Abstract
Decreased cardiac uptake of meta‐iodobenzylguanidine (MIBG) on [123I] MIBG myocardial scintigraphy has been reported in the early stages of Parkinson’s disease (PD), which suggests involvement of the cardiac sympathetic nerve in the early disease process of PD. For confirmation, we immunohistochemically examined cardiac tissue, sympathetic ganglia and medulla oblongata of 20 patients with incidental Lewy body disease (ILBD), which is thought to be a presymptomatic stage of PD, and 10 control subjects, using antibodies against tyrosine hydroxylase (TH) and neurofilament (NF). Immunoreactive nerve fibers of fascicles in the epicardium were well preserved in 10 of the 20 patients with ILBD and in the control subjects. In contrast, TH‐immunoreactive nerve fibers had nearly disappeared in six subjects and were moderately decreased in four of the 20 patients with ILBD. Neuronal cell loss in the dorsal vagal nucleus and the sympathetic ganglia was not detectable in any of the ILBD patients examined. These findings suggest that degeneration of the cardiac sympathetic nerve begins in the early disease process of PD and that it occurs before neuronal cell loss in the dorsal vagal nucleus.
INTRODUCTION
Decreased cardiac uptake of meta‐iodobenzylguanidine (MIBG), a physiological analog of norepinephrine, on [123I] MIBG myocardial scintigraphy, or of fluorodopamine on 6‐[18F] fluorodopamine positron emission tomography has been reported in patients with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) (4, 5, 6, 9, 13, 14, 27, 30, 32, 33, 34, 35). These imaging approaches are sensitive diagnostic tools that potentially differentiate PD and DLB from other related disorders such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Alzheimer’s disease (AD) and parkin‐associated PD (5, 9, 13, 14, 24, 26, 27, 31, 32, 33, 34, 35). Recently, we reported that tyrosine hydroxylase (TH)‐immunoreactive nerve fibers in fascicles of the epicardium from the anterior wall of the left ventricle were markedly decreased in PD, DLB and pure autonomic failure (PAF) with Lewy bodies (LBs), but not in MSA, PSP, CBD, AD and parkin‐associated PD (24, 25, 26). Moreover, we demonstrated that not only TH‐ but also neurofilament (NF)‐immunoreactive nerve fibers were markedly decreased in the advanced stage (Hoehn‐Yahr stage 4 or 5) PD (1). These findings suggest that cardiac sympathetic denervation is specific to Lewy body disease and accounts for the decreased cardiac uptake of MIBG in this disease (23, 25).
Cardiac uptake of MIBG is frequently decreased even in the early stages of PD (Hoehn‐Yahr stage 1 or 2), which suggests early involvement of the cardiac sympathetic nerve, even though routine autonomic function tests fail to detect abnormal autonomic functions (6, 27). Braak and colleagues have reported detailed pathological stages for the progression of PD and noted that early pathological change begins in the lower part of the brainstem, namely, in the dorsal vagal nucleus, before nigral involvement occurs (3, 8); however, when and how degeneration of the cardiac sympathetic nerve begins in PD remains to be elucidated.
In this study, we immunohistochemically examined cardiac tissue, sympathetic ganglia and medulla oblongata at the level of the dorsal vagal nucleus from patients with incidental Lewy body disease (ILBD), which is thought to be a presymptomatic stage of PD. We used anti‐TH as a marker for the sympathetic nerves and anti‐NF as a marker for axons.
MATERIALS AND METHODS
Subjects.
Tissue samples were obtained from the Department of Pathology, Brain Research Institute, University of Niigata. Patients with ILBD were defined as having no history of parkinsonian symptoms but had LBs in the substantia nigra and/or the locus coeruleus by routine histopathology or by α‐synuclein immunohistochemistry. ILBD is identical to incidental Parkinson Disease described by Del Tredici et al (8). The post‐mortem interval was within 12 h in all the patients and control subjects. The summary of clinical characteristics is shown in Table 1. Twenty patients with ILBD (13 men and seven women, aged 58–87 years, mean: 72.6 ± 7.7 years) without heart diseases were enrolled in this study. Two patients had diabetes mellitus (DM); one (patient 6) was well controlled with no complications and the other (patient 17) had diabetic neuropathy. ILBD was divided into two groups as follows: ILBD(A) was defined as ILBD without neurodegenerative disorders but with brain infarction (n = 7), brain tumor (n = 2), or ruptured aneurysm (n = 1) (six men and four women, aged 58–81 years, mean: 71.2 ± 8.3 years). ILBD(B) was defined as ILBD with neurodegenerative disorders such as AD (n = 4), amyotrophic lateral sclerosis (n = 4), Huntington’s disease (n = 1) or dentatorubropallidoluysian atrophy (n = 1) (seven men and three women, aged 62–87 years, mean: 74.0 ± 7.2 years). Each patient with ILBD was staged for the degree of LB pathology according to the staging of Braak et al (3), Braak staging 2 or 3 (Table 2). Control subjects without neurodegenerative disorders, heart diseases or DM (six men and four women, aged 55–83 years, mean: 67.0 ± 10.4 years) were also examined.
