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Decreased catecholamine content in parkinsonian adrenal medullae
EXPERIMENTAL
NEUROLOGY
104,22-27
(1989)
Decreased Catecholamine Content in Parkinsonian Adrenal Medullae SUSAN L. STODDARD,* GERTRUDE M. TYCE,~; J. ERIC AHLSKOG,~ ALAN R. ZINSMEISTER,§ AND STEPHEN W. CARMICHAEL~~ *Department of Anatomy, Indiana University School of Medicine, Fort Wayne, Indiana 46805; and Departments of ~Physiology and Biophysics, SNeurology, §Biostatistics, and lIAnatomy, Mayo Clinic/Foundation, Rochester, Minnesota 55905
METHODS Autopsy specimens of adrenal medullae from parkinsonian and nonparkinsonian patients were analyzed for free catecholamines by high-performance liquid chromatography with electrochemical detection. The total free catecholamine content (nanomoles free catecholamine per milligram protein) was significantly lower in the parkinsonian patients than in the control population when the values were corrected for age and time from death to organ harvest. It is not established whether this decreased catecholamine content in the adrenals of parkinsonian patients is a concomitant of the disease itself or whether it is secondary to drug therapies used to treat the symptoms of Parkinson’s disease. Q 1999 Academic Press, Inc.
INTRODUCTION Treatment of Parkinson’s disease by autologous transplantation of adrenal medullary tissue to the striaturn was first reported by Backlund et al. (3). The rationale for this procedure was based on two principles: (i) the transplanted tissue is capable of synthesizing dopamine to replace the deficit in the brain; and (ii) the transplanted tissue is immunologically identical to host tissue. Following the reported treatment success of this technique (25), the procedure was adopted by numerous surgical teams around the world. The efficacy of this technique is currently being questioned (36). Parkinson’s disease is a multisystem degeneration (5) and is frequently accompanied by autonomic disturbances (1). This raises the concern that the adrenal medullae of parkinsonian patients may be damaged by their disease process, which could obviously compromise the success of adrenal-brain transplantation. To address this question, we compared the adrenal medullary catecholamine contents at autopsy of parkinsonian and nonparkinsonian patients. Our analyses revealed that the total free catecholamine content of the adrenal medulla was significantly reduced in the parkinsonian group. Preliminary results of this study have been reported previously (7,37). 0014-4886/89 $3.00 Copyright 0 1989 hy Academic Press, All rights of reproduction in any form
22 Inc. reserved.
Adrenal glands were collected from 5 parkinsonian and 18 nonparkinsonian patients who came to autopsy at the Mayo Clinic between September 1984 and October 1987. The mean age (+SEM) of the parkinsonian patients was 78 + 3 years (range, 69-89 years), while that of the nonparkinsonian group was 58 + 5 years (range, 17-95 years). The median time from death to organ harvest was 6.9 h (range, 3.6-15.0 h) for the parkinsonian group and 4.0 h (range, 1.6-13.5 h) for the nonparkinsonian group. Both parkinsonian and nonparkinsonian patients died from a variety of causes (Tables 1 and 2). All parkinsonian patients were taking Sinemet at the time of death except one (Case 2), who was taking Symmetrel (amantidine). The existence of idiopathic Parkinson’s disease or Parkinson’s plus in the patients was confirmed neuropathologically by degeneration of the substantia nigra and locus ceruleus with the presence of Lewy bodies. Clinical diagnosis supported the neuropathological findings. Two additional patients with drug-induced parkinsonism were also studied. The neuropathological findings in these individuals were diffuse hypoxic encephalopathy (Case 3) and rare neurofibrillary tangles in the hippocampus (Case 15). After harvest adrenal medullary tissue was dissected from adrenal cortex and frozen at -80°C until assayed for catecholamines. Free catecholamines (CAs) were determined in adrenal medullary tissue by high-performance liquid chromatography (HPLC) with electrochemical detection (6). Protein was measured in medullary tissue by the Lowry and Bradford methods (28). The data were expressed as nanomoles free CA per milligram protein. The catecholamine values were first transformed to log scale to stabilize their variances over the range of age and time to harvest values in this study group and to provide a more symmetric (Gaussian) distribution. An analysis of covariance of the log transformed values was then used to compare catecholamine levels in normal vs parkinsonian patients, adjusting for age and time of harvest as the covariates (35).
PARKINSONIAN
ADRENAL
TABLE Parkinsonian
Case No.
Age
Sex
26
81
F
3.6
24 1 3 15
73 78 60 70
M F M F
3.8 6.9 9.2 13.9
25 2
69 89
F F
14.1 15.0
’ Classification of form of parkinsonism: ’ Dopaminergic antagonists or depletors administered approximately 6 years before in the two cases classified as drug-induced.
Cause
Patient
Case No.
