Reduced cardiac 123I-MIBG uptake reflects cardiac sympathetic dysfunction in Lewy body disease
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Abstract
Objective: To examine the relation between the results of cardiac 123I-meta-iodobenzylguanidine (MIBG) scintigraphy and cardiovascular autonomic function in Lewy body disease (LBD).
Methods: The subjects were 66 patients with LBD, 44 of whom had Parkinson disease (PD), 10 PD with dementia (PDD), and 12 dementia with Lewy bodies (DLB); 20 age-matched healthy subjects were studied as controls. Cardiovascular autonomic function was evaluated on the basis of cardiac 123I-MIBG uptake, cardiovascular autonomic response on the Valsalva maneuver (VM), and systolic blood pressure (SBP) response on head-up tilt table (HUT) testing.
Results: Patients with LBD had reduced cardiac 123I-MIBG uptake, cardiovascular autonomic response on the VM, and SBP response on HUT testing as compared with controls. Cardiac 123I-MIBG uptake and cardiovascular autonomic function in PDD and DLB were severely impaired as compared with those in PD. Cardiac 123I-MIBG uptake in LDB was not significantly related to vasomotor sympathetic function, baroreceptor reflex gain, cardiac parasympathetic function, or the changes in SBP on HUT testing. Cardiac 123I-MIBG uptake was, however, significantly related to the blood pressure overshoot in phase IV of the VM.
Conclusion: Cardiac 123I-meta-iodobenzylguanidine uptake clinically reflects cardiac sympathetic dysfunction in Lewy body disease.
GLOSSARY: BRS = baroreceptor reflex sensitivity; DLB = dementia with Lewy bodies; H/M ratio = the ratio of the average pixel count in the heart to that in the mediastinum; HUT = head-up tilt table test; LBD = Lewy body disease; MIBG = 123I-meta-iodobenzylguanidine; MMSE = Mini-Mental State Examination; PD = Parkinson disease; PDD = Parkinson disease with dementia; phase II E = systolic blood pressure decreases in early phase II; phase II L = systolic blood pressure increases in late phase II; PRT = pressure recovery time; VM = Valsalva maneuver; ROI = region of interest; SBP = systolic blood pressure; TH = tyrosine hydroxylase.
Cardiac uptake of 123I-meta-iodobenzylguanidine (MIBG), a physiologic analogue of norepinephrine, is reduced in patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB).1–7 Since MIBG is taken up and stored in sympathetic nerve endings, reduced levels in PD are considered to indicate myocardial postganglionic sympathetic dysfunction. In contrast, postganglionic sympathetic fibers remain intact in multiple system atrophy. MIBG uptake is reduced even in patients with very early PD according to the Hoehn-Yahr staging system, without clinically significant signs or symptoms of autonomic dysfunction.1–7 It was reported that that tyrosine hydroxylase (TH)-immunoreactive nerve fibers in the heart are markedly decreased in PD, but not in multiple system atrophy,8,9 suggesting that cardiac sympathetic denervation is responsible for decreased cardiac uptake of MIBG in PD.8–10 Decreased cardiac uptake of MIBG in Lewy body disease (LBD) reflects cardiac sympathetic denervation, which precedes neuronal loss in sympathetic ganglia.8
It remains unclear, however, whether cardiac MIBG uptake is clinically related to autonomic dysfunction on conventional autonomic function testing in LDB. We therefore studied the relation between cardiac 123I MIBG uptake and cardiovascular autonomic dysfunction in LBD.
METHODS
Subjects.
The subjects were 66 patients with LBD (32 men, 34 women, age 68.5 ± 4.7 years, range 52 to 85 years) with a disease duration of 1 to 10 years (4.0 ± 1.6 years) and a Hoehn-Yahr stage of 1 to 4 (2.5 ± 0.6). The patients with LBD consisted of 44 patients with PD, 10 patients with PDD, and 12 patients with DLB (table 1).
Table 1 Comparisons of patient characteristics, H/M ratio of cardiac 123I-meta-iodobenzylguanidine uptake, and indices of autonomic function among subjects with Parkinson disease (PD), dementia with PD (PDD), and dementia with Lewy bodies (DLB)
No patient had signs or symptoms of cardiac disease or any abnormalities on chest radiography, electrocardiography, or cardiac echography. We also excluded patients who were receiving medications with potential effects on autonomic function, such as beta-blockers, anticholinergic agents, and antihypertensive drugs. No patient had previously received drugs with potential effects on 123I-MIBG uptake at sympathetic nerve terminals.11
PD was diagnosed clinically according to the criteria of Calne et al.12 and required a score of 24 or higher on the Mini-Mental State Examination (MMSE).13 PDD met the same diagnostic criteria as the PD group, but additionally had to satisfy the Diagnostic and Statistical Manual of Mental Disorders–IV criteria for dementia and have a MMSE score of less than 24. Probable DLB was diagnosed according to the Third Report of the DLB Consortium.14 The diagnoses of PD, PDD, and DLB were confirmed by clinical observations and assessments performed by three neurologists over the course of at least 3 years after our investigations.
