JACQUELINE WILHELMY AND GARY LANDSBERG

Delaware Valley Veterinary Behavior, Philadelphia, Pennsylvania, USA; Fear Free Research, CanCog Technologies, Fergus, Ontario, Canada

Cognitive dysfunction syndrome (CDS) is a progressive neurodegenerative disease of aging dogs and cats. Although clinical signs are most commonly reported in pets over 11 years of age, they can appear in animals as young as 6 years (Araujo et al., 2005b; Studzinski et al., 2006; Salvin et al., 2010). The disease manifests in the form of behavioral changes, impaired learning and memory, altered awareness, and confusion. Clinical signs can be categorized as deficits in one of six areas, represented by the acronym DISHAA: disorientation, altered social interactions, sleep–wake disturbances, loss of housetraining and other learned behaviors, increased or decreased activity levels, and increased anxiety or fear (Osella et al., 2007; Rème et al., 2008; Azkona et al., 2009; Rosado et al., 2012; Fast et al., 2013; Madari et al., 2015). Basic functions such as self-hygiene, eating or drinking behavior, and response to stimuli can be compromised or altered (Rofina et al., 2006). In the laboratory (Fig. 15.1), validated neuropsychological tests reveal quantifiable impairment in the learning and memory of affected animals (Milgram et al., 2004; Tapp et al., 2004; Araujo et al., 2012; Pan et al., 2010, 2013).

The most common signs of CDS in dogs were found to include increased daytime sleep and nighttime restlessness (57%), altered social interactions (51%), disorientation (49%), and anxiety (46%). In mild cases, this study found increased daytime sleep was the most prevalent sign, affecting 70% of dogs (Fast et al., 2013). Another found owners were unlikely to report mild signs of cognitive dysfunction unless specifically asked, but that altered social interactions were most common. Moderately affected dogs were most likely to exhibit sleep–wake disturbances and altered social interactions, with 67% of dogs displaying both signs; in the most severely affected dogs, 67% displayed all four signs (Madari et al., 2015). In cats, affected animals aged 11–14 years were most likely to show altered social interactions, while cats over 15 years of age most commonly displayed aimless activity and vocalization (Gunn-Moore et al., 2007; Landsberg et al., 2010, 2011).

Freedom from fear and distress is crucial for all animals, and safety can be compromised when an animal signals for increased distance using aggression. One study found intermittent manifestations of anxiety to be reported in 61% of dogs with CDS (Rème et al., 2008). Salivary cortisol levels were higher in aged dogs during the Strange Situation Test (Mongillo et al., 2013). Clinically, there is a concern because pets with CDS may experience increased agitation or aggression (Fast et al., 2013), but also because these pets may be the target of aggression by other household pets. Due to decreased awareness (particularly if coupled with sensory decline or decreased mobility), cognitively impaired dogs or cats can fail to read the social signals of other pets or be perceived as alarming by these housemates due to their atypical behavior.

15.1.2 Prevalence

The reported prevalence of canine CDS in animals over 8 years of age ranges from 14% to over 60% (Neilson et al., 2001; Osella et al., 2007; Azkona et al., 2009; Salvin et al., 2010; Madari et al., 2015). Twenty-eight percent of dogs aged 11–12 years were reported by owners to show impairments in at least two categories of DISHAA, and 10% to show impairments in at least one category. In older dogs, aged 15–16 years, 68% were affected in at least one category, and 36% in two or more (Neilson et al., 2001). Another study found a prevalence of 5% in dogs aged 10–12 years, 23% in dogs aged 12–14 years, and 41% in dogs over 14 years of age (Salvin et al., 2010). Moderate to marked cognitive dysfunction was reported to occur in 13–16% of dogs aged 8–11 years, and 87–100% of dogs older than 13 years (Katina et al., 2016). When 85 of 300 dogs over 8 years of age were excluded due to medical problems, 159 of the remaining 215 dogs displayed signs of cognitive dysfunction (Madari et al., 2015). Thirty-five percent of cats over 11 years of age were diagnosed with CDS, with 28% of cats 11–15 years and 50% of cats over 15 years affected (Gunn-Moore et al., 2007).