Age
Sex
Time to organ harvest 0-d
19 22 6 8 23 5 7 10 13 20 18 11 21 12 14 17 16 9
43 56 67 17 49 72 77 95 77 62 42 19 58 75 76 71 59 38
M M M F M F M M F M M M F M M M F M
1.6 2.2 3.0 3.2 3.3 3.4 3.7 3.8 3.9 4.1 4.2 4.4 4.6 4.7 4.8 5.0 6.8 13.5
’ Legend
is as in Table
1.
of death
Hoehn
and Yahr
Classification4’
2-3
Simple
4-5 5 2-3 2-3
Parkinson’s Parkinson’s Drug-induced Drug-induced
5 5
Simple Simple
plus (1) plus (1,3) (1)
(2)
Simple = idiopathic. Parkinson’s plus implies involvement of additional neurologic complications. used within one month of death, unless otherwise noted. (1) Metoclopramide; (2) haloperidol, last death; (3) reserpine. The symptoms and signs of parkinsonism preceded use of these drugs except
Epinephrine (EPI) was the primary catecholamine in adrenal medullary tissue from all except one patient, ranging from 68.2 to 93.4% of the total free catecholamines. In Case 2, norepinephrine (NE) was the primary catecholamine (75.3%), and EPI was the secondary catecholamine (24.5%). In all patients, dopamine (DA) accounted for the smallest percentage of the total free catecholamines, comprising 0.09-0.96%. Levels of individual and total free catecholamines in each patient are shown
Nonparkinsonian
Population
Auto accident Hypovolemic shock Aspiration pneumonia Bronchopneumonia Hodgkin’s disease (IV) Acute necrotizing pancreatitis Probable septicemia Acute mucopurulent bronchitis
RESULTS
TABLE
1
Patient
Time to organ harvest (hr)
23
MEDULLAE
2 Population
Cause
of death”
Ischemic heart disease Ruptured cerebral aneurysm Cardiopulmonary arrest Auto accident Fall; brain stem transection Cardiac tamponade Lung cancer Aspiration of gastric contents (2) Multiple organ failure Diabetic complications Plane crash Thermal electrocution Adult respiratory distress syndrome Ischemic heart disease Abdominal aortic aneurysm Adult respiratory distress syndrome Auto accident Gunshot wound
in Figs. 1 and 2, while median levels of individual catecholamines are listed in Table 3. Since the mechanism of idiopathic parkinsonism is presumably different from that of drug-induced parkinsonism (cf. Discussion), the two drug-induced parkinsonian patients were not included in the parkinsonian group. It was initially noted that age and time from death to organ harvest were considerably greater in the parkinsonian group. Thus, an analysis of covariance of the log transformed values of NE, EPI, DA, and total CAs was used to compare groups after adjusting for these factors. The level of total free catecholamines was significantly lower in the parkinsonian patients (P < 0.05) after adjusting for age and time to harvest. Although the individual catecholamine levels were typically less in the parkinsonian patients (Table 3), the differences were not statistically significant after adjusting for age and time to harvest. Over both groups, EPI (P < 0.01) and DA (P < 0.01) were most sensitive to the time from death to organ harvest, while NE was affected by age (P < 0.05). The effect of time to harvest on EPI appeared to depend on age (P < 0.05). No differences in the amount of protein (per gram wet weight of medulla) were seen between groups. DISCUSSION These data indicate that the total free catecholamine content (per milligram protein) was significantly lower in a parkinsonian population than in a control group. It should be noted, however, that our samples were not randomly selected from two populations; thus the effects of a possible selection bias cannot be gauged. Although these data suggest the existence of a difference in the population studied, the mechanism for this difference remains to be elucidated.
STODDARD
ET
AL.
NOREPINEPHRINE
INDIVIDUAL
CASES
INDIVIDUAL
CASES
3200 2400
2800
EPINEPHRINE 2000
TOTAL CATECHOLAMINES
2400 2000 1600 1200 800 400 0 As INDIVIDUAL
CASES
INDIVIDUAL
CASES
FIG. 1. Levels of free norepinephrine (top) and free epinephrine (bottom) in parkinsonian (hatched bars) and nonparkinsonian (solid bars) autopsy specimens arranged in order from lowest to highest levels. Numbers above each bar indicate the case number. Drug-induced parkinsonian patients are indicated by a carat below the X-axis.
FIG. 2. Legend is the same as for Fig. 1, except that graphs present the levels of free dopamine (top) and total free catecholamines (bottom). Total free catecholamines were significantly lower (P < 0.05) in the non-drug-induced parkinsonian population compared to controls after adjusting for age and time to organ harvest.
Previous investigators have provided evidence that Parkinson’s disease involves more widespread neurological damage than simply destruction of the nigro-striatal system. Lewy bodies, the neuropathological hallmark of Parkinson’s disease have been demonstrated in the hypothalamus (34), the dorsal vagal nucleus, the substantia innominata (12), and the locus ceruleus (17). Additionally, various neurochemical abnormalities have been identified in the central nervous system of parkinsonian patients, including decreased dopamine in the hypothalamus (34), decreased dopamine P-hydroxylase in the CSF (20), decreased levels of [Met]- and [Leulenkephalin in the globus pallidus and putamen, and decreased opiate receptor binding and [Metlenkephalin levels in the substantia nigra (24,40). The peripheral manifestations of Parkinson’s disease have not been completely explored, although it is well established that many parkinsonian patients have concomitant autonomic nervous system dysfunction (1). Barbeau (5) proposed that Parkinson’s disease is a multisystem disorder that includes involvement of peripheral sympathetic structures; he cited observations from his previous studies that urinary DA excretion decreased
30-40% in parkinsonian patients. Similarly, WeilMalherbe and Van Buren (42) noted that parkinsonian patients regularly excreted less free DA than control individuals, while another population of parkinsonian patients was reported to have increased levels of urinary EPI (38). Limited evidence has suggested that the adrenal medulla may be affected by the Parkinson’s diseaseprocess.
