HPA axis responsivity to dexamethasone and cognitive impairment in dementia

Prog. Neuro-Psychopharmocof. & Biol. Psychiat. 1990. Vol. 14, pp. 297-308 Printed in Great Britain. All rights reserved

027~5846/90 $0.00 + so 0 1990 Pergamon Press plc

HPA AXIS RESPONSIVITY TO DEXAMETHASONE AND COGNITIVE IMPAIRMENT IN DEMENTIA

DAVID GUREVICHI, BARRY SIEGELl, MANUEL DUMLAOI, ELIEZER PERL1, PAMELA CHAITINI, CURTIS BAGNEl, AND GREGORY OXENKRUG*

IWayne State University, School of Medicine, Department of Psychiatry, Lafayette Clinic Detroit, Michigan, USA, and *Brown University,

College of Medicine, Department of Psychiatry and Human Behavior, Providence, RI, USA

(Final form, September 1989)

Abstract

Gurevich, David, Barry Siegel, Manuel Dumlao, Eliezer Perl, Pamela Chaitin, Curtis Bagne and Gregory Oxenkrug: HPA Axis Responsivity to Dexamethasone and Cognitive Impairment in Dementia. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, g:297-308

1. Animal and human studies suggest a possible relationship between dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and cognitive impairment.

2. In animals, prolonged exposure to high plasma cortisol levels causes irreversible hippocampal damage.

3. Abnormal cortisol plasma levels in response to dexamethasone challenge have been frequently observed in dementia of Alzheimer's type (DAT) patients.

4. The authors studied the relationship of responsivity of the HPA axis to cognitive impairment in 34 DAT patients drug free for at least 10 days. A decrease in HPA axis responsivity significantly correlated with greater cognitive impairment.

Keywords: cognitive impairment, cortisol, dementia, dexamethasone, HPA responsivity index.

Abbreviations: dementia of Alzheimer's type (DAT), dexamethasone (DEX), Global Deterior- ation Scale (GDS), Hamilton Rating Scale for Depression (HRSD), hypothalamic-pituitary- adrenal (HPA), major depressive disorder (MOD), Mini-Mental State Examination (MMSE), radioimmunoassay (RIA).

Introduction

Abnormal response of the hypothalamic-pituitary-adrenal (HPA) axis to desamethasone (DEX)

challenge, originally suggested as a biological marker for major depressive disorder (MDD)

(Carroll et al., 1981), is encountered in many demented patients. Several studies (Raskind

et al., 1982; Spar and Gerner, 1982; Balldin et al., 1983; Coppen et al., 1983; Pomara et

al., 1984; Jenike and Albert, 1984; Katona and Aldridge, 1985; Georgotas et al., 1986;

Greenwald et al., 1986; Davous et al., 1988) reported post-DEX plasma cortisol levels

that were above the normal cut-off point of 5ug/dl in a subgroup of patients with dementia

of the Alzheimer's type (DAT). Furthermore, 3 of these studies (Pomara et al., 1984;

Jenike and Albert., 1984; Davous et al., 1988) indicated that subjects with higher post-DEX

cortisol levels were also more cognitively impaired. One study (Jenike and Albert, 1984)

297

298 D. Gurevich et al.

found significantly higher post-DEX cortisol levels in

DeLeon et al. (1988) recently reported abnormal serum

following glucose challenge. Other studies did not find

the most impaired DAT patients.

cortisot levels in DAT patients

a relationship between cognitive

impairment and cortisol plasma level (Katona and Aldridge, 1985; Georgotas et al., 1986;

Greenwald et al., 1986; Castro et al., 1983; Carnes et al., 1983). A possible relationship

between cognitive impairment and HPA axis dysregulation (high plasma cortisol levels) has

been supported by animal studies (Sapolsky et al., 1986; Sapolsky and McEwen, 1986). This

relationship is also supported by studies in humans with pathological conditions such as

Cushing's Syndrome and MDD (Whelan et al., 1980; Starkman et al., 1981; Rubinow, 1984).

