Cognitive Dysfunction Syndrome A Disease of Canine and Feline Brain Aging

Abstract

Brain aging is a degenerative process manifest by impairment of cognitive function; although not all pets are affected at the same level, once cognitive decline begins it is generally a progressive disorder. Diagnosis of cognitive dysfunction syndrome (CDS) is based on recognition of behavioral signs and exclusion of other medical causes that might mimic CDS or complicate its diagnosis. Drugs, diets, and supplements are now available that might slow CDS progression by various mechanisms including reducing oxidative stress and inflammation or improving mitochondrial and neuronal function. Moreover, available therapeutics may provide some level of improvement in cognitive and clinical signs of CDS.

Full text

This article appeared in a journal published by Elsevier. The attached
copy is furnished to the author for internal non-commercial research
and education use, including for instruction at the authors institution
and sharing with colleagues.
Other uses, including reproduction and distribution, or selling or
licensing copies, or posting to personal, institutional or third party
websites are prohibited.
In most cases authors are permitted to post their version of the
article (e.g. in Word or Tex form) to their personal website or
institutional repository. Authors requiring further information
regarding Elsevier’s archiving and manuscript policies are
encouraged to visit:
http://www.elsevier.com/copyright

Author's personal copy
Cognitive Dysfunction Syndrome
A Disease of Canine and Feline Brain Aging
Gary M. Landsberg, DVM
a,b,
*, Jeff Nichol, DVM
c
,
Joseph A. Araujo, BSc
b,d,e
INTRODUCTION
As pets age, behavior changes may be the first indication of declining health and
welfare. This is particularly true for some of the most common problems associated
with aging, such as pain, sensory decline, and cognitive dysfunction syndrome (CDS).
Early identification of these signs provides an opportunity for effective intervention.
GML is an employee of CanCog Technologies Inc. JAA is an employee of InterVivo Solutions Inc
and a consultant for CanCog Technologies Inc.
The authors have nothing else to disclose.
a
North Toronto Animal Clinic, 99 Henderson Avenue, Thornhill, Ontario, Canada L3T 2K9;
b
CanCog Technologies Inc, 120 Carlton Street, Suite 204, Toronto, Ontario, Canada M5A 4K2;
c
Veterinary Emergency and Specialty Center of New Mexico, 4000 Montgomery Boulevard NE,
Albuquerque, NM 87109, USA;
d
InterVivo Solutions Inc, 120 Carlton Street, Suite 203, Toronto,
Ontario, Canada M5A 4K2;
e
Department of Pharmacology and Toxicology, University of
Toronto, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8
* Corresponding author. North Toronto Animal Clinic, 99 Henderson Avenue, Thornhill, Ontario,
Canada L3T 2K9.
E-mail address: gmlandvm@aol.com
Vet Clin Small Anim 42 (2012) 749–768
http://dx.doi.org/10.1016/j.cvsm.2012.04.003 vetsmall.theclinics.com
0195-5616/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
KEYWORDS
• Cognitive dysfunction syndrome • Brain aging • Behavior • Canine • Feline
KEY POINTS
• Brain aging is a degenerative process that for many dogs and cats ultimately progresses
to a loss of one or more cognitive domains or impairment of cognitive function.
• Diagnosis of cognitive dysfunction syndrome (CDS) is based on recognition of behavioral
signs and exclusion of other medical conditions and drug side effects, which in some
cases can mimic or complicate CDS.
• Clinical categories include disorientation, alterations in social interactions, sleep-wake
cycles, elimination habits, and activity, as well as increasing anxiety. Deficits in learning
and memory have also been well documented.
• Treatment is aimed at slowing the advancement of neuronal damage and cell death and
improving clinical signs. Drugs, diet, and supplements can be used alone or concurrently
to improve neurotransmission and reduce oxidative damage and inflammation.

Author's personal copy
During veterinary visits, pet owners are likely to report serious behavioral changes,
but subtle signs, which may be indicative of declining health or cognition, often go
unreported. Family members therefore need assistance in both identifying and
reporting any change from normal behavior to their veterinarian. Similarly, clinicians
must be proactive in asking about behavioral signs.
The current article focuses on how CDS in dogs and cats parallels neurodegen-
erative disorders in humans, particularly Alzheimer disease (AD). The goal is to help
the practitioner develop a senior care program incorporating behavioral screening to
aid in both the recognition of behavior changes consistent with CDS and the
implementation of appropriate treatment strategies.
BRAIN AGING AND COGNITIVE DYSFUNCTION
Most mammals show age-related neuropathologic changes. In humans, the most
common neurodegenerative disorder is AD, which progressively impairs cognition,
behavior, and quality of life. It is increasingly evident that humans, dogs, and cats
demonstrate parallels in brain aging associated with cognitive dysfunction. In fact, the
aged dog and, to a lesser extent, the aged cat are spontaneous models of AD and
therefore can play a valuable role in testing putative AD therapeutics. Conversely, the
knowledge gained from studying AD is highly relevant for understanding brain aging
and cognitive dysfunction in companion animals.
Lessons Learned from AD Research
Modern medicine has increased the life span across many species, which in turn has
increased the incidence of neurodegenerative diseases, such as AD. In humans, AD
is generally characterized by initial decline in episodic memory followed by progres-
sive decline across multiple cognitive domains.
1
Ultimately this results in behavioral
changes that impair social function and eventually results in death. Classical
diagnosis of AD has relied on post-mortem confirmation of 2 hallmark pathologies:
the presence of senile plaques, which consist of extracellular deposits of fibrilized
amyloid-beta protein (A
␤
), and neurofibrillary tangles, which consist of intracellular
paired helical fragments of cytoskeletal hyperphosphorylated tau protein.
2
However,
it is uncertain if either of these pathologic changes is a causal factor as several other
brain changes are documented, including neuronal loss; cortical atrophy including
atrophy of the hippocampus; alterations in neurochemical systems such as the
cholinergic, glutaminergic, dopaminergic, and GABAergic neurotransmitter systems;
and reduced neuronal and synaptic function.
3
Moreover, risk factors associated with
the development of AD include genetic, metabolic, and nutritional influences, which
may be equally relevant to pet aging.
Recent clinical and research criteria propose there are progressive stages of AD
from the preclinical stage (ie, prior to clinical signs) to mild cognitive impairment (MCI;
prodromal stage likely to proceed to AD) to a clinical diagnosis of AD based on
cognitive-behavioral status.
1
It is suggested that beta-amyloid deposition may occur
early in disease progression, followed by neuronal degeneration/synaptic dysfunction
(measured by biomarkers of tau pathology or functional imaging). Both of these
pathologies likely precede the clinically identifiable stage of MCI or AD in humans.
4
Therefore, clinical AD is now considered a late stage of disease progression, which
may explain the limited clinical success of therapeutic interventions (ie, initiated too
late in disease progression to improve outcome). Therefore, identification of current
and/or novel biomarkers predictive of AD progression will be essential for diagnostic
characterization of preclinical and prodromal AD stages and for assessing interven-
tions aimed at prevention or reversing progression of AD. It is theorized that AD risk
750 Landsberg et al

