Parkinsonism and Related Disorders 24 (2016) 129e131
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Increased body mass index associated with autonomic dysfunction in Parkinson's disease Hitoshi Mochizuki*, Akitoshi Taniguchi, Yuki Nakazato, Nobuyuki Ishii, Yuka Ebihara, Takashi Sugiyama, Kazutaka Shiomi, Masamitsu Nakazato Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 October 2015 Received in revised form 10 December 2015 Accepted 7 January 2016
Background: The association between Parkinson's disease (PD) and body mass index (BMI) has not been established. In this study, we investigated the correlation between BMI and autonomic dysfunction in patients with PD. Methods: Clinical features, BMI, cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy and the coefficient of variation of the electrocardiographic ReR interval (CVRR) were analyzed in 124 patients with PD who were naïve to anti-parkinsonian drugs. Results: BMI was negatively correlated with early heart-to-mediastinum ratio and CVRR in patients with PD, regardless of disease duration and severity. Conclusions: Autonomic dysfunction and BMI increase were associated with each other. Physicians should consider the possibility of autonomic dysfunction in PD patients with high BMI. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Body mass index Electrocardiography MIBG scintigraphy Coefficient of variation of the ReR interval
1. Introduction Parkinson's disease (PD) is a chronic neurodegenerative disease characterized pathologically by abundant a-synuclein neuronal inclusions in the brain. Human body weight is determined by many factors, including genetic, epigenetic, metabolic and environmental components. While one study reported a decrease in body weight prior to the diagnosis of PD, another study found a higher prediagnostic body mass index (BMI) [1]. The association between PD and BMI before or at disease onset has not been conclusively determined. In terms of their relationship after diagnosis, a recent meta-analysis of BMI in PD reported that patients with established PD had a lower BMI than controls, and that this difference was more pronounced in cases of more severe PD [2]. It has been speculated that body weight may be lower in patients with PD because
dyskinesia and rigidity increase resting energy expenditure, or because early anosmia in some patients might diminish appetite and lead to weight loss [1]. It is not yet clear how autonomic function affects body weight. However, the autonomic nervous system was shown to play a role in the metabolic syndrome [3]. The development of obesity was speculated to relate to decreased sympathetic and parasympathetic tone [3]. In this study, we investigated the relationship between autonomic function and BMI in patients with PD using two approaches, cardiac 123I-metaiodobenzylguanidine scintigraphy (MIBG), reflecting sympathetic nerve activity, and assessment of the coefficient of variation of the ReR interval (CVRR), reflecting parasympathetic nerve activity. 2. Subjects and methods 2.1. Subjects
* Corresponding author. Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan. E-mail addresses:
[email protected] (H. Mochizuki), akitoshi_taniguchi@ med.miyazaki-u.ac.jp (A. Taniguchi),
[email protected] (Y. Nakazato),
[email protected] (N. Ishii), yuka_iwakiri@med. miyazaki-u.ac.jp (Y. Ebihara),
[email protected] (T. Sugiyama),
[email protected] (K. Shiomi),
[email protected] (M. Nakazato). http://dx.doi.org/10.1016/j.parkreldis.2016.01.007 1353-8020/© 2016 Elsevier Ltd. All rights reserved.
From April 2008 to September 2014, 130 consecutive patients with possible PD who were naïve to anti-parkinsonian drugs were admitted to our hospital for diagnosis. All underwent MIBG scintigraphy and CVRR assessment, then began treatment with levodopa (100e450 mg/day). As all showed a substantial and sustained response to this therapy, they were clinically diagnosed with probable PD according to the National Institute of Neurological
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Table 1 Linear and multilinear correlation between BMI and clinical features of PD patients. Variables
Single correlation
age (years) duration (month) HeY MIBG scintigraphy early H/M delayed H/M washout ratio CVRR
Stepwise multivariate linear regression
Spearman's coefficient
P value
Coefficient
Standard error
Standardized coefficient
P value
0.045 0.106 0.112
0.620 0.240 0.215
e e 0.657
0.363
0.155
0.073
0.312 0.248 0.022 0.300
0.000* 0.005* 0.809 0.001*
1.780 e e 0.416
0.558
0.275
0.002*
0.202
0.177
0.042*
BMI, body mass index; HeY, Hoehn and Yahr scale. H/M, Heart-to-mediastinum uptake ratio; CVRR, coefficient of variation of ReR intervals.
