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The Journal of Neuroscience, March 15, 1999,
19(6):2356-2361 Veterans Affairs Puget Sound Health Care System, 1 Mental
Illness Research, Chronic exposure to increased glucocorticoid concentrations appears to lower
the threshold for hippocampal neuronal degeneration in the old rat.
It has been proposed that increased brain exposure to glucocorticoids
may lower the threshold for hippocampal neuronal degeneration in
human aging and Alzheimer's disease. Here, we asked whether chronic
administration of high-dose cortisol to older nonhuman primates
decreases hippocampal neuronal number as assessed by unbiased
stereological counting methodology. Sixteen Macaca nemestrina
(pigtailed macaques) from 18 to 29 years of age were age-,
sex-, and weight-matched into pairs and randomized to receive either
high-dose oral hydrocortisone (cortisol) acetate (4-6 mg/kg/d) or
placebo in twice daily palatable treats for 12 months.
Hypothalamic-pituitary-adrenal activity was monitored by measuring
plasma adrenocorticotropin and cortisol, 24 hr urinary cortisol,
and CSF cortisol. Urinary, plasma, and CSF cortisol were elevated,
and plasma adrenocorticotropin was reduced in the active treatment
group. Total hippocampal volume, subfield volumes, subfield neuronal
density, and subfield total neuronal number did not differ between
the experimental groups. These findings suggest that chronically
elevated cortisol concentrations, in the absence of stress, do not
produce hippocampal neuronal loss in nonhuman primates.
Key words: cortisol; aging; nonhuman primate; hippocampus; stereology; CSF
cortisol Rodent studies suggest that prolonged exposure to elevated glucocorticoid
(GC) concentrations lowers the threshold for hippocampal neuronal
degeneration and loss (Sapolsky et al., 1985). A
few studies suggest GC neurotoxic effects in primates (Uno et
al., 1989; Sapolsky
et al., 1990). Older
animals may be particularly vulnerable to this phenomenon (Landfield
et al., 1981; Kerr
et al., 1991). Based on
these observations, concern has been raised that prolonged elevation
of endogenous GCs caused by chronic stress or pharmacological doses
of GCs commonly administered to humans with inflammatory or
bronchospastic diseases might produce hippocampal neuronal loss and
resultant cognitive impairment, particularly in later life (Keenan et
al., 1996; Sapolsky,
1996). Most in vivo studies addressing GC effects on hippocampal neuronal
integrity have used either chronic stress or adrenalectomy versus
intact animal paradigms and have attributed effects on the
hippocampus to changes in endogenous GC levels produced by these
paradigms (Uno et al., 1989; Kerr et
al., 1991;
Watanabe et al., 1992; Magariños
et al., 1997;
Vollmann-Honsdorf et al., 1997). Few
studies actually have quantified the effects of chronic exogenous GC
administration on hippocampal neuronal number in adult animals, and
these few studies have produced inconsistent results. Loss of CA3
hippocampal neurons in young rats was reported after 3 months of
corticosterone administration that achieved corticosterone
concentrations approximating those seen during acute stress (Sapolsky
et al., 1985). In
contrast, there was no loss or shrinkage of hippocampal CA1 or CA3
neurons in middle-aged rats after 3 months of high-dose
exogenous corticosterone administration (Bodnoff et al., 1995). In the
only study that evaluated chronic exogenous GC effects in primates
(Sapolsky et al., 1990),
hippocampal neuronal loss was not observed in young vervet monkeys
1 year after cortisol-containing pellets had been implanted
stereotactically into their hippocampi. None of these exogenous GC
administration studies used stereological counting methods to
determine neuronal numbers in a manner unbiased by neuron size,
shape, or volumetric changes (West and Gundersen, 1990). Studies in nonhuman primates are more likely to be relevant than rodent
studies for evaluating the potential hippocampal neurotoxicity of
high-dose GC therapy in older humans or the potential role of
chronically elevated endogenous GC in the hippocampal neuronal loss
of Alzheimer's disease (Raskind et al., 1982; Peskind
et al., 1995). The
present study tested the hypothesis that older nonhuman primates
receiving chronic high-dose cortisol for 1 year would have fewer
hippocampal pyramidal neurons than an age-matched control group
receiving chronic placebo for 1 year. Neuronal counts were
determined by unbiased stereological counting methods (West and
Gundersen, 1990). Animals. Sixteen retired breeder pigtailed macaques (Macaca
nemestrina) in middle to late life [mean age,
23.1 ± 1.0 years (mean ± SEM) at termination
