HPA axis responsivity to dexamethasone and cognitive impairment in dementia

Prog. Neuro-Psychopharmocof. & Biol. Psychiat. Printed in Great Britain. All rights reserved

1990. Vol. 14, pp. 297-308 0

HPA AXIS RESPONSIVITY TO DEXAMETHASONE COGNITIVE IMPAIRMENT IN DEMENTIA

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

AND

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, HPA Axis Responsivity to Dexamethasone and Cognitive and Gregory Oxenkrug: Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990, g:297-308 Dementia. 1. 2. 3. 4.

Curtis Bagne Impairment in

Animal and human studies suggest a possible relationship between dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and cognitive impairment. prolonged exposure to high plasma cortisol levels causes irreversible In animals, hippocampal damage. Abnormal cortisol plasma levels in response to dexamethasone challenge have been frequently observed in dementia of Alzheimer's type (DAT) patients. 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 Deterioration Scale (GDS), Hamilton Rating Scale for Depression (HRSD), hypothalamic-pituitaryadrenal (HPA), major depressive disorder (MOD), Mini-Mental State Examination (MMSE), radioimmunoassay (RIA).

Introduction Abnormal challenge,

response

of the hypothalamic-pituitary-adrenal

originally

suggested

et al., 1981), is encountered

(Carroll et al.,

1982;

Spar

al., 1984; Jenike Greenwald

et

al.,

and Gerner, and

Albert,

1986;

that were above the normal of the

Alzheimer's

Jenike

and Albert.,

cortisol

as a biological

levels

were

type

Davous

1982; 1984; et

cut-off (DAT).

(HPA) axis to desamethasone

marker

for major depressive

in many demented Balldin Katona al.,

point

et al., and

1988)

reported

3

these

1984; Davous et al., 1988) indicated also more

cognitively

impaired. 297

studies

Georgotas

post-DEX

plasma

(Raskind

al.,

cortisol

(Pomara

that subjects

One study

et

of patients

studies

(MDD)

et al., 1983; Pomara

1985;

in a subgroup of

Several

1983; Coppen

Aldridge,

of 5ug/dl

Furthermore,

patients.

disorder

(DEX)

1986; levels

with dementia et

al.,

with higher

(Jenike

et

1984;

post-DEX

and Albert,

1984)

D. Gurevich et al.

298

found

significantly

DeLeon et

glucose

impairment Greenwald between

(1988)

al.

following

higher

and

post-DEX

recently

challenge.

cortisol

reported Other

plasma

been supported relationship Cushing's

impairment

by animal

is also

Syndrome

Oxenkrug

and Gershon

study was two

fold:

plasma cortisol dementia

levels

and 2.

to cognitive

1.

(Sapolsky

by

et

reviewed

and

To propose

and

Aldridge,

al.,

whether

cognitive a measure

1985;

1980;

for this

in

of HPA axis

patients

responsivity

1986).

primary

This

1984).

The purpose higher

has

such as

Rubinow,

between

1986;

levels)

conditions

1981;

with

cognitive

relationship

cortisol

relationship. exists

patients

et al.,

and McEwen,

et al.,

a correlation

dysfunction

between

pathological

Starkman

patients.

in DAT

A possible

(high plasma

with

DAT

Georgotas

et al., 1983).

in humans

evidence

To assess

levels

et al., 1986; Sapolsky

studies

(Whelan

(1987)

(Katona

cortisot

impaired

not find a relationship

and HPA axis dysregulation

studies

MDD

did

in the most

serum

et al., 1983; Carnes

supported

and

levels

abnormal

studies

level

et al., 1986; Castro

cognitive

cortisol

of this post-DEX

degeneration

and study it's

relationship

impairment.

Methods Subjects Thirty-four

inpatients

dementia

(DSM-III),

informed

consent.

(14 men

participated Subjects

cerebrovas~ular

involv~ent

and infarcts,

major

schizophrenia

and

response

to DEX

blood count, erized

attacks, (stable),

or focal neurological disorder,

signs.

alcoholism,

chronic

challenge

(Carroll

et al.,

1981).

functions,

and a family member signed

812, folate

functions

within the last

which

Lab tests

follows:

Arteriosclerotic

5; history

Medical heart

of hypothyroidism,

are

disorders

known

including

and VDRL were done.