Disorders and Stroke diagnostic criteria [4]. Disease stage was defined based on the Hoehn and Yahr (HeY) scale. No subjects had evidence of left ventricular hypertrophy or heart failure based on at least one of the following: clinical symptoms, electrocardiogram (ECG), chest X ray and echocardiographic analysis. None of the patients received l-threo-dihydroxyphenylserine (droxidopa), anticholinergics, antidepressants or other sympathomimetic drugs that potentially interfere with the uptake of 123I-MIBG in organs and target tissues. Written informed consent was obtained from all participants. The study protocol was approved by the Ethics Committee of the University of Miyazaki and was carried out in accordance with the Declaration of Helsinki. 2.2.
123
MIBG washout rate (WR) was defined as the percent change in activity from the early image to the delayed image within the left ventricle. 2.3. CVRR In all patients, ReR intervals were measured for 3 min with an ECG machine (FCP-7541; Fukuda Denshi, Tokyo, Japan). Patients rested in a supine position for 10 min or longer before recording began. The CVRR was obtained by dividing the standard deviation (SD) of the recorded ReR intervals by their mean value (M). Thus, CVRR (%) ¼ (SD/M) * 100. 2.4. Statistical analysis
I-MIBG myocardial imaging
Following a 20-min resting period, patients received an intravenous injection of 111 MBq 123I-MIBG (Fuji Film RI Pharma, Tokyo, Japan). A planar image of the chest was obtained with an anterior view for 5 min with a dual-head gamma-camera (eCAM, Siemens, New York, USA) at 15 min (early) and at 4 h (delayed) after injection of 111 MBq I-123 MIBG. The photopeak energy was centered at 159 keV with a 20% window. Relative 123I-MIBG organ uptake was determined by setting the region of interest on the anterior view. Average counts per pixel in the heart and mediastinum were used to calculate the heart-to-mediastinum (H/M) ratio. The cardiac
The correlations between BMI and clinical features were analyzed using Spearman's rank correlation coefficient and stepwise multivariate linear regression. The statistical significance level was set at P ¼ 0.05. SPSS version 22 software was used for statistical analysis. 3. Results Six out of 130 patients were excluded from the study due to concomitant diabetes mellitus. The final study population consisted
B: delayed H/M
A: early H/M ratio
C: CVRR
ratio
4
Rho = -0.312 P < 0.001
(%)
4
Rho = -0.248 P = 0.005
8
3
3
6
2
2
4
1
1
2
0
0 10
20
30
BMI
Rho = -0.300 P = 0.001
0 10
20
30
BMI
10
20
30
BMI
Fig. 1. Scatter diagrams show the relationship between body mass index (BMI) and early and delayed H/M ratios, and with coefficient of variation of ReR intervals (CVRR), in patients with PD. BMI is significantly negatively correlated with early and delayed H/M ratios and with CVRR.
