Acta Neuropathol (2005) 109: 583–588 DOI 10.1007/s00401-005-0995-7
R EG U L A R PA P E R
Satoshi Orimo Æ Takeshi Amino Æ Yoshinori Itoh Atsushi Takahashi Æ Tohru Kojo Æ Toshiki Uchihara Kuniaki Tsuchiya Æ Fumiaki Mori Koichi Wakabayashi Æ Hitoshi Takahashi
Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease Received: 3 December 2004 / Revised: 11 January 2005 / Accepted: 3 February 2005 / Published online: 3 June 2005 Ó Springer-Verlag 2005
Abstract Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) on [123I]MIBG myocardial scintigraphy has been reported in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). We hypothesized that cardiac sympathetic denervation might account for the pathomechanism. To elucidate the extent, frequency and pattern of cardiac sympathetic nerve involvement in Lewy body disease and related neurodegenerative disorders, we immunohistochemically examined heart tissues from patients with PD (n=11), DLB (n=7), DLB with Alzheimer’s disease (DLB/AD; n=4), multiple system atrophy (MSA; n=8), progressive supranuclear palsy (PSP; n=5), pure AD (n=10) and control subjects (n=5) together with sympathetic
S. Orimo (&) Æ T. Amino Department of Neurology, Kanto Central Hospital, 6-25-1 Kami-Yoga, Setagaya-ku, 158-8531 Tokyo, Japan E-mail:
[email protected] Tel.: +81-3-34291171 Fax: +81-3-34291293 Y. Itoh Department of Internal Medicine, Yokufukai Geriatric Hospital, Tokyo, Japan A. Takahashi Organ and Function Pathology Division, Yokufukai Geriatric Hospital, Tokyo, Japan T. Kojo Æ T. Uchihara Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan K. Tsuchiya Department of Laboratory Medicine and Pathology, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan F. Mori Æ K. Wakabayashi Department of Neuropathology, Institute of Brain Science, Hirosaki University School of Medicine, Hirosaki, Japan H. Takahashi Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan
ganglia from patients with PD (n=5) and control subjects (n=4), using an antibody against tyrosine hydroxylase (TH). TH-immunoreactive nerve fibers in the hearts had almost entirely disappeared in nearly all the patients with PD, DLB and DLB/AD, whereas they were well preserved in all the patients with PSP and pure AD as well as in all except for one patient with MSA. In PD, neurons in the sympathetic ganglia were preserved in all except for one patient. Decreased cardiac uptake of MIBG in Lewy body disease reflects actual cardiac sympathetic denervation, which precedes the neuronal loss in the sympathetic ganglia. Keywords meta-iodobenzylguanidine Æ Cardiac sympathetic denervation Æ Sympathetic ganglia Æ Parkinson’s disease Æ Dementia with Lewy bodies
Introduction Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG), a physiological analogue of noradrenaline (norepinephrine), on [123I]MIBG myocardial scintigraphy has been reported in patients with Parkinson’s disease (PD) with or without autonomic failure [3, 4, 5, 18, 24, 26, 29]. This imaging approach can be a sensitive diagnostic tool to differentiate PD from other movement disorders such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration and essential tremor [4, 5, 18, 21, 26, 29]. Cardiac MIBG uptake has also been reported to be decreased in patients with dementia with Lewy bodies (DLB), but not with Alzheimer’s disease (AD), suggesting that [123I]MIBG myocardial scintigraphy is a useful diagnostic tool to differentiate DLB from AD [28, 30]. It is now established that Lewy body (LB)type degeneration (LBs and Lewy neurites) can involve the central and peripheral autonomic nervous systems in patients with PD [27]. Recently, we reported that tyrosine hydroxylase (TH)-immunoreactive nerve fibers
584 Table 1 Clinical characteristics and TH immunopositivity. Immunopositivity is given as: absent or nearly absent, + sparse, ++ moderate,+++ numeorus (TH tyrosine hydroxylase, OH orthostatic hypotension, Number number of nerve fascile examined, PD
Parkinson’s disease, DLB dementia with Lewy bodies, AD Alzheimer’s disease,MSA multiple system atrophy, PSP progressive supranuclear palsy, C control)
Case
Diagnosis
Age (year)
Sex (year)
Duration
OH
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 C1 C2 C3 C4 C5
PD PD PD PD PD PD PD PD PD PD PD DLB DLB DLB DLB DLB DLB DLB DLB+AD DLB+AD DLB+AD DLB+AD AD AD AD AD AD AD AD AD AD AD MSA MSA MSA MSA MSA MSA MSA MSA PSP PSP PSP PSP PSP C C C C C
61 68 68 74 75 81 81 82 83 84 92 62 66 74 79 82 84 87 81 83 86 91 69 75 74 77 78 81 82 83 86 92 55 59 59 60 65 67 70 76 70 80 82 84 88 55 63 77 79 91
M F F M M M M M F F F M F M F M M F F F F F M M F F F F F F F M M F F M M F M F M F M F M F M M M F
30 9 11 3 27 2 6 3 3 11 15 12 10 1 14 3 20 11 7 7 2 8 14 5 10 10 10 6 8 21 13 7 5 8 10 2 8 6.5 5 7 4.8 10 4 6 4.2
+
were markedly decreased in patients with PD, but not in those with MSA [19, 20]. Moreover, we confirmed cardiac sympathetic denervation with preserved Schwann cells in PD by immunohistochemical analysis [2]. These findings suggest that cardiac sympathetic denervation might account for the decreased cardiac uptake of MIBG in PD [2, 19, 20]. However, we do not yet know whether or not cardiac sympathetic denervation occurs in DLB.