TABLE 3 Individual Catecholaminesin the Adrenal Medulla Catecholamine (nM/mg protein) Epinephrine
Control (N= 18) 814 (232-2481) 120 (62-570)
Norepinephrine
Parkinsonian (N=5) 210 (25-735) (41-71339)
Dopamine (0.5-43) Note.
Values
are medians
and (range).
(0.3-i)
PARKINSONIAN
ADRENAL
den Hartog Jager (13) reported the existence of “adrenal bodies” in the adrenal glands of parkinsonian patients which were entirely absent in 9 of 10 control glands. These adrenal medullary cytoplasmic inclusion bodies contained sphingomyelin, free fatty acids, and polysaccharides, while Lewy bodies contain only protein and sphingomyelin (12). Hart and Cyrus (18) observed hyaline globules in the adrenal medullae in 52% of the cases of Parkinson’s disease studied, but in none of the control population. Involvement of the adrenal medulla in Parkinson’s disease was also noted by Pouplard et al. (29) who identified the presence of an autoantibody in the serum of 43% of tested parkinsonian patients that crossreacted with an antigen in human fetal adrenal medullary cells. The involvement of the autonomic nervous system in Parkinson’s disease and, specifically, the histological and immunological evidence for the involvement of the adrenal medulla suggests that the lowered catecholamine levels seen in our parkinsonian population may be related to the disease process itself. A second explanation for our observations is that the decreased levels of total catecholamines occurred secondary to the drug therapies used to treat the symptoms of Parkinson’s disease. Sinemet was the principal drug used; it is a combination of levodopa (L-dopa), the precursor to dopamine, plus a-methyldopahydrazine (carbidopa), an aromatic L-amino acid decarboxylase inhibitor. Carbidopa, which is excluded from the brain by the blood-brain barrier and perhaps from adrenal medullary tissue by a blood-adrenal barrier (19), is administered to prevent the systemic decarboxylation of L-dopa to dopamine. Nevertheless, some dopamine is synthesized in the periphery (22). Effects of drug therapy could thus potentially result from the action of either L-dopa or dopamine. The most likely effect of administration of the catecholaminergic precursor, L-dopa, is to increase tissue catecholamines. However, it has been shown that Ldopa treatment increases concentrations of DA to a much greater extent than those of NE and EPI (10). Thus it might be anticipated that a portion of the adrenal medullary DA measured in our parkinsonian patients resulted from L-dopa treatment. In contrast, the activities of peripheral tissue catecholamine biosynthetic enzymes, tyrosine hydroxylase (lo), dopamine phydroxylase (26), and aromatic L-amino acid decarboxylase (9) decrease as a result of prolonged treatment with L-dopa alone. The decrease in these enzyme levels is presumably a compensatory change, secondary to the increased catecholamine levels resulting from administration of L-dopa. The activities of the catecholamine catabolic enzyme, monoamine oxidase, may either increase or decrease with chronic L-dopa treatment, depending on the substrate (31). In general, such enzymatic changes would tend to decrease the formation of amines and facilitate their breakdown; this could result, paradoxically, in decreased tissue CA levels even after ad-
MEDULLAE
25
ministration of a precursor, as was observed in our study. Of particular interest in this regard is a report by Riederer et al. (32) that mean tyrosine hydroxylase levels in the adrenal medulla were decreased fourfold from control levels in a population of five patients with Parkinson’s disease who were treated with L-dopa until several days before death. However, data are not available concerning the effects of L-dopa in combination with carbidopa on the activities of enzymes in the adrenal, brain, or periphery. Although carbidopa might be expected to decrease tissue levels of catecholamines by inhibiting the action of aromatic L-amino acid decarboxylase, Horita et al. (19) have shown that, in rats, carbidopa did not inhibit aromatic L-amino acid decarboxylase in adrenal medullary tissue, presumably because of the exclusion of this drug from the adrenal by a blood-adrenal barrier. Thus, administration of carbidopa would not be anticipated to decrease tissue levels of catecholamines in the adrenal medulla. Dopamine and dopaminergic drugs may also modulate the release and storage of adrenal medullary catecholamines. A dopaminergic receptor has been discovered on the chromaffin cell in the cat (2) and identified as the Dz subtype in cultured bovine tissue (16). In both types of tissue a DA agonist, apomorphine, inhibited catecholamine secretion triggered by stimulation of the nicotinic receptor (2,16). In contrast, haloperidol and droperidol, dopamine antagonists, enhanced catecholamine release in cultured bovine adrenal medullary cells (16) and perfused dog adrenals (39), respectively. The fact that the above studies were performed with isolated tissue, i.e., perfused adrenal glands and cultured cells, argues for the ability of dopaminergic agonists and antagonists to act locally to modulate catecholamine release. Similarly, domperidone, a relatively specific D2 antagonist with no central effects, increased the catecholamine content of the adrenal medulla of the rat (15). Observations in human patients support a facilitatory action of DA antagonists on catecholamine secretion. Intravenous injection of metoclopramide, a Dz antagonist that has both peripheral and central actions (27,41), resulted in a 4O-fold increase in free EPI, in addition to smaller increases in free NE and DA, in plasma samples taken from the left adrenal vein of a patient with essential hypertension (23). Metoclopramide is also known to precipitate hypertensive crisis in patients with pheochromocytoma (21). The action of metoclopramide to increase adrenal catecholamine release may result in decreased tissue levels. Thus, in the context of the present study, one patient (Case 15) with drug-induced parkinsonism, who presumably developed this condition secondary to the administration of metoclopramide, had reduced catecholamine levels. In light of these observations, one might expect L-dopa and dopamine agonists to have an opposite effect, i.e., to increase CA levels. If this is correct, then the low adrenal catecholamine levels