Oxenkrug and Gershon (1987) reviewed evidence for this relationship. The purpose of this

study was two fold: 1. To assess whether a correlation exists between higher post-DEX

plasma cortisol levels and cognitive dysfunction in patients with primary degeneration

dementia and 2. To propose a measure of HPA axis responsivity and study it's relationship

to cognitive impairment.

Subjects

Methods

Thirty-four inpatients (14 men and 20 women), diagnosed as having primary degenerative

dementia (DSM-III), participated in this study after each patient and a family member signed

informed consent. Subjects were drug free for at least 10 days before the study except for

prn doses of chloral-hydrate for sedation.

All subjects underwent medical and psychiatric evaluation. In all cases, history indicated

a progressive and insidious loss of m~ory and other cognitive functions and no evidence for

cerebrovas~ular involv~ent or focal neurological signs. Exclusion criteria were CNS masses

and infarcts, major affective disorder, alcoholism, chronic psychiatric disorders such as

schizophrenia and seizure disorder as well as conditions which are known to affect the

response to DEX challenge (Carroll et al., 1981). Lab tests including SMA 18, complete

blood count, thyroid functions, 812, folate and VDRL were done. All subjects had comput-

erized axial tomography of the head to rule out space occupying lesions and infarcts unless

a scan had been performed within the last 10 months. Medical problems encountered in this

patient group were as follows: Arteriosclerotic heart disease and transient ischemic

attacks, 7; hypertension, 5; history of hypothyroidism, 2; adult onset diabetes mellitus

(stable), 1.

HPA axis responsivity and cognitive impairment 299

Assessment

The Global Deterioration Scale (GDS) (Reisberg et al., 1987) was used to assess severity

of cognitive impairment. In the first 17 patients only the GDS was performed. In the last

17 patients, the GDS and the Mini-Mental State Examination (MMSE) (Folstein et al., 1975)

were used to assess more accurately the severity of impairment. Assessments were made

during the morning hours. Information needed to determine each GDS rating was obtained

from the patient's family.

The authors evaluated depression in this group of dementia patients. Previously Greenwald

et al. (1986) had described the difficulty of assessing depression in the presence of

dementia. We were able to complete the Hamilton Rating Scale for Depression (HRSD, Hamilton,

1960) in only 4 out of 34 cases. The range of HRSD scores was O-IO. Since the value of

the HRSD in the presence of DAT diagnosis is questionable, we relied on clinical assessment

(by B.S., M.S.D., LG.). Past history and family history for depression did not uncover

MDD in the patient group reported here. A scale for assessing depression in dementia

patients was published after these data were collected (Sunderland et al., 1988). HPA axis

activity was evaluated by DEX challenge. It has to be stressed that the goal of DEX

application in our study was not the laboratory diagnosis of depression (Carroll et al.,

1981), but the detection of the smallest degree of HPA overactivation. Cortisol response

to DEX challenge (DST) was originally introduced for the assessment of HPA function in

endocrine disorders (Nugent et al., 1965). According to the original interpretation of DST

the higher the dose of DEX needed to suppress the morning cortisol plasma level, the more

severe the dysregulation of the HPA axis. Considering that dementia might be associated

with a smaller degree of HPA abnormality than endocrine disorders, the dose of DEX to be

utilized for the detection of a slight increase of HPA activation ought to be smaller.

Previous studies (Krieger et al., 1971; Dilman et al., 1979) suggest that 0.5 mg of DEX may

be a sufficient dose to challenge the HPA axis. The study of cortisol response to 0.5 mg

of DEX in normal volunteers suggested that post-DEX cortisol plasma levels depend mainly

upon age (Oxenkrug et al., 1983; Rosenbaum et al., 1984) and, partly, upon pre-DEX cortisol

levels (Branconnier et al., 1984). Plasma cortisol levels were evaluated by the RIA method

described previously (Oxenkrug et al., 1983). Blood for determination or pre- and post-DEX

levels was drawn between 8 and 9 A.M.

300 D. Gurevich et al

The Index of HPA Responsivity was computed from the measured plasma cortisol levels using

this formula.

Pre-DEX Cortisol - Post-DEX Cortisol

Index =

Pre-DEX Cortisol + Post-DEX Cortisol

Evidently, higher Index values would suggest a more responsive HPA axis, while lower values

would suggest a less responsive system.

