BIOL PSYCHIATRY 1990;27:581-591
581
Co xisol, ACTH, and Beta-Endorphin After Dexamethasone Administration in Parkinson's Dementia J.M. Rabey, M. Scharf, Z. Oberman, M. Zohar, and E. Graft
The dexamethasone suppression test (DST) has been suggested as an effective tool for differentiating between depression and dementia. After administering 1 mg dexamethasone, we me¢s,.,,,red¢~rti~ol, ACTH, and beta-endorphin levels in 32 nondepressed patients with idiopathic Parkinson's disease (PD) (14 also with dementia) and 20 healthy, agematched controls. Four of the 20 controls, 9 of the 18 with PD alone, and 8 of the 14 with PD and dementia were dexamethasone nonsuppressors (cortisol value >~ 5 ttg/lO0 ml). PD patients without dementia (nonsuppressors) showed higher basal plasma values of cortisol (22.06 +- 5.30 ItgllO0 ml) compared with the suppressors (13.38 +_ 3.30 ttg/lO0 ml). Plasma ACTH and beta-endorphin responded in a coup~'ed way to dexamethasone challenge. Higher basal levels of both peptides were found among PD patient5 (demented and nondemented), nonresponders to DST. Thus, the DST does not appear to be effective in differentiating between depression and dementia in PD. In addition, PD nonsuppressors showed higher basal values of plasma ACTH, beta-endorphin, and cortirol (similar to patients with major depression). This suggests that although the depression is clinically undetectable, bo~h disorders may share some pathophysiological features at the hypothalamic hypophyseal adrenal level.
Introduction Over recent years, evidence has accumulated to suggest that derangement of the hypothalamic-pituitary-adrenal axis occurs in patients with major depression (Stokes et al. 1975; Carroll et al. 1976a; 1976b). With the overnight low-dose dexamethasone suppression test (DST), many depressed patients show adrenal cortisol hypersecretion, as well as ~attened cortisol circadian periodicity and failure to suppress plasma cortisol concentration. Carroll et al. (1981) reported a 67% sensitivity, 96% specificity, and 94% diagnosis of melancholia with the DST, in hospitalized patients. However, other studies have obtained both concordant (Schlesser et al. 1980; Schatzberg et al. 1983; Kaspers and Beckman 1983; Carroll 1982) and discordant findings (Amsterdam et al. 1982; Raskind
From the Department of Neurology and Clinical Chemistry, T~l-AvivMedical Center, Sackler School of Medicine, Tel Aviv University, Israel. Address reprint requests to Dr. Jose Martin Rabey, Department of Neurology, lchUov Hospital, 6 Weizman Street, Tel-Aviv 64239, Israel. Received December 7, 1988; revised June 8, 1989. © 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
582
BIOL PSYCHIATRY 1990;27:581-591
J.M. Rabey et al.
et al. 1982; Hallstrom et al. 1983; Arana et al. 1983). The differentiation between primary depression with cognitive impairment (pseudodementia) and true dementia, often associated with depressive symptoms, remains a major diagnostic issue for neurologists. The clinical utility of the DST in making this distinction has not been conclusively estabfished. Raskind et al. (1982), Spar and Gerner (1982), Coppen et al. (1983), and Balldin et al. (1983) found a substantial number of abnormal DST in patients with dementia without depression, but Cames et al. (1983) had normal DST results with a specificity of 100% when usitig ~i~ r~s , ~ T to distinguish between dementia and depressive pseudodementia. Similar results were also reported by Castro et al. (1983). An accurate differentiation betw~n depression and dementia is of particular importance when considering Parkinson's disease (PD). In this disorder there is an increased prevalence of psychological depression ranging from 39% (Mayeaux et al. 1981) to 90% (Mindham 1970). Although there appears to be little relationship between depression and the severity of PD (Mayeaux et al. 1981; Robins 1976), the question of whether depression is an integral part of the disease process itself (Robins 1976) or a situational reaction to the increased disability (Warburton 1967) remains unanswered. Moreover, bradykinesia and the facial masking of PD may obscure signs of depression such as psychomotor retardation, rendering the diagnosis more difficult. A progressive cognitive decline is well known in PD, and a positive relationship with depression might be expected if both were part of the same neurophysiological process. Although Mayeaux et al. (1981, 1,983) reported data supporting this hypothesis, others found no significant correlation with depression (Mindham et al. 1976). To clarify the issue, we administered the DST to a population of nondepressed parkinsonian patients (demented and nondemented) and compared the data to that. of agematched controls. It was recently proved that dexamethasone inhibits the hypothalamic hypophyseal pathway, acting via corticotmphin releasing factor (CRF) which modulates the release of adrenocorticotropic hormone (ACTH) and beta-endorphin from the hypophyseal cells. Therefore, in our study, after the administration of dexamethasone, we measured plasma levels of ACTH and beta-endorphin in addition to cortisol.