TH
+ + + + +
+
+ + +
+ +
+ + + + + +
+++ +++ +++++ +++++ +++ +++ +++ +++ +++++ +++ +++++ ++ +++ +++++ +++++ +++ +++ +++++ +++ +++ +++++ +++ +++++ +++++ +++++ +++ +++
Number 21 25 31 26 18 12 36 23 9 29 1 22 14 19 8 6 9 18 18 8 8 18 11 15 7 38 16 15 10 17 14 10 17 25 21 29 5 6 37 33 17 60 9 12 14 8 21 19 25 10
In the present study, an immunohistochemical investigation was conducted to elucidate the extent, frequency and pattern of cardiac sympathetic nerve involvement in LB disease and related neurodegenerative disorders. Here we report that cardiac sympathetic denervation is a consistent histopathological feature of LB disease and that the degeneration of the cardiac sympathetic nerves precedes the neuronal loss in the sympathetic ganglia.
585
Materials and methods Subjects Tissue samples were obtained from Organ and Function Pathology Division, Yokufukai Geriatric Hospital, Tokyo and the Department of Pathology, Brain Research Institute, University of Niigata. Eleven patients with PD (aged 61–92 years; mean 77.2 years), 8 with MSA (aged 55–76 years; mean 63.9 years), 5 with PSP (aged 70– 88 years; mean 80.8 years), 7 with DLB (aged 62– 87 years; mean 76.3 years), 4 with DLB associated with AD (DLB/AD; aged 81–91 years; mean 85.3 years), 10 with pure AD (aged 69–92 years; mean 79.4 years), and 5 control subjects with neither neurodegenerative diseases nor diabetes mellitus (aged 55–91 years; mean 73.0 years) were selected on the basis of their clinical and pathological findings (Table 1). The interval between death and autopsy was from 2 to 12 h in all the patients and control subjects. No patients with ischemic heart disease were included in the present study. The duration of the illness was 2–30 years (mean 10.9 years) in PD, 2– 10 years (mean 6.4 years) in MSA, 4–10 years (mean 5.8 years) in PSP, 1–20 years (mean 10.1 years) in DLB, 2–8 years (mean 6.0 years) in DLB/AD, and 5–21 years (mean 10.4 years) in pure AD. The pathological diagnosis of PD and MSA was confirmed by a-synuclein immunohistochemistry and was based on the National Institute of Neurological Disorders and Stroke neuropathological criteria for PSP and related disorders [8], Kosaka’s proposed neuropathological criteria for LB disease [14], and the Consortium to Establish a Registry for AD [16]. Orthostatic hypotension (OH) was defined as reduction of systolic blood pressure of at least
Fig. 1 TH immunostaining of the epicardium in controls (A), and patients with PD (B), DLB (C), multiple system atrophy (D), progressive supranuclear palsy (E), and Alzheimer’s disease (F). THimmunoreactive nerve fibers are completely depleted in PD and DLB (B, C) compared with controls (A). THimmunoreactive fibers are preserved in other neurological disorders (D–F) (TH tyrosine hydroxylase, PD Parkinson’s disease, DLB dementia with Lewy bodies). Bar 100 lm
20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 min of standing after being in the supine position for 10 min [25]. Three of the patients with PD, 2 with DLB, 1 with DLB/AD, 2 with AD, and 6 with MSA had OH (Table 1). Immunohistochemistry and semi-quantification In each of the 50 cases, blocks were taken from the anterior wall of the left ventricle. This region was selected based on the previous studies [2, 19, 20], because TH-immunoreactive nerve fibers were more numerous in the anterior than the posterior wall of the left ventricle [11] and cardiac uptake of MIBG is mainly observed in the left ventricle. We also examined the paravertebral sympathetic ganglia (stellate ganglia or upper thoracic) from 5 patients with PD (cases 1, 2, 4, 5 and 10) and 4 control subjects (control 1, 2, 3 and 4). Tissues were fixed with formalin for 3–4 weeks, embedded in paraffin, sectioned at a thickness of 4 lm, and stained with hematoxylin and eosin (H-E). Other sections were immunostained with monoclonal