Author's personal copy
factors, similar to high blood pressure or increased cholesterol in early diagnosis of
cardiovascular disease, will be identified and validated, permitting early intervention
and monitoring of disease progression.
Lessons Learned from Senior Dog and Cat Research
Most mammals show evidence of brain aging and consequential cognitive deficits.
5
CDS in companion animals parallels AD progression in several respects. For example,
not all aged dogs and cats show behavioral signs consistent with CDS, yet subclinical
alterations in cognitive function may be present, which might eventually progress to
CDS.
6
Therefore, it is prudent to commence treatment early. Understanding age-
related brain pathology and cognitive dysfunction is essential to fully appreciate the
potential value of using biomarkers and/or cognitive status in the future diagnosis and
treatment of CDS progression.
Effects of Aging on the Brains of Senior Dogs and Cats
In canine aging, frontal lobe volume decreases, ventricular size increases, and there
is evidence of meningeal calcification, demyelination, increased lipofuscin, increased
apoptic bodies, neuroaxonal degeneration, and reduced neurons.
7,8
In cats, age-
related pathologies include neuronal loss, cerebral atrophy, widening of sulci, and
increases in ventricular size.
9 –11
Perivascular changes, including microhemorrhage or
infarcts in periventricular vessels, are reported in senior dogs and cats, which may
contribute to signs of CDS.
7,9,12–15
With increasing age, there is an increase in
reactive oxygen species leading to oxidative damage in dogs and likely cats.
9,16
Increases in monoamine oxidase B activity in dogs is reported, which may increase
catalysis of dopamine with subsequent increases in free radicals.
17
A decline in
cholinergic tone occurs in canine aging as evidenced by hypersensitivity to anticho-
linergics and decreased brain muscarinic receptor density.
18
Diminished cholinergic
function is also reported in cats.
10,19
Collectively, these alterations may contribute to
working memory deficits or CDS, as well as alterations in motor function and REM
sleep.
9,10,20 –22
In aged dogs, cats, and humans, there are similarities in deposition of A
␤
in
extracellular plaques and perivascular infiltrates; however, dense core plaques seen
in AD are not found in dogs or cats, suggesting canine and feline plaques are less
mature than those seen in AD.
9,12,14,15,23
Moreover, similar to humans, A
␤
plaque
load is positively correlated with cognitive impairment in dogs.
13,14,24
By contrast,
cats demonstrate more diffuse A
␤
plaques than either human or dog.
9,12,15,25,26
Neurofibrillary tangles are not consistently reported in either species; however,
hyperphosphorylated tau is reported in brains of aged dogs and cats, which might
represent pre-tangle pathology.
7,9,13,25,26
Overall, both dogs and cats show A
␤
brain deposition and pre-tangle pathology
with increasing age similar to that seen in AD progression; however, these pathologies
do not achieve the severity seen in AD. Nonetheless, brain A
␤
deposition may prove
to be relatively early predictive biomarker of CDS consistent with preclinical and/or
prodromal stages of AD.
4
Effects of Age on Cognitive Ability of Senior Dogs and Cats
In humans, cognition is composed of multiple cognitive domains that include not only
learning and memory but also executive function, language, psychomotor ability,
attention, and spatial abilities. In the laboratory, there are protocols to assess many
of these domains in dogs and cats. Age-related and domain-specific cognitive decline
751
Cognitive Dysfunction Syndrome

Author's personal copy
is found in both species, but there is individual variation such that not all subjects are
affected.
Using the delayed nonmatching to position (DNMP) memory task (Fig. 1), old dogs
can be separated into 3 groups— unimpaired, impaired, and severely impaired—
which may be analogous to the various stages of AD progression.
27,28
Aged dogs
with DNMP impairments also demonstrate altered sleep-wake cycles, increased
stereotypy, and decreased social contact with humans, which suggests a link
between cognitive impairment and behavioral changes consistent with CDS.
29
Importantly, DNMP impairments can be detected as early as 6 years of age in some
Fig. 1. The DNMP is a test of short-term visuospatial working memory.
27,30
The test consists of
2 phases. In the sample phase, the subject is required to displace an object placed over 1 of 3
possible locations on a food well (top); in this case the cat is required to displace block S
covering food reward in the well on cat’s right. The second stage (bottom) occurs after a
delay and the subject is presented with 2 objects identical to that used in the sample phase.
One object (marked with an X) is located in the same position as the sample object. The
correct object is located in one of the remaining 2 positions (the nonmatch), and if the subject
displaces the object, it can retrieve the food reward beneath. Initially, subjects are trained
using a 5-second delay between the phases, but when the cat learns the rule that the food
will always be found under the block in the nonmatch position, gradually longer delays can
be introduced to assess memory.
752 Landsberg et al

Author's personal copy
dogs, which is consistent with early memory deficits in AD.
30
Also, brain amyloid
deposition is reported earliest at 8 to 9 years of age.
23
Collectively, this suggests that
memory impairment is an early consequence of canine aging that can precede both
clinically relevant behavioral changes and amyloid deposition.
When dogs are repetitively rewarded for approaching 1 of 2 objects that differ
substantially (ie, simple object discrimination learning), by contrast, no age effects on
learning are evident.
31
However, if the reward contingencies are reversed after
learning a simple object discrimination problem such that the dog must learn to
respond to the object that previously was not rewarded in the original learning task
(reversal learning), aged dogs require significantly more trials to learn to respond to
the newly rewarded object than young dogs.
31,32
This impairment is analogous to the
diminished executive function observed in human aging, AD, and other species.
32
On
the other hand, age-related learning deficits are apparent when complex discrimina-
tion learning is assessed (eg, objects more similar or more objects), which may be
related to age-related deficits in attention (Fig. 2).
33
Previous studies have identified eyeblink conditioning deficits in aged cats, and a
holeboard task revealed age effects on working memory, but not on spatial learn-
ing.
34,35
Age-related cognitive impairments are also seen in cats when feline adap-
tations of canine tests are used (see Figs. 1 and 2). Like dogs, cats demonstrate
reversal learning and DNMP impairments with increasing age.
36
While there are
insufficient data to determine age-of-onset of these impairments, reversal learning
impairments were evident in 7.7- to 9-year-old cats compared to 2- to 3.8-year-old
cats, suggesting that cognitive deficits precede clinical signs.
37
Similarly, while aged
cats demonstrate neuropathologic brain changes similar to those reported in aged
humans and dogs, the effect of neuropathologic changes on cognition have not been
thoroughly investigated in the cat.
9,26
Overall, both dogs and cats demonstrate
age-dependent and domain-specific cognitive decline consistent with those reported
in aged humans.
Fig. 2. In the attention task, the dog must select the correct object (covering a food reward),
which is presented concurrently with either 1, 2, or 3 incorrect objects (distracters). Studies
have demonstrated that performance declines and latency increases with increased distracter
number, consistent with a test that assesses selective attention.
33
753
Cognitive Dysfunction Syndrome

