Content uploaded by Benjamin L Hart
Author content
All content in this area was uploaded by Benjamin L Hart
Content may be subject to copyright.
JAVMA, Vol 219, No. 1, July 1, 2001 Scientific Reports: Original Study 51
SMALL ANIMALS/
EXOTICS
I
mproved veterinary care and nutrition and safer
home environments are allowing dogs to live well
into their senior years. Thus, there is increased interest
in the behavior and welfare of aging dogs. In addition
to age-related changes in the musculoskeletal, cardio-
vascular, and endocrine systems, caregivers of dogs and
their veterinarians have recognized a number of behav-
ioral changes that occur in senior dogs that appear to
reflect disturbances of memory and learning.
1
Because
memory and learning are integral components of ani-
mal cognition,
2,3
the terms cognitive impairment and
cognitive dysfunction have been introduced to refer to
these behavioral changes in senior dogs.
4-6
The term
canine cognitive dysfunction syndrome was recently
introduced in association with US Food and Drug
Administration approval of selegiline
a
for treatment of
this syndrome.
7
Behavioral changes in senior dogs with cognitive
impairment can be classified into 4 general cate-
gories
1,8
: disorientation in the home or yard, changes in
social interactions with human family members, loss of
house training, and changes in the sleep-wake cycle.
The first 3 categories comprise behavioral signs that
clearly reflect loss of memory and learning. Changes in
the sleep-wake cycle would appear to reflect disrup-
tions in the circadian rhythm; however, adaptation of
the crepuscular activity pattern of wild canids (active
at dusk and dawn) to the diurnal pattern of human
family members represents a type of learning, and dis-
ruption of the sleep-wake cycle is common in humans
with Alzheimer’s disease.
9,10
In a previous study,
1
the prevalence of behavioral
impairments in senior dogs was significantly associat-
ed with age. Twenty-eight percent of dogs 11 to 12
years old had impairments in 1 or more categories, and
10% had impairments in 2 or more. By contrast, 68%
of dogs 15 to 16 years old had impairments in 1 or
more categories, and 35% had impairments in 2 or
more. A related study
8
of dogs 11 to 14 years old found
that over a period of 6 to 18 months, almost all dogs
became more impaired or stayed the same. Only 2 of
37 dogs that were initially found to have impairments
in a particular category were later found not to have
impairments in that category. In addition, 13 of 27
(48%) dogs initially found to have impairments in only
1 category were later found to have impairments in 2
or more categories, whereas only 8 of 73 (11%) dogs
that did not initially have any impairments were later
found to have impairments in 2 or more categories.
Despite the obvious species-specific differences,
behavioral changes in senior dogs appear similar to
those in humans with dementia, particularly those
with Alzheimer’s disease, in which decreased recogni-
tion of family members, disorientation in the home or
neighborhood, disturbances of the sleep-wake cycle,
and, eventually, inappropriate urination or defecation
are common.
9,10
As in dogs with cognitive impairment,
changes in humans with Alzheimer’s disease are pro-
gressive.
11-14
The primary neuropathologic changes in humans
with Alzheimer’s disease are accumulation of β-amy-
Effect of gonadectomy on subsequent
development of age-related cognitive
impairment in dogs
Benjamin L. Hart, DVM, PhD, DACVB
Objective—To determine whether gonadectomy pre-
disposes dogs to development of age-related behav-
ioral changes linked to cognitive impairment.
Design—Cohort study.
Animals—29 sexually intact male dogs, 63 spayed
female dogs, and 47 castrated male dogs 11 to 14
years old.
Procedure—Information on possible impairments in
4 behavioral categories linked to cognitive impairment
(orientation in the home and yard, social interactions,
house training, and sleep-wake cycle) was obtained
from owners of the dogs by use of a structured tele-
phone interview format. A second interview was per-
formed 12 to 18 months after the initial interview, and
differences in responses were evaluated.
Results—Sexually intact male dogs were significant-
ly less likely than neutered dogs to progress from
mild impairment (ie, impairment in 1 category) to
severe impairment (ie, impairment in ≥ 2 categories)
during the time between the first and second inter-
views. This difference was not attributable to differ-
ences in ages of the dogs, duration of follow-up, or
the owners’ perceptions of the dogs’ overall health.
Conclusions and Clinical Relevance—Results sug-
gest that the presence of circulating testosterone in
aging sexually intact male dogs may slow the pro-
gression of cognitive impairment, at least among
dogs that already have signs of mild impairment.
Estrogens would be expected to have a similar pro-
tective role in sexually intact female dogs; unfortu-
nately, too few sexually intact female dogs were avail-
able for inclusion in the study to test this hypothesis.