10 months.

and no evidence

psychiatric

of the head to rule out space occupying

as

degenerative

for

for

Exclusion criteria were CNS masses

as conditions

were

primary

In all cases, history indicated

and other cognitive

as well

7; hypertension, 1.

evaluation.

disorder

a scan had been performed group

and psychiatric

seizure

thyroid

as having

in this study after each patient

loss of m~ory

affective

axial tomography

patient

diagnosed

for sedation.

All subjects underwent medical and insidious

20 women),

were drug free for at least 10 days before the study except

prn doses of chloral-hydrate

a progressive

and

to

SMA

All subjects lesions

problems

disease 2; adult

such as

affect

18,

complete

had comput-

and infarcts encountered

and onset

the

unless in this

transient

ischemic

diabetes

mellitus

HPA axis responsivity

and cognitive

299

impairment

Assessment The Global

Deterioration

of cognitive

impairment.

17 patients,

the

were used during

to

assess

more

dementia.

had

described

MDD in the

patient

needed

the

difficulty

of

(MMSE)

(Folstein

impairment.

to determine

of

each

GDS

activity

was

application

evaluated in our

challenge

by

(DST)

Previous

studies

be a sufficient

and

family

here.

A

challenge.

was not the

1975)

were

was

made

obtained

Previously in the

scale

for

laboratory

originally

degree

of the HPA

detection

of

a slight

(Sunderland

to

be

for

that

to the original

endocrine

increase

of

HPA

in normal

upon age (Oxenkrug

to challenge

volunteers

the HPA axis.

cortisol

suggested

that

et al., 1983; Rosenbaum

(Branconnier previously

et al., 1984). (Oxenkrug

levels was drawn between

post-DEX

activation

Plasma cortisol

8 and 9 A.M.

plasma

of

DEX

et al., response

function

in

of DST

level, the more be associated

the dose ought

of DEX to be

to

be

smaller.

that 0.5 mg of DEX may response

levels

to 0.5 mg

depend

upon pre-DEX

levels were evaluated

Blood for determination

goal

HPA

might

of cortisol

cortisol

HPA axis

(Carroll

plasma

disorders,

et al., 1984) and, partly,

et al., 1983).

the

of

that dementia

The study

in dementia

interpretation

(Krieger et al., 1971; Dilman et al., 1979) suggest dose

not uncover

Cortisol

assessment

of

assessment

et al., 1988).

of depression

the

Considering

did

depression

stressed

the morning

than

Since the value

of HPA overactivation.

According

axis.

of HPA abnormality

assessing

of

(HRSD, Hamilton,

for depression

diagnosis

introduced

to suppress

was O-IO.

Greenwald

presence

we relied on clinical

history

It has

of the smallest

of DEX needed

degree

for the

DEX

was

severe the dysregulation

utilized

is questionable,

(Nugent et al., 1965).

the dose

smaller

reported

study

disorders

the higher

et al.,

rating

depression

scores

after these data were collected

1981), but the detection

endocrine

severity

In the last

Assessments

patients.

assessing

The range of HRSD

Past history

group

was published

described

severity

of DAT diagnosis

LG.).

patients

levels

Examination

in this group of dementia

4 out of 34 cases.

(by B.S., M.S.D.,

of DEX

Information

depression

the HRSD in the presence

with a

the

only the GDS was performed.

We were able to complete the Hamilton Rating Scale for Depression

1960) in only

to DEX

State

was used to assess

family.

The authors evaluated (1986)

accurately

hours.

from the patient's

et al., 1987)

In the first 17 patients

GDS and the Mini-Mental

the morning

et al.

Scale (GDS) (Reisberg

mainly

cortisol

by the RIA method

or pre- and post-DEX

D. Gurevich

300

The Index of HPA Responsivity

was computed

et al

from the measured

plasma cortisol

levels

using

this formula. Pre-DEX Cortisol

- Post-DEX

Cortisol

Pre-DEX Cortisol

+ Post-DEX

Cortisol

Index =

Evidently, would

Index values would suggest a more responsive

higher

suggest a less responsive

HPA axis, while

lower values

system.

Data Analysis Pearson

correlation

(two tailed)

coefficients

were

were used to compare

used to

compute

correlations

and

Student

t-tests

groups.