Methods Thirty-two patients with idiopathic PD and 20 healthy controls (Table 1) were enrolled in the study at the outpatient clinic after giving informed consent. Patients were included if they were free of physical illness known to affect pituitary-adrenal activity (e.g., febrile illness, congestive heart failure, unstable diabetes) and not taking drugs known to affect dex~amethasone metabolism or response (e.g., phenytoin sodium, barbiturates, steroids). Evaluation of each subject ivcluded a complete medical, neurological (performed by the first author), and psychiatric examination (by a qualified psychiatrist). Other diseases were excluded by family and personal history, CT scan, and routine laboratory tests. All parkinsonian patients were on an optimal dose of levodopa alone at the time of the study. The motor function of the patients was assessed according to Hoehn and Yahr classification (1967); mental status was assessed by routine psychiatric interview which included the Research Diagnostic Criteria (RDC) and the Beck Structured Interview. Diagnosis of dementia was given according to DMS~III-R criteria. In addition, a special questionnaire for scoring mental performance was cornpleted by a qualified neurologist. This questionnaire (SMT), which is an Israeli version of the Mini Mental Test (Folstein
DST in Parkinson's Dementia
BIOL PSYCHIATRY 199o;27:581-591
583
Table 1. Patient Characteristics Parkinson'sDisease No. patients Age in yrs (mean) Range Duration of disease (yrs) (mean) Range L Dopa (mg/day) (mean) Range Motor scoring (Hoehn-Yahr) (mean) Range Short mental test (mean) Range
18 68 57-75 8 5-12 525 250-1000 3.3 2-4 87 85-95
Parkinson dementia 14 70 ~)-77 9 4-13 475 125-500 3.8 2-4 35 15-55
Controls 20 66 56-75 ---
97 90-100
et al. 1973), included 22 items of observation, memory, learning ability, calculation, naming, comprehension, visuospatial skill, reading, writing, and abstraction and was previously tested on 500 controls and 200 demented patients and found to be valid for our Hebrew-speaking population. Previous analysis of our group demonstrated that a score of 85% or more indicated a "normal" mental status, and a cut-off point of 62% was used to separate definitely demented patients (Korczyn et al. 1986). An overlap between normal and demented subjects exists for scores between 62 and 85. In the present study, we included parkinsonian patients that belonged to ~ o subgroups: 18 patients without dementia as ascertained in the clinical interview, with "normal scores" in the SMT (above 85%, aged 57-75; mean age 68) and 14 patients with moderate-to-severe dememia (scores below 62% in the SMT, aged 60-77; mean age 70) (Table 1). We excluded candidates who displayed depressive features in the psychiatric interview and ~ score of 10 or more in the Hamilton Depression Rating scale (Hamilton 1960) following the RDC. Three of 14 demented patients could not respond to the Hamilton scale and were evaluated only by the psychiatrist who excluded depression according to their behavior. These 3 patients showed a serious mental deterioration, with severe memory disturbances, difficulty in remembering names, and difficulty with abstract thinking. They were cooperative with their family and unaware of their mental status. They fitted the criteria for dementia according to DSM-HI-R, scored very low values in the SMT questionnaire, and did not show any signs of depression.
