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TRH stimulation test in dementia of the Alzheimer type and elderly controls
Psychiatry Research, 16, 269-275 Elsevier
269
TR H Stimulation Test in Dementia of the Alzheimer Type and Elderly Controls Trey Sunderland, Pierre N. Tariot, Edward A. Mueller, Paul A. Newhouse, Dennis L. Murphy, and Robert M. Cohen Received May 6, 1985; revised version received August 15, 1985; accepted August 27, 1985. Abstract. Dementia of the Alzheimer type (DAT) is known to be a heterogeneous
syndrome with many clinical manifestations, including depression. In the present study, the thyrotropin-releasing hormone (TRH) stimulation test, previously used as a possible biological marker of depression, was administered to i 5 DAT patients and l0 elderly controls. Seven out of 15 (47%) of the patients but none of the controls showed a blunted response with maximal changes of thyroid-stimulating hormone (TSH) from baseline of ~< 7 #lU/ml following injection of 500 p,g of TRH. The degree of blunting did not correlate with concurrent depression ratings. Key Words. Dementia of the Alzheimer type, depression, thyrotropin-releasing hormone test. Symptoms of depression have frequently been reported to coexist with dementia (Post, 1975; Wells, 1979; Demuth and Rand, 1980; Miller, 1980; Caine, 1981; McAllister and Price, 1982; Reifler et al., 1982; Kral, 1983; Wamboldt et al., 1985). Previous investigations of possible biological markers of depression in patients with dementia have led to contradictory results. Some authors have reported up to 50% nonsuppression of cortisol following the dexamethasone suppression test (DST) (Raskind et al., 1982; Spar and Gerner, 1982; Balldin et al., 1983), while Others have shown abnormal DSTs in ~< 13% of demented patients (Carnes et al., 1983b; Castro et al., 1983). One report cited DST nonsuppression only in demented patients who concurrently met D S M - I I I criteria (American Psychiatric Association, 1980) for major depressive illness (Carnes et al., 1983a). Overnight electroencephalographic (EEG) recordings have revealed abnormalities in sleep architecture and rapid eye movement (REM) duration but not REM latency in patients with dementia of the Alzheimer type (Feinberg et al., 1967; Lowenstein et al., 1982; Prinz et al., 1982). Since the thyrotropin-releasing hormone (TRH) stimulation test has been used extensively as a possible biological marker in depressed populations (Prange et al., 1972; Kirkegaard et al., 1975; Gold et al., 1980; Loosen and Prange, 1982), we were interested in the T R H response of demented patients and elderly controls.
Methods Subjects. Fifteen patients with dementia of the Alzheimer type (DAT) were studied during hospitalization at the National Institute of Mental Health. All patients met DSM-lllcriteria for Trey Sunderland, M.D., Pierre N. Tariot, M.D., Edward A. Mueller, M.D., and Paul A. Newhouse,M.D., are Staff Psychiatrists, and Dennis L. Murphy, M.D., is Chief, Laboratory of Clinical Science, National Institute of Mental Health (N1MH). Robert M. Cohen, M.D., Ph.D., is Chief, Section on Clinical Brain Imaging, Laboratoryof Cerebral Metabolism, N1MH. (Reprint requests to Dr. T. Sunderland, Laboratory of Clinical Science, NIMH, Bldg. 10, Rm. 3D41, 9000 Rockville Pike, Washington, DC 20892, USA.) 0165-1781/85 $03.30© 1985Elsevier Science Publishers B.V.
270 DAT and were rated as having mild (two patients), moderate (9 patients), or severe 1'4 patients) illness based on the criteria of Hughes et al. (1982). They were also evaluated for degree of observable depression with the 17-item Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960). Patients included seven males and eight females with an average age of 63.4 (range 42-77) years. Ten healthy elderly outpatient volunteers (six males and four femaIes) were also studied. The average age of the controls was 61.3 Irange 48-72) years. All subjects were free of significant medical and endocrine illness. Control subjects were screened with a complete clinical and neuropsychological evaluation to exclude psychiatric or cogmtive impairment. Subjects were off all medications for at least 3 weeks before testing.