of experiment; ranged from 18 to 29 years] were selected
from the Washington Regional Primate Research Center. There were five
males and 11 females. They had been housed in a reproduction
colony before the experimental protocol. For the protocol, all were
individually housed in the same room. Housing temperature and
humidity conditions conformed to the Animal Welfare Act and Guide for
the Care and Use of Laboratory Animals. All animals were in good
general health. Purina monkey chow was provided during the protocol
on a twice daily basis, with fruit supplements. The Washington
Regional Primate Research Center is fully accredited by American
Association for the Assessment and Accreditation of Laboratory Animal
Care International, and all procedures were reviewed and approved by
the University of Washington Animal Care and Use
Committee. Treatment protocol. The monkeys were divided into eight pairs matched
as closely as possible for age, gender, and weight. Each pair was
randomized to receive either high-dose hydrocortisone (cortisol)
acetate or placebo for 12 months. The groups did not differ in
age (cortisol-treated, 23.1 ± 1.3 years at time of death;
placebo, 23.1 ± 1.5 years at time of death) or pretreatment
weight (cortisol-treated, 11.1 ± 1.7 kg; placebo,
9.8 ± 1.9 kg; p = 0.63). Because
there were 11 females and five males, the groups could not be
matched evenly for gender (cortisol-treated, five females and three
males; placebo, six females and two males). The initial dose of
cortisol was 3.85 mg/kg/d (hydrocortisone acetate; Upjohn,
Kalamazoo, MI). This cortisol dose is approximately equivalent
to an adult human receiving the commonly prescribed synthetic
GC, prednisone, at a dose of 60 mg/d, a very high therapeutic
dose (Schimmer and Parker, 1996). Cortisol
was administered by mouth twice per day in a highly palatable treat
containing peanut butter, molasses, mashed potato flakes, and ground
monkey chow. After 2 weeks of treatment, the cortisol dose was
increased to 5.78 mg/kg/d in four cortisol treatment condition
monkeys in which plasma adrenocorticotropin (ACTH) was
inadequately suppressed. Neuroendocrine measures. Plasma cortisol, plasma ACTH, and 24 hr
urinary cortisol were measured during the week before the beginning
of drug treatment (baseline), after 2 weeks, and after
3, 6, 9, and 12 months of treatment. After a
24 hr adaptation period, total 24 hr urine for cortisol
measurement was collected in a metabolic cage designed for that
purpose. Containers placed on solid CO2 were positioned
under a collection spout and replaced at frequent intervals. Urine
containers remained frozen until thawed for volume determinations.
All containers from a given monkey for the 24 hr sampling
interval were mixed thoroughly after thawing. After volume
measurement, 3 ml aliquots of urine for each monkey from each
sampling period were stored frozen at 70°C.
Urine samples (500 µl) were extracted by mixing thoroughly with
1 ml of chilled methylene chloride, removing an aliquot of the
organic phase, and drying. Dried samples were reconstituted with
buffer and assayed as described previously for plasma cortisol
(Wilkinson et al., 1997).
Creatinine was determined by a quantitative colorimetric method
(Stanbio Laboratory, San Antonio, TX). Blood samples for plasma cortisol and ACTH measurements were collected from
sedated monkeys (ketamine hydrochloride, 10 mg/kg) using a
"squeeze cage" technique by which monkeys were briefly immobilized to
allow venipuncture. Blood samples for cortisol and ACTH measurements
were drawn within 10 min of sedation of animals. All sampling
was done between 9:00 and 10:15 A.M. Blood was stored on ice in
chilled polystyrene tubes and cold centrifuged within 1 hr of
sample collection; plasma was then separated and stored at 70°C until
assayed. Plasma cortisol and plasma ACTH were measured by
radioimmunoassay as described previously (Wilkinson et al., 1997). Monkeys were killed during an 8 hr period on 3 consecutive days,
with animals from cortisol and placebo groups alternating in
sequence. CSF was obtained after prekilling sedation by either lumbar
or cisternal puncture. Cortisol concentration was measured in
100 µl aliquots of unextracted CSF with a 125I-radioimmunoassay
kit (Pantex, Santa Monica, CA). All samples were measured in the same
assay. Interassay and intra-assay coefficients of variation for this
method in our laboratory are 7.1 and 3.7%, respectively. To
evaluate possible effects of elapsed time from A.M. cortisol dose on
cortisol concentrations achieved in the central compartment, we
performed Pearson product-moment correlations within treatment groups
between time from A.M. cortisol dose to CSF sampling.
