Ebook Mental health and well being in animals (2/E): Part 2

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Part 2 book "Mental health and well being in animals" includes contents: Cognitive and emotional disorders in the aging pet; mental health issues in farm animals - a music mixing board model of behavioral characteristics using the panksepp emotional system; mental health issues in the horse; mental health issues in shelter animals; the mental health of laboratory animals; mental health issues in captive birds; psychological well being in zoo animals,... and other contents.

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15 Cognitive and Emotional Disorders VetBooks.ir in the Aging Pet Jacqueline Wilhelmy and Gary Landsberg Delaware Valley Veterinary Behavior, Philadelphia, Pennsylvania, USA; Fear Free Research, CanCog Technologies, Fergus, Ontario, Canada Cognitive decline is a well-recognized group of et al., 2013; Madari et al., 2015). Basic functions disorders in domestic dogs. The problem is less such as self-hygiene, eating or drinking behavior, and common, but of increasing interest, in pet cats. It response to stimuli can be compromised or altered has been estimated that 45 million dogs around (Rofina et al., 2006). In the laboratory (Fig. 15.1), 7 years and older live in the US and Europe; however, validated neuropsychological tests reveal quantifia- this estimate does not include cats. Pet owners and ble impairment in the learning and memory of veterinarians may be tempted to dismiss changes in affected animals (Milgram et al., 2004; Tapp et al., cognition as a normal part of aging in dogs and 2004; Araujo et al., 2012; Pan et al., 2010, 2013). cats. Pet owners may even fail to recognize clinical Outside of the laboratory, CDS is a diagnosis of signs of what is a treatable disease, and the onus exclusion. Once suspicion is raised by signalment and lies on health professionals to proactively inquire clinical signs, it is the veterinarian’s job to rule out a about the behavior of aged patients. Extensive number of other physical ailments (not uncommon in research has shown that underlying changes in the an aged population) that mimic the same clinical brain (some of which are similar to those seen in signs. This job is complicated by the anxiety, fear, and the brains of aged humans with dementia) can aggression that can also occur or worsen in pets suf- manifest in a list of identifiable clinical signs. Even fering from CDS. This chapter will explore the clinical more importantly, it has been shown that treat- picture of CDS in dogs and cats, its identification or ments exist which can slow the progression of dis- diagnosis, and available treatment options. ease. This can improve quality of life for both pets and owners alike, as well as rescue the human–ani- mal bond from the damage it can otherwise incur. 15.1 The Clinical Picture Cognitive dysfunction syndrome (CDS) is a pro- 15.1.1 Characteristics of cognitive gressive neurodegenerative disease of aging dogs dysfunction syndrome and cats. Although clinical signs are most com- monly reported in pets over 11 years of age, they The most common signs of CDS in dogs were can appear in animals as young as 6 years (Araujo found to include increased daytime sleep and night- et al., 2005b; Studzinski et al., 2006; Salvin et al., time restlessness (57%), altered social interactions 2010). The disease manifests in the form of behav- (51%), disorientation (49%), and anxiety (46%). ioral changes, impaired learning and memory, In mild cases, this study found increased daytime altered awareness, and confusion. Clinical signs can sleep was the most prevalent sign, affecting 70% of be categorized as deficits in one of six areas, repre- dogs (Fast et al., 2013). Another found owners sented by the acronym DISHAA: disorientation, were unlikely to report mild signs of cognitive dys- altered social interactions, sleep–wake disturbances, function unless specifically asked, but that altered loss of housetraining and other learned behaviors, social interactions were most common. Moderately increased or decreased activity levels, and increased affected dogs were most likely to exhibit sleep– anxiety or fear (Osella et al., 2007; Rème et al., wake disturbances and altered social interactions, 2008; Azkona et al., 2009; Rosado et al., 2012; Fast with 67% of dogs displaying both signs; in the 212 © CAB International 2020. Mental Health and Well-being in Animals, 2nd Edition (ed. F. McMillan)