Author's personal copy
Do Dogs and Cats Get AD?
Dogs and cats show both neuropathologic and cognitive changes that share many
attributes of human aging and AD progression. However, late-stage AD progression
is associated with impairment in most, if not all, cognitive domains. By contrast, dogs
and cats do not show such extensive cognitive impairments (eg, ability to eat is
retained), which suggests that the disease progression in pets is more comparable to
earlier stages of AD progression. Consistent with this view, aged dogs show declining
CSF levels of A
␤
42, increased CSF levels of phospho-tau, and atrophy of the
hippocampus, all of which are biomarkers being investigated as early diagnostic
predictors of AD.
8,38,39
Future research better characterizing the longitudinal interac-
tion among neuropathologic, cognitive, and behavioral changes in aging dogs and
cats will be essential in better determining if and how CDS overlaps with AD
progression.
COGNITIVE DYSFUNCTION SYNDROME
Clinical Signs of CDS
Classic signs of CDS are summarized by the acronym DISHA, which refers to
disorientation; alterations in interactions with owners, other pets, and the environ-
ment; sleep-wake cycle disturbances; housesoiling; and changes in activity.
40
Although a decline in activity might be reported, laboratory studies suggest that
increased locomotor activity and decreased immobile time are associated with
greater cognitive impairment.
29,41
In addition, signs of fear, phobias, and anxiety,
which are commonly reported by owners of senior pets, may be analogous to the
finding of agitation and anxiety in humans with AD and might also be considered a
component of CDS (Table 1).
42– 46
Finally, memory deficits, which are some of the first
recognizable signs of cognitive impairment in humans, have been identified early in
the process of brain aging in both dogs and cats.
30,36
Therefore, learning or memory
deficits in aged dogs and cats would also be a sign of CDS. However, these are
difficult to recognize except perhaps in dogs that have been trained to a high level of
performance (eg, service dogs, dogs trained for detection tasks) or by highly
perceptive owners. For clinical signs of CDS, see the questionnaire in Table 1.
Differentiating Medical and Behavioral Problems from CDS
The determination of either a primary behavioral diagnosis or CDS must first be
approached by excluding medical causes (Table 2). In the senior pet, this can be
particularly challenging because with increasing age, there is an increased likelihood
of concomitant medical conditions. Potential behavioral effects of medications must
also be considered, especially those known to impact behavior. For example, steroids
can increase drinking, appetite, and panting and are also associated with behavioral
signs including nervousness, restlessness, irritable aggression, startling, food guard-
ing, avoidance, and increased barking.
47
Additionally, senior pets may be less able to
cope with stress, which may make them more susceptible to changes in their
environment.
Thus behavioral signs in the senior pet can be due to medical or behavioral causes,
cognitive dysfunction, or a combination thereof. For example, disruption of night time
sleep in senior pets may be due to CDS, sensory dysfunction, or medical conditions
that present with pain, polyuria, or hypertension, as well as alterations in the owner’s
schedule or home environment. Once problems arise, experience (ie, learning) further
influences whether the behavior is likely to be repeated. In establishing a diagnosis of
CDS, the clinician must be aware that the characteristic behavioral signs overlap with
those of many medical and behavioral disorders.
754 Landsberg et al

Author's personal copy
Table 1
CDS checklist
1
Signs: DISHAAL Age First Noticed Score 0–3
a
D: Disorientation/Confusion—Awareness—Spatial orientation
Gets stuck or cannot get around objects
Stares blankly at walls or floor
Decreased recognition of familiar people/pets
Goes to wrong side of door; walks into door/walls
Drops food/cannot find
Decreased response to auditory or visual stimuli
Increased reactivity to auditory or visual stimuli (barking)
I: Interactions—Social Relationships
Decreased interest in petting/avoids contact
Decreased greeting behavior
In need of constant contact, overdependent, “clingy”
Altered relationships other pets—less social/irritable/aggressive
Altered relationships with people—less social/irritable/aggressive
S: Sleep–Wake Cycles; Reversed Day/Night Schedule
Restless sleep/waking at nights
Increased daytime sleep
H: Housesoiling (Learning and Memory)
Indoor elimination at sites previously trained
Decrease/loss of signaling
Goes outdoors, then returns indoors and eliminates
Elimination in crate or sleeping area
A: Activity—Increased/Repetitive
Pacing/wanders aimlessly
Snaps at air/licks air
Licking owners/household objects
Increased appetite (eats quicker or more food)
A: Activity—Apathy/Depressed
Decreased interest in food/treats
Decreased exploration/activity/play
Decreased self-care (hygiene)
A: Anxiety
Vocalization, restlessness/agitation
Anxiety, fear/phobia to auditory or visual stimuli
Anxiety, fear/phobia of places (surfaces, locations)
Anxiety/fear of people
Separation anxiety
L: Learning and Memory—Work, Tasks, Commands
Decreased ability to perform learned tasks, commands
Decreased responsiveness to familiar commands and tricks
Inability/slow to learn new tasks
a
Score: 0 ⫽none; 1 ⫽mild; 2 ⫽moderate; 3 ⫽severe.
Adapted from Landsberg GM, Hunthausen W, Ackerman L. The effects of aging on the behavior of
senior pets. Handbook of behavior problems of the dog and cat. 2nd edition. Philadelphia: WB
Saunders; 2003. p. 273; with permission.
755
Cognitive Dysfunction Syndrome

Author's personal copy
The practitioner will need to consider physical examination findings (including
neurologic, sensory, and pain assessment) along with medical and behavioral signs to
select the appropriate diagnostic tests required to reveal the causes and contributing
factors of a patient’s signs. Identifying all influences on specific behavioral signs is
Table 2
Medical causes of behavioral signs
Medical Condition/Medical
Presentation Examples of Behavioral Signs
Neurologic: central (intracranial/
extracranial) particularly if
affecting forebrain, limbic/
temporal and hypothalamic;
REM sleep disorders
Altered awareness, response to stimuli, loss of learned
behaviours, housesoiling, disorientation, confusion,
altered activity levels, temporal disorientation,
vocalization, change in temperament (fear,
anxiety), altered appetite, altered sleep cycles,
interrupted sleep
Partial seizures: temporal lobe
epilepsy
Repetitive behaviors, self-traumatic disorders,
chomping, staring, alterations in temperament (eg,
intermittent states of fear or aggression), tremors,
shaking, interrupted sleep
Sensory dysfunction Altered response to stimuli, confusion, disorientation,
irritability/aggression, vocalization, house soiling,
altered sleep cycles
Endocrine: feline hyperthyroidism Irritability, aggression, urine marking, decreased or
increased activity, night waking
Endocrine: canine hypothyroidism Lethargy, decreased response to stimuli, irritability/
aggression
Endocrine: hyperadrenocorticism/
hypoadrenocorticism
Lethargy, house soiling, altered appetite, decreased
activity, anxiety
Endocrine: insulinoma, diabetes Altered emotional state, irritability/aggression,
anxiety, lethargy, house soiling, altered appetite
Endocrine: functional ovarian and
testicular tumors
Increased androgen-induced behaviors. Males:
aggression, roaming, marking, sexual attraction,
mounting. Females: nesting or possessive aggression
of objects.
Metabolic disorders: hepatic/renal Signs associated with organ affected: may be anxiety,
irritability, aggression, altered sleep, house soiling,
mental dullness, decreased activity, restlessness,
increase sleep, confusion
Pain Altered response to stimuli, decreased activity,
restless/unsettled, vocalization, house soiling,
aggression/irritability, self-trauma, waking at night
Peripheral neuropathy Self-mutilation, irritability/aggression, circling,
hyperesthesia
Gastrointestinal Licking, polyphagia, pica, coprophagia, fecal house
soiling, wind sucking, tongue rolling, unsettled
sleep, restlessness
Urogenital House soiling (urine), polydypsia, waking at night
Dermatologic Psychogenic alopecia (cats), acral lick dermatitis
(dogs), nail biting, hyperesthesia, other self-trauma
(chewing/biting/sucking/scratching)
Abbreviation: REM, rapid eye movement.
756 Landsberg et al