Table 1.
Clinical characteristics.
| Patient | Diagnosis | Underlying disease | Age/Sex (year) | Duration (month) | Cause of Death | Time Interval (month) |
|---|---|---|---|---|---|---|
| 1 | ILBD(A) | brain tumor | 58 f | 16 | pneumonia | 3 |
| 2 | ILBD(A) | brain tumor | 70 m | 2 | brain tumor | 2 |
| 3 | ILBD(B) | Alzheimer’s disease | 87 f | 200 | pneumonia | 36 (bedridden) |
| 4 | ILBD(B) | ALS | 62 f | 48 | asphyxia | 3 |
| 5 | ILBD(B) | Huntington’s disease | 66 m | 132 | pneumonia | 11 |
| 6 | ILBD(A) | brain infarction | 79 m | 3 | arrhythmia | 3 |
| 7 | ILBD(B) | ALS | 80 m | 60 | pneumonia | 32 (bedridden) |
| 8 | ILBD(B) | ALS | 72 m | 23 | asphyxia | 6 |
| 9 | ILBD(A) | brain infarction | 76 m | 1 | pneumonia | 1 |
| 10 | ILBD(A) | brain infarction | 71 m | 1 | pulmonary embolism | 1 d. |
| 11 | ILBD(B) | Alzheimer’s disease | 74 m | 60 | pneumonia | 11 |
| 12 | ILBD(A) | brain infarction | 61 m | 14 d. | brain infarction | 5 d. |
| 13 | ILBD(B) | Alzheimer’s disease | 77 m | 216 | renal failure | 48 (bedridden) |
| 14 | ILBD(A) | brain infarction | 75 m | 18 | pneumonia | 4 |
| 15 | ILBD(B) | ALS | 75 m | 204 | pneumonia | 36 (bedridden) |
| 16 | ILBD(B) | DRPLA | 76 f | 180 | pneumonia | 11 |
| 17 | ILBD(A) | brain infarction | 81 f | 9 d. | pneumonia | 8 d. |
| 18 | ILBD(B) | ALS | 69 m | 36 | respiratory failure | 22 d. |
| 19 | ILBD(A) | ruptured aneurysm | 62 f | 1 | pneumonia | 1 |
| 20 | ILBD(A) | brain infarction | 79 f | 51 | pneumonia | 12 (bedridden) |
| C | brain abscess | 55 f | ||||
| C | lymphoma | 55 m | ||||
| C | porphyria | 62 m | ||||
| C | encephalitis | 75 f | ||||
| C | multiple sclerosis | 77 m | ||||
| C | myasthenia gravis | 83 f | ||||
| C | anoxic encephalopathy | 60 m | ||||
| C | bacterial meningitis | 61 f | ||||
| C | brain tumor | 63 m | ||||
| C | brain infarction | 79 m |
ILBD(A) = incidental Lewy body disease without neurodegenerative disorders; ILBD(B) = ILBD with neurodegenerative disorders; C = control.
ALS = amyotrophic lateral sclerosis; DRPLA = dentatorubropallidoluisian atrophy; d. = day or days; Time Interval = time interval between last detailed examination and death; bedridden = time interval between the time patients became bedridden and death.
Table 2.
Immnohistochemical findings and Braak staging.