Interestingly, owners’ focus does not reflect the above when it comes to seeking veterinary assistance for behavioral concerns. In a group of 270 dogs over 7 years of age presenting for behavior problems, 32% displayed aggression to family members, 16% aggression to family dogs, 9% barking, 8% separation anxiety, 6% disorientation and aggression toward unfamiliar people, 5% house soiling, 4% destructive and compulsive disorders, and 3% noise fears (Mariotti et al., 2009). Yet in a study of 479 dogs over the age of 8, 14.2% were diagnosed with CDS despite only 13% of these having been previously diagnosed (Salvin et al., 2010). Biannual hospital visits with questionnaire screening for clinical signs of CDS are recommended in pets over age 8 years to provide the earliest possible diagnosis (Landsberg et al., 2010; Salvin et al., 2011; Katina et al., 2016) (Table 15.1).

Cognitive dysfunction is a progressive disease, and treatment is aimed at slowing progression. In dogs aged at least 11 years, 22% free of clinical signs developed signs within 12–18 months, and 48% of dogs with impairment in one category developed impairment in at least one additional category within this time frame (Bain et al., 2001). In dogs at least 8 years of age, 42% developed clinical signs and 24% progressed from mild to moderate impairment over a 6-month period. Over 1 year, 71.4% of this population developed mild impairment, and 50% progressed in classification from moderate to severe clinical signs (Madari et al., 2015). A third study found that 58% of dogs aged at least 8 years developed borderline CDS over the course of approximately 3 years, and 11% converted from borderline to CDS status (Fast et al., 2013).

15.1.4 Risk factors

Age is, of course, the key risk factor for canine CDS (Neilson et al., 2001; Azkona et al., 2009; Katina et al., 2016). A strong positive correlation (Pearson correlation coefficient r = 0.662, p < 0.0001) has also been found between age and cognitive decline in dogs. Although percentages differ between studies (possibly due to the instruments used), the prevalence of CDS increases gradually with age (Azkona et al., 2009; Salvin et al., 2010).

The impact of body size does not appear to be large, if present at all. Four studies have found no impact of body size on memory or cognitive impairment (Neilson et al., 2001; Salvin et al., 2010; Fast et al., 2013; Katina et al., 2016). CDS was found to be similarly prevalent in small and medium/large dogs aged 8–11 years, but more common in larger breeds aged 11–13 years (55% versus 41%).

A clear influence of sex or castration status has also not been found. Females were suggested as more likely to exhibit CDS (Azkona et al., 2009), but several other studies did not find support for such a difference (Neilson et al., 2001; Yalcin et al., 2010; Salvin et al., 2011; Fast et al., 2013; Katina et al., 2016). CDS was found by two studies to be more prevalent in castrated individuals (Hart, 2001; Azkona et al., 2009). However, two more recent investigations did not identify a difference in prevalence between castrated and intact older dogs (Fast et al., 2013; Katina et al., 2016).

Nutritional support for animals with CDS will be discussed later in this chapter. Risk factors associated with accelerated brain aging and Alzheimer’s disease in humans include docosahexaenoic acid deficiency, high homocysteine, low B vitamin levels, high blood pressure, chronic oxidative stress, and chronic low-grade inflammation. Dogs fed low-quality commercial diets or table scraps were significantly more likely to develop CDS than dogs fed commercial diets formulated for age, size, or health (Katina et al., 2016).

Environment may also play a role in the development of neurodegenerative disease. Wild dogs from areas with high air pollution exhibited early occurrence of β-amyloid plaques and elevation of proinflammatory markers. The former changes preceded by several years similar changes in the brains of dogs living in an environment with low air pollution (Calderon-Garciduenas et al., 2008). In 56% of children and 57% of dogs living in an urban area with excessive air pollution, magnetic resonance imaging (MRI) revealed lesions in the prefrontal subcortical white matter (Migliore and Coppede, 2009).

