Impaired myocardial 123I-metaiodobenzylguanidine uptake in Lewy body disease: Comparison between dementia with Lewy bodies and Parkinson's disease

Journal of the Neurological Sciences 240 (2006) 15 – 19 www.elsevier.com/locate/jns

Impaired myocardial 123I-metaiodobenzylguanidine uptake in Lewy body disease: Comparison between dementia with Lewy bodies and Parkinson’s disease Masahiko Suzuki a,*, Akira Kurita a, Masaya Hashimoto a, Nobuyoshi Fukumitsu b, Masahiro Abo c, Yasuhiko Ito a, Mitsuyoshi Urashima d, Kiyoharu Inoue a a

Department of Neurology, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan b Department of Radiology, The Jikei University School of Medicine, Tokyo, Japan c Rehabilitation Medicine, The Jikei University School of Medicine, Tokyo, Japan d Division of Clinical Research and Development, The Jikei University School of Medicine, Tokyo, Japan Received 16 February 2005; received in revised form 25 July 2005; accepted 22 August 2005 Available online 29 September 2005

Abstract Background: Iodine-123-labeled metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy has been used to evaluate cardiac sympathetic denervation in Lewy body disease (LBD) including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Patients with LBD had marked reductions in cardiac MIBG accumulation, indicative of severe impairment of the cardiac sympathetic nervous systems. However, the differences in scintigraphy between DLB and PD have not been determined. Objective: To compare cardiac sympathetic function in early disease stage measured with 123I-MIBG scintigraphy between DLB and PD. Methods: 123I-MIBG myocardial scintigraphy was performed in 22 patients with early-stage DLB, 41 patients with early idiopathic PD and 15 normal control subjects who were matched for age and disease duration. The heart-to-mediastinum (H/M) ratio was calculated. Results: 123I-MIBG uptake of the myocardium was significantly lower in patients with early DLB than in controls. The mean value of H/ M ratio in patients with DLB was significantly lower than those in patients with PD, independent of the Hoehn and Yahr stage. Conclusions: Our findings suggest that cardiac sympathetic function in DLB is severely impaired even in the early disease stage. D 2005 Elsevier B.V. All rights reserved. Keywords: Dementia with Lewy bodies; Metaiodobenzylguanidine; Parkinson’s disease; Heart

1. Introduction Metaiodobenzylguanidine (MIBG) is a physiological analogue of noradrenaline (norepinephrine) and is actively transported into noradrenaline granules of sympathetic nerve terminals by the noradrenaline transporter [1]. Recent functional imaging studies using 123I-MIBG cardiac scintigraphy have demonstrated a myocardial postganglionic sympathetic dysfunction in both Parkinson’s disease (PD) [2– 11] and dementia with Lewy bodies (DLB) [10,12,13].

* Corresponding author. Tel.: +81 3 3433 1111; fax: +81 3 3433 1344. E-mail address: [email protected] (M. Suzuki). 0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.08.011

In PD, cardiac uptake of 123I-MIBG uptake is reduced in almost all patients with a clinical severity stage of Hoehn and Yahr [14] (HY) II or higher [6,7,10]. In addition, previous studies suggested that cardiac MIBG uptake in DLB was also impaired even though the numbers of patients with DLB in these studies were relatively small [10,15]. However, the differences in the extent of cardiac sympathetic dysfunction in these two disorders in the early disease stage have not yet been determined. In the present study, we investigated cardiac sympathetic function in patients with early Lewy body disease (LBD), including both DLB and PD, using 123I-MIBG scintigraphy, and examined the relations between myocardial 123I-MIBG uptake and disease severity by HY stage in LBD.

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M. Suzuki et al. / Journal of the Neurological Sciences 240 (2006) 15 – 19

2. Subjects and methods 2.1. Subject population Subjects were selected from inpatients and those attending our outpatient department from April 2001 through December 2004. In each subject, 123I-MIBG scintigraphy was performed as a part of initial clinical evaluation of parkinsonism, after informed consent had been obtained. The subjects were 22 with DLB, 41 patients with PD, and 15 age-matched healthy control subjects free of neurological or cardiovascular abnormalities. There was no significant difference in age and gender among the DLB, PD, and control groups. In addition, there was no significant difference in disease duration and HY stage between DLB and PD (Table 1). No clinical evidence of diabetes mellitus or cardiovascular disease was noted in any of the patients or control subjects. All subjects underwent electrocardiography and chest radiography before 123I-MIBG imaging to exclude myocardial disorders such as cardiomyopathy and congestive heart disease. Patients with missing clinical information or any obvious medical complications that could lower the accuracy of clinical diagnoses were excluded. A board-certified neurologist established the clinical diagnosis of LBD based on detailed medical history, physiological and neurological examinations, and the results of routine laboratory investigations, and magnetic resonance imaging studies of the brain. The diagnosis of DLB was based on the criteria of the consortium on DLB International Workshop [16]. All patients with DLB had fluctuations in alertness and attention and spontaneous motor features of parkinsonism with or without recurrent visual hallucinations, delusions, sleep behavior disorder, and depression. In addition, to make the diagnosis more accurate, we performed N-isopropyl-p-[123I] iodoamphetamine brain single photon emission computed tomography (SPECT) using three-dimensional stereotactic surface projections, in all patients with DLB. The SPECT findings demonstrated hypoperfusion in both the occipital lobes and parietal lobes with relative sparing of the sensorimotor cortex in all Table 1 Demographic and clinical data of subjects DLB n Mean age (S.D.) (year) M/F Mean disease duration (S.D.) (year) HY stage I/II/III/IV