Author's personal copy
critical for both treatment selection and monitoring of behavioral and medical
disorders.
Effects of Stress on Health and Mental Well-Being
Stress is an altered state of homeostasis that can be caused by physical or emotional
factors that trigger psychological, behavioral, endocrine, and immune effects. Acute
and chronic stress can also impact both health and behavior.
48 –50
In addition, senior
pets, especially those with medical or behavioral issues, may be more affected by
stress and less able to adapt to change. Owners should pay particular attention to
their pet‘s emotional and behavioral state as well as its appetite, sleep, and
elimination to evaluate the role of stress. While enrichment can help maintain both
physical and mental health, changes in the elderly pet’s household or schedule should
be made slowly. Natural products or drugs may also be indicated (discussed later).
Prevalence of Behavioral Signs in Senior Pets
Spontaneously reported behavior problems
A number of studies have examined the prevalence of spontaneously reported
behavioral signs in senior pets referred to behavioral specialists.
44,45
In 2 canine
studies, behavioral complaints related to aggression, or fear and anxiety, were most
prevalent. In a similar senior cat study, most displayed signs of marking or soiling;
however, cases of aggression, vocalization, and restlessness were also serious
enough to solicit referral.
50
To further examine the distribution of problems reported by owners of senior dogs
and cats, the Veterinary Information Network (VIN) database was searched for
behavior problems of 50 senior dogs (aged 9 –17) and 100 senior cats (aged 12–22
years). Of dogs, 62% had signs consistent with CDS, but most demonstrated anxiety,
night waking, and vocalization. In the 100 feline cases reviewed, the most common
complaints were related to vocalization, especially at night, and soiling. Figs. 3 and 4
summarize the distribution of behavioral signs most commonly reported by owners of
senior pets across studies.
Solicited reports of behavior problems
Since many of the most common behavioral signs in senior pets go unreported, a
more proactive approach is required to establish their prevalence. In 1 study of dogs
aged 11 to 16, 28% of 11-to 12-year-old dogs and 68% of 15- to 16-year-old dogs
showed at least 1 sign consistent with CDS.
51
In another study of 102 dogs, 41% had
alterations in at least 1 category associated with CDS and 32% had alterations in 2
categories.
52
In a more recent study, females and neutered males were significantly
more affected than intact males with both prevalence and severity increasing with
age, which is consistent with previous reports.
46,53
Moreover, social interactions and
house training were the most impaired categories.
46
In a recent epidemiologic study using an internet survey format of 497 dogs ranging
in age from 8 to 19 years, the prevalence of CDS was 5% in 10- to 12-year-old dogs,
23.3% in dogs 12- to 14-year-old dogs, and 41% in dogs older than 14, with an
overall prevalence of 14.2%. However, only 1.9% of cases had a veterinary diagnosis
of CDS.
54
In 1 study of aged cats presented to veterinary clinics for routine annual
care, 28% of 95 cats aged 11 to 15 and 50% of 46 cats older than 15 years were
diagnosed with possible CDS.
37
757
Cognitive Dysfunction Syndrome

Author's personal copy
Importance of Client Education and Screening in the Veterinary Clinic
The data presented above indicate several important findings. First, behavioral signs
related to anxiety, vocalization, night waking, soiling in cats, and aggression in dogs
are more often spontaneously reported to veterinarians, which is likely related to the
impact of these behaviors on the owner. Second, behavioral changes consistent with
CDS are reported less frequently but are present in a significant proportion of the
population. Third, the prevalence of behavioral signs consistent with CDS increases
with age. Finally, because CDS is likely underdiagnosed when solicited reporting is
not used, proactive monitoring and assessment of behavioral signs should be
components of every veterinary visit involving senior pets. Veterinarians and their staff
must inform clients of the health and welfare consequences if these problems are
untreated. Handouts and web links on senior care and cognitive dysfunction
syndrome can be used to further educate owners. Questionnaires are particularly
effective for quick and comprehensive screening. Several are available for screening,
including Table 1, a scoring system known as age-related cognitive and affective
disorders, and a recently published 13-point data-based assessment tool.
40,54
THERAPEUTIC OPTIONS FOR PETS WITH CDS
Behavioral Support and Environmental Enrichment in the Management of CDS
Canine studies have shown that mental stimulation is an essential component in
maintaining quality of life and that continued enrichment in the form of training, play,
45%
29%
17%
15%
8%
5% 3%
3%
Prevalences of owner reported signs in
senior dogs
Aggression
Cognive dysfuncon
Separaon anxiety
Anxiety, Fears and Phobias
Vocalizaon
Compulsive
Destrucve
Soiling
Fig. 3. Fears and phobias (includes generalized anxiety), compulsive includes repetitive and
stereotypic behavior; cognitive dysfunction includes disorientation, wandering, waking and
anxious at night. Behavior signs were combined from 3 studies: a Spanish study of 270 dogs
older than age 7 that were presented for behavior problems, 103 dogs referred to a
veterinary behaviorist, and a search of the Veterinary Information Network (VIN) of 50 dogs
aged 9 to 17 years.
758 Landsberg et al

Author's personal copy
exercise, and novel toys can help to maintain cognitive function (ie, use it or lose it).
55
This is analogous to human studies in which increased mental activity and physical
exercise have been found to delay the onset of dementia.
56,57
Environmental enrichment can have positive effects on behavioral health and
quality of life in pets and is likely to improve cognitive function.
58
Inconsistency in the
management of the senior pet’s environment (especially for cats) can cause stress
and negatively impact health and behavioral well-being.
40,50
As sensory, motor, and
cognitive function decline, new odor, tactile, and/or sound cues may help the pet
better cope with its environment. Dogs with increased urine frequency may need
more frequent trips outdoors or even the addition of an indoor toilet area. Ramps and
physical support devices may be necessary to address mobility issues. For cats,
inappropriate elimination may be improved by providing more litter boxes with lower
sides and nonslip ramps.
Enrichment should focus on positive social interactions as well as new and varied
opportunities for exploration, climbing, perching, hunt-and-chase games, and other
stimulating ways to obtain food and treats. Food toys that require pushing, lifting,
dropping, batting, pawing, or rolling to release food help older dogs and cats to
remain active and alert (Fig. 5). By scattering favored food, treats, or catnip in different
locations, pets can learn to hunt, search, and retrieve.
Maintenance of a day-night cycle by opening blinds and providing outdoor
activities (where practical) to provide daylight during the day and reducing exposure
to artificial light at night may be considered. Increased daytime enrichment with
several quality interactive sessions, food toys, outdoor exercise (if appropriate), and
a final interactive play session prior to bed may help encourage better sleep.
Drug Therapy for CDS
CDS cannot be cured at present, but deterioration may be slowed and clinical signs
improved. Assuming concomitant medical and behavior problems are being controlled,
various drugs (Table 3) may be considered to improve cognitive function or control
clinical signs. For each pet, the clinician must weigh potential risks against potential
benefits.
48%
36%
35%
11%
2% 2%
Prevalences of owner reported signs in
senior cats
Soiling
Vocalizaon
Cognive Dysfuncon
Syndrome
Fear / Aggression
Overgrooming
Clingy
Fig. 4. Soiling includes marking, cognitive dysfunction includes disorientation, restless,
wandering and night waking, and fear/aggression (includes fear and hiding). Behavior signs
were combined from a VIN data search of 100 cats aged 12 to 22 years and 83 from 3 different
behavior referral practices.
759
Cognitive Dysfunction Syndrome