15.2 Evaluation: Identifying Welfare Concerns

15.2.1 Pathophysiology

Changes in the brain range from macroscopic to submicroscopic. MRI scans of dogs with CDS may reveal ventricular enlargement, frontal and temporal lobe atrophy, an increase in lesions in the frontal cortex and caudate nucleus, and a decrease in the diameter of interthalamic adhesions (Tapp et al., 2004, 2006; Hasegawa et al., 2005; Su et al., 2005). Imaging also reveals decreased cerebral regional blood volume in the brains of cognitively impaired dogs, and microhemorrhage and infarcts may contribute to the signs of CDS in dogs and cats. Although changes are not as notable as those seen in dogs, aged cats likewise demonstrate cerebral atrophy, ventricular enlargement, and a widening of sulci (Gunn-Moore et al., 2007; Landsberg et al., 2010; Chambers et al., 2015) (Fig. 15.2).

Microscopically, CDS in dogs is characterized by meningeal calcification, and an overall reduction in neuronal density (Borras et al., 1999; Colle et al., 2000; Tapp et al., 2004; Rofina et al., 2006). As in humans with Alzheimer’s disease, cognitively impaired dogs have significantly decreased numbers of noradrenergic neurons in the locus coeruleus (Insua et al., 2010). The dentate gyrus of aged dogs showed significantly fewer neurons, and decreased numbers of Purkinje cells in the cerebellum were associated with cognitive impairment (Pugliese et al., 2007; Siwak-Tapp et al., 2008). The progression of atrophy is regional, with prefrontal cortical volume decreasing prior to hippocampal volume (Tapp et al., 2004).

Aged cats also display multiple brain changes consistent with neuronal loss. The molecular layer of the cerebellum in 12- to 13-year-old animals shows neuronal loss relative to that of 2- to 3-year-old cats. Decreased neurofilament immunolabeling in older cats also suggests loss of Purkinje cells in the cerebellum (Zhang et al., 2006). Ultrastructural and electrophysiologic experiments in aged cats suggest loss of dendrites in the caudate nucleus, loss of function which may be associated with impaired motor function, and/or habituation to repeated stimuli (Villablanca et al., 1978; Levine et al., 1986, 1987, 1988; Levine, 1988). Hippocampal neuron loss is seen in cats over 14 years (Chambers et al., 2015).

Analogous to changes seen in human Alzheimer’s patients, the brains of aged dogs and cats display accumulations of diffuse beta amyloid plaques, as well as perivascular infiltrates (Cummings et al., 1996b; Colle et al., 2000; Tapp et al., 2004; Rofina et al., 2006; Gunn-Moore et al., 2007) (Fig. 15.3). Multiple associations have been found between the amount and location of plaque deposition and the severity of cognitive deficits in dogs (Cummings et al., 1996a,b; Colle et al., 2000; Rofina et al., 2006). Reversal learning deficits indicative of executive dysfunction are associated with amyloid deposits in the prefrontal cortex, and poor size discrimination with deposits in the prefrontal cortex (Cummings et al., 1996a,b; Tapp et al., 2004). Increased soluble Aβ levels in the cerebrospinal fluid (CSF) co-occur with decreased cognitive performance even prior to amyloid deposition (Head et al., 2010; Borghys et al., 2017).

Although the brains of aged cats also show evidence of Aβ plaques, these are more diffuse than those seen in dogs. Prevalence is increased in cats over 10 years of age, which may correlate with increasing cognitive decline (Cummings et al., 1996b; Nakamura et al., 1996; Brellou et al., 2005; Head et al., 2005; Gunn-Moore et al., 2007; Chambers et al., 2015). Tau hyperphosphorylation occurs in both dogs and cats, and has been associated with cognitive decline in dogs (Head et al., 2005; Gunn-Moore et al., 2007; Chambers et al., 2015; Smolek et al., 2016). Like humans with Alzheimer’s disease, the hyperphosphorylated tau of cats forms neurofibrillary tangles (Hyman and Trojanowski, 1997; Head et al., 2005; Markesbery, 2010) (Fig. 15.4).