(a) (b) VetBooks.ir (c) (d) Fig. 15.1. (a) Sample phase of the DNMP task. The dog is required to displace a single block in one of the three positions to obtain a food reward. (b) Choice phase of the DNMP task. Following sample presentation and a predetermined delay, the dog must select the block in the new (nonmatch) position to obtain a food reward. (c) Simple discrimination learning and reversal task. During learning, the dog is required to continually select one of the two objects until learning criteria are reached. Subsequently, the reward contingency is reversed during reversal learning discrimination. (d) Selective attention task. The animal is required to select a single object and not a distractor; however, the number of distractors (i.e., negative stimuli) can vary from 0 to 3 during each trial. (Reprinted 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.) most severely affected dogs, 67% displayed all four sensory decline or decreased mobility), cognitively signs (Madari et al., 2015). In cats, affected animals impaired dogs or cats can fail to read the social aged 11–14 years were most likely to show altered signals of other pets or be perceived as alarming by social interactions, while cats over 15 years of age these housemates due to their atypical behavior. most commonly displayed aimless activity and vocalization (Gunn-Moore et al., 2007; Landsberg 15.1.2 Prevalence et al., 2010, 2011). Freedom from fear and distress is crucial for all The reported prevalence of canine CDS in animals animals, and safety can be compromised when an over 8 years of age ranges from 14% to over 60% animal signals for increased distance using aggres- (Neilson et al., 2001; Osella et al., 2007; Azkona et al., sion. One study found intermittent manifestations 2009; Salvin et al., 2010; Madari et al., 2015). Twenty- of anxiety to be reported in 61% of dogs with CDS eight percent of dogs aged 11–12 years were reported (Rème et al., 2008). Salivary cortisol levels were by owners to show impairments in at least two catego- higher in aged dogs during the Strange Situation ries of DISHAA, and 10% to show impairments in at Test (Mongillo et al., 2013). Clinically, there is a least one category. In older dogs, aged 15–16 years, concern because pets with CDS may experience 68% were affected in at least one category, and 36% in increased agitation or aggression (Fast et al., 2013), two or more (Neilson et al., 2001). Another study but also because these pets may be the target of found a prevalence of 5% in dogs aged 10–12 years, aggression by other household pets. Due to 23% in dogs aged 12–14 years, and 41% in dogs over decreased awareness (particularly if coupled with 14 years of age (Salvin et al., 2010). Moderate to Cognitive and Emotional Disorders in the Aging Pet 213
marked cognitive dysfunction was reported to occur problems, 32% displayed aggression to family in 13–16% of dogs aged 8–11 years, and 87–100% members, 16% aggression to family dogs, 9% bark- VetBooks.ir of dogs older than 13 years (Katina et al., 2016). ing, 8% separation anxiety, 6% disorientation and When 85 of 300 dogs over 8 years of age were aggression toward unfamiliar people, 5% house excluded due to medical problems, 159 of the remain- soiling, 4% destructive and compulsive disorders, ing 215 dogs displayed signs of cognitive dysfunction and 3% noise fears (Mariotti et al., 2009). Yet in a (Madari et al., 2015). Thirty-five percent of cats over study of 479 dogs over the age of 8, 14.2% were 11 years of age were diagnosed with CDS, with 28% diagnosed with CDS despite only 13% of these hav- of cats 11–15 years and 50% of cats over 15 years ing been previously diagnosed (Salvin et al., 2010). affected (Gunn-Moore et al., 2007). Biannual hospital