H. Mochizuki et al. / Parkinsonism and Related Disorders 24 (2016) 129e131
of 124 patients (men 56, women 68; age (years, mean ± SD), 68 ± 9; duration (months), 25 ± 20; HeY, 2.3 ± 0.8; BMI, 22.6 ± 3.3). Table 1 shows the correlation coefficients between BMI and the clinical features of PD patients. BMI was negatively correlated with early and delayed H/M ratios and with CVRR, with distributions shown in Fig. 1. On the other hand, BMI was not significantly correlated with disease duration or severity. Also, multivariate linear regression showed that BMI increase was associated with decreased early H/M ratio and decreased CVRR. Patients with higher BMI demonstrated lower early H/M ratio and lower CVRR. 4. Discussion Few studies have investigated BMI in the context of disorders of autonomic function. This study in patients with PD is the first to show a negative correlation between BMI and both early H/M ratio, as determined by MIBG scintigraphy, and CVRR. Dopamine plays a central role in motivated behavior, however the role of the dopaminergic system in feeding behavior specifically is very complicated [1]. In order to reduce the influence of medications, we here enrolled PD patients who were naïve to anti-parkinsonian drugs. A previous pathological study of PD demonstrated profound degeneration of the cardiac sympathetic nerve, which was subsequently shown to be related to abnormal MIBG findings and to the accumulation of a-synuclein in the nerve [5]. CVRR reflects parasympathetic function and was reported to be low in PD [6]. The current study showed that dysfunction of the sympathetic and parasympathetic nerves was related to increased BMI in patients with PD. Parasympathetic nervous system activation was shown to reduce food intake [7] and increase energy expenditure [8]. Parasympathetic deactivation had the opposite effect and was associated with increased BMI [3]. Furthermore, the deactivation of sympathetic nerves decreases energy expenditure by reducing brown adipose tissue-derived thermogenesis, and thus also causes weight gain [9]. These previous studies, together with our own results, led us to conclude that autonomic dysfunction is associated with BMI increase in patients with PD. Abnormal cardiac MIBG scintigraphy has been observed in patients with early-stage PD [5,10]. Clinically, these patients manifest chronotropic insufficiency, an inadequate cardiovascular response during cardiac stress testing (insufficient increase of heart rate) [11]. The lower heart rate leads to decreased energy expenditure and increased BMI. Impairment of the cardiac sympathetic nerve itself may also induce an increase in BMI. The limitation of this study is the lack of control subjects to ascertain whether the relationship between increased BMI and
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impaired autonomic function is also present in subjects without PD. A study of healthy children, however, reported that decreased sympathetic and parasympathetic activity was associated with increased BMI [12]. This relationship between increased BMI and autonomic dysfunction might therefore be present not only in patients with PD but also in normal adult subjects. In patients with PD, BMI was shown to decrease with disease progression, and some patients exhibited severe autonomic dysfunction [2]. In this study, we demonstrated that autonomic dysfunction was related to increased BMI in patients with PD. Physicians should consider the possibility of autonomic dysfunction in PD patients with high BMI. Conflict of interest The authors declare that there are no conflicts of interest. Funding none. References e, P. Krack, Mechanisms of body weight fluctuations in [1] A. Kistner, E. Lhomme Parkinson's disease, Front. Neurol. 5 (2014) 84. [2] M.A. van der Marck, H.C. Dicke, E.Y. Uc, et al., Body mass index in Parkinson's disease: a meta-analysis, Park. Relat. Disord. 18 (2012) 263e267. [3] F. Kreier, A. Yilmaz, A. Kalsbeek, et al., Hypothesis: shifting the equilibrium from activity to food leads to autonomic unbalance and the metabolic syndrome, Diabetes 52 (2003) 2652e2656. [4] D.J. Gelb, E. Oliver, S. Gilman, Diagnostic criteria for Parkinson disease, Arch. Neurol. 56 (1999) 33e39. [5] S. Orimo, T. Uchihara, A. Nakamura, et al., Axonal a-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson's disease, Brain 131 (2008) 642e650. [6] T.H. Haapaniemi, V. Pursiainen, J.T. Korpelainen, et al., Ambulatory ECG and analysis of heart rate variability in Parkinson's disease, J. Neurol. Neurosurg. Psychiat. 70 (2001) 305e310. [7] S. Koda, Y. Date, N. Murakami, et al., The role of the vagal nerve in peripheral PYY3-36- induced feeding reduction in rats, Endocrinology 146 (2005) 2369e2375. [8] G.H. Vijgen, N.D. Bouvy, L. Leenen, et al., Vagus nerve stimulation increases energy expenditure: relation to brown adipose tissue activity, PLoS One 8 (2013) e77221. [9] S.F. Morrison, C.J. Madden, Central nervous system regulation of brown adipose tissue, Compr. Physiol. 4 (2014) 1677e1713. [10] J.A. Palma, H. Kaufmann, Autonomic disorders prediction Parkinson's disease, Park. Relat. Disord. 20 (2014) S94eS98. [11] J.A. Palma, M.M. Carmona-Abellan, N. Barriobero, et al., Is cardiac function impaired in premotor Parkinson's disease? A retrospective cohort study, Mov. Disord. 28 (2013) 591e596. [12] P. Baum, D. Petroff, J. Classen, et al., Dysfunction of autonomic nervous system in childhood obesity: a cross-sectional study, PLoS One 8 (2013) e54546.