Canine cognitive dysfunction syndrome: Prevalence,clinical signs and treatment with a neuroprotectivenutraceutical

Publishing Authors : Maria Cristina Osella, Giovanni Re, Rosangela Odore,Carlo Girardi, Paola Badino, Raff aella BarberoLuciana Bergamasco

Date Published : 2007

1. Introduction
Ageing represents a complex biological process characterized by a progressive modification
of tissues and cells (Kiatipattanasakul et al., 1996) with a gradual loss of adaptive capacity.
Ageing animals can show a decrease in their learning and memory performance (Milgram et al.,
1994; Landsberg and Ruehl, 1997; Adams et al., 2000; Chan et al., 2002). The behavioural signs
shown by ageing animals might be referred to as ‘‘aged dog syndrome’’ or, when severe, of
‘‘senile impairment’’. Sometimes, they are considered as features of ‘‘normal ageing’’. A
serious impairment of cognitive processes must be distinguished from a simple and mild
decrease in psychomotor activity and may be considered ‘‘pathological ageing’’ (Ruehl and
Hart, 1998).
In aged dogs behavioural problems are often related to organic and functional disorders.
Although a change in behaviour could have an entirely medical or behavioural cause, it is
actually the combined effects of disease and ageing on the pet’s mental and physical health
that cause geriatric behavioural disorders in the dog (Landsberg and Ruehl, 1997; Landsberg
and Araujo, 2005). Sometimes complications may develop in animals with pre-existing
behaviour problems that have been tolerated by the owners until the consequences are
exacerbated by a clinical geriatric problem (Houpt and Beaver, 1981; Chapman and Voith,
1990; Dodman, 1998). More recently a specific ‘‘Cognitive dysfunction syndrome’’ (CDS) of
senior dogs has been described (Ruehl et al., 1995; Ruehl and Hart, 1998). Other specific agerelated
disorders such as involutive depression, confusional syndrome of the ageing dog and
dysthymia of the ageing dog have also been suggested by Pageat (2001), as affective and
cognitive dysfunctions.
The dog represents a suitable animal model to study cognitive impairment observed in human
ageing (Ruehl et al., 1995; Cummings et al., 1996; Overall, 2000; Adams et al., 2000; Cotman
et al., 2002; Studzinski et al., 2005). Dogs normally share environmental conditions with humans
and present a sophisticated repertoire of complex cognitive behaviours. Furthermore, the brain in
aged dogs shows many pathological changes common to humans and the neuropathological
patterns are significantly associated with cognitive decline (Head et al., 2000). CDS shares some
analogies with Alzheimer’s disease (AD) in humans and is characterized by brain pathology that
298 M.C. Osella et al. / Applied Animal Behaviour Science 105 (2007) 297–310
negatively affects the interaction of dogs with their own environment (Cummings et al., 1996). In
fact the term canine CDS is used in veterinary literature to describe the progressive
neurodegenerative disorder of senior dogs that is a result of a gradual decline in cognitive
function (Landsberg, 2005). Typical behavioural changes in affected animals include signs of
disorientation, a decrease in or alteration of social interaction, impairment of normal
housetraining, and changes in both the usual sleep–wake cycle and general activity (Milgram
et al., 1994; Cummings et al., 1996; Ruehl and Hart, 1998); traditionally the clinical signs are
described by the acronym DISHA (disorientation, interaction changes, sleep/wake disturbances,
house soiling and activity changes) (Landsberg et al., 2003).
CDS is a common disorder among senior dogs but a great number of owners fail to discuss
geriatric-onset behaviour changes with their veterinarian because they incorrectly assume that
these problems are an unfortunate and untreatable aspect of ageing (Neilson et al., 2001; Bain et al.,
2001). Furthermore, differentiating normal from pathological ageing is a challenge since the
progressive decline of canine CDS, leading to functional impairment and eventually death, may be
greatly underestimated. Age-related neurodegenerative changes and associated behavioural signs
that characterize pathological brain ageing are progressive in nature; the sooner they are detected
the more effectively they can be corrected or at least slowed down (Head et al., 2000).