Results Severity

of Cognitive

Impairment

Age for the entire years

and

the

GDS,

Mean cortisol

group

of 34 patients

a global

plasma

and Response

measure

level prior

to 9.9526.70

ug/dl

following

t-test).

The average

Index

of HPA

of cognitive

each:

Moderate

t-test

results

challenge) levels were

less severely

cortisol

significantly impaired.

for the more severely Relationship

Between

the study.

levels. higher

functioning, was

5.251.1

ug/dl

not different following severely

DEX

(range

p
(GDS=6.2?0.4).

challenge, patients

to the

was significantly

functioning,

was obtained We divided

from the last 17 patients

lower

patients

(MMSE=16.8+2.9)

(MMSE=7.51r3.4).

and 10 severely functioning,

impaired

we found that for the more severely

levels were significantly

lower (Table 2).

patients

who

this group into less and more

There were 7 moderately

was significantly

cortisol

(Table 1).

Mean MMSE score was 11.3t5.7.

plasma cortisol

(prior to

compared

impaired subjects by using 13 as the cutoff score.

post-DEX

by

and Plasma Cortisol

of cognitive

of cognitive

paired

Unpaired

plasma

severely

as a measure

signi-

of 17 patients

in age or baseline

impaired

3-7).

the patients

two subgroups

impairment

of 59-92

but dropped

Grouping

the Index of HPA Responsivity

patients

a range

of 0.5mg DEX ft=6.23,

severe

were

more

was

17.0326.76

in Table 1, created and

in the

(mean k SD) with

was 0.31kO.27.

However,

Accordingly,

MMSE Scores

The MMSE, a measure entered

(GDS=4.2iO.6)

impaired

cognitive

Responsivity

show that the two subgroups

plasma

70.9+8.5

administration

decline, as indicated

impairment

was

to DEX challenge

ficantly

severity

of

to DEX

impaired

Using the MMSE

impaired

patients

higher and the Index of HPA Responsivity

HPA axis responsivity

and cognitive

301

impairment

Table 1 Severity

of Cognitive

Impairment

(Assessment

by GDS) and HPA Responsivity

Moderate Impairment (GDS 3-5)

Severe Impairment (GDS 6,7)

n=17

n=17

69.828.5

72.Ok8.5

-0.76

0.45 ns

Pre-DEX Cortisol (Wdl)

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

0.45+0.25

0.17kO.23

Age

(years)

Index of Responsivity

*

Unpaired

t*

P

3.29

0.002

t-test Table 2

Severity

of Cognitive

(Assessment

by MMSE) and HPA Responsivity

Moderate Impairment

Severe Impairment

n=7

n=lO

Age (years)

72.2-19.9

69.3k5.4

Pre-DEX Cortisol (Wdl)

16.52+11.84

Post-DEX Cortisol (ug/dl)

5.74k6.1

Index of Responsivity

* Effect

Impai~ent

Unpaired

P

0.72

0.48 ns

16.89k6.31

-0.07

0.94 ns

13.826.32

-2.63

0.019

2.54

0.032

0.48kO.33

0.14t0.17

t-test

of Age on Post-DEX

Since the relationship to increasing

t*

Plasma Cortisol between

age, we tested

HPA dysregulation

the correlation

and cognitive

between

impairment

pre- and post-DEX

may be simply due

plasma cortisol

levels

302

D. Gurevich et al.

and

age

between

for

the

entire

age and either

lation between

subject

group

baseline

age and plasma

(Table

or post-DEX

cortisol

3).

No

plasma

levels

significant

cortisol

following

correlation

levels.

was

However,

DEX challenge

the

approached

found corre-

signifi-

cance. Table 3 Correlation

Between Plasma Cortisol

P

Pre-DEX

Cortisol

0.006

0.00

0.97

Post-DEX

Cortisol

0.303

3.25

0.081 ns

*

Pearson

Cognitive

further

above,

evaluate the

and the Index of HPA Responsivity

severely the

impaired

relationship

correlation

between

shown in Table 4 and Figures of cognitive

ns

Correlation

Impairment

As noted

tested

F

r*

(n=34)

Levels and Age

the

patients

between Index

1 and 2.

had

a lower

cognitive and

both

Index

of HPA

impai~ent cognitive

The correlations

were

and

Responsivity.

plasma

measures

(GDS

significant

To

cortisol,

we

and

as

MMSE)

for both measures

function. Table 4

Correlation

Between

Index of HPA Responsivity

*

F

r*

N

and Severity

of Impairment

P

GDS

34

-0.43

7.11

0.012

MMSE

17

0.49

4.89

0.043

Pearson

Correlation

Discussion Two aspects which

of our study should be emphasized:

is seen in dementia

HPA axis; provides

2. more

patients,

The responsivity information

about

is correlated

1.