visits with questionnaire screen- Interestingly, owners’ focus does not reflect the ing for clinical signs of CDS are recommended in above when it comes to seeking veterinary assis- pets over age 8 years to provide the earliest possible tance for behavioral concerns. In a group of 270 diagnosis (Landsberg et al., 2010; Salvin et al., dogs over 7 years of age presenting for behavior 2011; Katina et al., 2016) (Table 15.1). Table 15.1. Senior canine and feline behavior questionnaire. SENIOR CANINE BEHAVIOR SCREENING QUESTIONNAIRE Date: _____________________ Owner: _____________________________________________ Pet’s Name: _______________________________ Breed: ______________________________ Weight: _______lb / kg BCS (Out of 9) ____ Male ___ Neutered: Y__ N__ Female ___ Spayed: Y__ N__ INSTRUCTIONS: The purpose of the questionnaire is to identify behavior changes or the onset of new behavior problems that have arisen since the age of 8 years using the following key: Scoring key (severity): 0 = none (no change) 1 = mild 2 = moderate 3 = severe BEHAVIORAL SIGNS Score A. Disorientation Gets stuck, difficulty getting around objects, goes to hinge side of door Stares blankly at walls, floor or into space Does not recognize familiar people or pets Gets lost in home or yard Less reactive to visual (sights) or auditory (sounds) stimuli B. Social interactions More irritable / fearful / aggressive with visitors, family or other animals Decreased interest in approaching, greeting or affection / petting C. Sleep–wake cycles Pacing / restless / sleeps less / waking at night Vocalization at night D. House soiling learning and memory Less able to learn new tasks or respond to previously learned commands / name / work Indoor soiling of urine __ or stools __ – decreased signaling to go out Difficulty getting dog’s attention / increased distraction / decreased focus E. Activity Decrease in exploration or play with toys, family members, other pets Increased activity – aimless pacing / wandering Repetitive behaviors e.g. circling ___ chewing ___ licking __ star gazing F. Anxiety Increased anxiety when separated from owners More reactive / fearful to visual (sights) or auditory (sounds) stimuli Increased fear of places / locations e.g. new environments / going outdoors Created by Dr. Gary Landsberg CanCog Technologies with support of Nestle Purina PetCare. Used with permission of Dr. Gary Landsberg and CanCog Technologies. 214 J. Wilhelmy and G. Landsberg
15.1.3 Progression with accelerated brain aging and Alzheimer’s disease in humans include docosahexaenoic acid deficiency, Cognitive dysfunction is a progressive disease, and VetBooks.ir high homocysteine, low B vitamin levels, high blood treatment is aimed at slowing progression. In dogs aged pressure, chronic oxidative stress, and chronic low- at least 11 years, 22% free of clinical signs developed grade inflammation. Dogs fed low-quality commercial signs within 12–18 months, and 48% of dogs with diets or table scraps were significantly more likely to impairment in one category developed impairment develop CDS than dogs fed commercial diets formu- in at least one additional category within this time lated for age, size, or health (Katina et al., 2016). frame (Bain et al., 2001). In dogs at least 8 years of Environment may also play a role in the develop- age, 42% developed clinical signs and 24% progressed ment of neurodegenerative disease. Wild dogs from from mild to moderate impairment over a 6-month areas with high air pollution exhibited early occur- period. Over 1 year, 71.4% of this population devel- rence of β-amyloid plaques and elevation of proin- oped mild impairment, and 50% progressed in classifi- flammatory markers. The former changes preceded cation from moderate to severe clinical signs (Madari by several years similar changes in the brains of et al., 2015). A third study found that 58% of dogs aged dogs living in an environment with low air pollu- at least 8 years developed borderline CDS over the tion (Calderon-Garciduenas et al., 2008). In 56% course of approximately 3 years, and 11% converted of children and 57% of dogs living in an urban from borderline to CDS status (Fast et al., 2013). area with excessive air pollution, magnetic reso- nance imaging (MRI) revealed lesions in the pre- frontal subcortical white matter (Migliore and 15.1.4 Risk factors Coppede, 2009). 