Dexamethasone Suppression Test Blood samples taken by venipuncture were obtained at 8 AM for determination of basal values of cortisol, ACTH, and beta-endorphin (predexamethasone measurements). On the s a m e d a y , at I 1 PM 1 mg dexame~hasone was administered orally. On the following d a y , at 4 PM and 11 PM, blood samplt~,~ were obtained for cortisol, ACTH, and betaendorphin (postdexamethasone measurements). DST non~uppression was defined as a plasma cortisol value equal to or greater than 5 ttg/100 nd~ after dexamethasone. Cortisol was determined using a Diagnostic Product Corporation Kit (DPC). The radioimmunoass~y kits for ACTH and beta-endorphin were supplied by Immuno-Nucle.:tr Corporation (INC) USA.
584
BIOLPSYCHIATRY 1990;27:581-591
J.M. Rabey et al.
Table 2. Frequency of Dexamethasone Nonsuppression by Diagnostic Category Response to dexamethasone Group Controls (n = 20) Parkinson nondemented (n =
Suppression n (%)
Nonsuppression n (%)
16 (80%) 9 (50%)
4 (20%) 9 (50%)
8 (57%)
6 (43%)
18)
Parkinson demented (n = 14)
Cortisol M~asurements The estimation of cortisol was done with a DPC kit. The kit coatma count cortisol is highly specific, with an extremely low cross-reactivity with other naturally occurring steroids or therapeutic drugs. In the coat, a count cortisol procedure tZSl-labeled cortisol competes with cortisol in the patients sample for sites on cortisol-specific antibody immobilized to the wall of a propylene tube. After incubation for a fixed period, separation of free from bound is accomplished simply by decanting.
Beta-Endorphin Measurements The procedure for beta-endorphin estimation utilizes a preliminary extraction of betaendotphin specific affinity particles made by coupling the peptide antibody to Sepharose followed by elution, neutralization, and a 17-hr radioimmunoassay procedure. The antibody to human beta-endorphin cross-reacts 100% with human beta-endorphin (Des-Tyr), beta-endorphin (2-Me-Ala), and N-acetyl beta-endorphin. The antibody demonstrates 5% cross-reactivity with beta lipoprotein, using this assay procedure. The normal beta-endorphin levels observed in the lane laboratory are 7 -4- 2 pmol/liter; the normal range ( - 2 SD) 3-11 pmol/liter.
ACTH Measurements The antibody to ACTH has been tested for cross-reactivity with numerous peptides and the only reactive substances are porcine ACTH 1-39 and human ACTH 1-24. The normal range of ACTH in EDTA plasma found in the INC laboratory was 0-73 pg/ml.
Statistical Analysis We utilized a two-way analysis of variance procedure in order to test if there were any differences or interaction between the diagnostic groups studied, before starting the trial; their res~nsiveness to dexamethasone challenge and the values of cortisol, beta-endorplain, and ACTH at 8 AM (dexamethasone pretest). In addition, statistical evaluations of cortisoi, ACTH, and beta-endorphin responses were made by utilizing a two-way analysis of variance and covariance test, with repeated measurements, where the grouping factors considered were (1) controls, Parkinson's, Parkinson's with dementia (in the clinical category); and (2) cortisol response to dexa-
DST in Parkinson's Dementia
BIOL P S Y C ~ T R Y 1990;27:581-591
Table 3. PlasmaCortisol (ttg/100 ml) Before and After Dexamethasoae (Mean _ Responders
585
SD)
Nonresponders
Group
8AM
4PM
11 PM
n
8AM
4PM
lltna
Con¢ol (n = 20) Parkinson's disease (n = 18) Parkinsons's with dementia ( n = 14)
14.29 ± 4.60 13.38 .4- 3.30
2.20 ± 1.40 1.53 ± 0.50
2.40 ± 1.50 1.85 __. 1.00
(20) (9)
15.35 _ 7.10 22.06 ± 5.30
6.50 - 1.40 13.30 ± 7.50
7.0 ± 1.50 12.9 _ 4.50
13.18 --. 6.01
1.08 ± 0.10
1.14 ± 0.30
(8)
14.60 ± 3.61
8.80 - 5.70
14.8 ± 7.10
(5)
(9)
Two-way analysis of variance appfied to cortisol levels at 8 AM. Differences among groups: p - 0.1121 (N.S.) Differences between responders and nonrespondem: p = 0,0265 (significant). Diff~,-rences between diagnostic groups and responders/nonresponders category: p = 0.0674 (almost significant).
methasone challenge (responders and nonresponders). The covariates were the plasma, measurements of cortisol, ACTH, and beta-endorphin at 8 AM, respectively.