The severity

with the severity

of the HPA axis can be described HPA axis

function

than

a single

of cognitive

impairment,

of dysregulation

by a dynamic measure post-DEX

cortisol

of the which level.

HPA axis responsivity and cognitive impairment

303

GDS SCORE Fig.

Index of HPA Responsivity

1

as a function

of GDS score.

l.Oz r =

0

06-

‘

2 2

0.6-

E 0.4 ”

d I b

0.2-

X

x E

0.0

-0.2

Pig.2

HPA Dysregulation Evidence

for

plasma cortisol In a

review

and Neuronal

a possible

of the

impaired corticoid

relationship

levels,

of cortisol

a reciprocal

changes

capacity

effects

between

which

HPA

axis

of MUSE score.

dysregulation,

between

mostly

glucocorticoid

in turn had further

resulting

in high

is derived from both animal and human studies.

on the hippocampus

relationship

in the hippocampus,

to terminate

as a function

Damage

levels, and impaired cognition

(1986) described Degenerative

Index of HPA Responsivity

in animals,

HPA activity

in the pyramidal secretion,

neurotoxic

and

effects

and cell

Sapolsky

brain

tissue

layer

consequently

et al., damage:

(CA3), led to

to high

on hippocampal

cells.

glucoSuch

D. Gurevichet aI.

304

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-ReitanCategory 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. primary degenerative dementia. al., 1982; Spar et al., 1982;

Several studies examined HPA activity in patients with In 10 studies reported between 1982 and 1988 (Raskind et

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,

HPA axis responsivity

deLeon

et al. (1988) reported

9 DAT patients matched

was

Moreover,

with hippocampal the studies

between

atrophy

mentioned

et al., 1986;

cognitive

impaired

(Tables 1 and 2).

patients

Aging

Older

ones

should

healthy

(Oxenkrug

correlation

due to

the

subjects

factor (Table

relatively

tend

to have

3) between

narrower

age

cortisol

the same post-challenge cortisol

Index

levels

(4.7ug/ml

when the baseline

to 8 age

status and

However,

et al., 1986;

sane

of

Greenwald

for an association

as evaluated

levels.

Results

and post-challenge

cortisol

to DEX challenge

with both the

for an Index of levels, indicate

in the more

had

range

different

post-DEX

0.40

and 16.3ug/ml,

severely

determining cortisol

plasma

levels than younger

cortisol

and post-DEX in our

Index of HPA

sample

plasma

because

they

compared

to the

respectively).

is encountered.

be

studies

is that whatever

the

point (pre-DEX

assune that 2 subjects

Is it important

have

that one of them had a

to an Index of 0.67) while the other

levels,

started

The

and age may

Responsivity

For example,

levels.

cortisol

and had an Index value of 0.27? cortisol

cortisol

In our sample, age does not seem to

(corresponding

values of plasma cortisol

how often this situation

post-DEX

level, say 4.0ug/ml.

level (7.0ug/ml)

of

(52-92)

importance.

level of ZO.Oug/ml

values

higher

factor

serum level) of the HPA axis may be, the starting

cortisol

from a different

identical

cortisol

both baseline

our proposed

serun level) may be of great

have

with mental

looked

subjects,

pre- or post-challenge

for computing

end point (post-DEX

jects may

impaired

in either

for the Index of HPA Responsivity

started

which

et al., 1984).

Rationale

pre-challenge

compared

scans.