As controls, 20 age-matched healthy subjects volunteers (13 men, 7 women, age 68.5 ± 4.7 years, range 61 to 84 years) with no neurologic disorders were studied. None of the controls had clinically significant illnesses potentially affecting the cardiac autonomic nervous system.
The ethics committee of Jikei University School of Medicine reviewed the protocol, and all subjects gave informed consent before enrollment.
Cardiac 123I-MIBG scintigraphy.
The subjects were given an IV injection of 111 MBq 123I-MIBG (Daiichi Radioisotope Laboratories Co., Tokyo, Japan). Relative organ uptake of 123I-MIBG was determined by region-of-interest (ROI) analysis in the anterior view. The ratio of the average pixel count in the heart (H) to that in the mediastinum (M) was calculated (H/M ratio) after 15 minutes (early) and after 3 hours (delayed).15,16
Cardiovascular autonomic response on the Valsalva maneuver (VM) and head-up tilt table (HUT) testing.
The VM was performed as described previously.15,16 Systolic blood pressure (SBP) and RR intervals (RR) were measured by tonometry, using a noninvasive blood pressure monitoring system (CBM3000, Nihon Colin Co., Ltd., Komaki, Japan). The changes in SBP and RR were divided into four phases on the VM17–20 (figure, A and B). Phase I is the inspiration phase. Phase II is the phase of blowing into the mouthpiece, with an increase in thoracic pressure to 40 mm Hg. SBP decreases in early phase II because of reduced cardiac output, in turn decreasing venous return and stroke volume, despite tachycardia caused by the withdrawal of cardiovagal control (phase II E, mm Hg). The decrease in SBP is arrested within 8 seconds at least. Late phase II is associated with an increase in blood pressure, reflecting the activation of vasomotor sympathetic nerves (phase II L, mm Hg). A transient fall in BP (phase III), lasting 1 to 2 seconds, occurs at the end of VM because of sudden drops in intrathoracic and abdominal pressures.17 Phase IV is the overshoot of blood pressure (phase IV, mm Hg) due to the activation of cardiac sympathetic nerves.18 Time intervals were determined for two periods of the VM, from the end of phase III to the complete return of SBP to the baseline value (blood pressure recovery time: PRT, s).21 Baroreceptor reflex sensitivity (BRS, ms/mm Hg) was derived from the correlation of RR with SBP during the early second phase of the VM.15,16,21
Figure Examples of blood pressure and RR interval profiles in a control subject (A) and patients with Lewy body disease (LBD) with autonomic failure (B)
Blood pressure (BP) fell in early phase II, but increased in late phase II because of an increase in efferent sympathetic gain in controls (A). In LBD with autonomic failure, there was no increase in BP, and BP decreased in late phase II (B). Transient BP overshoot in phase IV was noted in controls, but not in LBD with autonomic failure. Changes in RR intervals were lacking in LBD with autonomic failure as compared with controls. I: Phase I, II: phase II, III: phase III, IV: phase IV. SBP = systolic blood pressure, MBP = mean blood pressure, DBP = diastolic blood pressure.
We also measured changes in SBP on hut testing after the subjects rested for 20 minutes in the supine position.
Statistical analysis.
Statistical analyses were performed using a statistical data analysis system (Esumi Co., Ltd., Tokyo, Japan). Differences between groups were compared with the use of Welch’s t test for continuous variables. Significant differences among PD, PDD, and DLB were determined by two-tailed multiple t tests with the Bonferroni correction after analysis of variance. A p value of less than 0.05 was considered to indicate significance. Correlations between the H/M ratio of cardiac 123I-MIBG uptake and various indices of autonomic activity, such as the responses on the VM and the changes in SBP on HUT, were evaluated by multiple regression analysis.