26
STODDARD
seen in our idiopathic parkinsonian patients should not be secondary to their dopaminergic drugs. Unfortunately, not all studies of drug interactions with adrenal catecholamines have produced consistent results. Dopaminergic drugs have been reported to decrease (11) or increase adrenal tyrosine hydroxylase activity (30). Baksi et al. (4) reported that both bromocriptine (a dopamine agonist) and haloperidol (a dopamine antagonist) increased adrenal epinephrine content. Drug-adrenal interactions may be complex since adrenal medullary activity can be influenced directly or indirectly via effects mediated by the central nervous system (4,30). Thus, we are unable to conclude whether the decreased CA levels in our parkinsonian population were a result of the medications used in therapy. Data are also presented from the two patients with drug-induced parkinsonism (Figs. 1 and 2). The patient who received reserpine (Case 3) may be considered a control. Reserpine depletes CAs by blocking uptake into chromaffin vesicles. Although this depletion is slower and less complete in the adrenal medulla than in other tissues (43), administration of this drug would be expected to lower CA levels, as was observed. The second patient (Case 15) was discussed above. A recent report by Cervera et al. (8) is relevant to our observations. They found CA levels in parkinsonian adrenals collected at autopsy to be decreased, but not significantly, from a group of control subjects. Several factors may account for the differences between our results. The mean time from death to organ harvest in Cervera and colleagues’ patient population was approximately 19 h, notably greater than in the current study. Since CA levels decrease with *time after death, the longer postmortem delay may have been sufficient to obscure significant differences between groups. The fact that DA was below detection levels in their specimens supports this hypothesis. Additionally, Cervera et al. (8) did not mention whether all their parkinsonian patients had an idiopathic condition or whether the patients were taking Sinemet prior to death. If the decreased CA levels we observed are a function of the pharmacological treatment of parkinsonian symptoms, then the absence of such treatment in the subjects of Cervera et al. (8) might also explain the differences between our two studies. We noted that, in our patient population, specific CAs were variously affected by age and time from death to organ harvest. It is important to note, however, that the size and lack of random sampling in our population limited the power to detect interactions among CA levels, age, and time to organ harvest. It is possible that EPI was significantly decreased in relation to time from death to organ harvest due to a particular sensitivity of phenylethanolamine N-methyl transferase, the enzyme that converts NE to EPI, to postmortem changes. A similar significant relationship between DA and time to organ harvest could be explained by the occurrence of DA in both vesicles and cytoplasm; cytoplasmic DA might be
ET AL.
expected to be lost first as the cell undergoes autolysis. Decreases in NE were significantly related to age. Previous work has shown that there is decreased conversion of precursors to NE in specific brain regions in senescent male mice (14). Furthermore, levels of monoamine oxidase increase with age (33, 44); thus the catabolism of NE may increase, resulting in lower observed levels. Although it was not the aim of the current study to examine specifically the effects of age and time to harvest on adrenal medullary CA levels, this is clearly a relevant area that requires further investigation. In summary, our observations indicate that there may be a decrease in the catecholamine content of the adrenal medulla associated with Parkinson’s disease and parkinsonism. Whether this decrease is related to the mechanisms of the disease itself or whether it is a consequence of drug therapy has yet to be determined. If this reflects an adrenal medullary degenerative process linked to the development of idiopathic Parkinson’s disease, the successof autologous adrenal-brain transplantation as a treatment for Parkinson’s disease may be compromised. ACKNOWLEDGMENTS The authors thank Dr. H. Okazaki for neuropathological examinations, Mr. Robert Wilson for technical assistance, Ms. Sharon Chinnow for performing the catecholamine assays, Ms. Pam Hammond for the protein determinations, and Ms. Eva Gankiewicz and Ms. Julie Kettelkamp for preparation of the graphs. The comments of Drs. W. S. Brimijoin and L. J. Melton III throughout this project are appreciated. This work was supported, in part, by grants from the United Parkinson Disease Foundation (S.W.C.) and by NS 17858 (G.M.T.).