Georgotas

Rosenbaum

above.

cortisol

tomography

as the dominant

mentioned

The rationale

correlated

1985;

less responsive

be considered

et al., 1983;

act as a significant lack of

loading

test in

Levels

in itself

levels.

glucose

tolerance

levels, did not find one.

from pre-challenge

was significantly

to the glucose

et al., 1983),

Carnes

higher post-DEX

that the HPA axis

Age and Cortisol

and Aldridge,

was that the more severely

calculated

after

computerized

and cortisol

had significantly

HPA Responsivity,

on

(Katona

et al., 1983;

response

1-2 hours

305

impairment

levels were closely

as measured

impairment

The main finding

higher

cortisol

above

Castro

GDS and MMSE,

that serum cortisol

significantly

controls.

and cognitive

at

say very

2.0ug/ml different

Similarly and

2 sub-

7.0ug/ml,

pre-DEX

but

cortisol

We are aware that the Index has a limitation

are very Tow.

At present

it is not clear to us

D. Gurevich et al.

306

We believe

that

manipulations approach

the dynamic

such as those reported

was recommended

looking at the dynamic example

previously aspects

repeated measures

which are inherently The Index

of HPA

that system

by

P
relating

(Greden,

as revealed

by rather

and avoiding

1987).

One benefit

static descriptions,

data, may be a better

simple

A similar

and of great interest.

1987; Koslow and Gaist,

or rate of change

In our the

levels

sample,

between

before

1).

takes and

Index

plasma

Table the

here,

the

post-DEX

cortisol,

correlation

suggested

cortisol

than

for post-DEX

test the

systems,

here, are significant

of a system

Responsivity,

impai~ent

of biological

by using

understanding

of for

of systems

in a state of flux.

giving dexamethasone). conitive

aspect

and

after

of HPA

cortisol

Presently

Index

into

a dynamic

challenging

Responsivity

levels

we

other

account

are

more

may

(P
conducting

accurate

the

aspect

system better

for the a

measures

(i.e.

predict Index

study

that

of

of

vs

will

cognitive

dysfunction.

Conclusions Previous

suggest

and learning

effects

that

on the hippocampus

especially memory

studies

supports

a possible

provides

a measure

The authors

study

are mediated

relationship

between

for the responsivity

believe

that

is available.

creating

have

a

1986), a structure

neurotoxic

which

effect

is involved

(Dekosky et al., 1984) suggests

that cortisol

adrenergic

neurons.

cognitive

impairment

and high cortisol

The

in

present

study

levels and

of the HPA axis. which takes into account

which is unavailable

Such an index

the system which may be useful

levels

through

an index,

information

cortisol

and tiEwen,

Another

cells

of the HPA axis, provides challenge)

plasma

(Sapolsky

processes.

on hippocampal

high

provides

a dynamic

when

the actual

only a single

measure

response

value (post-

of the functioning

of

in other studies.

Acknowledgements This study

was

supported,

in part,

by

Yancey and Ms. Anne Houle for manuscript

NIH

grant

MH40924

(G.F.O.).

We thank

Ms. Alice

preparation.

References BALLDIN GOTTFRIES, C.G., KARLSSON, I., LINDSTEDT, G., LANGSTROM, G. and WALNDER, J. ..___? J., (lY83) Dexamethasone SUPPWSSiOrI Test and Serum Prolactin in Dementia Disorders. Br J Psychiatry, -143:277-281.

HPA axis responsivity

and cognitive

307

impairment

BRANCONNIER, R.J., OXENKRUG, G.F., MCINTYRE, I., POMARA, N., HARTO, N.E. and GERSHON, S. (1984) Prediction of Serum Cortisol Response to Dexamethasone in Normal Volunteers: A Multivariage Approach. Psychopharmacology, -84:274-275. CARNES, M., SMITH, J.C., KALIN, N.H. and BAUWENS, S.F. (1983) Test in Demented Outpatients With and Without Depression.

The Dexamethasone Suppression Psychiatry Res, 9:337-344.

CARROLL, B.J., FEINBERG, M., GREDEN, J.F., TARIKA, J., ALBALA, A.A., HASKETT, R.F., JAMES, NM., KROWOL, Z., LOHR, N., STEINER, M., DEVIGNE, J.P. and YOUNG, E. (1981) A Specific Laboratory Test for the Diagnosis of Melancholia. Arch Gen Psychiatry, -38:15-22. (1983) CASTRO, P., LEMAIRE, M., TOSCANO-AGUILAR, M. and HERCHUELZ, A. Dementia, and the Dexamethasone Suppression Test. Am J Psychiatry, -140:1386.