Data Analysis

Pearson correlation coefficients were used to compute correlations and Student t-tests

(two tailed) were used to compare groups.

Results

Severity of Cognitive Impairment and Response to DEX

Age for the entire group of 34 patients was 70.9+8.5 (mean k SD) with a range of 59-92

years and the GDS, a global measure of cognitive functioning, was 5.251.1 (range 3-7).

Mean cortisol plasma level prior to DEX challenge was 17.0326.76 ug/dl but dropped signi-

ficantly to 9.9526.70 ug/dl following administration of 0.5mg DEX ft=6.23, p<O.O01, paired

t-test). The average Index of HPA Responsivity was 0.31kO.27. Grouping the patients by

severity of cognitive decline, as indicated in Table 1, created two subgroups of 17 patients

each: Moderate impairment (GDS=4.2iO.6) and severe impairment (GDS=6.2?0.4). Unpaired

t-test results show that the two subgroups were not different in age or baseline (prior to

challenge) plasma cortisol levels. However, following DEX challenge, plasma cortisol

levels were significantly higher in the more severely impaired patients compared to the

less severely impaired. Accordingly, the Index of HPA Responsivity was significantly lower

for the more severely impaired patients (Table 1).

Relationship Between MMSE Scores and Plasma Cortisol

The MMSE, a measure of cognitive functioning, was obtained from the last 17 patients who

entered the study. Mean MMSE score was 11.3t5.7. We divided this group into less and more

severely impaired subjects by using 13 as the cutoff score. There were 7 moderately impaired

patients (MMSE=16.8+2.9) and 10 severely impaired patients (MMSE=7.51r3.4). Using the MMSE

as a measure of cognitive functioning, we found that for the more severely impaired patients

post-DEX plasma cortisol levels were significantly higher and the Index of HPA Responsivity

was significantly lower (Table 2).


Table 1

Severity of Cognitive Impairment (Assessment by GDS) and HPA Responsivity

Moderate Severe t* P Impairment (GDS 3-5)

Impairment (GDS 6,7)

n=17 n=17

Age (years)

Pre-DEX Cortisol (Wdl)

69.828.5 72.Ok8.5 -0.76 0.45 ns

16.92k8.26 17.15k5.09 -0.097 0.92 ns

Post-DEX Cortisol (ugldl)

7.04k6.25 12.8725.96 -2.7 0.009

Index of Responsivity

0.45+0.25 0.17kO.23 3.29 0.002

* Unpaired t-test

Table 2

Severity of Cognitive Impai~ent (Assessment by MMSE) and HPA Responsivity

Moderate Severe t* P Impairment Impairment

n=7 n=lO

Age (years)

Pre-DEX Cortisol (Wdl)

72.2-19.9 69.3k5.4 0.72 0.48 ns

16.52+11.84 16.89k6.31 -0.07 0.94 ns

Post-DEX Cortisol (ug/dl)

5.74k6.1 13.826.32 -2.63 0.019

Index of Responsivity

0.48kO.33 0.14t0.17 2.54 0.032

* Unpaired t-test

Effect of Age on Post-DEX Plasma Cortisol

Since the relationship between HPA dysregulation and cognitive impairment may be simply due

to increasing age, we tested the correlation between pre- and post-DEX plasma cortisol levels


and age for the entire subject group (Table 3). No significant correlation was found

between age and either baseline or post-DEX plasma cortisol levels. However, the corre-

lation between age and plasma cortisol levels following DEX challenge approached signifi-

cance.

Table 3

Correlation Between Plasma Cortisol Levels and Age

(n=34) r* F P

Pre-DEX Cortisol

Post-DEX Cortisol

* Pearson Correlation

0.006 0.00 0.97 ns

0.303 3.25 0.081 ns

Cognitive Impairment and the Index of HPA Responsivity

As noted above, severely impaired patients had a lower Index of HPA Responsivity. To

further evaluate the relationship between cognitive impai~ent and plasma cortisol, we

tested the correlation between the Index and both cognitive measures (GDS and MMSE) as

shown in Table 4 and Figures 1 and 2. The correlations were significant for both measures

of cognitive function.