Results According to the pretest values of cortisol, ACTH and beta-endorphin at 8 AM (before dexamethasone administration), there were no differences among the tlu'ee study groups (controls, PD, and PD with dementia) (two-way analysis of variance) (see Tables 3, 4, and 5 for p-values). Among the normal controls, 16/20 patients responded to dexamethasone (specificity of 80%) (Table 2). Among the patients with Parkinson's alone there were 9 responders and 9 nonresponders (specificity of 50%). In Parkinsonian patients with dementia, 8 were responders and 6 were nonresponders (specificity of 57%). Basal cortisol leveh (predexamethasone) were similar between responders and nonresponders in the control group and in the group with Parkinson's dementia, but were considerably higher among patients
Table 4. Plasma ACTH (pg/ml) Before and After Dexamethasone(Meaq --. sv) Responders
Nonresponders
Group
8 AM
4 PM
Control (n = 15)
55.83 ± 10.20
42.03 ± 12.30
31.60 ± 7.20
('3)
50.25 ± 7.30
39.00 ± 6.90
42.50 _4. 3,00
(5)
Parkinson's
44.85 ± 11.02
36.20 ± 10.10
26.20 ± 3.50
(8)
66.85 ± 9.92
51.80 ± 8.20
51.70 4. 14.90
(7)
27.00 ± 3.40
30.60 ± 5.50
(5)
97.33 ± 35.30
88.60 ± 30.20
70.30 ± 29.70
(5)
disease (n = 15) Parkinsons's 44.00 ± 6.92
l I eM
n
8 AM
4 i'M
with ~men~a ( n = 10)
Two-way analysis of variance applied to ACTH levels at 8 AM. Differences among groups: p = 0.0538 (almost significant). Differences between responders and nonresponders: p = 0.0265 (significant). Differences between diagnostic groups and responders/nomesponders category: p - 0.0016 (significant).
11 PM
n
586
J.M. Rabey et al.
BIOL PSYCHIATRY 1990;27:581-591
Table 5. Beta-Endorphin(pmol/1) Before and After Dexamethasone (Mean _ SD) Responders
Nonresponders
Group
8 AM
4 PM
11 PM
ti
8 AM
4 PM
11 PM
n
Conuot (n = 15) Parkinson's disease (n = 15) Parkinsons's with dementia (n = 10)
10.68 ± 1.30 6.84 ± 1.28
5.20 ± 1.40 3.80 ± 1.80
4.80 ± 0.90 2.50 ± 1.90
(10) (8)
7.05 ± 1.00 9.95 ± 5.93
7.90 _ 1.20 8.30 ± ~.70
6.40 ± 0.40 8.40 ± 4.50
(5) (7)
6.70 ± 3.57
3.60 ± 2.40
3.20 ± 1.80
(5)
11.10 ± 6.43
8.70 ± 0.80
7.60 ± 0.90
(5)
Two-way analysis of variance applied to beta-endorphin levels at 8 AM. Differences among groups: p = 0.9445 (N.S.). Differences between responders and nonresponders: p -- 0.4067 (N.S.). Differences between diagnostic groups and responders/nonresponders category: p - 0.0853 (almost significant).