There may be a need to evaluate possible methods
for counteracting the effects of loss of sex hormones
in gonadectomized dogs. (
J Am Vet Med Assoc
2001;
219:51–56)
From the Behavior Service, Veterinary Medical Teaching Hospital,
School of Veterinary Medicine, University of California, Davis, CA
95616.
Supported in part by the UC Davis Center for Companion Animal
Health.
The author thanks Drs. Kelly Cliff, Melissa Bain, and Jacqueline
Neilson for technical assistance and Dr. Neil Willits for assistance
with statistical analyses.
00_02_0086.QXD 10/10/2005 1:46 PM Page 51
52 Scientific Reports: Original Study JAVMA, Vol 219, No. 1, July 1, 2001
SMALL ANIMALS/
EXOTICS
loid peptide in the frontal cortex and hippocampus and
formation of β-amyloid plaques associated with neu-
ronal death.
9,10
The amount of β-amyloid correlates
with the severity of dementia in patients with
Alzheimer’s disease.
15
Aged dogs also accumulate
β-amyloid deposits in the hippocampus and frontal
cortex,
16-19
and these deposits are similar to the primi-
tive or early-stage plaques seen in the brains of humans
with Alzheimer’s disease.
20,21
Advanced senile plaques
have not been found in dogs, but laboratory research
on aging Beagles has shown that the degree of β-amy-
loid deposition corresponds to the degree of impair-
ment in learning complex tasks.
22,23
Interestingly,
selegiline not only improves behavioral signs in dogs
with cognitive impairment
7
but also slows the progres-
sion of degenerative changes in human patients with
Alzheimer’s disease.
24
Various studies
25-28
have found that post-
menopausal women receiving estrogen-replacement
therapy had a lower risk of developing Alzheimer’s dis-
ease, even when variables such as education, ethnicity,
socioeconomic status, age at menarche, age at
menopause, number of children, and ApoE
4
genotype
were taken into account. In addition, estrogen treat-
ment of postmenopausal women with Alzheimer’s dis-
ease enhanced cognition,
29
although whether estrogen
enhances cognitive function in older women without
dementia is less certain.
30,31
Clinical studies on the role of testosterone in cog-
nitive function in men are more limited, but recent
work suggests that among older men, those with high-
er testosterone concentrations and lower estradiol con-
centrations performed better than those with lower
testosterone concentrations on tests of cognitive func-
tion,
32
and testosterone can enhance verbal fluency in
hypogonadal men.
33
There is research that suggests estrogen potenti-
ates memory and learning in rodents, and ovariectomy
results in a decline in learning ability and memory.
34-37
Estradiol appears to enhance memory by interacting
with cholinergic systems involved in memory modula-
tion.
38,39
Estrogen maintains the neural circuitry and
neural transmitter systems in the hippocampus and
frontal cortex,
40-42
and both estrogen
43,44
and testos-
terone
45
reduce accumulation of the β-amyloid materi-
al that comprises the neural plaques associated with
cognitive impairment in humans and dogs.
Testosterone has also been found to prevent hyper-
phosphorylation of the neuroprotective protein tau,
which is abnormally hyperphosphorylated in human
patients with Alzheimer’s disease.
46
Cerebral glucose
utilization and cerebral blood flow are enhanced by
estrogen,
47,48
and estrogen serves to combat oxidative
stress.
49-51
Taken together, this research suggests that the sex
hormones may play a role in preventing development
of age-related cognitive impairment in dogs. The pur-
pose of the study reported here, therefore, was to deter-
mine whether gonadectomy predisposes dogs to devel-
opment of age-related behavioral changes linked to
cognitive impairment. Because in a previous study,
1
only 10% of castrated male and spayed female dogs
were found to have severe cognitive impairment
(ie, impairment in ≥ 2 behavioral categories), it seemed
unlikely that a cross-sectional study would be able to
detect significant differences in prevalence of severe
impairment between neutered and sexually intact dogs
unless an extremely large number of dogs were
enrolled in the study. Therefore, the present study was
structured to determine whether percentage of senior
dogs that progressed from mild cognitive impairment
(ie, impairment in only 1 behavioral category) to
severe impairment over a period of 6 to 18 months was
significantly different between sexually intact and
neutered dogs.
Materials and Methods
The study was conducted in parallel with a longitudinal
study of the progression of age-related behavioral impair-
ments in dogs.