antibodies against TH (mouse monoclonal, Sigma, St. Louis, MO; diluted 1:3,000), neurofilament (SMI-31, mouse monoclonal, SMI, Baltimore, MD; diluted 1:10,000) or phosphorylated a-synuclein [22] (a gift from Dr. Iwatsubo, diluted 1:5,000) using the avidin-biotin-peroxidase complex (ABC) method with a Vectastain ABC kit (Vector, Burlingame, CA). The peroxidase labeling was visualized with diaminobenzidine-nickel as a chromogen. As a positive control, tissue sections from adrenal glands were immunostained in parallel with the specimens of heart and sympathetic ganglia. For negative controls, the primary antibody was replaced with normal serum.
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The number of TH-immunoreactive nerve fibers in the heart was assessed according to a semi-quantitative rating scale: , absent or nearly absent; +, sparse; ++, moderate; +++, numerous.
fibers was further confirmed by neurofilament immunohistochemistry (data not shown). Sympathetic ganglia
Results Heart tissue On H-E staining, there were no abnormal findings in the nerve fibers in either the myocardium or epicardium of control subjects or patients. In controls, numerous TH-immunoreactive nerve fibers were seen in the epicardium (Fig. 1A) and in the subepicardial area of the myocardium. They were often found around the coronary arteries. TH-immunoreactive thick nerves in the epicardium ran into the myocardium along the vessels, and were ramified with thin branches reaching the cardiac muscles (perimysial nerve fibers). Because the number of TH-immunoreactive nerves in the epicardium was much greater than that in the myocardium, loss of TH-immunoreactive nerves was assessed semi-quantitatively in the epicardium (Table 1). No or few TH-immunoreactive nerves were observed in patients with PD (Fig. 1B), DLB (Fig. 1C) and DLB/AD. In contrast, TH-immunoreactive nerves were well preserved in patients with PSP (Fig. 1E) and pure AD (Fig. 1F). TH-immunoreactive nerves were also preserved in all except for one patient with MSA (Fig. 1D). In the myocardium, TH-immunoreactive nerve fibers were markedly decreased in PD, DLB and DLB/AD and were preserved in MSA, PSP and pure AD. Loss of TH-immunoreactive nerve
Fig. 2 Sympathetic ganglia at different degenerative stages in patients with PD. In stage I (A– C), a few Lewy bodies are observed in the ganglia but the number of neurons and TH immunoreactivity are well preserved. In stage II (D–F), many Lewy bodies are observed in the ganglia. Despite obvious neuronal loss, neuronal somata without detectable TH immunoreactivity are found. In stage III (G–I), apparent neuronal loss and a relatively small number of Lewy bodies in the ganglia are seen. A, D, G, Hematoxylin and eosin staining; B, E, H, TH immunostaining; C, F, I, phosphorylated a-synuclein immunostaining. Bar 200 lm
In controls, no LBs or neuronal loss was observed in the sympathetic ganglia. In PD, the degenerative process of the sympathetic ganglia was classified into the following three categories based on the histological and immunohistochemical findings. In stage I (Fig. 2A–C), a few LBs were observed in the ganglia, but the number of neurons and TH immunoreactivity were well preserved. In stage II (Fig. 2D–F), many LBs were found in the ganglia, but the number of neurons appeared to be normal on H-Estained sections. Interestingly, a significant number of neuronal somata (about 20–30% of neurons) were TH immunonegative. In stage III (Fig. 2G–I), there was apparent neuronal loss in the ganglia on H-E-stained or TH-immunostained sections. The number of LBs was decreased compared with stage II. In the present study, 2 patients with PD (cases 4 and 10) showed stage I, 2 with PD (cases 1 and 2) showed stage II, and 1 with PD (case 5) showed stage III. The patient presenting with stage III was a case of long duration (27 years).