Since age-related behavioural changes may be useful indicators for early diagnosis and
treatment, the first purpose of this study was to investigate the prevalence of clinical signs of CDS
in a general population of aged dogs, through a questionnaire designed by the authors. The
assessment scale sought to facilitate the earliest possible detection of pathology and to accurately
follow the changes in behaviour over the time. The second part of this study was to use this scale
to make a preliminary evaluation of the effectiveness of a nutraceutical for the treatment of CDS
(Senilife1, Innovet Italia s.r.l., Rubano, Italy) through a pilot prospective open-label clinical
trial. Senilife1 contains a combination of phosphatidylserine (PS), a standardized extract of
Ginkgo biloba (EGb), d-alpha-tocopherol and pyridoxine. These components have been reported
to have potentially neuroprotective properties on age-related brain neurodegenerative changes
(Landsberg, 2005).
2. Materials and methods
2.1. Animals
One hundred and twenty-four male and female dogs not referred for behavioural consultations were used
for the initial study. Inclusive criteria were the age (>7 years old), exclusive criteria were primary organ
failure and/or neurological signs and living with the owner for less than 1 year.
2.2. Procedure
First visit (V0). In order to determine prevalence of CDS signs a screening interview assessed if the dog
was suffering from any major medical problem that might have behavioural effects. Furthermore a
questionnaire adapted from other authors (Kiatipattanasakul et al., 1996; Colle et al., 2000; Pageat,
2001; Landsberg et al., 2003; Pugliese et al., 2005) was used to evaluate cognitive status (Table 1). It has
been reported that the requirements for CDS diagnosis in dogs include the presence of one or more of the
following signs: spatial disorientation and confusion, learning and memory disorders, ranging from
inappropriate elimination to inability to recall previously learned commands; modified activity levels
(general, pointless, repetitive) to hypoactivity; deterioration in social interaction; modified sleeping-wake
patterns; state of anxiety or restlessness; change in appetite (increase or decrease); decline in personal cleanliness; reduced perception of and/or response to stimuli. Thirty-nine items were identified which were
grouped as disorientation (9 items), socio-environmental interaction (13 items), sleep–wake cycles (4
items), house soiling (6 items) and general activity (7 items), as described in Table 1. Each owner
provided the required information rating the frequency of the behavioural signs as: never, rarely, often,
or always, scored 0–3 accordingly in subsequent analysis. At V0 a standard physical examination and a
laboratory assessment (complete blood count, basic biochemical profile, urinalysis, basic endocrine
screen) were performed to determine whether there were underlying medical problems. Further
diagnostic tests or specific consultations, such as a neurological examination were recommended
when necessary. Sensory evaluation (vision and hearing impairment) was assessed clinically by the
investigator.
From all of the animals assessed, 75 showed potential clinical signs of CDS and these owners were
advised to seek a behavioural consultation. From this referral population 18 dogs were diagnosed as having
CDS. One of the criteria for impairment in each category was that dogs had two or more distinct signs in that
category which had not been observed when they were younger, comparing the pet’s present cognitive status
to his or her behaviour prior to 7 years of age; additionally the dog had to have dysfunction signs in that
category at least once a week for at least the previous month (Neilson et al., 2001). Since an analysis of pilot
data showed that the prevalence of each category of signs did not vary with age group, all the categories were
treated in the same way. It was then determined whether each dog had impairment in 0, 1 or 2 or more
categories. As a result of the investigator’s assessment and the owners’ agreement, eight dogs were enrolled
on the Senilife1 trial.
At V0 the owners were briefed verbally about the procedure. No behavioural advice was given throughout
the study time. The owners were requested to administer Senilife1 at the dosage of 1 capsule per 5 kg body
weight per day Per Os (each capsule contains 25 mg phosphatidylserine, 50 mg Ginkgo biloba extracts,
33.5 mg/d-alpha tocopherol, 20.5 mg pyridoxine) for 3 months.
2.2.1. Further visits (V1, V2, V3)
After V0, dogs were checked in three control visits V1 (28 3 days after V0), V2 (56 3 days) and V3
(84 3 days). At V1, V2 and V3 the investigator referred to the aforementioned questionnaire (Table 1) and
asked the dog owners the frequency of each item and to rate the signs of each category on a five point change
scale (much better, slightly better, the same, slightly worse, much worse).
2.3. Data analysis
To assess the prevalence of clinical signs associated with CDS a descriptive analysis was conducted in
relation to age, sex and castration status, and the weight for all dog groups was considered (Wells and
Hepper, 2000).