with Parkinson's alone who were nonresponders (22.06 + 5.30 ttg/100 ml), compared with the responders (13.38 _+ 3.30 pLg/100 ml) (Table 3). Beta-endorphin and ACTH levels were measured in 15 of the control patients, 15 of the patients with PD alone, and 10 of the patients with Parkinson's dementia (Tables 4, 5). According to the data obtained, both peptides responded in a coupled way to the dexamethasone challenge in all the cases. Nonsuppressor patients with PD (demented and nondemented) showed group differences in the beta-endorphin and ACTH levels before dexamethasone (at 8 AM) with higher values of both peptides, compared with the control group (Tables 4 and 5). Considenng the cortisol response after dexamethasone (two-way analysis of variance) we found the following: 1. A significant difference among diagnostic groups (control, PD, and PD with dementia), (p < 0.05) [F¢2.39) = 3.68] 2. A significant difference between responders and nonresponders (p < 0.0001); [F¢1,39) = 81.06] 3. Interaction with dexamethasone response in the different group categories ( p
581
Co xisol, ACTH, and Beta-Endorphin After Dexamethasone Administration in Parkinson's Dementia J.M. Rabey, M. Scharf, Z. Oberman, M. Zohar, and E. Graft
The dexamethasone suppression test (DST) has been suggested as an effective tool for differentiating between depression and dementia. After administering 1 mg dexamethasone, we me¢s,.,,,red¢~rti~ol, ACTH, and beta-endorphin levels in 32 nondepressed patients with idiopathic Parkinson's disease (PD) (14 also with dementia) and 20 healthy, agematched controls. Four of the 20 controls, 9 of the 18 with PD alone, and 8 of the 14 with PD and dementia were dexamethasone nonsuppressors (cortisol value >~ 5 ttg/lO0 ml). PD patients without dementia (nonsuppressors) showed higher basal plasma values of cortisol (22.06 +- 5.30 ItgllO0 ml) compared with the suppressors (13.38 +_ 3.30 ttg/lO0 ml). Plasma ACTH and beta-endorphin responded in a coup~'ed way to dexamethasone challenge. Higher basal levels of both peptides were found among PD patient5 (demented and nondemented), nonresponders to DST. Thus, the DST does not appear to be effective in differentiating between depression and dementia in PD. In addition, PD nonsuppressors showed higher basal values of plasma ACTH, beta-endorphin, and cortirol (similar to patients with major depression). This suggests that although the depression is clinically undetectable, bo~h disorders may share some pathophysiological features at the hypothalamic hypophyseal adrenal level.
Introduction Over recent years, evidence has accumulated to suggest that derangement of the hypothalamic-pituitary-adrenal axis occurs in patients with major depression (Stokes et al. 1975; Carroll et al. 1976a; 1976b). With the overnight low-dose dexamethasone suppression test (DST), many depressed patients show adrenal cortisol hypersecretion, as well as ~attened cortisol circadian periodicity and failure to suppress plasma cortisol concentration. Carroll et al. (1981) reported a 67% sensitivity, 96% specificity, and 94% diagnosis of melancholia with the DST, in hospitalized patients. However, other studies have obtained both concordant (Schlesser et al. 1980; Schatzberg et al. 1983; Kaspers and Beckman 1983; Carroll 1982) and discordant findings (Amsterdam et al. 1982; Raskind
From the Department of Neurology and Clinical Chemistry, T~l-AvivMedical Center, Sackler School of Medicine, Tel Aviv University, Israel. Address reprint requests to Dr. Jose Martin Rabey, Department of Neurology, lchUov Hospital, 6 Weizman Street, Tel-Aviv 64239, Israel. Received December 7, 1988; revised June 8, 1989. © 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
582
BIOL PSYCHIATRY 1990;27:581-591
J.M. Rabey et al.
et al. 1982; Hallstrom et al. 1983; Arana et al. 1983). The differentiation between primary depression with cognitive impairment (pseudodementia) and true dementia, often associated with depressive symptoms, remains a major diagnostic issue for neurologists. The clinical utility of the DST in making this distinction has not been conclusively estabfished. Raskind et al. (1982), Spar and Gerner (1982), Coppen et al. (1983), and Balldin et al. (1983) found a substantial number of abnormal DST in patients with dementia without depression, but Cames et al. (1983) had normal DST results with a specificity of 100% when usitig ~i~ r~s , ~ T to distinguish between dementia and depressive pseudodementia. Similar results were also reported by Castro et al. (1983). An accurate differentiation betw~n depression and dementia is of particular importance when considering Parkinson's disease (PD). In this disorder there is an increased prevalence of psychological depression ranging from 39% (Mayeaux et al. 1981) to 90% (Mindham 1970). Although there appears to be little relationship between depression and the severity of PD (Mayeaux et al. 1981; Robins 1976), the question of whether depression is an integral part of the disease process itself (Robins 1976) or a situational reaction to the increased disability (Warburton 1967) remains unanswered. Moreover, bradykinesia and the facial masking of PD may obscure signs of depression such as psychomotor retardation, rendering the diagnosis more difficult. A progressive cognitive decline is well known in PD, and a positive relationship with depression might be expected if both were part of the same neurophysiological process. Although Mayeaux et al. (1981, 1,983) reported data supporting this hypothesis, others found no significant correlation with depression (Mindham et al. 1976). To clarify the issue, we administered the DST to a population of nondepressed parkinsonian patients (demented and nondemented) and compared the data to that. of agematched controls. It was recently proved that dexamethasone inhibits the hypothalamic hypophyseal pathway, acting via corticotmphin releasing factor (CRF) which modulates the release of adrenocorticotropic hormone (ACTH) and beta-endorphin from the hypophyseal cells. Therefore, in our study, after the administration of dexamethasone, we measured plasma levels of ACTH and beta-endorphin in addition to cortisol.