Procedure. Studies were performed while subjects were supine between 8:30 and 10:00 a.m. after an overnight fast (smoking was also prohibited). After insertion of an 18-gauge intravenous (i.v.) catheter, subjects were allowed to rest for at least 20 minutes before beginning the procedure. Baseline bloods were then collected through the i.v. catheter at -15 and 0 minutes before the infusion, Protirelin (500 ~g) was then administered as a rapid i.v, bolus. Bloods for measurement of thyroid-stimulating-hormone(TS H) were subsequently collected at 15. 20.30. and 45 minutes following the TRH injection. Samples were centrifuged for 10 minutes at 2400 r.p.m, before the serum was separated and stored at -20°C for subsequent assay. Assay. TSH levels were determined by a double-antibody radioimmunoassay technique (Beckman Immuno Systems). The interassay and intra-assay coefficients of variation were 8.9% and 9.6°~. respectively. Triiodothyronine (T3), thyroxine (T~), total protein, and free T~ were also measured by the clinical laboratory for patients and controls at baseline. Free T~ was determined by an equilibrium dialysis technique. All assays were conducted without knowledge of diagnosis.
Data Analysis. Baseline thyroid functions and total protein determinations for patients and controls were analyzed for between-group differences using Student's t test. The TRH test response was evaluated in two ways: (l) A two-way analysis of variance (ANOVA) with repeated measures was completed with Tukey's Honestly Significant Difference (HSD) for paired comparisons of diagnostic group effects across the six time points. (2) The maximal elevation of TSH above mean baseline value (Amax TSH I for each subject was determined and compared between groups using Fisher's exact test with a cutoff for a "'positive" ATSH as 7 ~IU ml. Since the cutoffscore for a positive result in the TRH test has been variably defined in previous studies as a Amax TSH response of 5/~IU/ml (Loosen and Prange, 1982) or 7 #l U ml (Gold et al.. 198 l), results from a Fisher's exact test with the 5 #IU ml cutoff definition are also included. Pearson's product-moment correlation was subsequently used to correlate the ~max TSH values with other variables such as age, severity of dementia, and depression rating.
Results There were n o significant differences between the two study groups in age, weight, or baseline thyroid f u n c t i o n tests (Table 1). The baseline T S H levels were slightly higher in the D A T patients (3.9 # I U / m l ) versus the contols (3.5 ~ d U / m l ) , but this difference did not reach statistical significance (t -- 0.72, p > 0.05). W h e n analyzed for g r o u p differences, the d e m e n t i a g r o u p had significantly lower A m a x T S H responses t h a n n o r m a l c o n t r o l s (9.07 ± S D 5.31 vs. 14.68 ± S D 7.37, t = 2 . 2 2 , p ( 0 . 0 5 ) , It c a n be seen in Fig. I that the difference i n s e r u m T S H between groups is significant (by A N O V A with repeated measures) at the 20, 30, a n d 4 5 m i n u t e timepoints. If a positive or a b n o r m a l T R H test is defined as a A m a x T S H ( 7/~l U / ml. then 7 of 15 d e m e n t i a p a t i e n t s (47%) showed b l u n t e d TS H responses, whereas n o n e of
271
Table 1. Age and baseline thyroid function levels before TRH test in dementia patients and normal elderly controls DemenUa patients
Normalcontrols
(n = 15)
(n = 10)
Variables A g e (years) Baseline TSH (#lU/ml) T o t a l T4 (/~g/dl) T3 ( n g / d l ) Free T4 ( n g / d l )
Mean
SD
Mean
SD
p
63.5 3.9 9.1 130.6
9.7 1.9 1.9 25.6
61.3 3.5 7.9 131.6
8.2 0.9 1.6 48.7
NS NS NS NS
1.8
0.4
1.6
0.3
NS
Significance values based on 2-tailed Student's t test.