Author's personal copy
Selegiline (Anipryl; Pfizer Animal Health, New York, NY, USA) is a selective and
irreversible inhibitor of monoamine oxidase B.
59
It may enhance dopamine and other
catecholamines in the cortex and hippocampus and has been shown both in the
laboratory and clinic to improve signs consistent with CDS in dogs.
59,61
Selegiline
Fig. 5. A food manipulation toy, the Kong Wobbler (Kong Company, Golden, CO, USA). This
toy is filled with food pieces and treats that are delivered through the opening as the dog
learns to tip the toy.
Table 3
Doses for drugs for behavior therapy of senior pets
Dog Cat
Selegiline (CDS) 0.5–1 mg/kg sid in am 0.5–1 mg/kg sid in am
Propentofylline (CDS) 2.5–5 mg/kg bid ¼ of a 50 mg tablet daily
Oxazepam
a
0.2–1 mg/kg sid–bid 0.2–0.5 mg/kg sid–bid
Clonazepam
a
0.1–1.0 mg/kg bid–tid 0.02–0.2 mg/kg sid–bid
Lorazepam
a
0.025–0.2 mg/kg sid–tid 0.025–0.05 mg/kg sid–bid
Diphenhydramine
a
2–4 mg/kg 1–4 mg/kg
Fluoxetine 1.0–2.0 mg/kg sid 0.5–1.5 mg/kg sid
Paroxetine 0.5–2 mg/kg 0.5–1.5 mg/kg
Sertraline 1–5 mg/kg sid or divided bid 0.5–1.5 mg/kg sid
Buspirone 0.5–2.0 mg/kg sid–tid 0.5–1 mg/kg bid
Trazodone 2–5 mg/kg (up to 8–10) prn–tid Not determined
Phenobarbital 2.5–5 mg/kg bid 2.5 mg/kg bid
Memantine 0.3–1 mg/kg sid Not determined
Gabapentin 10–30 mg/kg q 8–12 h 5–10 mg/kg q 12 h
Abbreviation: sid, once daily.
a
Use single dosing prior to sleep or anxiety-evoking event, up to maximum daily dosing for
control of ongoing anxiety.
760 Landsberg et al

Author's personal copy
also may be neuroprotective possibly by reducing free radical production and/or
increasing enzymes that scavenge free radicals such as superoxide dismutase and
catalase.
59,60
Selegiline is not licensed for use in cats but is used off label with
anecdotal reports of improvement in CDS-like signs.
62
Selegiline may require 2 weeks
or longer before clinical improvement is seen, should not be used concurrently with
other monoamine oxidase inhibitors (eg, amitraz), and should be avoided, or used
cautiously, with drugs that may enhance serotonin transmission (such as selective
serotonin reuptake inhibitors, tricyclic antidepressants, buspirone, trazodone, trama-
dol, and dextromethorphan).
Propentofylline (Vivitonin; Merck Animal Health, Milton Keyes, UK) is licensed in
some European countries for the treatment of dullness, lethargy, and depressed
demeanor in old dogs. Propentofylline may increase blood flow to the heart, skeletal
muscles, and brain and may have neuroprotective properties due to inhibiting the
uptake of adenosine and blocking phosphodiesterase. Propentofylline has been
anecdotally used in cats, but there is no clinical evidence of efficacy.
Drugs thought to enhance the noradrenergic system, such as adrafinil and modafinil,
might be useful in older dogs to improve alertness and help maintain normal sleep-wake
cycles (by increasing daytime exploration and activity).
63,64
However, dose and efficacy
in dogs are not well established. Newer treatment strategies include the N-methyl-D-
aspartate receptor antagonist memantine or hormone replacement therapy, but evidence
is currently lacking to make appropriate suggestions for treatment.
65
In canine and feline CDS, as well as in AD, there is evidence of cholinergic
decline (see earlier). Because the elderly are particularly susceptible to anticho-
linergic drugs, it is prudent to consider therapies with less anticholinergic effects.
Drugs and natural products that enhance cholinergic transmission might have
potential benefits for improving signs of CDS, but more research is required to
select appropriate drugs and doses.
66
Nutritional and Dietary Therapy for CDS
Nutritional and dietary interventions (Table 4) can improve antioxidant defense
thereby reducing the negative effects of free radicals. A senior diet (Canine b/d, Hills
Pet Nutrition, Topeka, KS, USA) for dogs improves signs and slows the progress of
cognitive decline.
67– 69
The diet improved performance on a number of cognitive tasks
when compared to a nonsupplemented diet as early as to 2 to 8 weeks after the onset
of therapy. However, the combined effect of the supplemented diet and environmen-
tal enrichment provided the greatest benefit and, when started prior to the onset of
behavioral signs, may extend cognitive health.
67
Another strategy is a diet containing medium-chain triglycerides (MCTs), which are
converted to ketone bodies by the liver. Since a decline in cerebral glucose
metabolism and reduced energy metabolism are associated with cognitive decline,
MCT-induced ketone bodies provide an alternate energy source that can be used by
the brain. When compared to control, the diet (Purina One Vibrant Maturity 7⫹
Formula; Nestlé Purina PetCare, St Louis, MO, USA) significantly improved perfor-
mance on several cognitive tasks.
70
Supplementation with MCTs also improves
mitochondrial function, increases polyunsaturated fatty acids in the brain, and
decreases amyloid precursor protein in the parietal cortex of aged dogs.
71,72
Supplementation with MCTs is also approved as a medical dietary supplement for AD
patients. Cognitive diets for cats have not yet been developed.
A number of clinical trials have shown improvements in signs associated with CDS
in dogs using dietary supplements containing phosphatidylserine, a membrane
phospholipid.
73,74
One product (Senilife; CEVA Animal Health, Libourne, France) was
761
Cognitive Dysfunction Syndrome

