure. In: Bannister R, Mathias CJ, eds. Autonomic Failure New York: Oxford University Press 1992: 334-358
92 Jordan J, Shannon J R, Biaggioni I, Norman R, Black B K, Robertson D. Contrasting actions of pressor agents in severe autonomic failure. Am J Med . 1998; 105 116-124
93 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 (Berl) . 1997; 94 192-196
94 Orimo S, Oka T, Miura H. et al . Sympathetic cardiac denervation in Parkinson's disease and pure autonomic failure but not in multiple system atrophy. J Neurol Neurosurg Psychiatry . 2002; 73 776-777
95 Black I B, Petito C K. Catecholamine enzymes in the degenerative neurological disease idiopathic orthostatic hypotension. Science . 1976; 192 910-912
96 Satoh A, Serita T, Tsujihata M. Total defect of metaiodobenzylguanidine (MIBG) imaging on heart in Parkinson's disease: assessment of cardiac sympathetic denervation. Nippon Rinsho . 1997; 55 202-206
97 Satoh A, Serita T, Seto M. et al . Loss of 123I-MIBG uptake by the heart in Parkinson's disease: assessment of cardiac sympathetic denervation and diagnostic value. J Nucl Med . 1999; 40 371-375
98 Druschky A, Hilz M J, Platsch G. et al . Differentiation of Parkinson's disease and multiple system atrophy in early disease stages by means of I-123-MIBG-SPECT. J Neurol Sci . 2000; 175 3-12
99 Braune S, Reinhardt M, Schnitzer R, Riedel A, Lucking C H. Cardiac uptake of [123I]MIBG separates Parkinson's disease from multiple system atrophy. Neurology . 1999; 53 1020-1025
100 Yoshita M, Hayashi M, Hirai S. Decreased myocardial accumulation of 123I-meta-iodobenzyl guanidine in Parkinson's disease. Nucl Med Commun . 1998; 19 137-142
101 Kanzaki N, Sato K, Hayabara T. Improved cardiac iodine-123 metaiodobenzylguanidine accumulation after drug therapy in a patient with Parkinson's disease. Clin Nucl Med . 1997; 22 697-699
102 Ohmura M. Loss of 123I-MIBG uptake by the heart in Parkinson's disease: assessment of cardiac sympathetic denervation and diagnostic value. J Nucl Med . 2000; 41 1594-1595
103 Reinhardt M J, Jungling F D, Krause T M, Braune S. Scintigraphic differentiation between two forms of primary dysautonomia early after onset of autonomic dysfunction: value of cardiac and pulmonary iodine-123 MIBG uptake. Eur J Nucl Med . 2000; 27 595-600
104 Braune S, Reinhardt M, Bathmann J, Krause T, Lehmann M, Lucking C H. Impaired cardiac uptake of meta-[123I]iodobenzylguanidine in Parkinson's disease with autonomic failure. Acta Neurol Scand . 1998; 97 307-314
105 Orimo S, Ozawa E, Oka T. et al . Different histopathology accounting for a decrease in myocardial MIBG uptake in PD and MSA. Neurology . 2001; 57 1140-1141
106 Senard J M, Brefel-Courbon C, Rascol O, Montastruc J L. Orthostatic hypotension in patients with Parkinson's disease: pathophysiology and management. Drugs Aging . 2001; 18 495-505
107 Takatsu H, Nishida H, Matsuo H. et al . Cardiac sympathetic denervation from the early stage of Parkinson's disease: clinical and experimental studies with radiolabeled MIBG. J Nucl Med . 2000; 41 71-77
108 Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H. (123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson's disease. J Neurol Neurosurg Psychiatry . 1999; 67 189-194
109 Yoshita M, Hayashi M, Hirai S. Iodine 123-labeled meta-iodobenzylguanidine myocardial scintigraphy in the cases of idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Rinsho Shinkeigaku . 1997; 37 476-482
110 Goldstein D S, Holmes C, Li S T, Bruce S, Metman L V, Cannon R O. Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med . 2000; 133 338-347
111 Goldstein D S, Holmes C, Dendi R, Bruce S, Li S-T. Orthostatic hypotension from sympathetic denervation in Parkinson's disease. Neurology . 2002; 58 1247-1255
112 Li S T, Dendi R, Holmes C, Goldstein D S. Progressive loss of cardiac sympathetic innervation in Parkinson's disease. Ann Neurol . 2002; 52 220-223
113 Goldstein D S, Holmes C, Cannon III O R, Eisenhofer G, Kopin I J. Sympathetic cardioneuropathy in dysautonomias. N Engl J Med . 1997; 336 696-702
114 Akincioglu C, Unlu M, Tunc T. Cardiac innervation and clinical correlates in idiopathic Parkinson's disease. Nucl Med Commun . 2003; 24 267-271
115 Taki J, Nakajima K, Hwang E H. et al . Peripheral sympathetic dysfunction in patients with Parkinson's disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med . 2000; 27 566-573