8
Briefly, information on possible behavioral
changes linked to cognitive impairment was obtained from
owners of dogs 11 to 14 years old by use of a structured tele-
phone interview format. A second interview was performed
12 to 18 months after the initial interview, and differences in
responses were evaluated. Because of the advanced age of the
dogs included in the study, some dogs were euthanatized or
died of disease before the second interview could be per-
formed. However, the second interview was still performed
and the data were used if the dog had lived at least 6 months
after the first interview.
Selection of dogs—Records of the University of
California, Davis, Veterinary Medical Teaching Hospital
were searched to identify dogs 11 to 14 years old. Hospital
records for these dogs were screened, and dogs with med-
ical problems that may induce signs similar to cognitive
impairment were eliminated. Owners of a random sample
of the remaining spayed female and male castrated dogs and
of all remaining sexually intact dogs were contacted by tele-
phone to determine whether dogs were still alive, whether
the dogs had any medical problems not apparent from the
hospital records that may induce signs similar to cognitive
impairment, and whether the owners were willing to par-
ticipate in the study. Owners of all sexually intact male dogs
that met the criteria for inclusion were invited to partici-
pate, because there were so few records of sexually intact
male dogs. Dogs were considered to be sexually intact if
they were intact at the time of the first interview or if they
had been castrated ≤ 1 year previously. Almost all female
dogs were spayed, so sexually intact female dogs were not
included in the study.
Interview format and questions—During the initial
telephone contact with owners who agreed to participate in
the study, an appointment for the first structured telephone
interview was made. These owners were sent an information
sheet about possible age-related behavioral changes prior to
the first interview. Owners were not told they would be called
for a second interview. Because clients were sent information
about possible behavioral changes prior to the first interview,
and there was a 12- to 18-month delay before the second
interview, bias associated with sensitization of owners to age-
related changes during the second interview should have
been minimal. The first and second interviews were con-
ducted by different veterinary behaviorists, but the same
structured format was used by both.
Dogs were considered to have an impairment in any par-
ticular behavioral category if they were exhibiting ≥ 2 specif-
ic signs related to an impairment in that category and had not
been exhibiting those signs earlier in their lives (ie, at 5 to 8
years of age). Dogs were considered to have an impairment in
orientation in the home or yard if they had ≥ 2 of the follow-
00_02_0086.QXD 10/10/2005 1:46 PM Page 52
JAVMA, Vol 219, No. 1, July 1, 2001 Scientific Reports: Original Study 53
SMALL ANIMALS/
EXOTICS
ing or similar signs: staring into space, getting lost in the
house or yard, getting stuck in corners, and standing at the
wrong door or at the wrong side of the door to go out or in.
Dogs were considered to have an impairment in social inter-
actions if they had ≥ 2 of the following signs: a decrease in
how frequently the dog would greet its owners, a decrease in
how frequently the dog would solicit attention from its own-
ers, and a definite increase or decrease in how frequently the
dog would follow its owners around the house. Dogs were
considered to have an impairment in house training if they
started to urinate or defecate in the house without any
apparent medical or other behavioral explanation (eg, uri-
nary incontinence or separation anxiety), and there was
decreased signaling to go out, decreased use of a doggy door,
or some other change reflecting a decrease in learned house-
training behavior (eg, urinating or defecating in the house
just after coming in from outdoors). Dogs were considered
to have an impairment in the sleep-wake cycle if they had ≥
2 of the following signs: waking up the owner at night by
some activity such as pacing or vocalizing, sleeping notice-
ably less at night, and sleeping noticeably more during the
day. In addition, dogs were considered to have impairment
in a particular category only if the associated signs had been
observed more than once a week for at least the previous
month.
Efforts were made to avoid leading the owners to expect
that there was a correct answer to any of the questions.
Before questions about specific signs associated with each
behavioral category were asked, owners were given an oppor-
tunity to provide their own open-ended comments to a gen-
eral question related to that category. During the second
interview, in addition to questions regarding signs of cogni-
tive impairment, owners were asked whether their dogs had
any evidence of visual or auditory impairments, arthritis, or
dental problems. These abnormalities did not necessarily
have to have been diagnosed by a veterinarian.
Data analysis—A cross-sectional analysis was conduct-
ed only on dogs 13 to 15 years old at the time of the second
interview to compare percentages of spayed female, castrated
male, and sexually intact male dogs with impairments in
each of the 4 behavioral categories as well as percentages of
dogs with impairments in 1 category, ≥ 1 category, and ≥ 2
categories. In a previous study,
1
a significant age by sex inter-
action was not detected for dogs with impairments in any
category. Therefore, data for dogs of all ages (13 to 15 years)
were combined, and for some analyses, percentages of
neutered dogs of both sexes with impairments were com-
pared with percentage of sexually intact male dogs.