RESULTS
The H/M ratio of cardiac 123I-MIBG uptake in the patients with LBD was lower than that in the controls (1.47 ± 0.25 vs 2.41 ± 0.26, p < 0.0001). Phase II E did not differ significantly between the patients with LBD and the controls (27.2 ± 11.6 vs 22.9 ± 10.9). Phase II L, BRS, IVp, and PRT were significantly lower in the patients with LBD than in the controls (phase II L: 4.0 ± 8.4 vs 12.1 ± 6.0, p < 0.001; BRS: 1.9 ± 0.9 vs 4.2 ± 2.4, p < 0.01; phase IV: 8.8 ± 8.8 vs 20.1 ± 10.0, p < 0.001; PRT: 7.3 ± 5.5 vs 2.0 ± 0.8, p < 0.001). Patients with LBD had a significantly greater fall in SBP on HUT testing than did the controls (fall in SBP on HUT: 13.2 ± 13.7 vs –2.5 ± 10.2, p < 0.001).
Patients with DLB were older than those with PD or PDD. Disease duration did not differ significantly among these three groups. The Hoehn-Yahr stage was higher in patients with PDD than in patients with PD or those with DLB. Patients with PDD or DLB had lower cardiac 123I-MIBG uptakes, phase II L, and phase IV and a longer PRT than did patients with PD. DLB had a higher phase II E and lower BRS as compared with PD. Patients with PDD or DLB had a greater fall in SBP on HUT testing than did patients with PD (table 1).
As for the correlation between the H/M ratio of cardiac 123I-MIBG uptake and various indices of autonomic activity in LBD, H/M ratio did not correlate with phase II E, phase II L, PRT, or BRS. H/M ratio was, however, significantly related to phase IV (table 2). Cardiac 123I-MIBG uptake began to decrease in association with the reduction in the overshoot of phase IV on the VM.
Table 2 Correlation of H/M ratio with cardiac 123I-meta-iodobenzylguanidine uptake and indices of autonomic function in patients with Lewy body disease on multiple regression analysis
DISCUSSION
LBD was associated with cardiovascular autonomic dysfunction, as indicated by reduced cardiac 123I-MIBG uptake and impaired cardiovascular autonomic function on the VM and HUT testing. Many studies have reported that cardiac 123I-MIBG uptake is reduced in PD without autonomic failure.1–7 Some studies have examined the association between cardiac 123I-MIBG uptake and cardiovascular autonomic function in PD.22,23 Cardiac sympathetic nerves are depleted in patients with DLB, independently of the duration of illness and the presence of orthostatic hypotension, and cardiac sympathetic denervation is a consistent histopathologic feature of LBD.8,9 The morphologic degeneration of cardiac sympathetic nerves has been found in PD, associated with the nearly complete disappearance of TH-immunoreactive axons and marked decreases in NF-immunoreactive axons.10 Cardiac autonomic symptoms such as dyspnea on effort or palpitations in LBD might be associated with reduced cardiac 123I-MIBG uptake. Despite these findings, whether reduced cardiac 123I-MIBG uptake correlates with cardiovascular autonomic dysfunction in LBD has remained a matter of debate.
We examined the relation between cardiac 123I-MIBG uptake and various indices of cardiovascular autonomic activity by means of the VM and HUT testing. Reduced cardiac 123I-MIBG uptake was not related to phase II E, phase II L, BRS, PRT, or fall in SBP on HUT, but correlated with the transient BP overshoot in phase IV on the VM.
Early phase II (phase II E) is characterized by a fall in BP due to reduced cardiac output and shortening of RR intervals caused by the attenuation of cardiovagal control. BRS is derived from the significant correlation between RR intervals and BP during this period and mainly reflects parasympathetic cardiovagal function of the sinus node. Late phase II (phase II L) is characterized by increased BP and reflects vasomotor sympathetic function, i.e., the activation of efferent sympathetic signals to muscle and an increase in plasma norepinephrine concentration induced by baroreflex response, consequently increasing total peripheral resistance.
Phase IV is more dependent on cardiac adrenergic tone than on systemic peripheral resistance18 and therefore reflects cardiac sympathetic function. PRT reflects the adrenergic component of baroreflex function, accompanied by muscle sympathetic neural activation with norepinephrine release and binding to α-adrenergic receptors, resulting in vasoconstriction and BP recovery.24 The significant relation of cardiac 123I-MIBG uptake to only phase IV on the VM suggested that cardiac 123I-MIBG uptake reflects cardiac adrenergic function, but not cardiovagal parasympathetic or α-adrenergic vasomotor functions.
It was reported that MIBG myocardial uptake is sometimes impaired in PD even in the absence of abnormal findings on autonomic testing, suggesting that MIBG myocardial scintigraphy is more sensitive than standard autonomic testing for the early detection of silent autonomic dysfunction.25 We previously reported that patients with PD, especially those with early stage disease, have relatively preserved α-adrenergic vasomotor and cardiac parasympathetic functions.15 Cardiovascular dysautonomia in PD is first expressed as cardiac sympathetic dysfunction, followed by vasomotor and cardiac parasympathetic impairment.15 Autonomic dysfunction in PD may differ between the parasympathetic and sympathetic nervous systems, as well as between the heart and blood vessels.