Depression,

COPPEN, A., ABOU-SALEH, M., MILLN, P., METCALFE, M. HARWOOD, J. and BAILEY, J. (1983) Dexamethasone Suppression Test in Depression and other Psychiatric Illness. Br J Psychiatry, -142:498-504. DAVOUS, P., ROUDIER, M., PIKETTY, M.L., ABRAMOWITZ, C. and LAMOUR, Y. (1988) Pharmacological Modulation of Cortisol Secretion and Dexamethasone Suppression in Alzheimer's Disease. Biol Psychiatry, 23:13-24. DEKOSKY, S.T., SCHEFF, S.W. &d COTMAN, C.W. (1984) Elevated Corticosterone Possible Cause of Reduced Axon Sprouting in Aged Animals. Neuroendocrinology, DELEON, M.J., MCRAE, T., TSAI, J.R., GEORGE, A.E., MARCUS, and MCEWEN, B. (1988) Abnormal Cortisol Response in Hippocampal Atrophy. Lancet, 391-392. DILMAN, V.M., LAPIN, I.P. in Health and Disease.

Levels: A -38:33-38.

D.L., FREEDMAN, M., WOLF, A.P. Alzheimer's Disease Linked to

and OXENKRUG, G.F. (1979) Serotonin and Aging. In: W. Essman (Ed.) pp 111-212, Spectrum Publications,

Serotonin New York.

(1975) "Mini-Mental State" A Practical FOLSTEIN, M.F., FOLSTEIN, S.E. and MCHUGH, P.R. Method for Grading the Cognitive State of Patients for the Clinician. J Psychiatr Res, -12:189-198. GEORGOTAS, A., MCCUE, R.E., KIM, O.M., HAPWORTH, W.E., REISBERG, B., STOLL, P.M., SINAIKO, (1986) Dexamethasone Suppression in Dementia, DepresE ., FANELLI, C. and STOKES, P.E. sion and Normal Aging. Am J Psychiatry -143:452-456. (1987) The Hypothalamic-Pituitary-Adrenal (HPA) System in Depression: ParaGREDEN, J.F. digms and Problems in Research and Practice. In: Hormones and Depression. U. Halbreich (Ed.) pp 59-75, Raven Press, New York. GREENWALD, B.S., MATHE, A.A., MOHS, R.C., LEVY, M.I., Cortisol and Alzheimer's Disease, II: Dexamethasone Am J Psychiatry 143:442-446. Affective Symptoms. HALSTEAD, W.C. (1947) Brain and Intelligence; Chicago:University of Chicago Press. HAMILTON,

JOHNS, C.A. and DAVIS, Suppression, Dementia

A Quantitative

M. (1960) A Rating Scale for Depression.

J Neurol

Study

Neurosurg

K.L. (1986) Severity and

of the Frontal Psychiatry,

Lobes.

23:56-62.

JENIKE, M.A. and ALBERT, M.S. (1984) The Dexamethasone Suppression Test in Patients with Presenile and Senile Dementia of the Alzheimer's Type. J Am Geriatr Sot, -32:441-444. KATONA, C.L.E. and ALDRIDGE, C.R. J Affective Signs in Dementia.

(1985) The Dexamcthasone Disord, 8:83-89.

Suppression

Test and Depressive

KO;;OW,

S.H. and GAIST, P.A. (1987) The Measurement of Neurotransmitters A.J. Marsella, R.M.A. Hlrschfeld, The Measurement of Depression. (Eds.) pp 109-152, The Guilford Press, New York.

:

KRIEGER, D.T., ALLEN, W., Normal Temporal Pattern -32:266-284.

(1971) RIZZO, F. and KRIEGER, H.P. of Plasma Corticosteroid Levels.

J

in Depression. and M.M. Katz,

Characterization Clin Endocrinol

(1965) Diagnosis of Cushing's NUGENT, C.A., NICHOLS, T. and TYLER, F.H. Dose Dexamethasone Suppression Test. Arch Intern Med, -116:172-176.

Syndrome:

of the Metab, Single

OXENKRUG, G.F., POMARA, N., MCINTYRE, I.M., BRANCONNIER, R.J., STANLEY, M., and GERSHON, S. (1983) Aging and Cortisol Resistance to Suppression by Dexamethasone: A Positive CorrePsychiatry Res, -10:125-130. lation.