Discussion There has been considerable evidence of postganglionic sympathetic nerve involvement in PD. Goldstein et al. [7] reported that cardiac sympathetic innervation was selectively affected in PD, but not in MSA, using 6[18F]fluorodopamine positron emission tomography and
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cardiac noradrenaline spillover. Decreased cardiac uptake of MIBG has been reported in PD, but not in MSA, using [123I]MIBG myocardial scintigraphy [4, 5, 20, 26, 29]. Histopathologically, in the peripheral autonomic nervous system in PD, LBs are widely distributed in the sympathetic ganglia, enteric nervous system of the alimentary tract, cardiac plexus, pelvic plexus and adrenal medulla [27]. Iwanaga et al. [10] have reported that Lewy neurites were found in the hearts from 9 of 11 patients with PD and from 7 of 7 patients with incidental LB disease. In the present study, cardiac sympathetic nerves were markedly decreased in all 11 patients with PD, irrespective of age, sex, duration of the illness or the presence of OH. These findings are similar to those in the previous reports [2, 20]. However, there were no abnormal findings in the nerve fibers in either the myocardium or epicardium on H-E stained sections, which was presumably due to well-preserved Schawann cells [2]. Recently, Watanabe et al. [28] reported that cardiac MIBG uptake was decreased in 11 patients with DLB, of whom 7 patients had OH. Horimoto et al. [9] have shown that autonomic dysfunctions were found in 28 of 29 cases of pathologically confirmed DLB. Thus, autonomic failure may be present much more often in DLB than previously thought. However, there have been no reports with respect to the morphological changes present in the visceral autonomic nervous system in DLB. In the present study, we demonstrated that cardiac sympathetic nerves were dramatically depleted in all 11 patients with DLB with or without AD, and this result was also independent of age, sex, duration of the illness or the presence of OH. These findings indicate that cardiac sympathetic denervation is a consistent histopathological feature of LB disease. In contrast, none of the patients with PSP and pure AD showed depletion of cardiac sympathetic nerves. Although sympathetic vasomotor dysfunction and blood pressure instability have been reported in some patients with AD [1, 6], cardiac uptake of MIBG is normal in AD [28, 30]. Two of 10 patients with AD had OH in the present series, but cardiac sympathetic nerves were not involved in such cases. In PSP, autonomic dysfunctions are unusual [12] and cardiac uptake of MIBG has been reported to be normal or slightly decreased [26, 29]. Although OH was observed in 6 of 8 patients with MSA, cardiac sympathetic nerves were preserved in all except for 1 patient. This may support the results of previous pharmacological and histopathological studies that autonomic failure in MSA is due to the degeneration of preganglionic neurons in the central autonomic nervous system, such as the dorsal vagal nucleus, intermediolateral nucleus and Onuf’s nucleus [13, 15, 22]. The MSA patient with depletion of cardiac sympathetic nerves had one LB in the Edinger-Westphal nucleus, but not in dorsal vagal nucleus, locus ceruleus or substantia nigra on H-E-stained sections. These findings suggest that this case was associated with incidental LB disease, which might be related to the
involvement of cardiac sympathetic nerves. Recent immunohistochemical study has revealed that accumulation of a-synuclein in the peripheral sympathetic ganglia, if any, is only minimal in patients with MSA [17]. Although sympathetic ganglia are well known as one of the predilection sites for LBs in PD, obvious neuronal loss is uncommon in the ganglia by conventional histopathological examination. In the present study, neurons in the sympathetic ganglia were preserved in all the patients with PD except for 1 patient. However, it was noteworthy that TH immunoreactivity of the neuronal somata was significantly diminished in 2 of the 4 patients, despite a well-preserved neuronal population. Considering that TH-immunoreactive nerves almost entirely disappeared in the hearts from patients with LB disease, it is likely that cardiac sympathetic denervation precedes the neuronal loss in the sympathetic ganglia. In conclusion, postganglionic cardiac sympathetic denervation is specific to LB disease (PD and DLB), accounting for the consistent decrease in cardiac uptake of MIBG. Acknowledgements We thank Dr. Iwatsubo for providing the phosphorylated a-synuclein antibody, and Ms. Yamada and Ms. Nakamura for their technical assistance. This work was supported in part by a grant from the Japan Foundation for Neuroscience and Mental Health (Tama Nakagawa Foundation).
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