the n o r m a l volunteers had a peak A T S H < 7 # I U / m l (Fisher's exact probability : 0.025). With a cutoff for A m a x T S H of 5 # I U / m l as the definition of a positive T R H test, 5 of the 15 D A T patients still showed blunted responses versus none of the controls (Fisher's exact probability = 0.056). There was no significant correlation in this sample between age and A m a x T S H for either the patients (r = -0.30) or controls (r = -0.22), but there was a trend toward sex differences in A m a x T S H , with females f r o m both groups combined having a greater A m a x TS H (13.3/~I U / ml vs. 9.5 # I U / ml, t = 1.45, p > 0.05). Within the D A T group, there was a mean A m a x T S H of 8.5/~IU/ml for the males and 11.0/~IU/ml for the females (t = 0.83, p > 0.05). Of the seven blunted T S H responses, three (43%) were females. The control g r o u p revealed a similar trend with a mean A m a x T S H of 12.5
Fig. 1. TSH responses to TRH across time in 15 dementia patients and 10 elderly controls :;
25
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20
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o FZ
-'
~
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10
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T E,der'y Controls ,.-10, **
Dementia .L PlaltiJln;~
Z
o I m k-Z
5 Z
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-15
0
15
20
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TIME (minutes) Data represent group means (+ standard errorl (*p < 0.05, **p < 0.01, difference from elderly control values).
272 # I U ml for the males a n d 17.9 # l U / m l for the females (t = 1.16, p > 0.05). Baseline T S H m e a s u r e s were c o r r e l a t e d with the A m a x T S H (r = 0.60, p < 0.05) in the D A ' f p o p u l a t i o n . The D A T patients w h o h a d b l u n t e d T S H responses had a lowe~ baseline T S H value (2.8 -+ I. ! / ~ I U / m l ) t h a n the patients with n o r m a l T S H r e s p o n s e s t49_+ 2.2 # I U / m l . t = 2.8. p < 0.05). W h e n the A m a x T S H r e s p o n s e was r e a n a l y z e d as p e r c e n t a g e c h a n g e f r o m baseline, there was still a significant difference between the D A T a n d c o n t r o l groups, with the D A T patients s h o w i n g a m e a n rise of 134% versus 295% for the c o n t r o l s (t = 3.10. p < 0.01). The H R S D score failed to show a significant a s s o c i a t i o n (r = -0.29) with the ~ m a x T S H r e s p o n s e in the D A T patients. T h e r e was one female patient who met D S M - I I I criteria for m a j o r depressive d i s o r d e r a n d had an H R S D score o f 25. b u t she did not s h o w evidence of T S H b l u n t i n g , with a A m a x T S H o f 11.5 # I U / ml. T h e H R S D score f o r the entire D A T g r o u p was 11.9 ( S D 7.2) versus < 5 for the c o n t r o l g r o u p . On the H R S D . the p a t i e n t g r o u p scored positively for d e p r e s s i o n in a r e a s o f sleep d i s o r d e r . d e c r e a s e d energy, a n d s o m a t i c c o m p l a i n t s . T h e seven D A T patients with b l u n t e d responses to T R H had a m e a n H R S D score of 13.1 I S D 7.7) versus 10.9 ( S D 7.1) for the r e m a i n i n g eight patients. A g a i n when the positive T R H test was defined as a A m a x T S H r e s p o n s e of < 7 ~ t l U / m l , only three of seven D A T patients with a blunted r e s p o n s e h a d H R S D scores a b o v e the g r o u p m e a n of 12, while three of the eight D A T patients w i t h o u t b l u n t i n g also had H R S D scores a b o v e 12 (Fis her's exact test. N S). T h e r e was no significant c o r r e l a t i o n between severity o f d e m e n t i a as m e a s u r e d by the H u g h e s scale a n d d e p r e s s i o n (r -- -0.33). H o w e v e r . there was a t r e n d in this small s a m p l e t o w a r d a negative c o r r e l a t i o n between severity o f d e m e n t i a a n d £kmax TSI-t (r = -0.42), which was evident in both sexes.