Methods Thirty-two patients with idiopathic PD and 20 healthy controls (Table 1) were enrolled in the study at the outpatient clinic after giving informed consent. Patients were included if they were free of physical illness known to affect pituitary-adrenal activity (e.g., febrile illness, congestive heart failure, unstable diabetes) and not taking drugs known to affect dex~amethasone metabolism or response (e.g., phenytoin sodium, barbiturates, steroids). Evaluation of each subject ivcluded a complete medical, neurological (performed by the first author), and psychiatric examination (by a qualified psychiatrist). Other diseases were excluded by family and personal history, CT scan, and routine laboratory tests. All parkinsonian patients were on an optimal dose of levodopa alone at the time of the study. The motor function of the patients was assessed according to Hoehn and Yahr classification (1967); mental status was assessed by routine psychiatric interview which included the Research Diagnostic Criteria (RDC) and the Beck Structured Interview. Diagnosis of dementia was given according to DMS~III-R criteria. In addition, a special questionnaire for scoring mental performance was cornpleted by a qualified neurologist. This questionnaire (SMT), which is an Israeli version of the Mini Mental Test (Folstein
DST in Parkinson's Dementia
BIOL PSYCHIATRY 199o;27:581-591
583
Table 1. Patient Characteristics Parkinson'sDisease No. patients Age in yrs (mean) Range Duration of disease (yrs) (mean) Range L Dopa (mg/day) (mean) Range Motor scoring (Hoehn-Yahr) (mean) Range Short mental test (mean) Range
18 68 57-75 8 5-12 525 250-1000 3.3 2-4 87 85-95
Parkinson dementia 14 70 ~)-77 9 4-13 475 125-500 3.8 2-4 35 15-55
Controls 20 66 56-75 ---
97 90-100
et al. 1973), included 22 items of observation, memory, learning ability, calculation, naming, comprehension, visuospatial skill, reading, writing, and abstraction and was previously tested on 500 controls and 200 demented patients and found to be valid for our Hebrew-speaking population. Previous analysis of our group demonstrated that a score of 85% or more indicated a "normal" mental status, and a cut-off point of 62% was used to separate definitely demented patients (Korczyn et al. 1986). An overlap between normal and demented subjects exists for scores between 62 and 85. In the present study, we included parkinsonian patients that belonged to ~ o subgroups: 18 patients without dementia as ascertained in the clinical interview, with "normal scores" in the SMT (above 85%, aged 57-75; mean age 68) and 14 patients with moderate-to-severe dememia (scores below 62% in the SMT, aged 60-77; mean age 70) (Table 1). We excluded candidates who displayed depressive features in the psychiatric interview and ~ score of 10 or more in the Hamilton Depression Rating scale (Hamilton 1960) following the RDC. Three of 14 demented patients could not respond to the Hamilton scale and were evaluated only by the psychiatrist who excluded depression according to their behavior. These 3 patients showed a serious mental deterioration, with severe memory disturbances, difficulty in remembering names, and difficulty with abstract thinking. They were cooperative with their family and unaware of their mental status. They fitted the criteria for dementia according to DSM-HI-R, scored very low values in the SMT questionnaire, and did not show any signs of depression.
Dexamethasone Suppression Test Blood samples taken by venipuncture were obtained at 8 AM for determination of basal values of cortisol, ACTH, and beta-endorphin (predexamethasone measurements). On the s a m e d a y , at I 1 PM 1 mg dexame~hasone was administered orally. On the following d a y , at 4 PM and 11 PM, blood samplt~,~ were obtained for cortisol, ACTH, and betaendorphin (postdexamethasone measurements). DST non~uppression was defined as a plasma cortisol value equal to or greater than 5 ttg/100 nd~ after dexamethasone. Cortisol was determined using a Diagnostic Product Corporation Kit (DPC). The radioimmunoass~y kits for ACTH and beta-endorphin were supplied by Immuno-Nucle.:tr Corporation (INC) USA.