| Patient | Diagnosis | Heart | Sympathetic ganglia | Dorsal vagal nucleus | Braak staging | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| TH | NF | F | NCL | Lewy | TH(−) | NCL | G | Lewy | |||
| 1 | ILBD(A) | +++ | +++ | 22 | − | + | − | − | − | + | 2 |
| 2 | ILBD(A) | +++ | +++ | 31 | − | ++ | − | − | − | − | 3 |
| 3 | ILBD(B) | +++ | +++ | 9 | − | + | − | − | − | + | 3 |
| 4 | ILBD(B) | +++/++ | +++ | 34 | − | − | − | − | − | − | 2 |
| 5 | ILBD(B) | +++/++ | +++ | 14 | − | + | − | − | − | + | 2 |
| 6 | ILBD(A) | ++/+++ | +++ | 20 | − | − | − | − | − | + | 2 |
| 7 | ILBD(B) | ++/+++ | ++/+++ | 15 | − | − | − | − | − | + | 3 |
| 8 | ILBD(B) | ++/+++ | +++ | 22 | − | ++ | − | − | − | + | 3 |
| 9 | ILBD(A) | ++/+++ | ++/+++ | 39 | − | + | − | − | + | ++ | 2 |
| 10 | ILBD(A) | ++/+++ | ++/+++ | 12 | − | + | − | − | − | + | 3 |
| 11 | ILBD(B) | ++ | ++/+++ | 12 | − | − | − | − | − | + | 3 |
| 12 | ILBD(A) | ++ | ++ | 8 | − | + | − | − | + | ++ | 2 |
| 13 | ILBD(B) | ++ | ++ | 4 | − | − | − | − | − | + | 3 |
| 14 | ILBD(A) | +/++ | ++ | 43 | − | ++ | − | − | + | ++ | 2 |
| 15 | ILBD(B) | −/++ | +/++ | 22 | − | + | − | − | − | + | 2 |
| 16 | ILBD(B) | −/+ | ++ | 14 | − | − | − | − | + | ++ | 2 |
| 17 | ILBD(A) | − | +/++ | 4 | − | + | − | n.e. | n.e. | n.e. | 2 |
| 18 | ILBD(B) | − | ++ | 24 | − | ++ | + | − | − | + | 2 |
| 19 | ILBD(A) | − | ++ | 7 | − | + | − | − | + | +++ | 3 |
| 20 | ILBD(A) | − | − | 5 | − | +++ | ++ | − | + | ++ | 3 |
| C | +++ | +++ | 13 | − | − | − | − | − | − | ||
| C | +++ | +++ | 23 | − | − | − | − | − | − | ||
| C | +++ | +++ | 3 | − | − | − | − | − | − | ||
| C | +++ | +++ | 14 | − | − | − | − | − | − | ||
| C | +++ | +++ | 13 | − | − | − | − | − | − | ||
| C | +++ | +++ | 7 | − | − | − | − | − | − | ||
| C | ++/+++ | +++ | 10 | − | − | − | − | − | − | ||
| C | ++/+++ | +++ | 11 | − | − | − | − | − | − | ||
| C | ++/+++ | ++/+++ | 13 | − | − | − | − | − | − | ||
| C | ++/+++ | +++ | 42 | − | − | − | − | − | − | ||
ILBD(A) = incidental Lewy body disease without neurodegenerative disorders; ILBD(B) = ILBD with neurodegenerative disorders; C = control.
TH = tyrosine hydroxylase; NF = neurofilament; F = the number of nerve fascicle examined; NCL = neuronal cell loss; TH(−) = the number of TH‐immunonegative neuron; G = gliosis; n.e. = not examined.
Immunohistochemistry.
In each of the 30 cases, blocks were taken from paravertebral sympathetic ganglia (stellate or upper thoracic ganglia), medulla oblongata at the level of the dorsal vagal nucleus, and from the anterior wall of the left ventricle as described previously (23). Tissues were fixed with formalin for 3–4 weeks, embedded in paraffin, sectioned at a thickness of 4 µm and stained with hematoxylin and eosin (H&E). Other sections were immunostained with monoclonal antibodies against TH (TH16; Sigma, St. Louis, MO, USA; 1:3000), phosphorylated NF (SMI‐31; Sternberger Immunochemicals, Baltimore, MD, USA; 1:10000) or phosphorylated α‐synuclein (♯64; WAKO, Osaka, Japan; 1:5000), as described previously (12), using the avidin–biotin–peroxidase complex (ABC) method with a Vectastain ABC kit (Vector, Burlingame, CA, USA). Peroxidase labeling was visualized with diaminobenzidine with or without nickel as a chromogen.
Double immunofluorolabeling.
Sections from the anterior wall of the left ventricles were incubated with a mixture of anti‐NF mouse monoclonal antibody (1:2000) and anti‐TH rabbit polyclonal antibody (CA‐101bTHrab, Protos Biotech Corp., NY, USA; 1:1000) at 4°C for 2 days. These antibodies were visualized with a mixture of anti‐mouse IgG made from sheep conjugated with Alexa568 (Molecular Probe, Eugene, OR, USA; 1:200) and anti‐rabbit IgG made from goat conjugated with Alexa488 (Molecular Probe; 1:200).
Semiquantification.