Discussion A l t h o u g h d e b a t e c o n t m u e s as to w h e t h e r d e p r e s s i o n is an i m p o r t a n t element in the p r o g r e s s i o n of D A T (Knesevich et al. 1983), there is little d o u b t that d e p r e s s i o n occurs in s o m e D A T patients (Miller. 1980'. Reifler et al.. 1982). Previous a t t e m p t s to assess n e u r o e n d o c r i n e responses in this p o p u l a t i o n with the D S T have p r o d u c e d mixed results ( R a s k i n d et al.. 1982: S p a r a n d Gerner. 1982: Carnes et al.. 1983a, 1983b). We have a d m i n i s t e r e d the T R H s t i m u l a t i o n test to D A T p a t i e n t s a n d f o u n d a b l u n t i n g in A m a x T S H r e s p o n s e in 7 15 (47%) of subjects, which is s i m i l a r to the incidence of r e d u c t i o n s p r e v i o u s l y f o u n d in depressed patients of all ages ( L o o s e n a n d Prange, 1982). This b l u n t i n g of T S H response is significant when c o m p a r e d to o u r results in an a g e - m a t c h e d c o n t r o l group, b o t h f o r A m a x T S H c h a n g e s a n d for a c t u a l T S H levels at m o s t time p o i n t s after T R H infusion, a n d calls into question the utility o f the F R H test m helping to distinguish d e m e n t i a patients f r o m elderly depressed C a l l o w a y et al. (1984) have recently s h o w n that depressed patients with a blunted T S H r e s p o n s e to T R H have a g e n e r a l l y lower b a s a l T S H when c o m p a r e d to those p a t i e n t s with a n o r m a l o r a u g m e n t e d T S H response. This a s s o c i a t i o n was also evident in o u r D A T patients. A l t h o u g h there were no significant differences between the patients a n d c o n t r o l g r o u p on m e a s u r e s o f baseline t h y r o i d function, the l o w e r mean b a s a l T S H in the p a t i e n t s with b l u n t e d r e s p o n s e s to T R H suggests that D A T patients with a d i m i n i s h e d T R H response, much like the depressed patients in the study of
273 Calloway et al. (1984), may have a subtly different thyroid set point at baseline. As has been noted previously (Snyder and Utiger, 1972), males in our study showed a trend toward lower Amax TSH responses than females in both the patient and control populations. Nonetheless, nearly half (43%) of the patients showing a blunted response in the DAT group were females, suggesting that sex alone was not primarily responsible for the T R H abnormality. There was a trend toward a reduced Amax TSH with increasing age, even within the limited age range of the patients studied, but this trend was evident in both groups and also would not explain the group differences in TSH response. Within the DAT group, there was also a suggestion that increasing severity of dementia may be associated with a greater likelihood of T R H blunting. Several of the DAT patients did show evidence of clinically apparent depression, but there was no significant correlation between H R S D scores and the Amax TSH in this small sample. While previous experience in depressed populations has also not revealed strong correlations between reduced ATSH and clinical measures of depression (Calloway et al., 1984), questions remain about the validity of the available depression scales in this population. The H R S D (Hamilton, 1960), Beck depression inventory (Beck et al., 1961), and Zung Self-Rating Depression Scale (Zung, 1965), all of which have been used with DAT patients, were never intended for a cognitively impaired population, and may well be reflecting some symptoms other than depression in the DAT population. The pathophysiological significance of a blunted T R H response in depressed patients or other psychiatric populations is poorly understood. Increased or decreased levels of cortisol, somatostatin, norepinephrine, serotonin, and dopamine have all been implicated as possibly influencing the TSH response to T R H (Besses et al., 1975; Tanjasiri et al., 1976; Martin et al., 1977; Gold et al., 1977; Loosen et al., 1978). Although some researchers have suggested that single neurotransmitter systems could be responsible for the blunted TSH response in affective illness (Gold et al., 1977; Loosen and Prange, 1982), there is no general consensus concerning a specific abnormality (Cohen and Cohen, 1981). Disruptions in these same hormonal and neurotransmitter systems have been previously described in DAT (Bowen et al., 1979; Terry and Davies, 1980; Bondareffet al., 1981; Spar and Gerner, 1982; Winblad et al., 1982; Raskind et al., 1984). Further empiric studies examining the interrelationships between specific neurotransmitters and the blunted TSH response to T R H in DAT may be of value. In summary, it appears that DAT patients can display evidence of blunting in the T R H stimulation test that cannot be explained simply on the basis of aging alone. This blunting is not the result of obvious baseline thyroid abnormalities and is in marked contrast to our observations in elderly control subjects. Ratings of concurrent depression do not correlate with the Amax TSH response and may themselves be measuring something other than depression in this cognitvely impaired population. In view of the fact that the T S H response to T R H has now been found to be blunted in several psychiatric populations, including depression and mania (Kirkegaard et al., 1975; Loosen et al., 1978), alcoholics (Loosen and Prange, 1979), and borderline personality disorders (Garbutt et al., 1983), its potential usefulness in differentiating dementia from pseudodementia appears limited. Further study of a broad range of DAT patients, elderly controls, and other populations such as the elderly depressed is needed.