In patients with DLB, cardiovascular autonomic function was considered to be more severely and extensively impaired than in patients with PD,26,27 and the reduction in cardiac 123I-MIBG uptake was more pronounced in patients with DLB than in those with PD.27,28 In our study, patients with DLB or PDD had markedly impaired cardiac 123I-MIBG uptakes and lower indices of cardiovascular autonomic activity on the VM and HUT testing as compared with patients with PD. These findings suggested that patients with PDD or DLB had impaired cardiac 123I-MIBG uptake in parallel with reduced cardiovascular autonomic function. However, the impairment of cardiac 123I-MIBG uptake in LDB correlated only with the transient BP overshoot in phase IV on the VM and was not related to other cardiovascular parameters. This fact indicated that cardiac 123I-I MIBG uptake was impaired in association with cardiac sympathetic failure in LBD.
In MSA, autonomic dysfunction is generally more severe than in PD.29,30,31 However, cardiac 123I-MIBG uptake in MSA was higher than that in PD, although it was slightly lower than the control value. Our previous study also demonstrated that cardiac 123I-MIBG uptakes were higher in MSA than in PD, although the decreases in transient BP overshoot in phase IV on the VM were similar in PD and MSA.16 We therefore assumed that cardiac sympathetic failure in MSA was not associated with cardiac 123I-MIBG uptake. These findings suggest that sympathetic cardiac dysfunction in MSA is caused by central or preganglionic lesions and not by postganglionic efferent lesions, although postsynaptic denervation has been attributed to the slightly reduced cardiac 123I-MIBG uptakes in MSA.32
Footnotes
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h.oka{at}jike.ac.jp
Disclosure: The authors report no conflicts of interest.
Received January 29, 2007. Accepted in final form April 24, 2007.
REFERENCES
- 1.↵
- 2.
Braune S, Reinhardt M, Schnitzer R, Riedel A, L′king CH. Cardiac uptake of [123I] MIBG separates Parkinson’s disease from multiple system atrophy. Neurology 1999;53:1020–1025.
- 3.
- 4.
Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H. 123I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;67:189–194.
- 5.
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.
- 6.
- 7.
- 8.↵
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.
- 9.
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.
- 10.↵
- 11.
- 12.↵
- 13.↵
- 14.↵
McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: Third report of the DLB consortium. Neurology 2005;65:1863–1872.
- 15.↵
- 16.↵
- 17.↵
Korner PI, Tonkin AM, Uther JB. Reflex and mechanical circulatory effects of graded Valsalva maneuvers in normal man. J Appl Physiol 1976;40:434–440.
- 18.↵
Sandroni P, Benarroch EE, Low PA. Pharmacological dissection of components of the Valsalva maneuver in adrenergic failure. J Appl Physiol 1991;71:1563–1567.
- 19.
- 20.
- 21.↵
Vogel ER, Sandroni P, Low PA. Blood pressure recovery from Valsalva maneuver in patients with autonomic failure. Neurology 2005;65:1533–1537.
- 22.↵
Oka H, Yoshioka M, Morita M, Mochio S, Inoue K. Cardiac sympathetic dysfunction in Parkinson’s disease: relationship between results of 123I-MIBG scintigraphy and autonomic nervous function evaluated by the Valsalva maneuver [in Japanese]. Clin Neurol 2003;43:465–469.
- 23.
Nakamura T, Hirayama M, Ito H, et al. Effective detection of cardiac sympathetic denervation using dobutamine infusion in Parkinson’s disease: correlation with cardiac 123I-metaiodobenzylguanidine (MIBG) uptake [in Japanese]. Auton Nerv Syst (Tokyo) 2005;42:295–300.
- 24.↵
Kirchheim HR. Systemic arterial baroreceptor reflexes. Physiol Rev 1976;56:100–177.
- 25.↵
- 26.↵
Thaisetthawatkul P, Boeve BF, Benarroch EE, et al. Autonomic dysfunction in dementia with Lewy body disease. Neurology 2004;62:1804–1809.
- 27.↵
- 28.
- 29.↵
Sandroni P, Ahlskog JE, Fealey RD, Low PA. Autonomic involvement in extrapyramidal and cerebellar disorders. Clin Auton Res 1991;1:147–155.
- 30.
- 31.
Gilman S. Multiple system atrophy. In: Jankovic J, Tolosa E, eds. Parkinson’s disease and movement disorders, 3rd ed. Baltimore: Williams & Wilkins; 1998:245–262.
- 32.↵
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