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NEUROLOGY
104,22-27
(1989)
Decreased Catecholamine Content in Parkinsonian Adrenal Medullae SUSAN L. STODDARD,* GERTRUDE M. TYCE,~; J. ERIC AHLSKOG,~ ALAN R. ZINSMEISTER,§ AND STEPHEN W. CARMICHAEL~~ *Department of Anatomy, Indiana University School of Medicine, Fort Wayne, Indiana 46805; and Departments of ~Physiology and Biophysics, SNeurology, §Biostatistics, and lIAnatomy, Mayo Clinic/Foundation, Rochester, Minnesota 55905
METHODS Autopsy specimens of adrenal medullae from parkinsonian and nonparkinsonian patients were analyzed for free catecholamines by high-performance liquid chromatography with electrochemical detection. The total free catecholamine content (nanomoles free catecholamine per milligram protein) was significantly lower in the parkinsonian patients than in the control population when the values were corrected for age and time from death to organ harvest. It is not established whether this decreased catecholamine content in the adrenals of parkinsonian patients is a concomitant of the disease itself or whether it is secondary to drug therapies used to treat the symptoms of Parkinson’s disease. Q 1999 Academic Press, Inc.
INTRODUCTION Treatment of Parkinson’s disease by autologous transplantation of adrenal medullary tissue to the striaturn was first reported by Backlund et al. (3). The rationale for this procedure was based on two principles: (i) the transplanted tissue is capable of synthesizing dopamine to replace the deficit in the brain; and (ii) the transplanted tissue is immunologically identical to host tissue. Following the reported treatment success of this technique (25), the procedure was adopted by numerous surgical teams around the world. The efficacy of this technique is currently being questioned (36). Parkinson’s disease is a multisystem degeneration (5) and is frequently accompanied by autonomic disturbances (1). This raises the concern that the adrenal medullae of parkinsonian patients may be damaged by their disease process, which could obviously compromise the success of adrenal-brain transplantation. To address this question, we compared the adrenal medullary catecholamine contents at autopsy of parkinsonian and nonparkinsonian patients. Our analyses revealed that the total free catecholamine content of the adrenal medulla was significantly reduced in the parkinsonian group. Preliminary results of this study have been reported previously (7,37). 0014-4886/89 $3.00 Copyright 0 1989 hy Academic Press, All rights of reproduction in any form
22 Inc. reserved.
Adrenal glands were collected from 5 parkinsonian and 18 nonparkinsonian patients who came to autopsy at the Mayo Clinic between September 1984 and October 1987. The mean age (+SEM) of the parkinsonian patients was 78 + 3 years (range, 69-89 years), while that of the nonparkinsonian group was 58 + 5 years (range, 17-95 years). The median time from death to organ harvest was 6.9 h (range, 3.6-15.0 h) for the parkinsonian group and 4.0 h (range, 1.6-13.5 h) for the nonparkinsonian group. Both parkinsonian and nonparkinsonian patients died from a variety of causes (Tables 1 and 2). All parkinsonian patients were taking Sinemet at the time of death except one (Case 2), who was taking Symmetrel (amantidine). The existence of idiopathic Parkinson’s disease or Parkinson’s plus in the patients was confirmed neuropathologically by degeneration of the substantia nigra and locus ceruleus with the presence of Lewy bodies. Clinical diagnosis supported the neuropathological findings. Two additional patients with drug-induced parkinsonism were also studied. The neuropathological findings in these individuals were diffuse hypoxic encephalopathy (Case 3) and rare neurofibrillary tangles in the hippocampus (Case 15). After harvest adrenal medullary tissue was dissected from adrenal cortex and frozen at -80°C until assayed for catecholamines. Free catecholamines (CAs) were determined in adrenal medullary tissue by high-performance liquid chromatography (HPLC) with electrochemical detection (6). Protein was measured in medullary tissue by the Lowry and Bradford methods (28). The data were expressed as nanomoles free CA per milligram protein. The catecholamine values were first transformed to log scale to stabilize their variances over the range of age and time to harvest values in this study group and to provide a more symmetric (Gaussian) distribution. An analysis of covariance of the log transformed values was then used to compare catecholamine levels in normal vs parkinsonian patients, adjusting for age and time of harvest as the covariates (35).
PARKINSONIAN
ADRENAL
TABLE Parkinsonian
Case No.
Age
Sex
26
81
F
3.6
24 1 3 15
73 78 60 70
M F M F
3.8 6.9 9.2 13.9
25 2
69 89
F F
14.1 15.0
’ Classification of form of parkinsonism: ’ Dopaminergic antagonists or depletors administered approximately 6 years before in the two cases classified as drug-induced.
Cause
Patient
Case No.