Correlations were nonsignificant (r = 0.199 and
0.273 for cortisol and placebo groups, respectively). Therefore,
there is no indication that a marked fluctuation in CSF cortisol
levels occurred during the 12 hr between successive cortisol
doses during the course of the study. Tissue preparation. After 12 months of treatment, the animals
were killed by valium-phenobarbitol injection. Brains were then
rapidly removed and sectioned into 0.5-cm-thick coronal blocks
of the cerebral hemispheres and 0.5-cm-thick horizontal blocks
of the brainstem. The right hemispheric blocks were fixed flat
(to maintain gross morphology) between 4% paraformaldehyde-soaked
sponges for 36 hr and then stored in PBS, pH 7.4, with 20%
sucrose and 0.02% sodium azide. Fixed blocks of temporal lobe from
the right hemisphere were serially sectioned on a cryostat at
50 µm. Every twelfth section (600 µm interval) was taken
for thionin staining. The left hemisphere and brainstem were rapidly
frozen between cooled aluminum plates in a 70°C freezer
and stored at that temperature for future studies. Stereological counting techniques. All counting was performed blind to
treatment condition. Principles of stereology were used to select and
count neurons within the subfields of the hippocampus (West and
Gundersen, 1990; West,
1993a). After
randomly selecting a starting point rostral to the hippocampus,
sections were taken at 600 µm intervals and thionin stained for
cell counts. The hippocampal subfield boundaries were outlined (Fig.
1)
on each stained slide for all cases according to previously published
criteria (Rosene and Van Hoesen, 1987). These
fields included the dentate granule cell layer, dentate hilus, CA2/3,
CA1 (including prosubiculum), and subiculum. Neuronal density within
the individual sections was based on counts using the optical
disector technique with a Nikon (Tokyo, Japan) Optiphot-2 microscope
with a chromatic aberration-free, N-series (CF N) Plan Apochromat
100× (1.4 NA) oil objective, a digital linear measuring system
for x- and y-axes (Boeckeler, Tucson, AZ), and a video
camera (DAGE-MTI, Michigan City, IN) output to a high-resolution
video screen (Sony, Tokyo, Japan). An unbiased counting frame with
extended exclusion lines (25 × 25 µm for all fields,
except the dentate granule cell layer for which
10 × 10 µm was used) was printed on an acetate sheet
(calibrated with a slide micrometer) and placed over the video
screen. For each section counted, a grid of potential disectors
was laid out over the entire section. A random starting point
was used for the first disector selected, and then subsequent
disectors were systematically sampled from that point. The frequency
of disector sampling was dependent on the neuronal density for
each hippocampal subfield. For example, the number of disectors
chosen in a section for the dentate granule cells was greater
than for CA1 because the likelihood of a particular disector
including the smaller granule cell layer (by area) was much less.
This method allowed for random but systematic disector sampling for
each subfield. In all subfields, at least 100 disectors were
counted. Subfield volumes were calculated by determining the subfield
areas on all sections counted, using a computerized image analysis
system (MCID; Imaging Research Inc., Ontario, Canada), and
multiplying by 600 µm. An unbiased estimate of total number of
neurons within each subfield was derived from the product of the
neuronal density and the estimated field volume
(N = Nv × Vref).
Neurohistology. Light microscopic examination for neuropathology was
performed (by J. B. Leverenz) on all thionin-stained
slides. Slides were examined blind to treatment condition. Statistical analyses. Values are expressed as mean ± SEM.
