Cardiac sympathetic denervation in Parkinson’s disease linked to SNCA duplication

Abstract

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), progressive 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 4m 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 S. Orimo (&) Department of Neurology, Kanto Central Hospital, 6-25-1 Kami-Yoga, Setagaya-ku, Tokyo 158-8531, Japan e-mail: orimo@kanto-ctr-hsp.com