584
BIOLPSYCHIATRY 1990;27:581-591
J.M. Rabey et al.
Table 2. Frequency of Dexamethasone Nonsuppression by Diagnostic Category Response to dexamethasone Group Controls (n = 20) Parkinson nondemented (n =
Suppression n (%)
Nonsuppression n (%)
16 (80%) 9 (50%)
4 (20%) 9 (50%)
8 (57%)
6 (43%)
18)
Parkinson demented (n = 14)
Cortisol M~asurements The estimation of cortisol was done with a DPC kit. The kit coatma count cortisol is highly specific, with an extremely low cross-reactivity with other naturally occurring steroids or therapeutic drugs. In the coat, a count cortisol procedure tZSl-labeled cortisol competes with cortisol in the patients sample for sites on cortisol-specific antibody immobilized to the wall of a propylene tube. After incubation for a fixed period, separation of free from bound is accomplished simply by decanting.
Beta-Endorphin Measurements The procedure for beta-endorphin estimation utilizes a preliminary extraction of betaendotphin specific affinity particles made by coupling the peptide antibody to Sepharose followed by elution, neutralization, and a 17-hr radioimmunoassay procedure. The antibody to human beta-endorphin cross-reacts 100% with human beta-endorphin (Des-Tyr), beta-endorphin (2-Me-Ala), and N-acetyl beta-endorphin. The antibody demonstrates 5% cross-reactivity with beta lipoprotein, using this assay procedure. The normal beta-endorphin levels observed in the lane laboratory are 7 -4- 2 pmol/liter; the normal range ( - 2 SD) 3-11 pmol/liter.
ACTH Measurements The antibody to ACTH has been tested for cross-reactivity with numerous peptides and the only reactive substances are porcine ACTH 1-39 and human ACTH 1-24. The normal range of ACTH in EDTA plasma found in the INC laboratory was 0-73 pg/ml.
Statistical Analysis We utilized a two-way analysis of variance procedure in order to test if there were any differences or interaction between the diagnostic groups studied, before starting the trial; their res~nsiveness to dexamethasone challenge and the values of cortisol, beta-endorplain, and ACTH at 8 AM (dexamethasone pretest). In addition, statistical evaluations of cortisoi, ACTH, and beta-endorphin responses were made by utilizing a two-way analysis of variance and covariance test, with repeated measurements, where the grouping factors considered were (1) controls, Parkinson's, Parkinson's with dementia (in the clinical category); and (2) cortisol response to dexa-
DST in Parkinson's Dementia
BIOL P S Y C ~ T R Y 1990;27:581-591
Table 3. PlasmaCortisol (ttg/100 ml) Before and After Dexamethasoae (Mean _ Responders
585
SD)
Nonresponders
Group
8AM
4PM
11 PM
n
8AM
4PM
lltna
Con¢ol (n = 20) Parkinson's disease (n = 18) Parkinsons's with dementia ( n = 14)
14.29 ± 4.60 13.38 .4- 3.30
2.20 ± 1.40 1.53 ± 0.50
2.40 ± 1.50 1.85 __. 1.00
(20) (9)
15.35 _ 7.10 22.06 ± 5.30
6.50 - 1.40 13.30 ± 7.50
7.0 ± 1.50 12.9 _ 4.50
13.18 --. 6.01
1.08 ± 0.10
1.14 ± 0.30
(8)
14.60 ± 3.61
8.80 - 5.70
14.8 ± 7.10
(5)
(9)
Two-way analysis of variance appfied to cortisol levels at 8 AM. Differences among groups: p - 0.1121 (N.S.) Differences between responders and nonrespondem: p = 0,0265 (significant). Diff~,-rences between diagnostic groups and responders/nonresponders category: p = 0.0674 (almost significant).
methasone challenge (responders and nonresponders). The covariates were the plasma, measurements of cortisol, ACTH, and beta-endorphin at 8 AM, respectively.