D. Gurevichet al.

308

OXENKRUG, G.F. and GERSHON, S. (1987) Cognitive Function and Brain-Adrenal Axis Activity Alzheimer's Disease: Problems, Prospects, and in Aging, Depression and Dementia. In: Perspectives. H. J. Altman (Ed.), pp 59-66, Plenum Press, New York. OXENKRUG, G.F., GUREVICH, D., SIEGEL, B., DUMLAO, M.S. and GERSHON, S. (1989) Correlation Between Brain Adrenal Axis Activation and Cognitive Impairment in Alzheimer's Disease: Is There a Gender Effect? Psychiatry Res, -29:169-175. POMARA, N., OXENKRUG, G.F., MCINTYRE, I.M., BLOCK, R., STANLEY, M. and GERSHON, S. (1984) Does Severity of Dementia Modulate Response to Dexamethasone in Individuals with Primary Degenerative Dementia? Biol Psychiatry, -19:1481-1487. RASKIND, M., PESKIND, E., RIVARD, M.F., VEITH, R. and BARNES, R. (1982) Dexamethasone Suppression Test and Cortisol Circadian Rhythm in Primary Degenerative Dementia. Am J Psychiatry, 139:1468-1471. (1982) The Global Deterioration REISBERG, B., FERRIS, S.H., DELEON, M.J. and CROOK, T. Am J Psychiatry, -139:1136Scale for the Assessment of Primary Degenerative Dementia.

1139.

ROSENBAUM, A.H., SCHATZBERG, A.F., MACLAUGHLIN, R.A., SNYDER, K., JIANG, N.S., ILSTRUP, D., (1984) The Dexamethasone Suppression Test in Normal ROTHSCHILD, A.J. and KLIMAN, B. Am J Psychiatry, Comparison of Two Assays and Effect of Age. Control Subjects: -141:1550-1555.

(1984) Cortisol RUBINOW, D.R., POST, R.M., SAVARD, R. and GOLD, P.W. Cognitive Impairment in Depression. Arch Gen Psychiatry, 41:279-283.

Hypersecretion

(1986) The Neuroendocrinology SAPOLSKY, R.M., KREY, L.C. and MCEWEN, B.S. Aging: The Glucocorticoid Cascade Hypothesis. Endocr Rev, 1:284-301.

of Stress

and and

SAPOLSKY, R.M. and MCEWEN, B.S. (1986) Stress, Glucocorticoids, and Their Role in Degenerative Changes in the Aging Hippocampus. In: Treatment Development Strategies for Alzheimer's Disease. T. Crook, R. Bartus, S. Ferris and S. Gershon (Eds.), pp 151-171, Mark Powley Associates, Madison, Connecticut, USA. SMITH, A. (1980) Principles Underlying Human Brain Functions in Neuropsychological SequeHandbook of Clinical Neuropsychology lae of Different Neuropathological Processes. In: S.B. Filskov and T.J. Boll (Eds.) pp 175-226, John Wiley & Sons, New York. SPAR, J.E. and GERNER, R. Dementia from Depression?

(1982) Does the Dexamethasone Pm J Psychiatry, -139:238-240.

Suppression

Test

Distinguish

(1981) Depressed Mood and Other PsychiSTARKMAN, M.N., SCHTEINGART, D.E. and SCHORK, M.A. Relationship to Hormone Levels. Psychosom atric Manifestations of Cushing's Syndrome: Med, -43:3-18. SUNDERLAND, T., ALTERMAN, I.S., YOUNT, D., HILL, J.L., TARIOT, P.N., NEWHOUSE, P.A., (1988) A New Scale for the Assessment of MUELLER, E.A., MELLOW, A.M. and COHEN, R.M. Depressed Mood in Demented Patients. Am J Psychiatry, E:955-959. WHELAN, T.B., SCHTEINGART, D.E., STARKMAN, M.N. and SMITH, A. Deficits in Cushing's Syndrome. J Nerv Ment Dis, -168:753-757. Inquiries

and reprint requests

David Gurevich, M.D., Ph.D. Department of Psychiatry Wayne State University Lafayette Clinic 951 E. Lafayette Detroit, MI 48207 U.S.A.

should be addressed

to:

(1980)

Neuropsychological