Differences in neuroendocrine measures over time within each treatment
group were evaluated by repeated measures ANOVA. A significant
difference over time prompted paired t test comparisons
between each treatment time point value and the baseline value in
that group. Differences in neuroendocrine measures between
treatment groups at each time point were evaluated by unpaired
t tests. Differences in hippocampal subfield neuronal counts
and volumes between groups also were evaluated by unpaired t
tests. To minimize the likelihood of type II error, no correction was
made for multiple comparisons. Animals' general condition during study All monkeys survived the 12 month treatment period in good general
health, except for one of the cortisol-treated monkeys. This monkey
died of Klebsiella sepsis 2 weeks after the 9 month
evaluation point. Although this monkey's brain was removed within
60 min of death, the brain was not used for the analysis of
neuronal number in the hippocampal formation. The 12 month
weight and weight gain of the placebo-treated monkeys
(9.8 ± 1.9 and 0.4 ± 0.3 kg) did not
differ from the 12 month weight and weight gain of the
cortisol-treated monkeys (11.1 ± 1.7 and
1.0 ± 0.4 kg) (t = 0.87;
p = 0.40; and t = 0.82;
p = 0.43, respectively, for end weights and
weight gain). Brain weights did not differ between cortisol-treated
monkeys (93.0 ± 2.6 gm) and placebo-treated monkeys
(99.5 ± 4.0 gm) (t = 1.32;
p = 0.21). Endocrine effects of cortisol treatment Cortisol-treated monkeys tended toward greater, but not statistically
significant, weight gain (see previous section) versus the placebo
group. Many of the cortisol-treated monkeys, but not those in the
placebo group, developed cushingoid features (facial puffiness,
buffalo hump). Two of the cortisol-treated animals developed mild
glucose intolerance, but none required insulin treatment. Twenty-four hour urinary cortisol excretion (expressed as nanomoles of
cortisol per millimoles of creatinine) at baseline, after
2 weeks, and after 3, 6, 9, and 12 months of treatment
are presented in Figure 2.
Baseline pretreatment 24 hr urinary cortisol did not differ
between cortisol and placebo groups. Within the cortisol-treated
group, 24 hr urinary cortisol was significantly increased from
baseline at all time points (p < 0.05). Twenty-four
hour urinary cortisol was significantly higher in the
cortisol-treated group compared with the placebo group at
2 weeks and 3, 6, 9, and 12 months of
treatment (p < 0.01). Plasma cortisol concentrations
in the cortisol treatment group were significantly higher than
baseline values during exogenous cortisol administration at all
time points (p < 0.01) and significantly higher than
in the placebo treatment group at 3, 6, 9, and
12 months of treatment (p <0.05) (data not shown).
Plasma ACTH concentrations at the same time points are presented in Figure 3.
Plasma ACTH did not differ between groups at baseline
(p = 0.12). Exogenous cortisol administration
appropriately suppressed plasma ACTH concentrations, which were
significantly lower than baseline at all treatment time points in the
cortisol-treated group (p < 0.01). Plasma ACTH in
the cortisol-treated group was significantly lower than in the
placebo group at 6, 9, and 12 months of treatment
(p < 0.05). Plasma ACTH did not differ over time
in the placebo group.
CSF cortisol concentrations before death are presented in Figure 4. CSF
cortisol levels were significantly higher in the cortisol-treated
group than in the placebo group (p < 0.01).
Hippocampal subfield neuronal numbers and volumes Hippocampal subfield neuronal numbers, volumes, and density are presented in
Table 1.
There were no significant differences in neuronal number between
groups in any hippocampal subfield (p > 0.20) nor
were there significant differences in subfield volumes or densities
between treatment groups (p > 0.10). Total
hippocampal volumes between groups did not significantly differ
(p = 0.64) (data not shown).
Neurohistology There were no apparent differences in perikaryal size, nuclear size, or
nuclear density between treatment groups in any hippocampal subfield.