PD

NC

Total

N.S.a

13/9 23/18 1.5 (0.7) 1.4 (0.9)

N.S.b N.S.c

9/5/8/0

15/13/11/2

48/30

2.2.

123

I-MIBG myocardial scintigraphy

Any drugs that could interfere with MIBG uptake by sympathetic nerve terminals, such as tricyclic and tetracyclic antidepressants, calcium antagonists, and sympathomimetics [19], were not prescribed before 123I-MIBG imaging. Following thyroid gland blocking with potassium iodide (300 mg), 123I-MIBG myocardial scintigraphy was performed in all subjects with an intravenous injection of 111 MBq of 123I-MIBG (Daiichi Radioisotope Laboratories Co., Tokyo, Japan). Anterior planar images of the chest were obtained after 4 h for images using a triple-headed gamma camera (MULTISPECT 3, Siemens, Erlangen, Germany) equipped with low-energy and high-resolution collimators. The photopeak of 123I was centered at 159 keV with a 20% energy window. The data were acquired for 4 min with a 256  256 matrix for image acquisition. The organ uptake of 123I-MIBG was determined by setting the region of interest (ROI) on the left cardiac ventricle and an angular ROI in the upper mediastinum in images. To calculate the heart to mediastinum ratio (H/M ratio), the average counts per pixel in the heart and mediastinum were determined. 2.3. Statistical analysis The results are expressed as group mean values (TS.D.). Differences in age and disease duration between groups were examined for statistical significance using analysis of variance, Student’s t-test, or the Chi-square test. The Kruskal – Wallis test, developed as a nonparametric test for trend across three or more groups [20], was used for group comparison of unpaired continuous data. All tests were performed with the STATA 8.0 software program (STATA Corporation, College Station, TX).

P value

22 41 15 78 71.1 (7.8) 67.3 (8.8) 64.8 (9.4) 12/3

patients with DLB [17]. A diagnosis of idiopathic PD was made based on Criteria of the United Kingdom Brain Bank [18]. Patients with PD were excluded if they had atypical PD syndromes, such as progressive supranuclear palsy and multiple system atrophy. Additional exclusion criteria for PD included the following: history of stroke, cerebral tumor, traumatic brain injury, epilepsy, and psychiatric illness.

24/18/19/2 N.S.b

F: female; M: male; n: number of subjects; NC: normal control subjects; N.S.: not significant. a By analysis of variance. b By Chi-square test. c By Student’s t-test.

3. Results In our hospital, the normal mean value of the H/M ratio obtained in 15 control subjects was 2.08 T 0.14 (range: 1.91– 2.38). The mean value of H/M ratio was 1.25 T 0.11 (range: 1.03– 1.46) in patients with DLB, and 1.58 T 0.32 (range: 1.07 – 2.32) in those with PD. The H/M ratios in the PD and DLB groups were both significantly lower than those of the control. In addition, the mean value of the H/M ratio of the DLB group was significantly lower than that of the PD group (Fig. 1).

M. Suzuki et al. / Journal of the Neurological Sciences 240 (2006) 15 – 19

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* *

2.5

H/M ratio

2

1.5

N.S

1

P < 0.03

DLB

.5 total

I

PD II

III

total I

II

NC III

IV

total

HY stage Fig. 1. Comparison of the H/M ratio of 123I-MIBG uptake among patients with DLB, PD and normal control subjects (NC), and relation between both early and delayed H/M ratios and HY stage in DLB and PD. The box plots show the median values (thick line), the 25th (lower line of box) and 75th percentiles (upper line of box); T bars indicate 1.5 times the height of the box beyond either quartile. Early and delayed H/M rations were compared among DLB (n = 22), PD (n = 41), and NC (n = 15) with one-way analysis of variance. In Bonferroni correction, a P-value less than 0.01 was considered significant. *: P < 0.001. Trend of early and delayed H/M ratios across three HY stages were assessed using the Kruskal – Wallis test. N.S.: not significant. Horizontal lines: group median values.

The clinical severity as assessed by the HY stage did not correlate with H/M ratio in patients with DLB, while the progression of cardiac sympathetic nerve disturbances in PD correlated with the severity of the disease ( P < 0.03) (Fig. 1).