The longitudinal analysis was performed comparing the
percentages of 11- to 14-year-old spayed female, castrated
male, and sexually intact male dogs that progressed from
having no impairments at the time of the first interview to
having impairments in 1 category at the time of the second
interview. Similarly, percentages of dogs that progressed from
having no impairments at the time of the first interview to
having impairments in ≥ 2 categories at the time of the sec-
ond interview were compared among groups, as were per-
centages of dogs that progressed from having impairments in
1 category at the time of the first interview to having impair-
ments in ≥ 2 categories at the time of the second interview.
Percentages of dogs positive for 0 or 1 sign associated with a
particular behavioral category at the time of the first inter-
view that had impairments in that category (ie, positive for
≥ 2 signs) at the time of the second interview were also deter-
mined.
The Fisher exact test or the Pearson χ
2
statistic was used
for all analyses. Values of P < 0.05 were considered signifi-
cant. Because it was hypothesized that behavioral signs of
cognitive impairment would not progress as quickly in sexu-
ally intact male dogs as in spayed female and castrated male
dogs, some tests were performed as 1-tailed tests.
Results
Prevalence of cognitive impairments among
groups—The cross-sectional analysis included 20 sex-
ually intact male dogs, 33 castrated male dogs, and 41
spayed female dogs. For each of the 4 behavioral cate-
gories, percentages of spayed female, castrated male,
and sexually intact male dogs with impairment in that
category at the time of the second interview were not
significantly different (Fig 1). However, the P value for
impairment in house training (P = 0.056) was close to
the cutoff for significance, and when spayed female
and castrated male dogs were combined, the percent-
age of neutered dogs with an impairment in house
training at the time of the second interview was signif-
icantly (P = 0.029) higher than the percentage of sexu-
ally intact male dogs with an impairment in that cate-
gory. Percentages of dogs with impairments in 1 cate-
gory, percentages of dogs with impairments in ≥ 1 cat-
egory, and percentages of dogs with impairments in ≥ 2
categories at the time of the second interview were not
significantly different among groups.
Progression of signs of cognitive impairment—
This analysis involved 29 sexually intact male dogs, 47
castrated male dogs, and 63 spayed female dogs.
Twenty of the 29 (69%) sexually intact male dogs, 29
of the 47 (62%) castrated male dogs, and 34 of the 63
(54%) spayed female dogs were still alive at the time of
the second interview. The remaining 56 dogs had died
or been euthanatized prior to the second interview, but
all 56 had survived at least 6 months after the first
interview. Mean follow-up time for all 139 dogs in the
study (ie, mean time from the first to the second inter-
view or mean time from the first interview to time of
death) was 15.3 months (SD, 2.6 months). Mean age at
which spayed female dogs had been spayed was 2.8
years (SD, 0.1); mean age at which castrated male dogs
had been castrated was 4.8 years (SD, 1.2). At the time
of the first interview (ie, when dogs were 11 to 14 years
old), 41 of the 63 (65%) spayed female dogs did not
have impairments in any of the behavioral categories,
18 (29%) had impairments in 1 category, and 4 (6%)
had impairments in ≥ 2 categories. Thirty-two of the 47
(68%) castrated male dogs did not have impairments in
Figure 1—Percentages of dogs between 13 and 15 years old
that had impairments in each of 4 behavioral categories associ-
ated with cognitive function and that had impairments in 1 cat-
egory, ≥ 1 category, or ≥ 2 categories. FS = Spayed female. MC
= Castrated male. MI = Sexually intact male.
00_02_0086.QXD 10/10/2005 1:46 PM Page 53
54 Scientific Reports: Original Study JAVMA, Vol 219, No. 1, July 1, 2001
SMALL ANIMALS/
EXOTICS
any of the behavioral categories, 9 (19%) had impair-
ments in 1 category, and 6 (13%) had impairments in
≥ 2 categories. Nineteen of the 29 (66%) sexually intact
male dogs did not have impairments in any of the
behavioral categories, 6 (21%) had impairments in 1
category, and 4 (13%) had impairments in ≥ 2 cate-
gories.
For all groups, between 27 and 41% of dogs that
did not have any impairments at the time of the first
interview had impairments in ≥ 1 category at the time
of the second interview, and approximately 10% had
impairments in ≥ 2 categories. Analysis of the percent-
ages of dogs progressing from impairments in 0 cate-
gories at the time of the first interview to impairments
in 1 category at the time of the second interview and of
dogs progressing from impairments in 0 categories at
the time of the first interview to impairments in ≥ 2
categories at the time of the second interview did not
reveal any significant differences among groups (Fig 2;
P = 0.124 to 1.00).