Author's personal copy
tested in aged dogs using a cross-over design in which DNMP memory performance
was improved after 60 days of treatment with Senilife.
75
Although labeled for use in
cats, efficacy studies are not published.
Another product containing phosphatidylserine (Activait; Vet Plus Ltd, Lytham St.
Annes, UK) demonstrated significant improvement over placebo on signs of disori-
entation, social interactions, and house soiling in dogs.
74
A feline version of Activait,
with no alpha-lipoic acid, is also available but has not been tested in clinical trials.
Another available supplement for cognitive health (Novifit; Virbac Animal Health, Ft
Worth, TX, USA) contains S-adenosyl-L-methionine (SAMe) tosylate, which is found in
all living cells and is formed from methionine and adenosine triphosphate. SAMe may
help to maintain cell membrane fluidity, receptor function, and the turnover of
monoamine transmitters, as well as increase the production of the endogenous
antioxidant glutathione.
76
In a recent placebo-controlled trial, greater improvement in
activity and awareness was reported in the SAMe group after 8 weeks.
77
Since SAMe
might increase central serotonin levels, caution should be used when combining with
Table 4
Ingredients and doses of natural therapeutics for senior pets
Ingredients Dose
Senilife Phosphatidylserine, Gingko biloba,
vitamin B6 (pyridoxine),
vitamin E, resveratrol
Dogs and cats (see label)
Activait Phosphatidylserine, omega-3 fatty
acids, vitamins E and C,
L-carnitine, alpha-lipoic acid,
coenzyme Q, selenium
Separate dog and cat products
Activait Cat Note: no alpha-lipoic acid in feline
version
See label
Novifit S-Adenosyl-L-methionine-tosylate
disulfate (SAMe)
Dog: 10–20 mg/kg sid
Cat: 100 mg sid
Neutricks Apoaequorin Dogs: 1 tablet per 18 kg
Prescription diet b/d
Canine aging and
alertness
Flavonoids and carotenoids from
fruits and vegetables, vitamin E,
vitamin C, beta-carotene,
selenium, L-carnitine, alpha-lipoic
acid, omega 3 fatty acids
Dogs
Purina One Vibrant
Maturity 7⫹Senior
Medium chain triglycerides (from
coconut oil)
Dogs
Melatonin Endogenous-based peptide Dogs: 3–9 mg
Cats: 1.5–6 mg
Anxitane Suntheanine Dogs: 2.5–5 mg/kg bid
Cats: 25 mg bid
Harmonease Magnolia and phellodendron Dogs: up to 22 kg ½ tablet daily;
⬎22 kg 1 tablet daily
Cats: N/A
Zylkene Alpha-casozepine Dogs: 15–30 mg/kg/d
Cats: 15 mg/kg/d
Pheromones Adaptil collar, diffuser, or spray for
dogs
Feliway spray or diffuser for cats
As per label
Lavender Aromatherapy for dogs As per label
762 Landsberg et al

Author's personal copy
other drugs that might increase serotonin. On the other hand, SAMe has been used
in human patients to enhance the effects of serotonin reuptake inhibitors in the
treatment of depressive disorders.
78
In laboratory aged dog and cat studies, SAMe
improved measures of executive function and possibly attention.
79,80
In cats, these
effects were mainly evident in the least cognitively impaired subjects, suggesting that
supplementation with SAMe early in disease progression, rather than in more severely
impaired subjects, should be most beneficial.
80
Apoaequorin (Neutricks; Quincy Animal Health, Madison, WI, USA), recently
released in the United States, improved learning and attention in laboratory trials
compared to both placebo and selegiline.
81
Apaoequorin is a calcium buffering
protein that has been postulated to provide neuroprotection in aging and conse-
quently have positive effects on signs of brain aging.
Last, curcumin, an antioxidant, antiamyloid, and antiinflammatory compound found
in the turmeric and catechin spices, is postulated to be helpful.
82
Adjunctive Therapies for Anxiety and Night Waking
Because behavioral signs associated with anxiety and night waking are highly
prevalent in senior pets and greatly impact the owner-pet bond, it is prudent for the
practitioner to rapidly address them. Drugs and natural remedies that help reduce
anxiety and aid in reestablishing normal sleep-wake cycles can also be of benefit in
senior pets alone or in conjunction with drugs for CDS (see Tables 3 and 4).
Melatonin is best given to dogs 30 minutes before bedtime. Diphenhydramine,
phenobarbital, or trazodone can also promote sedation. For the dog or cat that has
difficulty settling at night but then sleeps well, situational use of anxiolytics can be
helpful. Benzodiazepines have rapid onset, are generally short acting, and have
sedative effects at the higher end of the recommended dosage range. In pets where
liver function is compromised, clonazepam, lorazepam, or oxazepam is recom-
mended because they have no active metabolites. Since pain may contribute to
unsettled sleep or night waking, gabapentin can be added both as an adjunctive
therapy for pain management and for its behavioral calming effects.
For senior pets with generalized anxiety, noise phobias, or separation anxiety,
buspirone or selective serotonin reuptake inhibitors like fluoxetine (Reconcile; Elanco,
Greenfield, IN, USA) and sertraline may be considered because of their low risk of side
effects. Paroxetine and tricyclic antidepressants have varying degrees of anticholin-
ergic effects and therefore should not be a first-choice therapeutic. However, these
drugs should not be used concurrently with selegiline.
Natural compounds that may reduce anxiety and help pets settle at night include
suntheanine (Anxitane; Virbac Animal Health, Ft Worth, TX, USA), honokiol and
berberine extracts (Harmonease; VPL, Phoenix, AZ, USA), alpha casozepine (Zylkene;
Vetoquinol Canada, Lavaltrie, PQ, Canada), pheromones (Adaptil and Feliway; CEVA
Animal Health, Libourne, France), and lavender essential oils.
40
SUMMARY
CDS is an underdiagnosed behavioral problem that affects a substantial number of
aged pets. Because changes in behavior are often early indicators of medical or
behavior problems in senior pets, the veterinarian faces the challenge of ruling out the
influence of medical problems, sleep disturbances, anxiety, concurrent medications,
and pain before a diagnosis of CDS can be made. While there are several options for
treatment of CDS, many therapeutics have not been adequately tested. Moreover,
early intervention is likely to be most beneficial. As we learn more about biomarkers
of brain aging, objective tests for identifying pets likely to progress to CDS may be
763
Cognitive Dysfunction Syndrome

Author's personal copy
developed. In the meantime, a proactive approach for early identification and
monitoring of behavioral signs is essential for establishing a diagnosis and monitoring
treatment success.
REFERENCES
1. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to
Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheim-
er’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Al-
zheim Dem 2011;7:263–9.
2. Jakob-Roetne R, Jacobsen H. Alzheimer’s disease: from pathology to therapeutic
approaches. Angew Chem Int 2009;48:3030 –59.
3. Reinikainen KJ, Soininen H, Riekkinen PJ. Neurotransmitter changes in Alzheimer’s
disease: implications to diagnostics and therapy. J Neurosci Res 1990;27:576 – 86.
4. Jack CR, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers
of the Alzheimer’s pathological cascade. Lancet Neurol 2010;9:119 –28.
5. Berchtold NC, Cotman CW. Normal and pathological aging: from animals to humans.
In: Bizon JL, Woods A, editors. Animal models of human cognitive aging. New York:
Humana Press; 2009. p. 1–28.
6. Salvin HE, Greevy PD, Sachdev PS, et al. Growing old gracefully-behavioral changes associ-
ated with “successful aging” in the dog. Canis familiaris. J Vet Behav 2011;6:313–20.
7. Borras D, Ferrer I, Pumarola M. Age related changes in the brain of the dog. Vet Pathol
1999;36:202–11.
8. Tapp PD, Siwak CT, Gao FQ, et al. Frontal lobe volume, function, and beta-amyloid
pathology in a canine model of aging. J Neurosci 2004;24:8205–13.
9. Gunn-Moore D, Moffat K, Christie LA, et al. Cognitive dysfunction and the neurobiol-
ogy of ageing in cats. J Small Anim Pract 2007;48:546 –53.
10. Zhang C, Hua T, Zhu Z, et al. Age related changes of structures in cerebellar cortex of
cat. J Biosci 2006;31:55– 60.
11. Dobson H, Denenberg S. Ageing and imaging based neuropathology in the cat. In:
Programs and abstracts of the 17th Congress of ESVCE and 1st Congress of
ECAWBM. Avignon: 2011.
12. Cummings BJ, Satou T, Head E, et al. Diffuse plaques contain C-terminal AB42 and
not AB40: evidence from cats and dogs. Neurobiol Aging 1996;17:653–9.
13. Cummings BJ, Head E, Afagh AJ, et al. B-Amyloid accumulation correlates with
cognitive dysfunction in the aged canine. Neurobiol Learn Mem 1996;66:11–23.
14. Colle M-A, Hauw J-J, Crespau F, et al. Vascular and parenchymal beta-amyloid deposition in
the aging dog: correlation with behavior. Neurobiol Aging 2000;21:695–704.
15. Nakamura S, Nakayama H, Kiatipattanasakul W, et al. Senile plaques in very aged
cats. Acta Neuropathol 1996;91:437–9.
16. Head E, Liu J, Hagen TM, et al. Oxidative damage increases with age in a canine
model of human brain aging. J Neurochem 2002;82:375– 81.
17. Ruehl WW, Bruyette WW, DePaoli DS, 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;106:217–25.
18. Araujo JA, Nobrega JN, Raymond R, et al. Aged dogs demonstrate both increased
sensitivity to scopolamine and decreased muscarinic receptor density. Pharmacol
Biochem Behav 2011;98(2):203–9.
19. Zhang JH, Sampogna S, Morales FR, et al. Age-related changes in cholinergic
neurons in the laterodorsal and the pedunculo-pontine tegmental nuclei of cats: a
combined light and electron microscopic study. Brain Res 2005;1052:47–55.
764 Landsberg et al