The number of TH‐ and NF‐immunoreactive nerve fibers of fascicles in the epicardium and TH‐immunonegative neurons in the sympathetic ganglia were assessed according to a semiquantitative rating scale (Figure 1): −, absent or nearly absent; +, sparse; ++, moderate; +++, numerous. The severity of LB pathology including LBs and Lewy neurites (LNs) in the sympathetic ganglia and the dorsal vagal nucleus was assessed semiquantitatively as follows: −, absent or not discernible; +, slight; ++, moderate; +++, severe (3). In these two regions, neuronal cell loss was recorded as “not noticed (–)” or “evident (+).”
Figure 1.
Semiquantitative rating scale of tyrosine hydroxylase‐ and neurofilament‐immunoreactive nerve fibers of fascicles in the epicardium. −, absent or nearly absent (A); +, sparse (B); ++, moderate (C); +++, numerous (D). Bar = 50 µm.
RESULTS
The summary of the semiquantitative rating scale of the TH‐immunoreactive nerve fibers of fascicles in the epicardium in patients with ILBD and control subjects is shown in Table 2. Typical immunohistochemical findings of the cardiac tissue, sympathetic ganglia and medulla oblongata at the level of the dorsal vagal nucleus in ILBD and control subjects are shown in Figure 2.
Figure 2.
Immunohistochemical findings of the heart tissues, sympathetic ganglia and medulla oblongata at the level of the dorsal vagal nucleus in incidental Lewy body disease (ILBD) and control subjects. In the control, tyrosine hydroxylase (TH)‐ or neurofilament (NF)‐immunoreactive nerve fibers of a fascicle in the epicardium are well preserved (A,B). No neuronal cell loss (C), abundant TH‐immunoreactive neurons (D) and no α‐synuclein‐immunoreactive Lewy neurites and Lewy bodies (E) are observed in the sympathetic ganglia. Neuronal cell loss and α‐synuclein‐immunoreactive Lewy neurites and Lewy bodies are not observed in the dorsal vagal nucleus (F). In ILBD, there are different degenerating stages of nerve fibers in the fascicles (G,H,M,N,S,T). No neuronal cell loss is noticed in the sympathetic ganglia (I,O,U). TH immunoreactivity of neurons is well preserved in 18 patients (J), and the number of TH‐immunonegative neurons is slightly increased in one patient (P) and moderately increased in one patient with ILBD (V). The severity of Lewy pathology is slight (K), moderate (Q) and severe (W) in the sympathetic ganglia, and slight (L,R) and moderate (X) in the dorsal vagal nucleus. A, B, C, D, E, F: control; G, H, I, J, K, L: case 3; M, N, O, P, Q, R: case 18; S, T, U, V, W, X: case 20; A, G, M, S: cardiac tissue/TH; B, H, N, T: cardiac tissue/NF; C, I, O, U: sympathetic ganglia (SG)/hematoxylin and eosin; D, J, P, V: SG/TH; E, K, Q, W: SG/phosphorylated α‐synuclein; F, L, R, X: dorsal vagal nucleus/phosphorylated α‐synuclein. Bar = 50 µm.
Cardiac tissue (2, 3, Table 2).
Figure 3.
The nerve fascicle in the epicardium immunofluorolabeled with anti‐tyrosine hydroxylase (TH) (green) (A,D,G,J,M) and anti‐neurofilament (NF) (red) antibodies (B,E,H,K,N). C, F, I, L and O are merged images. Control (A,B,C), ILBD (case 4: D,E,F), ILBD (case 15: G,H,I), ILBD (case 19: J,K,L), ILBD (case 20: M,N,O). Numerous TH (green) (D) and NF (red) (E) double‐positive cardiac sympathetic nerves (yellow) (F) are observed in half of the patients with ILBD, similar to the findings in the control subjects shown in A, B and C. In the next stage, both TH‐ and NF‐immunoreactive nerve fibers are moderately decreased (G,H,I). TH‐immunoreactive nerve fibers are markedly decreased with relatively preserved NF‐immunoreactive nerve fibers (J,K,L). Finally, not only TH‐ but also NF‐immunoreactive nerve fibers almost entirely disappeared in one patient with ILBD (M,N,O). Bar = 50 µm.
