Differential diagnosis between PD and multiple-system atrophy (MSA) is often difficult, especially in early disease stages. Recent studies have shown that [123I]metaiodobenzylguanidine (MIBG) myocardial scintigraphy is useful to separate PD from MSA; MIBG uptake in PD is significantly lower than in MSA.1-3⇓⇓ However, a pathophysiologic mechanism for the decrease in myocardial MIBG uptake in PD and MSA remains to be elucidated. We describe a patient with PD and a patient with MSA. Postmortem examination revealed a severe loss of myocardial sympathetic nerve fibers in the former but not in the latter.
Case reports.
Patient 1.
An 80-year-old woman developed bradykinesia and gait disturbance, followed by right dominant resting hand tremor and rigidity, postural instability, severe constipation, and orthostatic hypotension. Dopaminergic therapy such as levodopa/carbidopa was given and effective for bradykinesia, rigidity, and tremor. She was diagnosed as having PD at the age of 82 years. Her condition deteriorated; she occasionally experienced syncope. She died of bronchopneumonia at 84 years old. MIBG myocardial scintigraphy, at the age of 83 years, showed a severe decrease of MIBG uptake and impairment of the early-phase heart/mediastinum (H/M) ratio (1.37; normal 1.94 to 2.57). Postmortem examination 2 hours after death revealed marked loss of neurons with many Lewy bodies in the substantia nigra, locus ceruleus, and dorsal vagal nucleus. Lewy bodies were also found in the stellate sympathetic ganglia.
Patient 2.
A 58-year-old man noticed gait disturbance, followed by syncope and urinary incontinence. At the age of 59 years, he developed cerebellar signs, parkinsonism, pyramidal tract signs, and severe autonomic disturbances such as orthostatic hypotension and urinary incontinence; he was diagnosed as having MSA. Thereafter, his condition deteriorated rapidly, and he died suddenly at 60 years old. MIBG myocardial scintigraphy, at age 60, showed a slight decrease of MIBG uptake and mild impairment of the early-phase H/M ratio (1.82). Postmortem examination 2 hours after death revealed pathologic changes typical of MSA: a severe neuronal loss in the pontine nuclei, cerebellar cortex (Purkinje cell), putamen, substantia nigra, inferior olive, and intermediolateral nucleus of the spinal cord. No obvious neuronal loss was noted in the peripheral sympathetic ganglia. Glial cytoplasmic inclusions were distributed throughout the brain, being more numerous in the brainstem and cerebellar white matter.
Results.
The anterior walls of the left ventricles of the hearts from the Patients 1 and 2 and a 57-year-old control patient (3 hours after death) were fixed with formalin for 3 to 4 weeks and embedded in paraffin. Paraffin-embedded sections were stained with hematoxylin and eosin (H-E) and immunostained with a monoclonal antibody against tyrosine hydroxylase (TH; Sigma, St. Louis, MO; diluted 1:5,000) or a polyclonal antibody against α-synuclein (NACP-5; diluted 1:1,000)4 by the avidin/biotin/peroxidase method with a Vectastain ABC kit (Vector, Burlingame, CA). Microwave retrieval was performed six times, 3 minutes each, for TH immunocytochemistry. On H-E staining, no abnormal findings were apparent in either the myocardium and the nerve fibers in the pericardial space (figure, A through C) of each patient. The mean diameter of the nerve fibers in the pericardial space from Patients 1 and 2 and the control subject was 79.1 ± 32.2 μm (n = 44; 141.3 mm2), 114.9 ± 66.8 μm (n = 29; 57.3 mm2), and 89.6 ± 45.8 μm (n = 28; 24.3 mm2), respectively. All the nerve fibers from Patient 1 showed markedly decreased immunostaining with TH (figure, F) compared with those from Patient 2 (figure, E) and the control subject (figure, D). No α-synuclein-immunoreactive abnormal structures were noted in the myocardium of any subject.
Figure. Figure shows hematoxylin and eosin (H-E) and tyrosine hydroxylase (TH) staining of the nerve fibers in the pericardial space from a control subject (A and D), a patient with multiple-system atrophy (MSA; B and E), and a patient with PD (C and F). On H-E staining, no abnormal findings are apparent in any subject (A to C). However, TH-immunoreactive nerve fibers in the patient with PD are markedly decreased (F) compared with those in the patient with MSA (E) and the control subject (D). Bar = 100 μm.
Discussion.
In the current study, TH-immunoreactive nerve fibers in the heart were markedly decreased in the patient with PD who had autonomic disturbances. Goldstein et al.5 reported damage of myocardial sympathetic function in patients with PD using 6-[18F]fluorodopamine PET and cardiac norepinephrine spillover. Recently, Iwanaga et al.6 reported Lewy body-type degeneration in the postganglionic sympathetic nerves in the heart from patients with PD. These findings suggest that the involvement of postganglionic sympathetic nerves accounts for a decrease in myocardial MIBG uptake in PD and, together with the previous report,7 suggest widespread involvement of the peripheral autonomic system in PD. On the contrary, TH-immunoreactive nerve fibers were preserved in the patient with MSA, suggesting that postganglionic sympathetic nerves were not involved in this patient. Based on the above findings, we propose that postganglionic involvement predominates in PD, especially with autonomic disturbances, but that central and preganglionic lesions account for a decrease in MIBG uptake in MSA.
Acknowledgments
Supported by a grant from the Ueda Memorial Trust Fund for Research of Heart Diseases.
- Received November 7, 2000.
- Accepted May 12, 2001.
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