Author's personal copy
20. Araujo JA, Studzinski, CM, Milgram NW. Further evidence for the cholinergic hypoth-
esis of aging and dementia from the canine model of aging. Prog Psychopharmacol
Biol Psychiatry 2005;29:411–22.
21. Araujo JA, Chan ADF, Winka LL, et al. Dose-specific effects of scopolamine on canine
cognition: impairment of visuospatial memory, but not visuospatial discrimination.
Psychopharmacology 2004;175:92– 8.
22. Pugliese M, Cangitano C, Ceccariglia S, et al. Canine cognitive dysfunction and the
cerebellum: acetylcholinesterase reduction, neuronal and glial changes. Brain Res
2007;1139:85–94.
23. Head E, McCleary R, Hahn FF, et al. Region-specific age at onset of beta-amyloid in
dogs. Neurobiol Aging 2000;21:89 –96.
24. Näslund J, Haroutunian V, Mohs R et al. Correlation between elevated levels of
amyloid
␤
-peptide in the brain and cognitive decline. JAMA 2000;283:1571–7.
25. Gunn-Moore DA, McVee J, Bradshaw JM, et al.
␤
-Amyloid and hyper-phosphory-
lated tau deposition in cat brains. J Fel Med Surg 2006;8:234 – 42.
26. Head E, Moffat K, Das P, et al. Beta-amyloid deposition and tau phosphorylation in
clinically characterized aged cats. Neurobiol Aging 2005;26:749 – 63.
27. Adams B, Chan A, Callahan H, et al. Use of a delayed non-matching to position task to
model age-dependent cognitive decline in the dog. Behav Brain Res 2000;108:47–56.
28. Adams B, Chan A, Callahan H, et al. The canine as a model of human brain aging: recent
developments. Prog Neuropsychopharmacol Biol Psychiatry 2000;24:675–92.
29. Siwak CT, Tapp PD, Milgram NW. Effect of age and level of cognitive function on
spontaneous and exploratory behaviours in the beagle dog. Learn Mem 2001;8:65–70.
30. Studzinski CM, Christie L-A, Araujo JA et al. Visuospatial function in the beagle dog:
An early marker of cognitive decline in a model of human cognitive aging and
dementia. Neurobiol Learn Mem 2006;86(2):197–204.
31. Milgram NW, Head E, Weiner E, et al. Cognitive functions and aging in the dog:
acquisition of nonspatial visual tasks. Behav Neurosci 1994;108:57– 68.
32. Tapp PD, Siwak CT, Estrada J, et al. Size and reversal learning in the beagle dog as
a measure of executive function and inhibitory control in aging. Learn Mem 2003;10:
64 –73.
33. Snigdha S, Christie L, De Rivera C, et al. Age and distraction are determinants of
performance on a novel visual search task in aged Beagle dogs. Age (Dordr)
2012;34(1):67–73.
34. Harrison J, Buchwald J. Eyeblink conditioning deficits in the old cat. Neurobiol Aging
1983;4:45–51.
35. McCune S, Stevenson J, Fretwell L, et al. Aging does not significantly affect perfor-
mance in a spatial learning task in the domestic cat (Felis silvestris catus). Appl Anim
Behav Sci 2008;3:345–56.
36. Milgram NW, Landsberg GM, De Rivera C, et al. Age and cognitive dysfunction in
the domestic cat. In: Proceedings of the ACVB/AVSAB Symposium. St Louis;
2011. p. 28 –9.
37. Landsberg G, Denenberg S, Araujo J. Cognitive dysfunction in cats. A syndrome we
used to dismiss as old age. J Fel Med Surg 2010;12:837– 48.
38. Head E, Pop V, Sarsoza F, et al. Amyloid-beta peptide and oligomers in the brain and
cerebrospinal fluid of aged canine. J Alzheimer Dis 2010;20:637– 46.
39. Araujo JA, Higgins GA, de Rivera C, et al. Evaluation of translation Alzheimer’s disease
biomarkers in the aged dog: the effects of age and BACE inhibition on CSF amyloid.
In: Abstracts of the Alzheimer’s Association International Conference. Paris; 2011.
765
Cognitive Dysfunction Syndrome