Of the 18 spayed female dogs with impairments in
1 category at the time of the first interview, 9 (50%)
had impairments in ≥ 2 categories at time of the second
interview. Of the 9 castrated male dogs with impair-
ments in 1 category at the time of the first interview,
4 (44%) had impairments in ≥ 2 categories at time of
the second interview (1 of these castrated males
improved to no impairments on the second interview).
By contrast, none of the 6 sexually intact male dogs
with impairments in 1 category at the time of the first
interview had impairments in ≥ 2 categories at time of
the second interview (Fig 2). Percentages of dogs pro-
gressing from impairments in 1 category at the time of
the first interview to impairments in ≥ 2 categories at
the time of the second interview were not significantly
different between spayed female and castrated male
dogs (P = 0.512). Numbers of dogs were too small to
allow comparisons between sexually intact male dogs
and castrated male dogs or spayed female dogs.
However, when castrated male and spayed female dogs
were combined, the percentage of sexually intact male
dogs that progressed from impairments in 1 category at
the time of the first interview to impairments in ≥ 2
categories at the time of the second interview was sig-
nificantly less (1-tailed Fisher exact test, P = 0.035;
2-tailed Pearson χ
2
statistic, P = 0.03) than the per-
centage of neutered dogs that progressed.
The difference between sexually intact male dogs
and neutered dogs was not attributable to a major dif-
ference in age of the dogs at the time of the first inter-
view, as 14 of the 29 (49%) sexually intact male dogs,
25 of the 47 (53%) castrated male dogs, and 37 of the
63 (59%) spayed female dogs were 11 to 12 years old
at the time of the first interview. The difference was
also not a reflection of major differences in follow-up
time. Mean follow-up times for spayed female, castrat-
ed male, and sexually intact male dogs with impair-
ments in 1 behavioral category at the time of the first
and second interviews were 13.1 months (SD, 5.3
months; n = 9), 17.0 months (SD, 2.1 months; 4), and
17.0 months (SD, 2.8 months; 6), respectively. Mean
follow-up times for spayed female and castrated male
dogs that progressed from impairments in 1 behavioral
category at the time of the first interview to impair-
ments in ≥ 2 categories were 16.3 months (SD, 5.2
months; n = 9) and 15.9 months (SD, 0.8 months; 4),
respectively.
Percentages of dogs with visual and hearing
impairments, arthritis, or dental problems did not dif-
fer between sexually intact male dogs and neutered
dogs. Of the 6 sexually intact male dogs with impair-
ments in 1 behavioral category at the first and second
interviews, 4 (67%) had arthritis, 1 (17%) had dental
disease, 5 (83%) had visual impairments, and 5 (83%)
had hearing impairments. Of the 13 neutered dogs
with impairments in 1 behavioral category at the first
and second interviews, 6 (46%) had arthritis, 1 (8%)
had dental disease, 10 (77%) had visual impairments,
and 12 (92%) had hearing impairments. Of the 13
neutered dogs that progressed from impairments in 1
behavioral category at the time of the first interview to
impairments in ≥ 2 categories at the time of the second
interview, 5 (38%) had arthritis, 6 (46%) had dental
disease, 11 (85%) had visual impairments, and all 13
(100%) had hearing impairments. Although these
problems were not necessarily verified by examination
by a veterinarian, results suggest that differences
between sexually intact male and neutered dogs were
likely attributable to differences in cognitive function
and not a reflection of the owners’ perceptions of their
dogs’ overall health.
Discussion
Results of previous studies
1,8
of behavioral
changes in aging dogs performed at the same institu-
tion as the present study indicated that abnormalities
in 4 behavioral categories (disorientation in the
home and yard, disturbances in social interactions,
impairment of house training, and disruption of the
sleep-wake cycle) can be evaluated by use of a struc-
tured telephone interview format. These behavioral
signs presumably reflect disruptions of cognitive
function, have a gradual onset, and progress over
time. All 4 of these behavioral categories involve
learning or memory in one way or another, and signs
associated with these categories comprise most of the
behavioral signs improved by use of selegiline in
aging dogs.
7
Figure 2—Percentages of dogs 11 to 14 years old that pro-
gressed, over a period of 6 to 18 months, from not having
impairments in any behavioral category to having impairments in
1 category or to having impairments in ≥ 2 categories and that
progressed from having impairments in 1 behavioral category to
having impairments in ≥ 2 categories.
See
Figure 1 for key.