In the assessment of the therapeutic effects of the nutraceutical, an exact percentage confidence interval
test (SAS System, Version 8) was used to investigate the changes after treatment with Senilife between V3
and V0.
3. Results
3.1. Demographic information
Twenty-two of the 124 dogs tested in the survey were removed based on exclusion criteria
clinical concerns and/or severe sensory impairment. Twenty-seven of the 102 dogs included in
the study expressed ageing without any signs of CDS, 42 dogs had alterations in one category and
33 dogs had signs in 2 or more categories. Consequently 75 dogs had signs referring to CDS.
The general activity category has been scored separately in order to compare the results with
other existing data as discussed below.
M.C. Osella et al. / Applied Animal Behaviour Science 105 (2007) 297–310 301
3.1.1. Dogs with alterations in one category (n = 42)
Among the 42 dogs, 15 were females, 10 neutered females, 15 males, and 2 were castrated
males. The age range was 8–17 years (mean: 12.61), whereas weight ranged from 21 to 30 kg
(mean: 25.69). Mix breeds and pure breeds were equally represented. Twenty-one dogs (50%)
had mild clinical complications, 22 (52.38%) were undergoing some form of therapy and 10 dogs
(23.81%) required further clinical evaluation.
Twenty-five dogs had alterations in socio-environmental interaction (59.52%), 16 in sleep–
wake cycles (38.10%) and 1 in house soiling (2.38%). Eighteen dogs (42.86%) had general
activity changes with 12 dogs being hypoactive.
3.1.2. Dogs with alterations in two categories (n = 26)
Females and males were equally represented (50% of each), 8 females were spayed and all the
males were entire. Age range was 9–19 years (mean: 12.61). Mix breeds were most prevalent
with 15 dogs. Weight range was 3.5–62 kg (mean: 21.03). Fifteen dogs had mild clinical
complications, 18 were undergoing some form of therapy and 6 required further clinical
evaluation.
Thirteen dogs had alterations in socio-environmental interaction (50%), 16 in sleep–wake
cycles (61.53%) and 2 in house soiling (7.69%), 20 dogs (76.92%) had general activity changes,
with 8 dogs (30.76%) being hypoactive.
3.1.3. Dogs with alterations in three categories (n = 5)
All the dogs in this group were females; four of them were spayed. Two dogs were 12 years old
and the others were each 13, 14 and 15 years old, respectively. Weights ranged from 4 to 40 kg
(mean: 16.60). One dog had a mild clinical complication and one dog was undergoing some form
of therapy. About 33.33% had alterations in socio-environmental interactions, 33.33% in sleep–
wake cycles, 20% disorientation and 13.34 % in house soiling. All the dogs showed marked
hypoactivity.

 

3.1.4. Dogs with alterations in four categories (n = 2)
Two dogs were included, an 18 years old female Yorkshire Terrier weighing 5 kg and a 16
years old male mix breed weighing 6 kg. The dogs showed neither clinical signs of organic
disorders nor were they undergoing therapy and further examinations were unnecessary.
The dogs had impairment in all categories and they had a severe impairment in activity
(hypoactivity, repetitive activities).
3.2. Senilife1 treated dogs (n = 8)
Eight dogs among the 75 with CDS signs were enrolled in the second step of the project and
treated with Senilife1. The dogs showed mild impairment and they had impairment in two or
more categories. Four dogs belonged to the group of dogs with alterations in two categories; two
dogs were included in the group of dogs with three alterations and the other two dogs were among
the animals showing alterations in four categories.

For each animal and item, the variation between score at V0 and V3 was calculated. This
variation was classified as Positive, Unchanged and Negative depending on improvement or
worsening of the behaviour. Only items with scores different from zero were considered. Data are
reported in Table 2.
Except for the subset D where it was not possible to perform any statistical analysis, the
hypothesis that changes are due to a random effect ( p = 0.5) is rejected with a p-value < 0.001,
as showed in Table 3.
The eight dogs showed a highly significant difference at V3 versus V0, in all the categories as
well as the overall assessment ( p < 0.001), even if some items did not significantly differ when
analysed individually (Table 4).
4. Discussion
Data on the prevalence of CDS suggest that the phe
emotional and cognitive signs with biological markers and post-mortem brain lesion analysis.
Moreover, in dogs it seems suitable to perform visual-spatial tests instead of the human
batteries of neuropsychological tests. Adams et al. (2000) have demonstrated that in aged dogs,
on the basis of cognitive test performance it is possible to identify the following categories of
cognitive impairment: successful ageing, mildly impaired dogs and severely impaired dogs.