Correlation Between Index of HPA Responsivity and Severity of Impairment

Table 4

N r* F P

GDS

MMSE

* Pearson Correlation

34 -0.43 7.11 0.012

17 0.49 4.89 0.043

Discussion

Two aspects of our study should be emphasized: 1. The severity of cognitive impairment,

which is seen in dementia patients, is correlated with the severity of dysregulation of the

HPA axis; 2. The responsivity of the HPA axis can be described by a dynamic measure which

provides more information about HPA axis function than a single post-DEX cortisol level.


GDS SCORE

Fig. 1 Index of HPA Responsivity as a function of GDS score.

l.O-

z r 06- = ‘ 2 2 0.6-

E

d 0.4 ”

I

b 0.2-

0

X

x E 0.0

-0.2

Pig.2 Index of HPA Responsivity as a function of MUSE score.

HPA Dysregulation and Neuronal Damage

Evidence for a possible relationship between HPA axis dysregulation, resulting in high

plasma cortisol levels, and impaired cognition is derived from both animal and human studies.

In a review of the effects of cortisol on the hippocampus in animals, Sapolsky et al.,

(1986) described a reciprocal relationship between HPA activity and brain tissue damage:

Degenerative changes in the hippocampus, mostly in the pyramidal cell layer (CA3), led to

impaired capacity to terminate glucocorticoid secretion, and consequently to high gluco-

corticoid levels, which in turn had further neurotoxic effects on hippocampal cells. Such

304 D. Gurevich et aI.

effects are a decrease in the number of glu~ocorticoid receptors per neuron and loss of

hippocampal neurons.

HPA Dysregulation and Cognitive Deficits

People who suffer from pathological conditions such as Gushing's syndrome and MDD, which

are associated with high plasma cortisol levels, also show cognitive impairments. In a

review of cognitive deficits in Cushing's syndrome, Whelan et al. (1980) reported on 35

untreated patients who were evaluated with the Michigan Weu~psychological Test Battery

(Smith 1980). These patients were younger (mean age, 35.9 years; range 21-57) than the

patients in our study. Twenty-two of 35 patients had evidence of neuropsychological

dysfunction of varying severity and no function was spared (Whelan et al., 1980). A

significant relationship between overall psychiatric disability and cortisol levels was

described by Starkman et al. (1981). These authors found a disturbance of attention and

concentration (serial 7s) in 51% of the cases and memory impairment (recall of presidents)

in 46% of the cases.

Major affective disorder is sometimes associated with HPA dysregulation. Rubinow et al.

(1984) reported on 29 medication free patients (mean age 40.3 years) with major affective

disorder who were evaluated by the Halstead-Reitan Category Test (Halstead, 1947). Urinary

free cortisol excretion was significantly and positively correlated with the number of

errors on the Halstead-Reitan Test and all patients with higher urinary excretion levels

had a higher number of errors. Several studies examined HPA activity in patients with

primary degenerative dementia. In 10 studies reported between 1982 and 1988 (Raskind et

al., 1982; Spar et al., 1982; Balldin et al., 1983; Coppen et al., 1983; Pomara et al.,

1984; Jenike and Albert, 1984; Katona and Aldridge, 1985; Georgotas et al., 1986; Greenwald

et al., 1986; Davous et al., 1988) 206 patients with DAT were tested. In the majority of

studies RIA was used for determination of plasma cortisol levels. Eighty-eight out of 206

subjects were found to have post-DEX cortisol levels above 5ug/dl. Furthermore, results

from 3 studies (Pomara et al., 1984; Jenike and Albert, 1984; Davous et al., 1988) suggest

that more severely impaired subjects show higher mean cortisol plasma levels following DEX

challenge. A previous study (Oxenkrug and Gershon, 1987) suggested that there may be a

relationship between the impaired cognition seen in DAT patients and the high post-DEX

cortisol levels. Two studies (Jenike and Albert, 1984; Oxenkrug et al., 1988) found a

correlation between post-DEX cortisol plasma levels and cognitive impairment. Recently,


deLeon et al. (1988) reported that serum cortisol response to the glucose tolerance test in

9 DAT patients was significantly higher 1-2 hours after glucose loading compared to 8 age

matched controls. Moreover, cortisol levels were closely correlated with mental status and

with hippocampal atrophy as measured on computerized tomography scans. However, sane of

the studies mentioned above (Katona and Aldridge, 1985; Georgotas et al., 1986; Greenwald

et al., 1986; Castro et al., 1983; Carnes et al., 1983), which looked for an association

between cognitive impairment and cortisol levels, did not find one.