00_02_0086.QXD 10/10/2005 1:46 PM Page 54
JAVMA, Vol 219, No. 1, July 1, 2001 Scientific Reports: Original Study 55
SMALL ANIMALS/
EXOTICS
In the present study, the percentage of sexually
intact male dogs with impairments in house training at
the time of the second interview (ie, when dogs were
13 to 15 years old) was significantly less than the per-
centage of neutered dogs. No other differences between
groups were detected at the first or second interview;
however, the low percentages of dogs with impair-
ments in any particular category may have precluded
detection of differences.
When results for the first and second interviews
were compared, there were no significant differences
among groups in regard to percentages of dogs that
progressed from not having any impairments to having
impairments in 1 category or to having impairments in
≥ 2 categories. However, percentage of dogs that pro-
gressed from being mildly impaired (ie, impairments in
1 behavioral category) at the time of the first interview
to being severely impaired (ie, impairments in ≥ 2 cat-
egories) at the time of the second interview was signif-
icantly higher for neutered than sexually intact male
dogs. Thirteen of the 27 (48%) neutered dogs pro-
gressed from being mildly impaired to being severely
impaired, whereas none of the 6 sexually intact male
dogs did.
There were not any differences among groups in
regard to prevalence of owner-reported visual or hear-
ing impairment, arthritis, or dental problems suggest-
ing that owners of sexually intact male dogs did not
perceive their dogs as being in better overall health.
Also, there were no differences among groups in regard
to age or follow-up time that could explain the differ-
ence between sexually intact male and neutered dogs.
Thus, the difference in percentage of dogs that pro-
gressed from mild to severe impairment was likely a
reflection of hormone-related differences in cognitive
function, suggesting that the presence of circulating
testosterone in the sexually intact male dogs may have
slowed the progression of cognitive impairment in
dogs that already had signs of mild impairment. This
finding is in line with current research on the neuro-
protective roles of testosterone and estrogen at the cel-
lular level and the role of estrogen in preventing
Alzheimer’s disease in human females. One would pre-
dict that estrogens would have a similar protective role
in sexually intact female dogs; unfortunately, too few
sexually intact female dogs were available for inclusion
in the present study to test this hypothesis.
Clearly, more work is needed to confirm and extend
these findings. While the veterinary community is wait-
ing for additional research on this subject to be per-
formed, the implications of these findings on the prac-
tice of early spaying and neutering of dogs that are kept
into their senior years as family companions should be
considered. First, it should be pointed out that only a
small percentage of dogs progress to the level of severe
cognitive impairment. Thus, the risk associated with
loss of the protective effects of gonadal hormones may
be a small price to pay for the advantages of gonadecto-
my (eg, prevention of ovarian, uterine, and testicular
cancer). For some dog owners, however, the increased
likelihood of progression to severe cognitive impairment
may be more of a concern, particularly given the higher
prevalence of impairments in house training among
neutered dogs, compared with sexually intact male dogs.
It may also be a concern in working dogs for which a
high level of cognitive function is required, such as
those used for police work, to provide assistance to the
disabled, and for scent detection.
Results of the present study may also stimulate a
search for alternative means of fertility control that
leave gonadal hormone production intact. Tubal
(oviduct) ligation could be used in females and vasec-
tomy could be used in males, but both of these proce-
dures have drawbacks, in that female dogs that under-
go tubal ligation will still cycle into estrus and will not
be protected from uterine disease or mammary cancer,
and male dogs that undergo vasectomy would not
receive the advantages of decreased likelihood of prob-
lem aggression, urine marking, and sexual behavior
associated with castration.
52
Alternatively, the benefits
of hormonal replacement therapy in senior gonadec-
tomized male and female dogs should be determined,
or the benefits of prophylactic treatment with appro-
priate drugs to reduce the likelihood of cognitive
impairment should be investigated.
a
Anipryl, Pfizer Animal Health, Exton, Pa.
References
1. Neilson JC, Hart BL, Cliff KD, et al. Prevalence of behav-
ioral changes associated with age-related cognitive impairment in
dogs. J Am Vet Med Assoc 2001;218:1787–1791.
2. Czeschi T. Animal cognition—the phylogeny of cognitive
abilities. Anim Cogn 1998;1:1–2.
3. Shettleworth SJ. Cognition, evolution and behavior. New
York: Oxford University Press, 1998;3–48.
4. Cummings BJ, Head E, Ruehl WW, et al. The canine as an
animal model of human aging and dementia. Neurobiol Aging 1996;
209:259–268.
5. Ruehl WW, Bruyette DS, De Paoli A, et al. Canine cognitive
dysfunction as a model for human age-related cognitive decline,
dementia and Alzheimer’s disease: clinical presentation, cognitive
testing, pathology and response to L-deprenyl therapy. Prog Brain Res
1995;106:217–225.
