Acta Neuropathol (2008) 116:575–577 DOI 10.1007/s00401-008-0428-5
C O R RE S P O N D E N CE
Cardiac sympathetic denervation in Parkinson’s disease linked to SNCA duplication Satoshi Orimo · Toshiki Uchihara · Ayako Nakamura · Fumiaki Mori · Takeshi Ikeuchi · Osamu Onodera · Masatoyo Nishizawa · Atsushi Ishikawa · Akiyoshi Kakita · Koichi Wakabayashi · Hitoshi Takahashi
Received: 20 July 2008 / Revised: 21 August 2008 / Accepted: 22 August 2008 / Published online: 28 August 2008 © Springer-Verlag 2008
Parkinson’s disease (PD) linked to SNCA multiplication is an autosomal dominant trait of familial PD, and is characterized by early age at onset, autonomic disturbance, and rapidly progressive dopa-responsive parkinsonism, followed by dementia [1]. Reduced cardiac uptake of meta-iodobenzylguanidine (MIBG) on MIBG myocardial scintigraphy or Xuorodopamine on positron emission tomography has been reported in patients with SNCA multiplication as well as PD [2, 4, 7, 9]. Recently, we reported a profound depletion of the cardiac sympathetic nerve in patients with Lewy bodies as in PD and dementia with Lewy bodies (DLB) but not in patients without Lewy bodies as in multiple system atrophy (MSA), pro-
S. Orimo (&) Department of Neurology, Kanto Central Hospital, 6-25-1 Kami-Yoga, Setagaya-ku, Tokyo 158-8531, Japan e-mail:
[email protected] S. Orimo · T. Uchihara · A. Nakamura Department of Neurology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan F. Mori · K. Wakabayashi Department of Neuropathology, Institute of Brain Science, Hirosaki University School of Medicine, Hirosaki, Japan T. Ikeuchi · O. Onodera · M. Nishizawa Department of Neurology, Brain Research Institute, University of Niigata, Niigata, Japan A. Ishikawa Department of Neurology, Brain Disease Center, Agano Hospital, Niigata, Japan A. Kakita · H. Takahashi Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan
gressive supranuclear palsy (PSP), PD linked to Parkin mutations, and Alzheimer disease (AD), which strongly suggests that the presence of Lewy bodies is linked to the profound depletion of the cardiac sympathetic nerve, accounting for reduced cardiac uptake of MIBG or Xuorodopamine [5, 6]. In this study, we immunohistochemically examined heart tissues from three patients with PD linked to SNCA duplication and three control subjects (aged 74.3 § 19.0 years) to determine whether the cardiac sympathetic nerve is pathologically involved. The proband (patient 1) developed parkinsonism at age 61 and died at age 70. Her uncle (patient 2), who was also her husband, developed parkinsonism at age 71 and died at age 78. Their elder son (patient 3) developed parkinsonism at age 39 and died at age 54. The clinical and neuropathological Wndings of these patients were reported by Wakabayashi [10]. Quantitative PCR analysis demonstrated that all the patients were heterozygous for SNCA duplication [3]. In each of the six subjects, blocks were taken from the anterior wall of the left ventricle and the paravertebral sympathetic ganglia as previously described [5]. A 4-m thick paraYn-embedded sections were immunostained with antibodies against tyrosine hydroxylase (TH) (TH16; Sigma, St. Louis, MO), phosphorylated neuroWlament (NF) (SMI-31; Sternberger Immunochemicals, Baltimore) or phosphorylated -synuclein (#64; WAKO, Osaka, Japan), using the avidin–biotinperoxidase complex method with a Vectastain ABC kit (Vector, Burlingame, CA). In controls, numerous TH- (Fig. 1a) and NF-immunoreactive (ir) (Fig. 1e) axons were seen both in the epicardial nerve fascicles and in the myocardium. However, there were no -synuclein aggregates in either the epicardial nerve fascicles (Fig. 1i) or myocardium. The number of the epicardial nerve fascicles examined of controls 1, 2, and 3
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Fig. 1 Immunohistochemical Wndings in Parkinson’s disease (PD) linked to SNCA duplication and control subjects. In controls, tyrosine hydroxylase (TH)- (a) and neuroWlament (NF)-immunoreactive (ir) axons (e) were abundant, and there were no -synuclein aggregates in the epicardial nerve fascicles (i) or paravertebral sympathetic ganglia (m). In patients with PD linked to SCNA duplication, TH-ir axons were absent to nearly absent (b–d), while NF-ir axons were sparse to moderate with scattered swollen axons (f–h) in the epicardial nerve
fascicles. -Synuclein aggregates were observed in the epicardial nerve fascicles and the severity of -synuclein aggregates was slight (j–l). In the paravertebral sympathetic ganglia, -synuclein aggregates were abundant (n–p). a, e, i, m: control 1; b, f, j, n: patient 1; c, g, k, o: patient 2; d, h, l, p: patient 3, a–d: TH (epicardial nerve fascicle); e–h: NF (epicardial nerve fascicle); i–l: -synuclein (epicardial nerve fascicle); m–p: -synuclein (paravertebral sympathetic ganglia), Bar indicates 100 m
was 23, 14, and 16, respectively. In all patients, TH-ir axons were absent to nearly absent (Fig. 1b–d), while NF-ir axons were sparse to moderate with scattered swollen axons (Fig. 1f–h). The relative frequency of the epicardial nerve fascicles with -synuclein aggregates of patients 1, 2, and 3 were 24/25 (96%), 12/14 (86%), and 9/10 (90%),
respectively. The severity of -synuclein aggregates of all patients was slight (Fig. 1j–l). In the sympathetic ganglia, neither neuronal loss nor -synuclein aggregates were observed in controls (Fig. 1m) and both slight neuronal loss and abundant -synuclein aggregates were demonstrated in all patients (Fig. 1n–p).
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In this study, we observed severe degeneration of the cardiac sympathetic nerve and sparse -synuclein aggregates in the epicardial nerve fascicles of all patients, which is similar to the Wnding observed in idiopathic PD [8]. In addition, swollen NF-ir axons were scattered especially in patients 2 and 3, suggesting a possible impairment of axonal Xow [8]. In patients with PD and DLB, who have Lewy bodies in the nervous system, cardiac uptake of MIBG or Xuorodopamine is markedly reduced and the cardiac sympathetic nerves are almost completely depleted [5]. In patients with MSA, PSP, and AD, who have no Lewy bodies in the nervous system, cardiac uptake of MIBG or Xuorodopamine is normal and the cardiac sympathetic nerve is well preserved with few exceptions [5]. In contrast, the absence of Lewy bodies as seen in patients with PD linked to Parkin mutations is associated with normal cardiac uptake of MIBG and preserved cardiac sympathetic nerves as well [6]. In patients with PD linked to SNCA mutations or multiplication, who have Lewy bodies in the nervous system, cardiac uptake of MIBG or Xuorodopamine is reduced [4, 9] and this pathological study demonstrated that the cardiac sympathetic nerve is severely involved. Therefore, cardiac sympathetic denervation is closely related to the presence of Lewy bodies in not only sporadic Lewy body disorders but also in familial PD with diVerent mutations or multiplication of SNCA. Taken together, we conclude that reduced cardiac uptake of MIBG or Xuorodopamine is a potential biomarker for the presence of Lewy bodies not only in sporadic but also in familial PD. Acknowledgments This work was supported in part by grants from the Research Committee on Neurodegenerative Diseases, Ministry of Health, Labor and Welfare, Japan and the Japan Foundation for Neuroscience and Mental Health.
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