274
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269
TR H Stimulation Test in Dementia of the Alzheimer Type and Elderly Controls Trey Sunderland, Pierre N. Tariot, Edward A. Mueller, Paul A. Newhouse, Dennis L. Murphy, and Robert M. Cohen Received May 6, 1985; revised version received August 15, 1985; accepted August 27, 1985. Abstract. Dementia of the Alzheimer type (DAT) is known to be a heterogeneous
syndrome with many clinical manifestations, including depression. In the present study, the thyrotropin-releasing hormone (TRH) stimulation test, previously used as a possible biological marker of depression, was administered to i 5 DAT patients and l0 elderly controls. Seven out of 15 (47%) of the patients but none of the controls showed a blunted response with maximal changes of thyroid-stimulating hormone (TSH) from baseline of ~< 7 #lU/ml following injection of 500 p,g of TRH. The degree of blunting did not correlate with concurrent depression ratings. Key Words. Dementia of the Alzheimer type, depression, thyrotropin-releasing hormone test. Symptoms of depression have frequently been reported to coexist with dementia (Post, 1975; Wells, 1979; Demuth and Rand, 1980; Miller, 1980; Caine, 1981; McAllister and Price, 1982; Reifler et al., 1982; Kral, 1983; Wamboldt et al., 1985). Previous investigations of possible biological markers of depression in patients with dementia have led to contradictory results. Some authors have reported up to 50% nonsuppression of cortisol following the dexamethasone suppression test (DST) (Raskind et al., 1982; Spar and Gerner, 1982; Balldin et al., 1983), while Others have shown abnormal DSTs in ~< 13% of demented patients (Carnes et al., 1983b; Castro et al., 1983). One report cited DST nonsuppression only in demented patients who concurrently met D S M - I I I criteria (American Psychiatric Association, 1980) for major depressive illness (Carnes et al., 1983a). Overnight electroencephalographic (EEG) recordings have revealed abnormalities in sleep architecture and rapid eye movement (REM) duration but not REM latency in patients with dementia of the Alzheimer type (Feinberg et al., 1967; Lowenstein et al., 1982; Prinz et al., 1982). Since the thyrotropin-releasing hormone (TRH) stimulation test has been used extensively as a possible biological marker in depressed populations (Prange et al., 1972; Kirkegaard et al., 1975; Gold et al., 1980; Loosen and Prange, 1982), we were interested in the T R H response of demented patients and elderly controls.
Methods Subjects. Fifteen patients with dementia of the Alzheimer type (DAT) were studied during hospitalization at the National Institute of Mental Health. All patients met DSM-lllcriteria for Trey Sunderland, M.D., Pierre N. Tariot, M.D., Edward A. Mueller, M.D., and Paul A. Newhouse,M.D., are Staff Psychiatrists, and Dennis L. Murphy, M.D., is Chief, Laboratory of Clinical Science, National Institute of Mental Health (N1MH). Robert M. Cohen, M.D., Ph.D., is Chief, Section on Clinical Brain Imaging, Laboratoryof Cerebral Metabolism, N1MH. (Reprint requests to Dr. T. Sunderland, Laboratory of Clinical Science, NIMH, Bldg. 10, Rm. 3D41, 9000 Rockville Pike, Washington, DC 20892, USA.) 0165-1781/85 $03.30© 1985Elsevier Science Publishers B.V.
270 DAT and were rated as having mild (two patients), moderate (9 patients), or severe 1'4 patients) illness based on the criteria of Hughes et al. (1982). They were also evaluated for degree of observable depression with the 17-item Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960). Patients included seven males and eight females with an average age of 63.4 (range 42-77) years. Ten healthy elderly outpatient volunteers (six males and four femaIes) were also studied. The average age of the controls was 61.3 Irange 48-72) years. All subjects were free of significant medical and endocrine illness. Control subjects were screened with a complete clinical and neuropsychological evaluation to exclude psychiatric or cogmtive impairment. Subjects were off all medications for at least 3 weeks before testing.