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 15.2 Evaluation: Identifying correlation coefficient r = 0.662, p < 0.0001) has Welfare Concerns also been found between age and cognitive decline 15.2.1 Pathophysiology in dogs. Although percentages differ between stud- ies (possibly due to the instruments used), the Changes in the brain range from macroscopic to prevalence of CDS increases gradually with age submicroscopic. MRI scans of dogs with CDS (Azkona et al., 2009; Salvin et al., 2010). may reveal ventricular enlargement, frontal and The impact of body size does not appear to be temporal lobe atrophy, an increase in lesions in large, if present at all. Four studies have found no the frontal cortex and caudate nucleus, and a impact of body size on memory or cognitive impair- decrease in the diameter of interthalamic adhe- ment (Neilson et al., 2001; Salvin et al., 2010; Fast sions (Tapp et al., 2004, 2006; Hasegawa et al., et al., 2013; Katina et al., 2016). CDS was found to 2005; Su et al., 2005). Imaging also reveals be similarly prevalent in small and medium/large decreased cerebral regional blood volume in the dogs aged 8–11 years, but more common in larger brains of cognitively impaired dogs, and microhe- breeds aged 11–13 years (55% versus 41%). morrhage and infarcts may contribute to the signs A clear influence of sex or castration status has of CDS in dogs and cats. Although changes are also not been found. Females were suggested as not as notable as those seen in dogs, aged cats more likely to exhibit CDS (Azkona et al., 2009), likewise demonstrate cerebral atrophy, ventricular but several other studies did not find support for enlargement, and a widening of sulci (Gunn- such a difference (Neilson et al., 2001; Yalcin et al., Moore et al., 2007; Landsberg et al., 2010; 2010; Salvin et al., 2011; Fast et al., 2013; Katina Chambers et al., 2015) (Fig. 15.2). et al., 2016). CDS was found by two studies to be Microscopically, CDS in dogs is characterized by more prevalent in castrated individuals (Hart, meningeal calcification, and an overall reduction in 2001; Azkona et al., 2009). However, two more neuronal density (Borras et al., 1999; Colle et al., recent investigations did not identify a difference in 2000; Tapp et al., 2004; Rofina et al., 2006). As in prevalence between castrated and intact older dogs humans with Alzheimer’s disease, cognitively (Fast et al., 2013; Katina et al., 2016). impaired dogs have significantly decreased num- Nutritional support for animals with CDS will be bers of noradrenergic neurons in the locus coer- discussed later in this chapter. Risk factors associated uleus (Insua et al., 2010). The dentate gyrus of aged Cognitive and Emotional Disorders in the Aging Pet 215
1996a,b; Colle et al., 2000; Rofina et al., 2006). Reversal learning deficits indicative of executive VetBooks.ir 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 evi- dence 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., Fig. 15.2. MRI of an aged cat brain showing widening of the sulci (arrow) indicating brain atrophy. (Reprinted 1996b; Nakamura et al., 1996; Brellou et al., 2005; by permission from Springer Nature: Springer; Head et al., 2005; Gunn-Moore et al., 2007; Canine and Feline Dementia: Molecular Basis, Chambers et al., 2015). Tau hyperphosphorylation Diagnostics and Therapy by Gary Landsberg, Aladár occurs in both dogs and cats, and has been associ- Mad’ari, Norbert Žilka [eds.]; © 2017.) ated with cognitive decline in dogs (Head et al., 2005; Gunn-Moore et al., 2007; Chambers et al., dogs showed significantly fewer neurons, and 2015; Smolek et al., 2016). Like humans with decreased numbers of Purkinje cells in the cerebel- Alzheimer’s disease, the hyperphosphorylated tau lum were associated with cognitive impairment of cats forms neurofibrillary tangles (Hyman and (Pugliese et al., 2007; Siwak-Tapp