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Three neurodegenerative diseases causing primary autonomic failure are pure autonomic failure (PAF), Parkinson's disease (PD), and multiple system atrophy (MSA). Differential diagnoses among these diseases are often difficult especially in early disease stage. For example, it may be difficult to determine whether a patient with parkinsonism and autonomic failure has PD or MSA. Recently, a decrease in myocardial uptake of meta-iodobenzylguanidine (MIBG), an analogue of norepinephrine, has been reported in PD but not in MSA using [123I]MIBG myocardial scintigraphy.1 This new imaging approach is thought to be of significance in the diagnosis and characterisation of akinetic rigid syndromes, especially PD. After that, we reported severe loss of cardiac sympathetic nerves in one patient with PD but not in one patient with MSA, which accounts for a difference in myocardial uptake of MIBG between PD and MSA.2 However, our observation was based on the study in only a single patient of each disease. In this study, we immunohistochemically examined the heart tissues from four patients with PD, three patients with MSA, and one patient with PAF, and showed the involvement of postganglionic cardiac sympathetic nerves in PD and PAF but not in MSA.
Pathologically verified patients with PD (n=4; 70, 78, 81, and 82 years of age, three men and one woman), MSA (n=3; 55, 59, and 59 years of age, one man and two women), PAF (n=1; 81 years of age, one man), and control subjects (n=5; 55, 57, 72, 76, and 91 years of age, four men and one woman) participated in this study, which did not include the previous patients.2 The clinical diagnosis of PAF was according to the criteria of The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. The duration of the illness was 2, 4.6, 8, and 10 years in PD, 5, 8, and 10 years in MSA, and 2 years in PAF. Three of four patients with PD, all the patients with MSA and the PAF patient had orthostatic hypotension (OH). [123I]MIBG myocardial scintigraphy was examined for one patient with PD performed four years before the death and the patient with PAF performed one month before the death. Early phase of heart-mediastinum (H/M) ratio was 1.3 in PD and 1.38 in PAF (reference range: 1.94–2.57).1 Postmortem examination revealed marked loss of neurons with numerous Lewy bodies in the substantia nigra, locus ceruleus, and dorsal vagal nucleus in the patients with PD. In the patients with MSA, marked loss of neurons in the pontine nuclei, cerebellar cortex, putamen, substantia nigra, inferior olive and intermediolateral nucleus of the spinal cord with widespread occurrence of glial cytoplasmic inclusions. No Lewy bodies were present. The patient with PAF showed prominent neuronal loss and a moderate number of Lewy bodies in the substantia nigra and locus ceruleus. Neuronal loss with gliosis was observed in the intermediolateral nucleus but there were no Lewy bodies observed in the intermediolateral nucleus, Onuf's nucleus, or Auerbach's plexus.
The anterior wall of the left ventricle from each subject was fixed with formalin for three to four weeks, and embedded in paraffin wax. The sections were stained with haematoxylin and eosin (H&E) or immunostained with a monoclonal antibody against tyrosine hydroxylase ((TH) Sigma, St Louis, MO; diluted 1:1000) by the avidin/biotin/peroxidase method with a Vectastain ABC kit (Vector, Burlingame, CA). On H&E staining, no abnormal findings were apparent in the nerve fibres both in the myocardium and epicardial space (fig 1 A, B, C, D) of each patient and control subjects. All the specimens from control subjects showed TH immunoreactive fibres both in the myocardium and epicardial space as well as those from all the patients with MSA. In contrast, TH immunoreactive fibres markedly decreased in number in the patients with PD and the patient with PAF (fig 1 G, H) compared with the MSA patients (fig 1 F) and the control subjects (fig 1 E).
Neurophysiological, neuropharmacological, and neuroendocrine evidence has revealed that postganglionic sympathetic nerves were involved in PAF and PD but not in MSA.3 Pathologically, Iwanaga and colleagues reported Lewy bodies and α-synuclein positive neurites in the hearts from the patients with PD.4 Recently, we reported a severe loss of cardiac sympathetic nerves in one patient with PD but not in one patient with MSA, which suggests the involvement of postganglionic sympathetic nerves in PD but not in MSA.2 In the present study, TH immunoreactive nerve fibres markedly decreased in number in all the patients with PD, associated with or without OH, and the patient with PAF. In contrast, TH immunoreactive nerve fibres were well preserved in all the patients with MSA. These results confirm our previous observation that postganglionic cardiac sympathetic nerves are involved in PD but not in MSA, and show the involvement of cardiac sympathetic nerves in PAF. On the basis of these results and the previous report,5 we infer that the involvement of postganglionic sympathetic nerves including the cardiac sympathetic nerves predominates in PD and PAF, but not in MSA, which accounts for a difference in myocardial uptake of MIBG among PD, PAF, and MSA.
Funding: this work is supported by a grant from The Ueda Memorial Trust Fund For Research of Heart Diseases.
Competing interests: none declared.