Procedure. Studies were performed while subjects were supine between 8:30 and 10:00 a.m. after an overnight fast (smoking was also prohibited). After insertion of an 18-gauge intravenous (i.v.) catheter, subjects were allowed to rest for at least 20 minutes before beginning the procedure. Baseline bloods were then collected through the i.v. catheter at -15 and 0 minutes before the infusion, Protirelin (500 ~g) was then administered as a rapid i.v, bolus. Bloods for measurement of thyroid-stimulating-hormone(TS H) were subsequently collected at 15. 20.30. and 45 minutes following the TRH injection. Samples were centrifuged for 10 minutes at 2400 r.p.m, before the serum was separated and stored at -20°C for subsequent assay. Assay. TSH levels were determined by a double-antibody radioimmunoassay technique (Beckman Immuno Systems). The interassay and intra-assay coefficients of variation were 8.9% and 9.6°~. respectively. Triiodothyronine (T3), thyroxine (T~), total protein, and free T~ were also measured by the clinical laboratory for patients and controls at baseline. Free T~ was determined by an equilibrium dialysis technique. All assays were conducted without knowledge of diagnosis.
Data Analysis. Baseline thyroid functions and total protein determinations for patients and controls were analyzed for between-group differences using Student's t test. The TRH test response was evaluated in two ways: (l) A two-way analysis of variance (ANOVA) with repeated measures was completed with Tukey's Honestly Significant Difference (HSD) for paired comparisons of diagnostic group effects across the six time points. (2) The maximal elevation of TSH above mean baseline value (Amax TSH I for each subject was determined and compared between groups using Fisher's exact test with a cutoff for a "'positive" ATSH as 7 ~IU ml. Since the cutoffscore for a positive result in the TRH test has been variably defined in previous studies as a Amax TSH response of 5/~IU/ml (Loosen and Prange, 1982) or 7 #l U ml (Gold et al.. 198 l), results from a Fisher's exact test with the 5 #IU ml cutoff definition are also included. Pearson's product-moment correlation was subsequently used to correlate the ~max TSH values with other variables such as age, severity of dementia, and depression rating.
Results There were n o significant differences between the two study groups in age, weight, or baseline thyroid f u n c t i o n tests (Table 1). The baseline T S H levels were slightly higher in the D A T patients (3.9 # I U / m l ) versus the contols (3.5 ~ d U / m l ) , but this difference did not reach statistical significance (t -- 0.72, p > 0.05). W h e n analyzed for g r o u p differences, the d e m e n t i a g r o u p had significantly lower A m a x T S H responses t h a n n o r m a l c o n t r o l s (9.07 ± S D 5.31 vs. 14.68 ± S D 7.37, t = 2 . 2 2 , p ( 0 . 0 5 ) , It c a n be seen in Fig. I that the difference i n s e r u m T S H between groups is significant (by A N O V A with repeated measures) at the 20, 30, a n d 4 5 m i n u t e timepoints. If a positive or a b n o r m a l T R H test is defined as a A m a x T S H ( 7/~l U / ml. then 7 of 15 d e m e n t i a p a t i e n t s (47%) showed b l u n t e d TS H responses, whereas n o n e of
271
Table 1. Age and baseline thyroid function levels before TRH test in dementia patients and normal elderly controls DemenUa patients
Normalcontrols
(n = 15)
(n = 10)
Variables A g e (years) Baseline TSH (#lU/ml) T o t a l T4 (/~g/dl) T3 ( n g / d l ) Free T4 ( n g / d l )
Mean
SD
Mean
SD
p
63.5 3.9 9.1 130.6
9.7 1.9 1.9 25.6
61.3 3.5 7.9 131.6
8.2 0.9 1.6 48.7
NS NS NS NS
1.8
0.4
1.6
0.3
NS
Significance values based on 2-tailed Student's t test.
the n o r m a l volunteers had a peak A T S H < 7 # I U / m l (Fisher's exact probability : 0.025). With a cutoff for A m a x T S H of 5 # I U / m l as the definition of a positive T R H test, 5 of the 15 D A T patients still showed blunted responses versus none of the controls (Fisher's exact probability = 0.056). There was no significant correlation in this sample between age and A m a x T S H for either the patients (r = -0.30) or controls (r = -0.22), but there was a trend toward sex differences in A m a x T S H , with females f r o m both groups combined having a greater A m a x TS H (13.3/~I U / ml vs. 9.5 # I U / ml, t = 1.45, p > 0.05). Within the D A T group, there was a mean A m a x T S H of 8.5/~IU/ml for the males and 11.0/~IU/ml for the females (t = 0.83, p > 0.05). Of the seven blunted T S H responses, three (43%) were females. The control g r o u p revealed a similar trend with a mean A m a x T S H of 12.5
Fig. 1. TSH responses to TRH across time in 15 dementia patients and 10 elderly controls :;
25
E
20
uJ Or) +I .....