On H&E staining, there were no abnormal findings in the nerves in either the myocardium or epicardium of control subjects or patients. In controls, numerous TH‐ and NF‐immunoreactive nerve fibers were seen in the fascicle of the epicardium (Figure 2A and B) and in the subepicardial area of the myocardium. As the number of TH‐immunoreactive nerve fibers in fascicles of the epicardium was much greater than in the myocardium, the loss of TH‐immunoreactive nerve fibers was assessed semiquantitatively in the fascicle of the epicardium as described previously (23). In ILBD, TH‐ and NF‐immunoreactive nerve fibers varied in number from case to case. In 10 patients with ILBD, made up of five ILBD(A) and five ILBD(B), both TH‐ and NF‐immunoreactive nerve fibers were well preserved (Figure 2G and H), as they were in the control subjects (Figure 2A and B). In contrast, TH‐immunoreactive nerve fibers were moderately decreased in four subjects and were markedly decreased in six subjects with ILBD. In five of these patients, NF‐immunoreactive nerve fibers were preserved to some extent (Figure 2M and N). In one patient with ILBD, both TH‐ and NF‐immunoreactive nerve fibers had almost entirely disappeared (Figure 2S and T).
On double immunofluorolabeling, the process of degeneration of the cardiac sympathetic nerve is shown in Figure 3. Numerous TH (green) (Figure 3D) and NF (red) (Figure 3E) double‐positive cardiac sympathetic nerves (yellow) (Figure 3F) were observed in half of the patients with ILBD, similar to the findings in control subjects, as shown in Figure 3A, B and C. In the next stage, both TH‐ and NF‐immunoreactive nerve fibers were moderately decreased (Figure 3G, H and I). In other cases, TH‐immunoreactive nerve fibers were markedly decreased, with relative preservation of NF‐immunoreactive nerve fibers (Figure 3J, K and L). Finally, not only TH‐ but also NF‐immunoreactive nerve fibers almost entirely disappeared, as seen in one patient with ILBD (Figure 3M, N and O).
The thickness of the left ventricle wall ranged from 1.1 to 2.2 cm (1.62 ± 0.32) in the ILBD patients and from 1.0 to 2.0 cm (1.51 ± 0.35) in the control subjects, and there was no significant difference between these groups. The thickness of the left ventricular wall ranged from 1.1 to 2.0 cm (n = 10, 1.55 ± 0.12) in ILBD with normal cardiac sympathetic nerve and from 1.2 to 2.2 cm (n = 10, 1.70 ± 0.11) in ILBD patients with degeneration of the cardiac sympathetic nerve. There was also no significant difference between these two groups.
Sympathetic ganglia (Figure 2, Table 2).
In controls, neuronal cell loss, LBs or LNs were not observed in the sympathetic ganglia (Figure 2C and E). TH immunoreactivity of the neurons was well preserved (Figure 2D). In ILBD, no neuronal cell loss was noticed (Figure 2I, O and U). In six of 20 patients with ILBD, LBs and LNs were not seen. In 18 patients with ILBD, TH immunoreactivity of the neurons was well preserved (Figure 2J). The number of TH‐immunonegative neurons was slightly increased in one patient (Figure 2P) and moderately increased in another patient with ILBD (Figure 2V). The severity of LB pathology was slight in nine patients (Figure 2K), moderate in four (Figure 2Q) and severe in one patient with ILBD (Figure 2W).
Medulla oblongata (Figure 2, Table 2).
On H&E staining, neuronal cell loss in the dorsal vagal nucleus was not detectable in the control subjects (Figure 2F) or in any of the ILBD patients examined (Figure 2L, R and X) (in one patient with ILBD, the dorsal vagal nucleus was not available). Slight gliosis was found in the background in six of 19 patients with ILBD. The severity of LB pathology was absent in two patients, slight in 11 (Figure 2L and R) moderate in five (Figure 2X) and severe in one patient with ILBD on α‐synuclein immunostained sections.
DISCUSSION
In this study, we found various degrees of involvement of the cardiac sympathetic nerve in patients with ILBD irrespective of the underlying diseases, age or sex. In half of the patients with ILBD, namely, five associated with and five not associated with neurodegenerative disorders, the cardiac sympathetic nerve was already involved. Despite a limited number of cases, involvement of the cardiac sympathetic nerve is presumably not related to the presence of underlying neurodegenerative disorders, at least not with diseases with α‐synucleinopathies. In one patient, diabetic neuropathy, in addition to LB pathology, may have contributed to neurodegeneration. There were almost no TH‐immunoreactive nerve fibers in six of the 20 patients with ILBD, while the involvement of NF‐immunoreactive axons remained slight to moderate in five of these patients. Surprisingly, in one patient with ILBD, not only TH‐ but also NF‐immunoreactive nerve fibers were nearly depleted, as is commonly seen in advanced cases of PD or DLB (1, 23).