6. Ruehl WW, Hart BL. Canine cognitive dysfunction. In:
Dodman N, Shuster L, eds. Psychopharmacology of animal behavior
disorders. Malden, Mass: Blackwell Science, 1998;283–304.
7. FDA freedom of information summary, Selegiline. Exton, Pa:
Pfizer Animal Health, 1998.
8. Bain MJ, Hart BL, Cliff KD, et al. Predicting behavioral
changes associated with age-related cognitive impairment in dogs. J
Am Vet Med Assoc 2001;218:1792–1795.
9. Ashford JW, Schmitt F, Kumar V. Diagnosis of Alzheimer’s
disease. In: Kumar V, Eisdorfer C, eds. Advances in the diagnosis and
treatment of Alzheimer’s disease. New York: Springer Publishing Co,
1998;111–151.
10. Frances A, Pincus HA, First MB. Diagnostic and statistical
manual of mental disorders. Washington, DC: American Psychiatric
Association, 1994;133–155.
11. Masur D, Silwinski M, Lipton R, et al. Neuropsychological
prediction of dementia and the absence of dementia in healthy elder-
ly persons. Neurology 1994;44:1427–1432.
12. Linn R, Wolf P, Bachman D, et al. The “preclinical phase” of
probable Alzheimer’s disease. Arch Neurol 1995;52:485–490.
13. Bowen J, Teri L, Kukull W, et al. Progression to dementia in
patients with isolated memory loss. Lancet 1997;349:763–765.
14. Jack CR, Petersen RC, Xu YC, et al. Prediction of AD with
MRI-based hippocampal volume in mild cognitive impairment.
Neurology 1999;52:1397–1403.
15. Cummings BJ, Cotman DW. Image analysis of β-amyloid
load in Alzheimer’s disease and relation to dementia severity. Lancet
1995;346:1524–1528.
00_02_0086.QXD 10/10/2005 1:46 PM Page 55
56 Scientific Reports: Original Study JAVMA, Vol 219, No. 1, July 1, 2001
SMALL ANIMALS/
EXOTICS
16. Wisniewski H, Johnson AB, Raine CS, et al. Senile plaques
and cerebral amyloidosis in aged dogs. A histochemical and ultra-
structural study. Lab Invest 1970;23:287–296.
17. Uchida K, Miyauchi Y, Kakayama H, et al. Amyloid
angiopathy with cerebral hemorrhage and senile plaques in aged
dogs. Jpn J Vet Sci 1990;52:605–611.
18. Russell MJ, Bobik M, White RG. Age specific onset of
β-amyloid in Beagle brains. Neurobiol Aging 1996;17:269–273.
19. Hou Y, White RG, Bobik M, et al. Distribution of β-amyloid
in the canine brain. Neuroreport 1997;8:1009–1012.
20. Cummings B, Su JH, Cotman CW, et al. β-Amyloid accu-
mulation in aged canine brain. A model of early plaque formation in
Alzheimer’s disease. Neurobiol Aging 1993;14:547–560.
21. Cummings BJ, Satou T, Head E, et al. Diffuse plaques con-
tain C-terminal Aβ
42
and not Aβ
40
; evidence from cats and dogs.
Neurobiol Aging 1996;17:653–659.
22. Cummings BJ, Head E, Afagh AJ, et al. β-Amyloid accumu-
lation correlates with cognitive dysfunction in the aged canine.
Neurobiol Learn Mem 1996;66:11–23.
23. Head E, Callahan H, Muggenburg BA, et al. Visual-discrim-
ination learning ability and β-amyloid accumulation in the dog.
Neurobiol Aging 998;19:415–425.
24. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of
selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s dis-
ease. N Engl J Med 1997;336:1216–1222.
25. Haskell SG, Richardson ED, Horowitz RI. The effect of
estrogen replacement therapy on cognitive function in women: a
critical review of the literature. J Clin Epidemiol 1997;11:1249–1264.
26. Paganini-Hill A, Henderson VW. Estrogen replacement
therapy and risk of Alzheimer disease. Arch Intern Med 1996;156:
2213–2217.
27. Baldereschi M, Di Carlo A, Lepore V, et al. Estrogen-replace-
ment therapy and Alzheimer’s disease in the Italian longitudinal
study on aging. Neurology 1998;4:996–1002.
28. Kawas C, Resnick S, Morrison A, et al. A prospective study
of estrogen replacement therapy and the risk of developing
Alzheimer’s disease: the Baltimore longitudinal study of aging.