T Z
o FZ
-'
~
15 /
F"
10
~
*
** I
J"
~
~
T E,der'y Controls ,.-10, **
Dementia .L PlaltiJln;~
Z
o I m k-Z
5 Z
< I
I
I
I
I
I
-15
0
15
20
30
45
TIME (minutes) Data represent group means (+ standard errorl (*p < 0.05, **p < 0.01, difference from elderly control values).
272 # I U ml for the males a n d 17.9 # l U / m l for the females (t = 1.16, p > 0.05). Baseline T S H m e a s u r e s were c o r r e l a t e d with the A m a x T S H (r = 0.60, p < 0.05) in the D A ' f p o p u l a t i o n . The D A T patients w h o h a d b l u n t e d T S H responses had a lowe~ baseline T S H value (2.8 -+ I. ! / ~ I U / m l ) t h a n the patients with n o r m a l T S H r e s p o n s e s t49_+ 2.2 # I U / m l . t = 2.8. p < 0.05). W h e n the A m a x T S H r e s p o n s e was r e a n a l y z e d as p e r c e n t a g e c h a n g e f r o m baseline, there was still a significant difference between the D A T a n d c o n t r o l groups, with the D A T patients s h o w i n g a m e a n rise of 134% versus 295% for the c o n t r o l s (t = 3.10. p < 0.01). The H R S D score failed to show a significant a s s o c i a t i o n (r = -0.29) with the ~ m a x T S H r e s p o n s e in the D A T patients. T h e r e was one female patient who met D S M - I I I criteria for m a j o r depressive d i s o r d e r a n d had an H R S D score o f 25. b u t she did not s h o w evidence of T S H b l u n t i n g , with a A m a x T S H o f 11.5 # I U / ml. T h e H R S D score f o r the entire D A T g r o u p was 11.9 ( S D 7.2) versus < 5 for the c o n t r o l g r o u p . On the H R S D . the p a t i e n t g r o u p scored positively for d e p r e s s i o n in a r e a s o f sleep d i s o r d e r . d e c r e a s e d energy, a n d s o m a t i c c o m p l a i n t s . T h e seven D A T patients with b l u n t e d responses to T R H had a m e a n H R S D score of 13.1 I S D 7.7) versus 10.9 ( S D 7.1) for the r e m a i n i n g eight patients. A g a i n when the positive T R H test was defined as a A m a x T S H r e s p o n s e of < 7 ~ t l U / m l , only three of seven D A T patients with a blunted r e s p o n s e h a d H R S D scores a b o v e the g r o u p m e a n of 12, while three of the eight D A T patients w i t h o u t b l u n t i n g also had H R S D scores a b o v e 12 (Fis her's exact test. N S). T h e r e was no significant c o r r e l a t i o n between severity o f d e m e n t i a as m e a s u r e d by the H u g h e s scale a n d d e p r e s s i o n (r -- -0.33). H o w e v e r . there was a t r e n d in this small s a m p l e t o w a r d a negative c o r r e l a t i o n between severity o f d e m e n t i a a n d £kmax TSI-t (r = -0.42), which was evident in both sexes.