These categories are analogous to the human groups: successful ageing, mild cognitive
impairment and dementia. Another important question is whether the experimental method
designed to test learning ability and memory in ageing dogs correlates with clinical behavioural
observation. In the laboratory studies have shown some correlation between levels of
impairment in learning ability and memory and clinical signs such as exploration and social
interaction. (Milgram et al., 1994; Siwak et al., 2001, 2002, 2003; Tapp et al., 2003). Even if
findings suggest that the dog shows age-dependent deterioration in cognitive function there
may be differences related to breed and previous experience (Head et al., 1997). In the present
study, the dog population did not provide an opportunity to investigate these factors, not least
because a variety of breeds were represented including a large number of mixed breed dogs, so
further research is necessary.
It has been suggested that it is necessary to know exactly the main patho-genetic mechanisms
of ageing to formulate a precise diagnosis and establish successful treatment protocols in order to
manage geriatric behavioural problems (Overall, 2001). In human and canine senile brains the
main neurodegenerative changes are both grossly neuropathological (e.g. thickening of the
meninges, gliosis and diffuse plaques) (Borras et al., 1999; Gonzalez-Soriano et al., 2001;
Fukuoka et al., 2004) and neurochemical (e.g. neuronal apoptosis, beta-amyloid deposits)
(Anderson et al., 2000; Papaioannou et al., 2001; Dimakopoulos and Mayer, 2002; Head et al.,
2002). In humans, a variety of neurotransmitter abnormalities have been described in patients
affected by age-related dementia and even aged animals may show modifications of
neurotransmitter levels and/or their receptor concentrations. In patients with Alzheimers
Disease (AD), a decrease in muscarinic receptor (Araujo et al., 2005) and acetylcholinesterase
activity occurs (Rinne, 1987). A decrease in catecholamines, especially dopamine, has been
reported to correlate with cognitive and degenerative changes (Kalaria et al., 1989; Kalaria and
Andorn, 1991; Meana et al., 1992; Arnsten, 1993; Palmer, 1996; Sastre et al., 2001). The
serotonergic system also seems to be involved in ageing and in pathogenesis of AD in humans
(Baker and Reynolds, 1989; Reinikainen et al., 1990; Tohgi et al., 1992; Kumar et al., 1995; Lai
et al., 2002). Oxidative stress plays a pivotal role in the neurodegenerative processes associated
with age-related dementia (Anderson et al., 2001; Milgram et al., 2002; Cotman et al., 2002;
Skoumalova et al., 2003; Rofina et al., 2004). A decline in NMDA glutamate receptors, mainly
affecting the cortex and hippocampus areas, has also been demonstrated in aged dogs
(Magnusson et al., 2000). Advanced research has also demonstrated significant quantitative
reductions in neurotrophic factors such as BDNF (Brain Derived Neurotrophic Factor) and NGF
(Nerve Growth Factor) (Head et al., 2000).
The first therapeutic agent approved for use in dogs based on the results of both
neuropsychological testing including reversal and spatial memory as well as clinical trials was
selegiline (Milgram et al., 1995; Ruehl et al., 1995; Head et al., 1996; Campbell et al., 2001), a
selective and irreversible inhibitor of monoamino-oxidase B (MAO B). Drugs for enhancing
cerebral perfusion and/or alertness in aged dogs, antidepressants and anxiolytics, cholinergic
agonists have also been considered (Landsberg, 2005). Complementary products have also been
suggested as useful in improving or preventing cognitive decline, but so far data to validate their
efficacy is very limited (Overall, 2001).
M.C. Osella et al. / Applied Animal Behaviour Science 105 (2007) 297–310 305
The results of this preliminary trial on Senilife1 showed a marked improvement in CDS related
signs even but it should be noted that the average score at V0 and percentage of observed items were
very low, which means the status of animals at baseline was not very severe. Furthermore dogs did
not show complete remission of symptoms, but their signs became less severe. In human medicine
mild cognitive impairment is considered a transitory state between normal ageing and dementia;
patients in this category may represent a potential clinical population cohort targeted for early
intervention (Lockhart and Lestage, 2003), due to the better prognosis.