The main finding was that the more severely impaired subjects, as evaluated with both the

GDS and MMSE, had significantly higher post-DEX cortisol levels. Results for an Index of

HPA Responsivity, calculated from pre-challenge and post-challenge cortisol levels, indicate

that the HPA axis was significantly less responsive to DEX challenge in the more severely

impaired patients (Tables 1 and 2).

Age and Cortisol Levels

Aging in itself should be considered as the dominant factor determining plasma cortisol

levels. Older healthy subjects tend to have higher post-DEX cortisol levels than younger

ones (Oxenkrug et al., 1983; Rosenbaum et al., 1984). In our sample, age does not seem to

act as a significant factor in either pre- or post-challenge cortisol plasma levels. The

lack of correlation (Table 3) between both baseline and post-DEX cortisol and age may be

due to the relatively narrower age range (52-92) in our sample compared to the studies

mentioned above.

Rationale for the Index of HPA Responsivity

The rationale for computing our proposed Index of HPA Responsivity is that whatever the

end point (post-DEX cortisol serum level) of the HPA axis may be, the starting point (pre-DEX

cortisol serun level) may be of great importance. For example, assune that 2 subjects have

the same post-challenge cortisol level, say 4.0ug/ml. Is it important that one of them had a

pre-challenge cortisol level of ZO.Oug/ml (corresponding to an Index of 0.67) while the other

started from a different level (7.0ug/ml) and had an Index value of 0.27? Similarly 2 sub-

jects may have had different post-DEX cortisol levels, say 2.0ug/ml and 7.0ug/ml, but

identical Index values of 0.40 because they started at very different pre-DEX cortisol

levels (4.7ug/ml and 16.3ug/ml, respectively). We are aware that the Index has a limitation

when the baseline values of plasma cortisol are very Tow. At present it is not clear to us

how often this situation is encountered.


We believe that the dynamic aspect of biological systems, as revealed by rather simple

manipulations such as those reported here, are significant and of great interest. A similar

approach was recommended previously (Greden, 1987; Koslow and Gaist, 1987). One benefit of

looking at the dynamic aspects of a system and avoiding static descriptions, by using for

example repeated measures or rate of change data, may be a better understanding of systems

which are inherently in a state of flux.

The Index of HPA Responsivity, suggested here, takes into account a dynamic aspect of

that system by relating cortisol levels before and after challenging the system (i.e.

giving dexamethasone). In our sample, the Index of HPA Responsivity may better predict

conitive impai~ent than the post-DEX plasma cortisol levels (P<O.OOZ for the Index vs

P<O.O09 for post-DEX cortisol, Table 1). Presently we are conducting a study that will

test the correlation between the Index and other more accurate measures of cognitive

dysfunction.

Previous

especially

memory and

effects on

supports a

provides a

Conclusions

studies suggest that high plasma cortisol levels have a neurotoxic effect

on the hippocampus (Sapolsky and tiEwen, 1986), a structure which is involved in

learning processes. Another study (Dekosky et al., 1984) suggests that cortisol

hippocampal cells are mediated through adrenergic neurons.

possible relationship between cognitive impairment and high

measure for the responsivity of the HPA axis.

The authors believe that creating an index, which takes into account

of the HPA axis, provides information which is unavailable when only a

challenge) is available. Such an index provides a dynamic measure of

the system which may be useful in other studies.

the actual response

single value (post-

the functioning of

Acknowledgements

This study was supported, in part, by NIH grant MH40924 (G.F.O.).

Yancey and Ms. Anne Houle for manuscript preparation.

We thank Ms. Alice

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HPA axis responsivity to dexamethasone and cognitive impairment in dementia

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