et al., 2008). The Trojanowski, 1997; Head et al., 2005; Markesbery, progression of atrophy is regional, with prefrontal 2010) (Fig. 15.4). cortical volume decreasing prior to hippocampal Even at a metabolic level, differences exist volume (Tapp et al., 2004). between the aging brain and brains of cognitively Aged cats also display multiple brain changes normal younger animals. Impaired cerebral glucose consistent with neuronal loss. The molecular layer metabolism results in dogs with severe cognitive of the cerebellum in 12- to 13-year-old animals dysfunction showing increased CSF levels of pyru- shows neuronal loss relative to that of 2- to 3-year- vate, lactate, and potassium (Pugliese et al., 2005; old cats. Decreased neurofilament immunolabeling Borghys et al., 2017). One potential source of neu- in older cats also suggests loss of Purkinje cells in rodegeneration in aged dogs is an increase in oxida- the cerebellum (Zhang et al., 2006). Ultrastructural tive stress and reduced antioxidant capacity. These and electrophysiologic experiments in aged cats are linked to cognitive deficits, and may be due to age- suggest loss of dendrites in the caudate nucleus, related mitochondrial dysfunction (Kiatipattanasakul loss of function which may be associated with et al., 1997; Papaioannou et al., 2001; Head et al., impaired motor function, and/or habituation to 2002, 2009; Skoumalova et al., 2003; Rofina et al., repeated stimuli (Villablanca et al., 1978; Levine 2004, 2006; Hwang et al., 2008; Opii et al., 2008). et al., 1986, 1987, 1988; Levine, 1988). Hippocampal Muscarinic receptor numbers are reduced in multi- neuron loss is seen in cats over 14 years (Chambers ple brain regions in aged dogs (Reinikainen et al., et al., 2015). 1987, 1990; Araujo et al., 2011b). Impaired cholin- Analogous to changes seen in human Alzheimer’s ergic function may contribute to decreased cogni- patients, the brains of aged dogs and cats display tive and motor function, as well as sleep–wake accumulations of diffuse beta amyloid plaques, as disturbances (Zhang et al., 2005; Pugliese et al., well as perivascular infiltrates (Cummings et al., 2007; Araujo et al., 2011b). 1996b; Colle et al., 2000; Tapp et al., 2004; Rofina et al., 2006; Gunn-Moore et al., 2007) (Fig. 15.3). 15.2.2 Diagnosis Multiple associations have been found between the amount and location of plaque deposition and the Definitive diagnosis of cognitive dysfunction can occur severity of cognitive deficits in dogs (Cummings et al., only postmortem, with confirmation of representative 216 J. Wilhelmy and G. Landsberg
(a) (a) (a) a (b) (b (b VetBooks.ir 0.3 0 3x 0.3x 3.5 3 5x 3.5x 3334 um 333 3334 um 3 286 um 86 um 6 (c) (c) (c) c (d) ) (d) 2.5 2.5x 5 2.5x 10 10x 10x 0x 400 400 um 400 um 0 100 um 100 um 0 Fig. 15.3. Neuropathology in aging dogs. (a) Aβ immunostaining (6E10 antibody) in the parietal cortex of an aged pet dog (15-year-old Siberian husky) shows extensive plaque deposition affecting deep cortical layers. (b) CAA (6E10 immunostaining – arrows) in the parietal cortex of an aged dog (14-year-old sheltie) shows that vascular pathology can be extensive and tends to occur in clusters. Diffuse plaques are also identified by arrowheads. (c) Low-power photograph showing extensive microglial cell labeling (IBA-1 antibody) in gray matter along with intense labeling in the white matter (area below arrows) of a 15-year-old shih tzu. (d) Higher magnification photograph from (c) showing that individual microglia contain phagocytic vacuoles and have thickened processes suggesting that some have an activated morphology. (Reprinted 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.) microscopic changes in the brain. Imaging can sug- clinical practice to identify affected animals. In all gest disease premortem. Brain atrophy on MRI is cases, the ruling out of differential diagnoses (both compatible with, although not diagnostic for, CDS intracranial and extracranial) that mimic the signs (Ettinger and Feldman, 2009). Standardized tests of cognitive dysfunction is paramount. In a recent for evaluating cognitive function provide an invalu- study in which dogs were excluded due to possible able research tool and questionnaires can be used in medical causes for altered behavior, 15 of 100 dogs Cognitive and Emotional Disorders in the Aging Pet 217