The regularity of pyramidal cell layers was indistinguishable
between groups. These results do not confirm the hypothesis that high-dose chronic exogenous
GC administration produces loss of hippocampal neurons in older
nonhuman primates. The threefold increase in CSF cortisol found in
the treated monkeys indicates that substantial elevations in cortisol
concentration were achieved in the CNS. There were no effects of
cortisol treatment on neuronal number, density, or volume of any
hippocampal subfield. In particular, there was no suggestion that
cortisol treatment reduced neuronal number in CA2/3, the area
considered most vulnerable to GC neurotoxic effects (Landfield et
al., 1981; Sapolsky
et al., 1985). The
subiculum also did not show evidence of significant neuronal loss,
despite its apparent susceptibility to neuronal loss with normal
aging (West, 1993b; Simic et
al., 1997). The current study is not alone in failing to demonstrate that chronic GC
administration produces hippocampal neuronal loss. Bodnoff et al.
(1995)
administered exogenous corticosterone to middle-aged rats for
3 months at doses that mimicked corticosterone concentrations
normally achieved at the diurnal peak or the even higher
concentrations normally achieved during stress. Although
corticosterone-treated rats demonstrated spatial learning impairment
and electrophysiological changes, suggesting impaired hippocampal
synaptic plasticity, there were no effects of corticosterone
treatment on hippocampal neuronal number, neuronal size, or subfield
volume, nor were any other neurohistological abnormalities noted.
Sapolsky et al. (1990) implanted a
cortisol-containing pellet in one hippocampus and a
cholesterol-containing placebo pellet in the other hippocampus of
four young vervet monkeys. After 1 year, there were no differences
in hippocampal subfield neuronal number between the cortisol
pellet-exposed side and the cholesterol pellet-exposed side.
Qualitative changes interpreted as consistent with neurodegeneration,
including shrinkage and condensation of soma and nucleus, dendritic
atrophy, and cell layer irregularity, were more intense and frequent
in the cortisol pellet-exposed hippocampal CA2/3 subfields. Neither
systemic nor local hippocampal cortisol concentrations were
determined in this study. Neither of these studies confirmed Sapolsky
et al. (1985)
report in rats of hippocampal neuronal loss after chronic exogenous
GC administration, but they suggest other effects of exogenous
GC on hippocampal neuronal integrity. Consistent with this
possibility is the demonstration in single-section Golgi preparations
that exogenous corticosterone administration to rats produces
atrophy of the apical dendritic tree of CA3 pyramidal neurons
(Woolley et al., 1990; Watanabe
et al., 1992). Although
no evidence of neuronal morphological abnormalities with exogenous
cortisol treatment was found in the present study, further studies of
dendritic morphology may reveal cortisol effects. Several studies have inferred GC-induced hippocampal neuronal loss in
chronically stressed older rats (Kerr et al., 1991),
chronically stressed orchiectomized rats (Mizoguchi et al., 1992),
and socially subordinate wild vervet monkeys that died spontaneously
during episodes of apparent severe stress (Uno et al., 1989).
In the latter naturalistic monkey study, cortisol concentrations
were not determined, and decreased neuronal numbers were found
only in CA3 in the subordinate male vervets. That these reported
effects of stress on hippocampal neuronal number can be attributed
to the elevated GC levels accompanying stress is a viable hypothesis
(Sapolsky, 1992), but other
effects of stress could also have accounted for these effects on
hippocampal neuronal integrity. None of the above stress paradigm
studies used unbiased stereological counting techniques. A recent
study that used unbiased stereological counting techniques to
determine the effects of a 28 d "psychological conflict" stress
paradigm on hippocampal neuronal number in the tree shrew, a
phylogenetic intermediate between insectivores and primates (Martin,
1990), did not
confirm stress-induced hippocampal neuronal loss (Vollmann-Honsdorf
et al., 1997). This
stress paradigm increased urinary cortisol concentrations more than
threefold, but there was no effect on neuronal numbers in the
hippocampal CA3 or CA1 subfields. This psychosocial conflict paradigm
in tree shrews has produced CA3 pyramidal neuron apical dendritic
atrophy, as determined by the single-section Golgi technique
(Magariños et al., 1997). Whether
the CA3 apical dendritic atrophy and alterations in mossy fiber CA3
synaptic ultrastructure after chronic stress represent early signs of
neuronal degeneration or adaptive and reversible responses to stress
and/or increased GC concentrations remains unclear (Magariños et al.,
1997). Application of unbiased stereological counting techniques to nonhuman primate
studies has failed to demonstrate hippocampal neuronal loss after
exogenous cortisol administration in macaques in the current study or
after chronic stress associated with increased cortisol secretion in
tree shrews (Vollmann-Honsdorf et al., 1997).