There have been several reports with respect to TH protein content and TH activity of the nigrostriatal dopaminergic system in PD. TH protein content in the substantia nigra, putamen and caudate decreased to 16%, 5.3% and 2.7% of controls, respectively (20). TH activity in the substantia nigra, putamen and caudate decreased to 11.9%–35.1%, 4.2%–21.6% and 9.2%–27.4% of controls, respectively (17, 19, 20, 22). The cardinal symptomatic threshold of dopaminergic neuronal cell loss in the substantia nigra has been calculated to be 68% in the lateral ventral tier and 48% in the caudal nigra as a whole (11). Taken together, these findings suggest that degeneration of the cardiac sympathetic nerve begins earlier than that of the nigrostriatal dopaminergic system, which accounts for the decreased cardiac uptake of MIBG even in the early disease stages of PD.
Recently, Braak and colleagues reported detailed pathological stages for the progression of PD and suggested that early pathological change in the central nervous system begins in the lower part of the brainstem, namely, in the dorsal vagal nucleus, and in the olfactory bulb (anterior olfactory nucleus), even in the absence of nigral involvement (3, 8). Saito et al confirmed that α‐synucleinopathy begins in the medulla oblongata in PD if it is independent of AD (29). In these studies, however, the peripheral nervous system, especially the sympathetic ganglia and postganglionic nerve fibers, was not examined (3, 8, 29). Comparison between epicardial nerve fibers and the dorsal vagal nucleus in ILBD allowed us to determine a possible chronological relationship between degenerative changes in these areas in the earliest stage of PD. The cardiac sympathetic nerve was already involved in 10 of 20 patients with ILBD, whose Braak staging was 2 or 3. Moreover, profound cardiac sympathetic denervation as seen in advanced‐stage PD or DLB had already occurred in one patient. However, neuronal cell loss of the dorsal vagal nucleus was not detectable in any of the patients examined, and only a slight gliosis was seen in six patients. These findings suggest that degeneration of the cardiac sympathetic nerve precedes neuronal cell loss and dysfunction in the dorsal vagal nucleus during the early disease process of PD. This regional difference is potentially related to the possibility that the cardiac sympathetic nerve is more vulnerable than that of other organs, which is supported by reports that disturbance of the cardiac sympathetic nerve is specific to the decreased uptake of MIBG in the heart detected by [123I] MIBG myocardial scintigraphy (18, 32). The enhanced oxidative deamination of norepinephrine in the cardiac sympathetic nerve may account for this heart selectivity (10). Moreover, this difference is probably caused by the preferential involvement of axons rather than neuronal somata. Indeed, our previous study demonstrated that cardiac sympathetic denervation in PD precedes neuronal cell loss in the sympathetic ganglia (23). In this study, histopathological and immunohistochemical examinations revealed very mild change in the sympathetic ganglia even though TH‐immunoreactive nerve fibers almost entirely disappeared from the hearts of six out of 20 patients with ILBD. Moreover, one of the six patients who had almost absent TH‐immunoreactive nerve fibers had no LBs in the sympathetic ganglia. These findings strongly support our previous conclusion that cardiac sympathetic denervation precedes neuronal cell loss in the sympathetic ganglia in PD and further suggest that retrograde degeneration of the cardiac sympathetic nerve begins in a much earlier stage of PD than expected.
Primary autonomic dysfunction failure involves MSA, PD, PAF and also DLB (15, 16). The lesion responsible for dysautonomia, and particularly the clinical manifestation of orthostatic hypotension (OH), is in the central nervous system in MSA, and is both peripheral and central in PD, as suggested in pharmacological and pathological studies (7, 21, 28). Recent immunohistochemical study revealed that in LB disease, the medullary lesions involving the rostral ventrolateral and medullary raphe nuclei, which control sympathetic output, are milder in degree than those in MSA (2). Braak et al have studied LB pathology in the medullary lesions in ILBD; the extent of the lesions in the dorsal vagal nucleus has been reported to be much more severe than that in the ventrolateral and raphe nuclei (8). Our findings strongly suggest that in LB disease, the principal neuropathologic substrate for OH is not in the medulla, but is elsewhere, possibly including the cardiac sympathetic nerve.
In conclusion, we suggest that in PD, degeneration of the cardiac sympathetic nerve begins in the early disease process and that this may account for the decreased cardiac uptake of MIBG in the early stages of PD, before neuronal cell loss in the dorsal vagal nucleus.
ACKNOWLEDGMENTS
We thank Ms. Nakamura for her technical assistance. This work was supported in part by a grant from the Japan Foundation for Neuroscience and Mental Health.