Age
Sex
Time to organ harvest 0-d
19 22 6 8 23 5 7 10 13 20 18 11 21 12 14 17 16 9
43 56 67 17 49 72 77 95 77 62 42 19 58 75 76 71 59 38
M M M F M F M M F M M M F M M M F M
1.6 2.2 3.0 3.2 3.3 3.4 3.7 3.8 3.9 4.1 4.2 4.4 4.6 4.7 4.8 5.0 6.8 13.5
’ Legend
is as in Table
1.
of death
Hoehn
and Yahr
Classification4’
2-3
Simple
4-5 5 2-3 2-3
Parkinson’s Parkinson’s Drug-induced Drug-induced
5 5
Simple Simple
plus (1) plus (1,3) (1)
(2)
Simple = idiopathic. Parkinson’s plus implies involvement of additional neurologic complications. used within one month of death, unless otherwise noted. (1) Metoclopramide; (2) haloperidol, last death; (3) reserpine. The symptoms and signs of parkinsonism preceded use of these drugs except
Epinephrine (EPI) was the primary catecholamine in adrenal medullary tissue from all except one patient, ranging from 68.2 to 93.4% of the total free catecholamines. In Case 2, norepinephrine (NE) was the primary catecholamine (75.3%), and EPI was the secondary catecholamine (24.5%). In all patients, dopamine (DA) accounted for the smallest percentage of the total free catecholamines, comprising 0.09-0.96%. Levels of individual and total free catecholamines in each patient are shown
Nonparkinsonian
Population
Auto accident Hypovolemic shock Aspiration pneumonia Bronchopneumonia Hodgkin’s disease (IV) Acute necrotizing pancreatitis Probable septicemia Acute mucopurulent bronchitis
RESULTS
TABLE
1
Patient
Time to organ harvest (hr)
23
MEDULLAE
2 Population
Cause
of death”
Ischemic heart disease Ruptured cerebral aneurysm Cardiopulmonary arrest Auto accident Fall; brain stem transection Cardiac tamponade Lung cancer Aspiration of gastric contents (2) Multiple organ failure Diabetic complications Plane crash Thermal electrocution Adult respiratory distress syndrome Ischemic heart disease Abdominal aortic aneurysm Adult respiratory distress syndrome Auto accident Gunshot wound
in Figs. 1 and 2, while median levels of individual catecholamines are listed in Table 3. Since the mechanism of idiopathic parkinsonism is presumably different from that of drug-induced parkinsonism (cf. Discussion), the two drug-induced parkinsonian patients were not included in the parkinsonian group. It was initially noted that age and time from death to organ harvest were considerably greater in the parkinsonian group. Thus, an analysis of covariance of the log transformed values of NE, EPI, DA, and total CAs was used to compare groups after adjusting for these factors. The level of total free catecholamines was significantly lower in the parkinsonian patients (P < 0.05) after adjusting for age and time to harvest. Although the individual catecholamine levels were typically less in the parkinsonian patients (Table 3), the differences were not statistically significant after adjusting for age and time to harvest. Over both groups, EPI (P < 0.01) and DA (P < 0.01) were most sensitive to the time from death to organ harvest, while NE was affected by age (P < 0.05). The effect of time to harvest on EPI appeared to depend on age (P < 0.05). No differences in the amount of protein (per gram wet weight of medulla) were seen between groups. DISCUSSION These data indicate that the total free catecholamine content (per milligram protein) was significantly lower in a parkinsonian population than in a control group. It should be noted, however, that our samples were not randomly selected from two populations; thus the effects of a possible selection bias cannot be gauged. Although these data suggest the existence of a difference in the population studied, the mechanism for this difference remains to be elucidated.
STODDARD
ET
AL.
NOREPINEPHRINE
INDIVIDUAL
CASES
INDIVIDUAL
CASES
3200 2400
2800
EPINEPHRINE 2000
TOTAL CATECHOLAMINES
2400 2000 1600 1200 800 400 0 As INDIVIDUAL
CASES
INDIVIDUAL
CASES
FIG. 1. Levels of free norepinephrine (top) and free epinephrine (bottom) in parkinsonian (hatched bars) and nonparkinsonian (solid bars) autopsy specimens arranged in order from lowest to highest levels. Numbers above each bar indicate the case number. Drug-induced parkinsonian patients are indicated by a carat below the X-axis.
FIG. 2. Legend is the same as for Fig. 1, except that graphs present the levels of free dopamine (top) and total free catecholamines (bottom). Total free catecholamines were significantly lower (P < 0.05) in the non-drug-induced parkinsonian population compared to controls after adjusting for age and time to organ harvest.
Previous investigators have provided evidence that Parkinson’s disease involves more widespread neurological damage than simply destruction of the nigro-striatal system. Lewy bodies, the neuropathological hallmark of Parkinson’s disease have been demonstrated in the hypothalamus (34), the dorsal vagal nucleus, the substantia innominata (12), and the locus ceruleus (17). Additionally, various neurochemical abnormalities have been identified in the central nervous system of parkinsonian patients, including decreased dopamine in the hypothalamus (34), decreased dopamine P-hydroxylase in the CSF (20), decreased levels of [Met]- and [Leulenkephalin in the globus pallidus and putamen, and decreased opiate receptor binding and [Metlenkephalin levels in the substantia nigra (24,40). The peripheral manifestations of Parkinson’s disease have not been completely explored, although it is well established that many parkinsonian patients have concomitant autonomic nervous system dysfunction (1). Barbeau (5) proposed that Parkinson’s disease is a multisystem disorder that includes involvement of peripheral sympathetic structures; he cited observations from his previous studies that urinary DA excretion decreased
30-40% in parkinsonian patients. Similarly, WeilMalherbe and Van Buren (42) noted that parkinsonian patients regularly excreted less free DA than control individuals, while another population of parkinsonian patients was reported to have increased levels of urinary EPI (38). Limited evidence has suggested that the adrenal medulla may be affected by the Parkinson’s diseaseprocess.