These results do not rule out the possibility that GC-induced
modifications of hippocampal neuronal structure or function
contribute to the cognitive deficits reported in persons receiving
acute and chronic GC therapy and in persons with Cushing's disease
or that hypothalamic-pituitary-adrenal axis hyperactivity may
contribute to exacerbation of cognitive and noncognitive
abnormalities in aging and Alzheimer's disease (Starkman et al.,
1992;
Newcomer et al., 1994; Raskind et
al., 1994; Keenan et
al., 1996;
Wolkowitz et al., 1997). However,
they provide some reassurance that therapeutic use of GCs in older
humans is unlikely to produce hippocampal neuronal death as a common
adverse effect. Further studies in nonhuman primates and humans will
be necessary to evaluate the possible effects of stress-associated
endogenous cortisol elevations and aging-associated changes in
hypothalamic-pituitary-adrenal axis regulation on hippocampal
structure and function in human aging and Alzheimer's
disease. Received July 10, 1998; revised Dec. 1, 1998; accepted Jan.
5, 1999. This work was supported by National Institutes of Health Grant 2P51RR00166,
National Institute on Aging Grant AGO6136, the Alzheimer's
Association, and the Department of Veterans Affairs. We gratefully
acknowledge the assistance of Bradley T. Hyman and
T. Gomez-Isla with the stereological methods, the assistance of
William R. Morton as Director of the Washington Regional Primate
Research Center, and the tireless technical assistance of Lynne
Greenup, Elizabeth Colasurdo, Richard Vertz, Judy Johnson, and
Mark Murchison.
Correspondence should be addressed to Dr. Elaine R. Peskind, Veterans
Affairs Puget Sound Health Care System, Mental Illness Research,
Education and Clinical Center (116 MIRECC), 1660 South
Columbian Way, Seattle, WA 98108.
Effect of Chronic High-Dose Exogenous Cortisol on Hippocampal Neuronal
Number in Aged Nonhuman Primates
ABSTRACT
Top
Abstract
Introduction
References
INTRODUCTION
Top
Abstract
Introduction
References
MATERIALS AND METHODS
View larger version
(74K):
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Figure 1.
Representative coronal sections from rostral to caudal hippocampus
(A, C, E, G) and outlines of dentate
granule cell layer, hilus, CA2/3, CA1, and subiculum as used in
stereological cell counting (B, D, F,
H). CA1' (Rosene and Van Hoesen, 1987) was not included within the assessed CA1 subfield.
RESULTS
View larger version
(48K):
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Figure 2.
Twenty-four hour urinary cortisol concentrations (expressed as
nanomoles per millimoles creatinine) in placebo- and
cortisol-treated groups at baseline (BL), after 2 weeks
(wk), and after 3, 6, 9, and 12 months
(m) of treatment. *p < 0.05, higher
than baseline; p < 0.01, higher than
placebo group.
View larger version
(50K):
[in a new window]
Figure 3. Plasma
ACTH concentrations (expressed as picomoles per liter) in placebo-
and cortisol-treated groups at baseline (BL), after
2 weeks (wk), and after 3, 6, 9, and
12 months (m) of treatment.
*p < 0.01, lower than baseline; p < 0.05, lower than placebo
group.
View larger version
(21K):
[in a new window]
Figure 4. CSF
cortisol concentrations (expressed as nanomoles per liter) in
placebo- and cortisol-treated groups after 12 months of
treatment obtained by lumbar or cisternal puncture in sedated
animals before death. *p < 0.01, higher in
placebo group.
Table
1. Neuronal volume, density, and cell number in
five hippocampal regions
DISCUSSION
FOOTNOTES
REFERENCES
Top
Abstract
Introduction
References
Copyright © 1999
Society for Neuroscience 0270-6474/99/1962356-06$05.00/0
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