4. Discussion The main findings of the present study were 1) 123IMIBG uptake of the myocardium was significantly lower in patients with early LBD than the control, and 2) the mean H/ M ratio of patients with DLB was significantly lower than that of patients with PD, independent of the HY stage. Evidence for postganglionic sympathetic nerve involvement in LBD was provided in recent studies. 123I-MIBG cardiac scintigraphy demonstrated apparently decreased cardiac MIBG uptake in LBD [2– 13]. Goldstein et al. [21] also reported that cardiac sympathetic innervation was selectively affected in patients with PD using 6-[18F]fluorodopamine positron emission tomography. Iwanaga et al. [22] provided pathological evidence for the involvement of cardiac postganglionic sympathetic and intrinsic neurons in PD. Recent immunohistochemical studies also indicated that tyrosine hydroxylase (TH)-immunoreactive nerve fibers in the heart were markedly decreased in patients with PD, indicating cardiac sympathetic denervation [23 – 25]. In addition, immunohistochemical studies of cardiac tissues of patients with pathologically confirmed LBD using monoclonal antibody against TH showed almost complete

disappearance of TH-immunoreactive epicardial nerve fibers in nearly all patients with LBD, irrespective of duration of illness or presence of orthostatic hypotension [26], compared with the preserved neurons in the sympathetic ganglia in LBD. These results suggest that postganglionic cardiac sympathetic nerve denervation also occurs in DLB, as well as in PD, which also accounts for the decreased cardiac uptake of MIBG in DLB, and precedes the neuronal loss in the sympathetic ganglia [27]. Considered with these observations, our findings of reduced cardiac MIBG uptake in early LBD suggest that decreased cardiac MIBG uptake in LBD reflects actual cardiac sympathetic denervation. In the present study, cardiac MIBG uptake tended to decrease with the disease progression of HY stage in PD, which was in agreement with the previous reports [6,7,10]. On the other hand, cardiac MIBG uptake in patients with early DLB was significantly lower than those in patients with early PD, independent of the HY stage. The H/M ratio was within normal range in four patients with early-stage PD (HY stage I) as shown in Fig. 1. A regional MIBG uptake alteration might precede global uptake reduction assessed by H/M ratios. Regional heterogeneity of cardiac MIBG uptake will be the earliest event and precede the decrease in H/M ratio [28]. Sympathetic neuroimaging with 6-[18F]fluorodopamine positron emission tomography scanning also demonstrated that the loss of sympathetic innervation progresses over time in patients with PD who have normal cardiac sympathetic innervation [29]. With these previous reports and the present study taken together,

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cardiac sympathetic nerve might be involved already in early disease stage even though H/M ratios is preserved within the normal range. These results also suggest that disturbances of cardiac sympathetic nerve progress over time. Clinically, autonomic dysfunctions were found in almost all cases of pathologically confirmed DLB, suggesting that autonomic failure may be present much more often in DLB than previously thought [30]. In addition, the frequency of orthostatic intolerance and the severity of autonomic dysfunction were also greater in DLB compared with PD [31]. Autonomic dysfunction in PD becomes apparent as the disease progresses [32] and patients with orthostatic hypotension had much lower cardiac uptake of 6-[18F]fluorodopamine than those without the condition [33]. Based on these findings, we speculate that marked reduction of cardiac MIBG uptake in DLB relative to PD might due to greater postganglionic cardiac sympathetic denervation and/ or the degree of Lewy body pathology itself and neuronal loss in the sympathetic ganglia [27]. On the other hand, Frysinger and Harper [34] found that hippocampal structures, including the amygdala, in which Lewy bodies and Lewy neuritis are frequently seen in DLB [35], are among the centers at the highest level of cardiovascular autonomic control. In addition, Druschky et al. [36] reported impaired cardiac 123I-MIBG uptake in patients with temporal lobe epilepsy and speculated that this finding was due to transsynaptic degeneration of autonomic nervous system fibers. Although we have no definitive explanation for the structural impairment of sympathetic cardiac innervation, we cannot exclude the possibility that the greater reduction of 123I-MIBG uptake in DLB than in PD is related to greater number and wider distribution of Lewy bodies in DLB. Thus, we assume that the outcomes of 123I-MIBG scintigraphy observed in DLB, indicating a reduction in postganglionic sympathetic neurons, resulted from lesions of the central autonomic control system, such as the amygdala and the hippocampus, and involvement of postganglionic cardiac sympathetic nerves. In conclusion, the present findings and those of earlier studies suggest that reduced uptake of MIBG is not a specific finding for PD, is considered to reflect lesions in postganglionic cardiac sympathetic neurons in LBD and postganglionic sympathetic dysfunction in DLB is severely affected even in the early disease stage. Further studies in large numbers of subjects with early disease stage of both DLB and PD are needed to confirm our findings.

Acknowledgments We gratefully acknowledge the helpful suggestions and assistance of Dr. Satoshi Orimo, Department of Neurology, Kanto Central Hospital. This research was supported by The Jikei University research fund.

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