TABLE 3 Individual Catecholaminesin the Adrenal Medulla Catecholamine (nM/mg protein) Epinephrine
Control (N= 18) 814 (232-2481) 120 (62-570)
Norepinephrine
Parkinsonian (N=5) 210 (25-735) (41-71339)
Dopamine (0.5-43) Note.
Values
are medians
and (range).
(0.3-i)
PARKINSONIAN
ADRENAL
den Hartog Jager (13) reported the existence of “adrenal bodies” in the adrenal glands of parkinsonian patients which were entirely absent in 9 of 10 control glands. These adrenal medullary cytoplasmic inclusion bodies contained sphingomyelin, free fatty acids, and polysaccharides, while Lewy bodies contain only protein and sphingomyelin (12). Hart and Cyrus (18) observed hyaline globules in the adrenal medullae in 52% of the cases of Parkinson’s disease studied, but in none of the control population. Involvement of the adrenal medulla in Parkinson’s disease was also noted by Pouplard et al. (29) who identified the presence of an autoantibody in the serum of 43% of tested parkinsonian patients that crossreacted with an antigen in human fetal adrenal medullary cells. The involvement of the autonomic nervous system in Parkinson’s disease and, specifically, the histological and immunological evidence for the involvement of the adrenal medulla suggests that the lowered catecholamine levels seen in our parkinsonian population may be related to the disease process itself. A second explanation for our observations is that the decreased levels of total catecholamines occurred secondary to the drug therapies used to treat the symptoms of Parkinson’s disease. Sinemet was the principal drug used; it is a combination of levodopa (L-dopa), the precursor to dopamine, plus a-methyldopahydrazine (carbidopa), an aromatic L-amino acid decarboxylase inhibitor. Carbidopa, which is excluded from the brain by the blood-brain barrier and perhaps from adrenal medullary tissue by a blood-adrenal barrier (19), is administered to prevent the systemic decarboxylation of L-dopa to dopamine. Nevertheless, some dopamine is synthesized in the periphery (22). Effects of drug therapy could thus potentially result from the action of either L-dopa or dopamine. The most likely effect of administration of the catecholaminergic precursor, L-dopa, is to increase tissue catecholamines. However, it has been shown that Ldopa treatment increases concentrations of DA to a much greater extent than those of NE and EPI (10). Thus it might be anticipated that a portion of the adrenal medullary DA measured in our parkinsonian patients resulted from L-dopa treatment. In contrast, the activities of peripheral tissue catecholamine biosynthetic enzymes, tyrosine hydroxylase (lo), dopamine phydroxylase (26), and aromatic L-amino acid decarboxylase (9) decrease as a result of prolonged treatment with L-dopa alone. The decrease in these enzyme levels is presumably a compensatory change, secondary to the increased catecholamine levels resulting from administration of L-dopa. The activities of the catecholamine catabolic enzyme, monoamine oxidase, may either increase or decrease with chronic L-dopa treatment, depending on the substrate (31). In general, such enzymatic changes would tend to decrease the formation of amines and facilitate their breakdown; this could result, paradoxically, in decreased tissue CA levels even after ad-
MEDULLAE
25
ministration of a precursor, as was observed in our study. Of particular interest in this regard is a report by Riederer et al. (32) that mean tyrosine hydroxylase levels in the adrenal medulla were decreased fourfold from control levels in a population of five patients with Parkinson’s disease who were treated with L-dopa until several days before death. However, data are not available concerning the effects of L-dopa in combination with carbidopa on the activities of enzymes in the adrenal, brain, or periphery. Although carbidopa might be expected to decrease tissue levels of catecholamines by inhibiting the action of aromatic L-amino acid decarboxylase, Horita et al. (19) have shown that, in rats, carbidopa did not inhibit aromatic L-amino acid decarboxylase in adrenal medullary tissue, presumably because of the exclusion of this drug from the adrenal by a blood-adrenal barrier. Thus, administration of carbidopa would not be anticipated to decrease tissue levels of catecholamines in the adrenal medulla. Dopamine and dopaminergic drugs may also modulate the release and storage of adrenal medullary catecholamines. A dopaminergic receptor has been discovered on the chromaffin cell in the cat (2) and identified as the Dz subtype in cultured bovine tissue (16). In both types of tissue a DA agonist, apomorphine, inhibited catecholamine secretion triggered by stimulation of the nicotinic receptor (2,16). In contrast, haloperidol and droperidol, dopamine antagonists, enhanced catecholamine release in cultured bovine adrenal medullary cells (16) and perfused dog adrenals (39), respectively. The fact that the above studies were performed with isolated tissue, i.e., perfused adrenal glands and cultured cells, argues for the ability of dopaminergic agonists and antagonists to act locally to modulate catecholamine release. Similarly, domperidone, a relatively specific D2 antagonist with no central effects, increased the catecholamine content of the adrenal medulla of the rat (15). Observations in human patients support a facilitatory action of DA antagonists on catecholamine secretion. Intravenous injection of metoclopramide, a Dz antagonist that has both peripheral and central actions (27,41), resulted in a 4O-fold increase in free EPI, in addition to smaller increases in free NE and DA, in plasma samples taken from the left adrenal vein of a patient with essential hypertension (23). Metoclopramide is also known to precipitate hypertensive crisis in patients with pheochromocytoma (21). The action of metoclopramide to increase adrenal catecholamine release may result in decreased tissue levels. Thus, in the context of the present study, one patient (Case 15) with drug-induced parkinsonism, who presumably developed this condition secondary to the administration of metoclopramide, had reduced catecholamine levels. In light of these observations, one might expect L-dopa and dopamine agonists to have an opposite effect, i.e., to increase CA levels. If this is correct, then the low adrenal catecholamine levels