Results According to the pretest values of cortisol, ACTH and beta-endorphin at 8 AM (before dexamethasone administration), there were no differences among the tlu'ee study groups (controls, PD, and PD with dementia) (two-way analysis of variance) (see Tables 3, 4, and 5 for p-values). Among the normal controls, 16/20 patients responded to dexamethasone (specificity of 80%) (Table 2). Among the patients with Parkinson's alone there were 9 responders and 9 nonresponders (specificity of 50%). In Parkinsonian patients with dementia, 8 were responders and 6 were nonresponders (specificity of 57%). Basal cortisol leveh (predexamethasone) were similar between responders and nonresponders in the control group and in the group with Parkinson's dementia, but were considerably higher among patients
Table 4. Plasma ACTH (pg/ml) Before and After Dexamethasone(Meaq --. sv) Responders
Nonresponders
Group
8 AM
4 PM
Control (n = 15)
55.83 ± 10.20
42.03 ± 12.30
31.60 ± 7.20
('3)
50.25 ± 7.30
39.00 ± 6.90
42.50 _4. 3,00
(5)
Parkinson's
44.85 ± 11.02
36.20 ± 10.10
26.20 ± 3.50
(8)
66.85 ± 9.92
51.80 ± 8.20
51.70 4. 14.90
(7)
27.00 ± 3.40
30.60 ± 5.50
(5)
97.33 ± 35.30
88.60 ± 30.20
70.30 ± 29.70
(5)
disease (n = 15) Parkinsons's 44.00 ± 6.92
l I eM
n
8 AM
4 i'M
with ~men~a ( n = 10)
Two-way analysis of variance applied to ACTH levels at 8 AM. Differences among groups: p = 0.0538 (almost significant). Differences between responders and nonresponders: p = 0.0265 (significant). Differences between diagnostic groups and responders/nomesponders category: p - 0.0016 (significant).
11 PM
n
586
J.M. Rabey et al.
BIOL PSYCHIATRY 1990;27:581-591
Table 5. Beta-Endorphin(pmol/1) Before and After Dexamethasone (Mean _ SD) Responders
Nonresponders
Group
8 AM
4 PM
11 PM
ti
8 AM
4 PM
11 PM
n
Conuot (n = 15) Parkinson's disease (n = 15) Parkinsons's with dementia (n = 10)
10.68 ± 1.30 6.84 ± 1.28
5.20 ± 1.40 3.80 ± 1.80
4.80 ± 0.90 2.50 ± 1.90
(10) (8)
7.05 ± 1.00 9.95 ± 5.93
7.90 _ 1.20 8.30 ± ~.70
6.40 ± 0.40 8.40 ± 4.50
(5) (7)
6.70 ± 3.57
3.60 ± 2.40
3.20 ± 1.80
(5)
11.10 ± 6.43
8.70 ± 0.80
7.60 ± 0.90
(5)
Two-way analysis of variance applied to beta-endorphin levels at 8 AM. Differences among groups: p = 0.9445 (N.S.). Differences between responders and nonresponders: p -- 0.4067 (N.S.). Differences between diagnostic groups and responders/nonresponders category: p - 0.0853 (almost significant).
with Parkinson's alone who were nonresponders (22.06 + 5.30 ttg/100 ml), compared with the responders (13.38 _+ 3.30 pLg/100 ml) (Table 3). Beta-endorphin and ACTH levels were measured in 15 of the control patients, 15 of the patients with PD alone, and 10 of the patients with Parkinson's dementia (Tables 4, 5). According to the data obtained, both peptides responded in a coupled way to the dexamethasone challenge in all the cases. Nonsuppressor patients with PD (demented and nondemented) showed group differences in the beta-endorphin and ACTH levels before dexamethasone (at 8 AM) with higher values of both peptides, compared with the control group (Tables 4 and 5). Considenng the cortisol response after dexamethasone (two-way analysis of variance) we found the following: 1. A significant difference among diagnostic groups (control, PD, and PD with dementia), (p < 0.05) [F¢2.39) = 3.68] 2. A significant difference between responders and nonresponders (p < 0.0001); [F¢1,39) = 81.06] 3. Interaction with dexamethasone response in the different group categories ( p