Neurology 1997;6:1517–1521.
29. Asthana S, Craft S, Baker LD, et al. Cognitive and neuroen-
docrine response to transdermal estrogen in postmenopausal women
with Alzheimer’s disease: results of a placebo-controlled, double-
blind, pilot study. Psychoneuroendocrinology 1999;24:657–677.
30. Jacobs DM, Tang MX, Stern Y, et al. Cognitive function in
nondemented older women with estrogen treatment after
menopause. Neurology 1998;2:368–373.
31. Matthews K, Cauley J, Yaffe K, et al. Estrogen replacement
therapy and cognitive decline in older community women. J Am
Geriatr Soc 1999;47:518–523.
32. Barrett-Connor E, Goodman-Gruen D, Patay B.
Endogenous sex hormones and cognitive function in older men. J
Clin Endocrinol Metab 1999;84:3681–3685.
33. Alexander GM, Swerdloff RS, Wang C, et al. Androgen-
behavior correlations in hypogonadal men and eugonadal men. II.
Cognitive abilities. Horm Behav 1998;33:85–94.
34. Gibbs RB, Burke AM, Johnson DA. Estrogen replacement
attenuates effects of scopolamine and lorazepam on memory acqui-
sition and retention. Horm Behav 1998;34:112–125.
35. Luine VN. Steroid hormone modulation of hippocampal
dependent spatial memory. Stress 1997;2:21–36.
36. Luine VN, Richards ST, Wu VY, et al. Estradiol enhances
learning and memory in a spatial memory task and effects levels of
monoaminergic neurotransmitters. Horm Behav 1998;34:149–162.
37. Packard MG. Post-training estrogen and memory modula-
tion. Horm Behav 1998;2:126–139.
38. Packard MG, Teather LA. Post-training estradiol injections
enhance memory in ovariectomized rats: cholinergic blockade and
synergism. Neurobiol Learn Mem 1997;68:172–188.
39. Gibbs RB, Aggarwal P. Estrogen and basal forebrain cholin-
ergic neurons: implications for brain aging and Alzheimer’s disease-
related cognitive decline. Horm Behav 1998;2:98–111.
40. Woolley CS. Estrogen-mediated structural and functional
synaptic plasticity in the female rat hippocampus. Horm Behav 1998;
34:140–148.
41. McEwen BS, Alves SE, Bulloch K, et al. Ovarian steroids and
the brain: implications for cognition and aging. Neurology
1997;48(suppl 7):8–15.
42. Stone DJ, Rozovsky I, Morgan TE. Increased synaptic
sprouting in response to estrogen via an apolipoprotein E-dependent
mechanism: implications for Alzheimer’s disease. J Neurosci 1998;
18:3180–3185.
43. Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces
neuronal generation of Alzheimer beta-amyloid peptides. Nature Med
1998;4:447–451.
44. Jaffe AB, Toran-Allerand CD, Greengard P, et al. Estrogen
regulates metabolism of Alzheimer amyloid β precursor protein. J
Biol Chem 1994;269:13065–13068.
45. Gouras GK, Xu H, Gross RS, et al. Testosterone reduces
neuronal secretion of Alzheimer’s β-amyloid peptides. Proc Natl Acad
Sci U S A 2000;97:1202–1205.
46. Papasozomenos SC. The heat shock-induced hyperphos-
phorylation of tau is estrogen-independent and prevented by andro-
gens: implications for Alzheimer disease. Proc Natl Acad Sci U S A
1997;94:6612–6617.
47. Bishop J, Simpkins JW. Role of estrogens in peripheral and
cerebral glucose utilization. Rev Neurosci 1992;3:121–137.
48. Ohkura T, Teshima Y, Isse K, et al. Estrogen increases cere-
bral and cerebellar blood flows in postmenopausal women.
Menopause 1995;2:13–218.
49. Behl C. Alzheimer’s disease and oxidative stress: implications
for novel therapeutic approaches. Prog Neurobiol 1999;57:301–323.
50. Reosler M, Retz W, Thome J, et al. Free radicals in
Alzheimer’s dementia: currently available therapeutic strategies. J
Neural Trans 1998;54(suppl):211–219.
51. Mooradian AD. Antioxidant properties of steroids. J Steroid
Biochem Mol Biol 1993;45:509–511.
52. Neilson JC, Eckstein RA, Hart BL. Effects of castration on
problem behaviors in male dogs with reference to age and duration
of behavior. J Am Vet Med Assoc 1997;211:180–182.
00_02_0086.QXD 10/10/2005 1:46 PM Page 56