26
STODDARD
seen in our idiopathic parkinsonian patients should not be secondary to their dopaminergic drugs. Unfortunately, not all studies of drug interactions with adrenal catecholamines have produced consistent results. Dopaminergic drugs have been reported to decrease (11) or increase adrenal tyrosine hydroxylase activity (30). Baksi et al. (4) reported that both bromocriptine (a dopamine agonist) and haloperidol (a dopamine antagonist) increased adrenal epinephrine content. Drug-adrenal interactions may be complex since adrenal medullary activity can be influenced directly or indirectly via effects mediated by the central nervous system (4,30). Thus, we are unable to conclude whether the decreased CA levels in our parkinsonian population were a result of the medications used in therapy. Data are also presented from the two patients with drug-induced parkinsonism (Figs. 1 and 2). The patient who received reserpine (Case 3) may be considered a control. Reserpine depletes CAs by blocking uptake into chromaffin vesicles. Although this depletion is slower and less complete in the adrenal medulla than in other tissues (43), administration of this drug would be expected to lower CA levels, as was observed. The second patient (Case 15) was discussed above. A recent report by Cervera et al. (8) is relevant to our observations. They found CA levels in parkinsonian adrenals collected at autopsy to be decreased, but not significantly, from a group of control subjects. Several factors may account for the differences between our results. The mean time from death to organ harvest in Cervera and colleagues’ patient population was approximately 19 h, notably greater than in the current study. Since CA levels decrease with *time after death, the longer postmortem delay may have been sufficient to obscure significant differences between groups. The fact that DA was below detection levels in their specimens supports this hypothesis. Additionally, Cervera et al. (8) did not mention whether all their parkinsonian patients had an idiopathic condition or whether the patients were taking Sinemet prior to death. If the decreased CA levels we observed are a function of the pharmacological treatment of parkinsonian symptoms, then the absence of such treatment in the subjects of Cervera et al. (8) might also explain the differences between our two studies. We noted that, in our patient population, specific CAs were variously affected by age and time from death to organ harvest. It is important to note, however, that the size and lack of random sampling in our population limited the power to detect interactions among CA levels, age, and time to organ harvest. It is possible that EPI was significantly decreased in relation to time from death to organ harvest due to a particular sensitivity of phenylethanolamine N-methyl transferase, the enzyme that converts NE to EPI, to postmortem changes. A similar significant relationship between DA and time to organ harvest could be explained by the occurrence of DA in both vesicles and cytoplasm; cytoplasmic DA might be
ET AL.
expected to be lost first as the cell undergoes autolysis. Decreases in NE were significantly related to age. Previous work has shown that there is decreased conversion of precursors to NE in specific brain regions in senescent male mice (14). Furthermore, levels of monoamine oxidase increase with age (33, 44); thus the catabolism of NE may increase, resulting in lower observed levels. Although it was not the aim of the current study to examine specifically the effects of age and time to harvest on adrenal medullary CA levels, this is clearly a relevant area that requires further investigation. In summary, our observations indicate that there may be a decrease in the catecholamine content of the adrenal medulla associated with Parkinson’s disease and parkinsonism. Whether this decrease is related to the mechanisms of the disease itself or whether it is a consequence of drug therapy has yet to be determined. If this reflects an adrenal medullary degenerative process linked to the development of idiopathic Parkinson’s disease, the successof autologous adrenal-brain transplantation as a treatment for Parkinson’s disease may be compromised. ACKNOWLEDGMENTS The authors thank Dr. H. Okazaki for neuropathological examinations, Mr. Robert Wilson for technical assistance, Ms. Sharon Chinnow for performing the catecholamine assays, Ms. Pam Hammond for the protein determinations, and Ms. Eva Gankiewicz and Ms. Julie Kettelkamp for preparation of the graphs. The comments of Drs. W. S. Brimijoin and L. J. Melton III throughout this project are appreciated. This work was supported, in part, by grants from the United Parkinson Disease Foundation (S.W.C.) and by NS 17858 (G.M.T.).
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