The effects observed in treated dogs may be related to the neuroprotective activities exerted by
its active constituents. Senilife1 contains phosphatidylserine (PS), a standardized Gingko biloba
extract (EGb), pyridoxine and d-alpha-tocopherol. PS is a phospholipid associated with
membrane proteins that regulate the fluidity of neural membranes (Tsakiris and Deliconstantinos,
1984) which may be severely compromised in aged brains (Samson, 1987). Administration of PS
both to human patients and laboratory animals with cognitive decline has produced excellent
results in terms of improved learning and memory (Crook et al., 1992; Cenacchi et al., 1993;
Blokland et al., 1999; Suzuki et al., 2001). Such results are also considered to be related to other
neuroprotective activities of PS (Milan et al., 1988; Suzuki et al., 1999). Furthermore PS
stimulates acetylcholine release in the cerebral cortex of elderly animals (Vannucchi et al., 1990;
Yamatoya et al., 2000), modulates acetylcholinesterase activity in the synaptosome of the canine
brain (Tsakiris and Deliconstantinos, 1984, 1985) and activates the synthesis and release of
dopamine (Raitieri et al., 1988). PS also inhibits the age-related loss of NMDA receptors,
cholinergic muscarinic receptors and hippocampus NGF receptors (Cohen and Mueller, 1992;
Gelbmann and Muller, 1992; Nunzi et al., 1992). The safety of its use has been confirmed through
a toxicological study conducted on dogs (Heywood et al., 1987) and through clinical trials
conducted in humans (Cenacchi et al., 1987).
EGb has a PS co-adjuvant activity, since it stimulates the cholinergic, serotonergic,
noradrenergic and glutaminergic systems in aged animals (Taylor, 1986; Chopin and Briley,
1992; Huguet and Tarrade, 1992; Huguet et al., 1994; Nathan, 2000; Lee et al., 2004). EGb
reversibly inhibits MAO A and B in the brains of laboratory animals thus increasing the levels of
dopamine (White et al., 1996). Interestingly, EGb also protects the neurons against apoptosis
induced by beta-amyloid protein (Yao et al., 2001), one of the main pathogenic processes of
cognitive age-related decline in dogs (Colle et al., 2000; Le Bars et al., 2002). This effect seems
to be primarily mediated by the marked antioxidant properties possessed by the active
constituents of EGb (Sastre et al., 1998; Bastianetto and Quirion, 2002). Finally, EGb has been
demonstrated to increase brain metabolism (DeFeudis and Drieu, 2000; McKenna et al., 2001), to
promote short-term retention of spatial memory (Hoffman et al., 2004), and to exert reproducible
effects on cognitive functions in Alzheimer’s disease (Gertz and Kiefer, 2004).
Pyridoxine is synergistic with the neurotransmission restoring effects of both PS and EGb, since
it is an essential co-factor in the biosynthesis of many neurotransmitters (dopamine, noradrenaline
and serotonin) (Dakshinamurti et al., 1995). As oxidative stress is considered to be one of the main
pathogenic factors in the age-related cognitive decline in dogs (Head et al., 2002; Skoumalova et al.,
2003; Rofina et al., 2004), compounds that prevent free radical production or scavenge them, have
been suggested to augment cognitive function (Overall, 2002; Head and Zicker, 2004). The marked
antioxidant properties of d-alpha-tocopherol make the compound an excellent candidate for
controlling pathological brain ageing in the dog. Clinical and experimental evidence have
demonstrated its neuroprotective potential (Behl and Moosmann, 2002) and beneficial cognitive
effect (Guerriero et al., 1999). In particular, tocopherol slows the functional deterioration clinically
observable in patients with pathological brain ageing (Sano et al., 1997).
306 M.C. Osella et al. / Applied Animal Behaviour Science 105 (2007) 297–310
In conclusion, further studies are necessary to validate the screen used in this study, but it
appears to be a simple and practical tool for initial assessment of geriatric subjects. Results of
treatment with Senilife1 suggest further studies investigating the effects of complementary
therapy in canine cognition should be encouraged as the quality of life of senior dogs has the
potential to be improved.
Acknowledgements
The authors thank Dr. K.L. Overall for help and advice on English, Dr. C. Schievano for his
statistical support, Dr. L. Berger and Dr. L. Ponzetto for their help in clinical cases collection.
Final revision made by Mrs. Linda Massari, Mother Language Lecturers for Scientific English
University of Turin.
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