Even at a metabolic level, differences exist between the aging brain and brains of cognitively normal younger animals. Impaired cerebral glucose metabolism results in dogs with severe cognitive dysfunction showing increased CSF levels of pyruvate, lactate, and potassium (Pugliese et al., 2005; Borghys et al., 2017). One potential source of neurodegeneration in aged dogs is an increase in oxidative stress and reduced antioxidant capacity. These are linked to cognitive deficits, and may be due to age-related mitochondrial dysfunction (Kiatipattanasakul et al., 1997; Papaioannou et al., 2001; Head et al., 2002, 2009; Skoumalova et al., 2003; Rofina et al., 2004, 2006; Hwang et al., 2008; Opii et al., 2008). Muscarinic receptor numbers are reduced in multiple brain regions in aged dogs (Reinikainen et al., 1987, 1990; Araujo et al., 2011b). Impaired cholinergic function may contribute to decreased cognitive and motor function, as well as sleep–wake disturbances (Zhang et al., 2005; Pugliese et al., 2007; Araujo et al., 2011b).

15.2.2 Diagnosis

Definitive diagnosis of cognitive dysfunction can occur only postmortem, with confirmation of representative microscopic changes in the brain. Imaging can suggest disease premortem. Brain atrophy on MRI is compatible with, although not diagnostic for, CDS (Ettinger and Feldman, 2009). Standardized tests for evaluating cognitive function provide an invaluable research tool and questionnaires can be used in clinical practice to identify affected animals. In all cases, the ruling out of differential diagnoses (both intracranial and extracranial) that mimic the signs of cognitive dysfunction is paramount. In a recent study in which dogs were excluded due to possible medical causes for altered behavior, 15 of 100 dogs were excluded due to baseline laboratory findings alone (Pan et al., 2017).

There is an extensive list of medical rule outs for each category comprising the aforementioned DISHAA group of signs (see Table 15.2). For instance, both acute and chronic pain have been associated with increased irritability, withdrawal, altered activity levels, decreased playfulness, and aggression (Camps et al., 2012). Hyperthyroid cats may display sleep–wake disturbances, increased vocalization, aggression (particularly related to food), and repetitive behaviors (Neilson, 2004). Other rule outs may include sensory decline and diseases of the cardiovascular, endocrine, gastrointestinal, or urinary systems. Diseases of the central and peripheral nervous systems may also directly alter mentation and responsiveness.

Ruling out each differential may require diagnostics beyond basic physical examination and history (see Table 15.3). For instance, any dog or cat with polyuria, polydipsia, periuria, dysuria, or house soiling with inappropriate urination is a candidate for a complete urinalysis with urine cytology, urine protein:creatinine ratio, and urine culture. MRI should be considered prior to establishing a presumptive diagnosis of CDS, and CSF analysis may also be appropriate. Elevated cell count or protein level suggests an inflammatory process, and cytology may identify infectious agents, viral inclusions, or neoplastic cells (Nelson and Couto, 2014) (Fig. 15.5).

Table 15.3. Medical conditions to rule out.

Condition	Common causes	Testing suggested
Hypoglycemia	Insulinoma (dogs), neoplasia, Addison	Repeated fasting blood glucose, fructosamine
Hyperglycemia	Diabetes mellitus, hyperadrenocorticism	Blood glucose
Hepatic encephalopathy	Congenital portosystemic shunt, chronic hepatopathies and acquired portosystemic shunt	Fasting blood ammonia, dynamic bile acid stimulation test
Hyperthyroidism	Thyroid adenoma (cats)	Total T4
Uremic encephalopathy	Renal insufficiency	Serum urea, creatinine, symmetric dimethylarginine (SDMA) test, urine specific gravity
Hypothyroidism	Lymphoplasmacytic adenitis, idiopathic atrophy (dogs)	Total T4, Thyroid stimulating hormone (TSH)
Hypernatremia	Hyperaldosteronism (cats), adipsia, diabetes insipidus	Serum sodium
Hyponatremia	Hyperadrenocorticism, GI or renal losses, cardiac or hepatic insufficiency	Serum sodium
Hypercalcemia	Paraneoplastic, osteolytic lesions, hyperparathyroidism, renal insufficiency	Ionized calcium
Hypocalcemia	Hypoparathyroidism, nutritional secondary hyperparathyroidism, renal insufficiency	Ionized calcium

Adapted by permission from Springer Nature: Springer; Canine and Feline Dementia: Molecular Basis, Diagnostics and Therapy by Gary Landsberg, Aladár Mad’ari, Norbert Žilka (eds.); © 2017.

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