Author's personal copy
40. Landsberg GM, Hunthausen W, Ackerman L. The effects of aging on the behavior of
senior pets. In: Handbook of behavior problems of the dog and cat. 3rd edition.
Philadelphia: WB Saunders; in press.
41. Rosado B, Gonzalez MA, Pesini P, et al. Effects of age and severity of cognitive
dysfunction on spontaneous behaviour in companion dogs. In: Abstract in ESVCE-
ECAWBM Congress. Avignon; 2011.
42. Senanarong V, Cummings JL, Fairbanks L, et al. Agitation in Alzheimer’s disease is a
manifestation of frontal lobe dysfunction. Dement Geratr Cogn Disord 2004;17:14 –20.
43. McCurry SM, Gibbons LE, Logsdon RG, et al. Anxiety and nighttime behavioral
disturbances. Awakenings in patients with Alzheimer’s disease. J Gerontol Nurs
2004;30:12–20.
44. Mariotti VM, Landucci M, Lippi I, et al. Epidemiological study of behavioural disorders
in elderly dogs. In: Heath S, editor. Proceedings 7th International Meeting of Veterinary
Behaviour Medicine, ESVCE. Belgium: 2009. p. 241–3.
45. Horwitz D. Dealing with common behavior problems in senior dogs. Vet Med 2001;
96:869 – 87.
46. Azkona G, Garcia-Beleguer S, Chacon G, et al. Prevalence and risk factors of
behavioral changes associated with age-related cognitive impairment in geriatric
dogs. J Sm Anim Pract 2009;50:87–91.
47. Notari L, Mills D. Possible behavioral effects of exogenous corticosteroids on dog
behavior: a preliminary investigation. J Vet Behav 2011;6:321–7.
48. Berteselli GV, Servidaq F, DallAra P, et al. Evaluation of the immunological, stress and
behavioral parameters in dogs (Canis familiaris) with anxiety-related disorders. In: Mills
D, Levine E, Landsberg G, et al, editors. Current issues and research in veterinary
behavioral medicine. West Lafayette (IN): Purdue Press; 2005. p. 18 –22.
49. Overall KL. Dogs as “natural” models of human psychiatric disorders: assessing
validity and understanding mechanism. Prog Neuropsychopharmacol Biol Psychiatry
2000;24:727– 6.
50. Landsberg GM, DePorter T, Araujo JA. Management of anxiety, sleeplessness and cognitive
dysfunction in the senior pet. Vet Clin North Am Small Anim Pract 2011;41:565–90.
51. Nielson JC, Hart BL, Cliff KD, et al. Prevalence of behavioral changes associated with
age-related cognitive impairment in dogs. J Am Vet Med Assoc 2001;218:1787–91.
52. Osella MC, Re G, Odore R, et al. Canine cognitive dysfunction syndrome: prevalence,
clinical signs and treatment with a neuroprotective nutraceutical. Appl Anim Behav Sci
2007;105:297–310.
53. Hart BL. Effect of gonadectomy on subsequent development of age-related cognitive
impairment in dogs. J Am Vet Med Assoc 2001;219:51– 6.
54. Salvin HE, McGreevy PD, Sachev PS, et al. Under diagnosis of canine cognitive
dysfunction; a cross-sectional survey of older companion dogs. Vet J 2011;188:
331– 6.
55. McMillan FD. Maximizing quality of life in ill animals. J Am Anim Hosp Assoc 223;39:
227–35.
56. Valenzuela M, Sachdev P. Harnessing brain and cognitive reserve for the prevention
of dementia. Ind J Psychiatry 2009;51:16 –21.
57. Yonas E G, Roberts RO, Knopman DS, et al. Aging and mild cognitive impairment. A
population-based study. Arch Neurol 2010;67:80 – 6.
58. Head E. Combining an antioxidant-fortified diet with behavioral enrichment leads to
cognitive improvement and reduced brain pathology in aging canines: strategies for
healthy aging. Ann N Y Acad Sci 2007;1114:398 – 406.
59. Milgram NW, Ivy GO, Head E, et al. The effect of l-deprenyl on behavior, cognitive
function, and biogenic amines in the dog. Neurochem Res 1993;18:1211–9.
766 Landsberg et al

Author's personal copy
60. Carillo MC, Milgram NW, Ivy GO, et al. (–)Deprenyl increases activities of superoxide
dismutase (SOD) in striatum of dog brain. Life Sci 1994;54:1483–9.
61. Campbell S, Trettien A, Kozan B. A non-comparative open label study evaluating the
effect of selegiline hydrochloride in a clinical setting. Vet Ther 2001;2(1):24 –39.
62. Landsberg G. Therapeutic options for cognitive decline in senior pets. J Am Anim
Hosp Assoc 2006;42:407–13.
63. Siwak CT, Gruet P, Woehrle F, et al. Behavioral activating effects of adrafinil in aged
canines. Pharmacol Biochem Behav 2000;66:293–300.
64. Siwak CT, Gruet P, Woehrle F, et al. Comparison of the effects of adrafinil, propento-
fylline and nicergoline on behavior in aged dogs. Am J Vet Res 2000;61:1410 – 4.
65. Martinez-Coria H, Green KN, Billings LM, et al. Memantine improves cognition and
reduces Alzheimer’s-like neuropathology in transgenic mice. Am J Pathol 2010;
176(2): 870 – 80.
66. Araujo JA, Greig NH, Ingram DK, et al. Cholinesterase inhibitors improve both memory
and complex learning in aged Beagle dogs. J Alzheimer Dis 2011;26:143–55.
67. Milgram NW, Head EA, Zicker SC, et al. Long term treatment with antioxidants and a
program of behavioral enrichment reduces age-dependent impairment in discrimina-
tion and reversal learning in beagle dogs. Exp Gerentol 2004;39:753– 65.
68. Milgram NW, Zicker SC, Head E, et al. Dietary enrichment counteracts age-associ-
ated cognitive dysfunction in canines. Neurobiol Aging 2002;23:737– 45.
69. Araujo JA, Studzinski, CM, Head E, et al. Assessment of nutritional interventions for
modification of age-associated cognitive decline using a canine model of human
aging. AGE 2005;27:27–37.
70. Pan Y, Larson B, Araujo JA, et al. Dietary supplementation with medium-chain TAG has
long-lasting cognition-enhancing effects in aged dogs. Br J Nutr 2010;103:1746 –54.
71. Taha AY, Henderson ST, Burnham WM. Dietary enrichment with medium chain-
triglycerides (AC-1203) elevates polyunsaturated fatty acids in the parietal cortex of
aged dogs; implications for treating age-related cognitive decline. Neurochem Res
2009;34:1619 –25.
72. Studzinski CM, MacKay WA, Beckett TL, et al. Induction of ketosis may improve
mitochondrial function and decrease steady-state amyloid-beta precursor protein
(APP) levels in the aged dog. Brain Res 2008;1226:209 –17.
73. Osella MC, Re G, Odore R, et al. Canine cognitive dysfunction syndrome: prevalence,
clinical signs and treatment with a neuroprotective nutraceutical. Appl Anim Behav Sci
2007;105:297–310.
74. Heath SE, Barabas S, Craze PG. Nutritional supplementation in cases of canine
cognitive dysfunction-a clinical trial. Appl Anim Behav Sci 2007;105:274 – 83.
75. Araujo JA, Landsberg GM, Milgram NW, et al. Improvement of short-term memory
performance in aged beagles by a nutraceutical supplement containing phosphati-
dylserine, Ginkgo biloba, vitamin E and pyridoxine. Can Vet J 2008;49:379 – 85.
76. Bottiglieri T. S-Adenosyl-L-methionine (SAMe): from the bench to the bedside—
molecular basis of a pleiotrophic molecule. Am J Clin Nutr 2002;76:1151–7S.
77. Rème CA, Dramard V, Kern L, et al. Effect of S-adenosylmethionine tablets on the
reduction of age-related mental decline in dogs: a double-blind placebo-controlled
trial. Vet Ther 2008;9:69 – 82.
78. Papakostas GI, Mischoulon D, Shyu I, et al. S-Adenosyl methionine (SAMe) augmen-
tation of serotonin reuptake inhibitors for antidepressant nonresponders with major
depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry 2010;
167:942– 8.
767
Cognitive Dysfunction Syndrome

Author's personal copy
79. Mongillo P, Araujo JA, de Rivera C, et al. The effects of novifit on cognitive function in
aged beagle dogs. J Vet Behav 2010;5:39. [In: Abstract of the 7th International IVBM
International Veterinary Behavior Meeting. Edinburgh (Scotland), 2009].
80. Araujo JA, Faubert ML, Brooks ML, et al. Novifit (NoviSAMe) tablets improves
executive function in aged dogs and cats: implications for treatment of cognitive
dysfunction syndrome. Intern J Appl Res Vet Med 2012;10:90 – 8.
81. Milgram NW, Landsberg GM, Visnesky M. Effect of apoaequroin on cognitive function
in aged canines. In: Abstracts of the 17th Congress of ESVCE and 1st Annual
Congress of ECAWBM. Avignon; 2011.
82. Ringman JM, Frautschy SA, Cole GM, et al. A potential role of the curry spice
curcumin in Alzheimer’s disease. Curr Alzheimer Res 2005;2:131– 6.
768 Landsberg et al