Discussion A l t h o u g h d e b a t e c o n t m u e s as to w h e t h e r d e p r e s s i o n is an i m p o r t a n t element in the p r o g r e s s i o n of D A T (Knesevich et al. 1983), there is little d o u b t that d e p r e s s i o n occurs in s o m e D A T patients (Miller. 1980'. Reifler et al.. 1982). Previous a t t e m p t s to assess n e u r o e n d o c r i n e responses in this p o p u l a t i o n with the D S T have p r o d u c e d mixed results ( R a s k i n d et al.. 1982: S p a r a n d Gerner. 1982: Carnes et al.. 1983a, 1983b). We have a d m i n i s t e r e d the T R H s t i m u l a t i o n test to D A T p a t i e n t s a n d f o u n d a b l u n t i n g in A m a x T S H r e s p o n s e in 7 15 (47%) of subjects, which is s i m i l a r to the incidence of r e d u c t i o n s p r e v i o u s l y f o u n d in depressed patients of all ages ( L o o s e n a n d Prange, 1982). This b l u n t i n g of T S H response is significant when c o m p a r e d to o u r results in an a g e - m a t c h e d c o n t r o l group, b o t h f o r A m a x T S H c h a n g e s a n d for a c t u a l T S H levels at m o s t time p o i n t s after T R H infusion, a n d calls into question the utility o f the F R H test m helping to distinguish d e m e n t i a patients f r o m elderly depressed C a l l o w a y et al. (1984) have recently s h o w n that depressed patients with a blunted T S H r e s p o n s e to T R H have a g e n e r a l l y lower b a s a l T S H when c o m p a r e d to those p a t i e n t s with a n o r m a l o r a u g m e n t e d T S H response. This a s s o c i a t i o n was also evident in o u r D A T patients. A l t h o u g h there were no significant differences between the patients a n d c o n t r o l g r o u p on m e a s u r e s o f baseline t h y r o i d function, the l o w e r mean b a s a l T S H in the p a t i e n t s with b l u n t e d r e s p o n s e s to T R H suggests that D A T patients with a d i m i n i s h e d T R H response, much like the depressed patients in the study of
273 Calloway et al. (1984), may have a subtly different thyroid set point at baseline. As has been noted previously (Snyder and Utiger, 1972), males in our study showed a trend toward lower Amax TSH responses than females in both the patient and control populations. Nonetheless, nearly half (43%) of the patients showing a blunted response in the DAT group were females, suggesting that sex alone was not primarily responsible for the T R H abnormality. There was a trend toward a reduced Amax TSH with increasing age, even within the limited age range of the patients studied, but this trend was evident in both groups and also would not explain the group differences in TSH response. Within the DAT group, there was also a suggestion that increasing severity of dementia may be associated with a greater likelihood of T R H blunting. Several of the DAT patients did show evidence of clinically apparent depression, but there was no significant correlation between H R S D scores and the Amax TSH in this small sample. While previous experience in depressed populations has also not revealed strong correlations between reduced ATSH and clinical measures of depression (Calloway et al., 1984), questions remain about the validity of the available depression scales in this population. The H R S D (Hamilton, 1960), Beck depression inventory (Beck et al., 1961), and Zung Self-Rating Depression Scale (Zung, 1965), all of which have been used with DAT patients, were never intended for a cognitively impaired population, and may well be reflecting some symptoms other than depression in the DAT population. The pathophysiological significance of a blunted T R H response in depressed patients or other psychiatric populations is poorly understood. Increased or decreased levels of cortisol, somatostatin, norepinephrine, serotonin, and dopamine have all been implicated as possibly influencing the TSH response to T R H (Besses et al., 1975; Tanjasiri et al., 1976; Martin et al., 1977; Gold et al., 1977; Loosen et al., 1978). Although some researchers have suggested that single neurotransmitter systems could be responsible for the blunted TSH response in affective illness (Gold et al., 1977; Loosen and Prange, 1982), there is no general consensus concerning a specific abnormality (Cohen and Cohen, 1981). Disruptions in these same hormonal and neurotransmitter systems have been previously described in DAT (Bowen et al., 1979; Terry and Davies, 1980; Bondareffet al., 1981; Spar and Gerner, 1982; Winblad et al., 1982; Raskind et al., 1984). Further empiric studies examining the interrelationships between specific neurotransmitters and the blunted TSH response to T R H in DAT may be of value. In summary, it appears that DAT patients can display evidence of blunting in the T R H stimulation test that cannot be explained simply on the basis of aging alone. This blunting is not the result of obvious baseline thyroid abnormalities and is in marked contrast to our observations in elderly control subjects. Ratings of concurrent depression do not correlate with the Amax TSH response and may themselves be measuring something other than depression in this cognitvely impaired population. In view of the fact that the T S H response to T R H has now been found to be blunted in several psychiatric populations, including depression and mania (Kirkegaard et al., 1975; Loosen et al., 1978), alcoholics (Loosen and Prange, 1979), and borderline personality disorders (Garbutt et al., 1983), its potential usefulness in differentiating dementia from pseudodementia appears limited. Further study of a broad range of DAT patients, elderly controls, and other populations such as the elderly depressed is needed.
274
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