REFERENCES
- 1. Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H (2005) Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol 15:29–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Benarroch EE, Schmeichel AM, Low PA, Boeve BF, Sandroni P, Parisi JE (2005) Involvement of medullary regions controlling sympathetic output in Lewy body disease. Brain 128:338–344. [DOI] [PubMed] [Google Scholar]
- 3. Braak H, Del Tredici K, Rüb U, De Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211. [DOI] [PubMed] [Google Scholar]
- 4. Braune S, Reinhardt M, Bathmann J, Krause T, Lehmann M, Lücking CH (1998) Impaired cardiac uptake of meta‐[123I]iodobenzylguanidine in Parkinson’s disease with autonomic failure. Acta Neurol Scand 97:307–314. [DOI] [PubMed] [Google Scholar]
- 5. Braune S, Reinhardt M, Schnitzer R, Riedel A, Lücking CH (1999) Cardiac uptake of [123I]MIBG separates Parkinson’s disease from multiple system atrophy. Neurology 53:1020–1025. [DOI] [PubMed] [Google Scholar]
- 6. Courbon F, Brefel‐Courbon C, Thalamas C, Alibelli MJ, Berry I, Montastruc JL, Rascol O, Senard JM (2003) Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson’s disease. Mov Disord 18:890–897. [DOI] [PubMed] [Google Scholar]
- 7. Daniel SE (1999) The neuropathology and neurochemistry of multiple system atrophy. In: Autonomic Failure: a Textbook of Clinical Disorders of the Autonomic Nervous System. Mathias CJ, Bannister R (eds), pp. 321–328. Oxford University Press: New York. [Google Scholar]
- 8. Del Tredici K, Rüb U, De Vos RA, Bohl JR, Braak H (2002) Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426. [DOI] [PubMed] [Google Scholar]
- 9. Druschky A, Hilz MJ, Platsch G, Radespiel‐Tröger M, Drushky K, Kuwert T, Neundörfer B (2000) Differentiation of Parkinson’s disease and multiple system atrophy in early disease stages by means of I‐123‐MIBG‐SPECT. J Neurol Sci 175:3–12. [DOI] [PubMed] [Google Scholar]
- 10. Eisenhofer G, Meredith IT, Dart A, Cannon RO III, Quyyumi AA, Lambert G, Chin J, Jennings GL, Goldstein DS (1992) Sympathetic nervous function in human heart as assessed by cardiac spillover of dihydroxyphenylglycol and norepinephrine. Circulation 85:1775–1785. [DOI] [PubMed] [Google Scholar]
- 11. Fearnley JM, Lees AJ (1991) Aging and Parkinson’s disease: substantia nigra regional selectivity. Brain 114:2283–2301. [DOI] [PubMed] [Google Scholar]
- 12. Fujiwara H, Hasegawa M, Dohmae N, Kwashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) α‐Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164. [DOI] [PubMed] [Google Scholar]
- 13. Goldstein DS, Holmes C, Cannon RO III, Eisenhofer G, Kopin IJ (1997) Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336:696–702. [DOI] [PubMed] [Google Scholar]
- 14. Goldstein DS, Holmes C, Li S‐T, Bruse S, Metman LV, Cannon RO III (2000) Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 133:338–347. [DOI] [PubMed] [Google Scholar]
- 15. Horimoto Y, Matsumoto M, Akatsu H, Ikari H, Kojima K, Yamamoto T, Otsuka Y, Ojika K, Ueda R, Kosaka K (2003) Autonomic dysfunctions in dementia with Lewy bodies. J Neurol 250:530–533. [DOI] [PubMed] [Google Scholar]
- 16. Kaufmann H (2000) Primary autonomic failure: three clinical presentations of one disease? Ann Intern Med 133:382–384. [DOI] [PubMed] [Google Scholar]
- 17. Lloyd KG, Davidson L, Hornykiewicz O (1975) The neurochemistry of Parkinson’s disease: effect of L‐dopa therapy. J Pharmacol Exp Ther 195:453–464. [PubMed] [Google Scholar]
- 18. Matsui H, Udaka H, Oda M, Kubori T, Nishinaka K, Kameyama M (2005) Metaiodobenzylguanidine (MIBG) scintigraphy at various parts of the body in Parkinson’s disease and multiple system atrophy. Auton Neurosci 119:56–60. [DOI] [PubMed] [Google Scholar]
- 19. McGeer PL, McGeer EG (1976) Enzymes associated with the metabolism of catecholamines, acetylcholine and GABA in human controls and patients with Parkinson’s disease and Huntington’s chorea. J Neurochem 26:65–76. [PubMed] [Google Scholar]
- 20. Mogi M, Harada M, Kiuchi K, Kojima K, Kondo T, Narabayashi H, Rausch D, Riederer P, Jellinger K, Nagatsu T (1988) Homospecific activity (activity per enzyme protein) of tyrosine hydroxylase increases in parkinsonian brain. J Neural Transm 72:77–81. [DOI] [PubMed] [Google Scholar]
- 21. Montastruc JL, Senard J‐M, Rascol O, Rascol A (1996) Autonomic nervous system dysfunction and adrenoceptor regulation in Parkinson’s disease: clinical and pharmacologic consequences. In: Advances in Neurology. Parkinson’s disease. Battistin L, Scarlato G, Caraceni T, Ruggieri S (eds), pp. 377–381. Lippincott‐Raven Press: Philadelphia. [PubMed] [Google Scholar]
- 22. Nagatsu T, Yamaguchi T, Rahman MK, Trocewicz J, Oka K, Hirata Y, Nagatsu I, Narabayashi H, Kondo T, Iizuka R (1984) Catecholamine‐related enzymes and the biopterin cofactor in Parkinson’s disease and related extrapyramidal diseases. In: Advances in Neurology. Parkinson‐Specific Motor and Mental Disorders: Role of the Pallidum: Pathophysiological, Biochemical, and Therapeutic Aspects. Hassler RG, Christ JF (eds), pp. 467–473. Raven Press: New York. [PubMed] [Google Scholar]
- 23. Orimo S, Amino T, Ito Y, Takahashi A, Kojo T, Uchihara T, Tsuchiya K, Mori F, Wakabayashi K, Takahashi H (2005) Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease. Acta Neuropathol (Berl) 109:583–588. [DOI] [PubMed] [Google Scholar]
- 24. Orimo S, Amino T, Yokochi M, Kojo T, Uchihara T, Takahashi A, Wakabayashi K, Takahashi H, Hattori N, Mizuno Y (2005) Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in PARK2. Mov Disord 20:1350–1353. [DOI] [PubMed] [Google Scholar]
- 25. Orimo S, Oka T, Miura H, Tsuchiya K, Mori F, Wakabayashi K, Nagao T, Yokochi M (2002) Sympathetic cardiac denervation in Parkinson’s disease and pure autonomic failure but not in multiple system atrophy. J Neurol Neurosurg Psychiatry 73:776–777. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Orimo S, Ozawa E, Nakade S, Hattori H, Tsuchiya K, Takahashi A (2003) [ 123I]MIBG myocardial scintigraphy differentiates corticobasal degeneration from Parkinson’s disease. Intern Med 42:127–128. [DOI] [PubMed] [Google Scholar]
- 27. Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H (1999) 123I‐metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 67:189–194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Polinsky RJ, Kopin IJ, Ebert MH, Weise V (1981) Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology 31:1–7. [DOI] [PubMed] [Google Scholar]
- 29. Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated α‐synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654. [DOI] [PubMed] [Google Scholar]
- 30. Satoh A, Serita T, Seto M, Tomita I, Satoh H, Iwanaga K, Takashima H, Tsujihata M (1999) Loss of 123I‐MIBG uptake by the heart in Parkinson’s disease: assessment of cardiac sympathetic denervation and diagnostic value. J Nucl Med 40:371–375. [PubMed] [Google Scholar]
- 31. Suzuki M, Hattori N, Orimo S, Fukumitsu N, Abo M, Kono Y, Sengoku R, Kurita A, Honda H, Inoue K (2005) Preserved 123I‐metaiodbenzylguanidine uptake in autosomal recessive juvenile parkinsonism: first case report. Mov Disord 20:634–636. [DOI] [PubMed] [Google Scholar]
- 32. Taki J, Nakajima K, Hwang E‐H, Matsunari I, Komai K, Yoshita M, Sakajiri K, Tonami N (2000) Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 27:566–573. [DOI] [PubMed] [Google Scholar]
- 33. Watanabe H, Ieda T, Katayama T, Takeda A, Aiba I, Doyu M, Hirayama M, Sobue G (2001) Cardiac 123I‐meta‐iodobenzylguanidine (MIBG) uptake in dementia with Lewy bodies: comparison with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 70:781–783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Yoshita M (1998) Differentiation of idiopathic Parkinson’s disease from striatonigral degeneration and progressive supranuclear palsy. J Neurol Sci 155:60–67. [DOI] [PubMed] [Google Scholar]
- 35. Yoshita M, Taki J, Yamada M (2001) A clinical role for[123I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer’s‐type and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 71:583–588. [DOI] [PMC free article] [PubMed] [Google Scholar]