(a) AT8 VetBooks.ir (b) AT8 RD4 RD3 Entorhinal cortex Locus coeruleus Fig. 15.4. Hyperphosphorylated tau accumulation in the entorhinal cortex and locus coeruleus of cat brains. (a) Immunohistochemistry of the entorhinal cortex of a cat with mild hyperphosphorylated tau accumulation (15-year-old, case no. 13) (AT8). The neuronal soma and dendrites are positively stained for hyperphosphorylated tau. Bar = 20 μm. (b) Immunohistochemistry of the entorhinal cortex and locus coeruleus of a cat with severe hyperphosphorylated tau accumulation (14-year-old, case no. 12) for AT8, 3-repeat tau (RD3), and 4-repeat tau (RD4). AT8-positive aggregates are also positively stained for 3-repeat tau and 4-repeat tau on consecutive sections. Bar = 300 μm. (Reprinted 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.) were excluded due to baseline laboratory findings DISHAA group of signs (see Table 15.2). For alone (Pan et al., 2017). instance, both acute and chronic pain have been There is an extensive list of medical rule outs for associated with increased irritability, withdrawal, each category comprising the aforementioned altered activity levels, decreased playfulness, and 218 J. Wilhelmy and G. Landsberg
Table 15.2. Medical differentials of cognitive dysfunction in dogs and cats. VetBooks.ir System Possible causes Possible behavioral signs Sensory Cataracts/lenticular sclerosis Fear/anxiety Loss of vision Disorientation Loss of hearing Decreased response to stimuli Reduced learning ability Aggression Avoidance Vocalization Pain/musculoskeletal Degenerative diseases Avoidance Arthritis Reduced interest in exercise or play Muscular dystrophy Altered response to stimuli Aggression Reduced self-hygiene Increased vocalization Cardiovascular Mitral insufficiency Disorientation Hypertension Tiredness or reduced interest in play and activity Cardiomyopathy Withdrawal/avoidance Irritability Fear/anxiety Changes in appetite Vocalization Endocrine Diabetes mellitus All signs of cognitive dysfunction Insulinoma House soiling/urine marking Diabetes insipidus Appetite – increased/decreased Hypothyroidism Activity – increased/decreased/apathy Hyperthyroidism Irritability Hyperadrenocorticism Aggression Hypoadrenocorticism Changes in sleep–wake cycle Stereotypic behavior, e.g., licking Restlessness, e.g., pacing Vocalization Digestive Dental diseases Reduced appetite Hepatic diseases Aggression/irritability Infectious/inflammatory Avoidance/withdrawal Constipation Nighttime waking House soiling Stereotypic behavior, e.g., pacing, licking Nutritional imbalances Coprophagia Pain Urinary Renal diseases House soiling/marking Urinary tract infection Aggression Idiopathic cystitis Withdrawal/avoidance Urolithiasis Pacing Urinary incontinence Sleep–wake changes 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. aggression (Camps et al., 2012). Hyperthyroid cats and peripheral nervous systems may also directly may display sleep–wake disturbances, increased alter mentation and responsiveness. vocalization, aggression (particularly related to Ruling out each differential may require diagnos- food), and repetitive behaviors (Neilson, 2004). tics beyond basic physical examination and history Other rule outs may include sensory decline and (see Table 15.3). For instance, any dog or cat with diseases of the cardiovascular, endocrine, gastroin- polyuria, polydipsia, periuria, dysuria, or house testinal, or urinary systems. Diseases of the central soiling with inappropriate urination is a candidate Cognitive and Emotional Disorders in the Aging Pet 219
Table 15.3. Medical conditions to rule out. VetBooks.ir 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 Fasting blood ammonia, dynamic bile acid hepatopathies and acquired stimulation test portosystemic shunt Hyperthyroidism Thyroid adenoma (cats) Total T4 Uremic encephalopathy Renal insufficiency Serum urea, creatinine, symmetric dimethylarginine (SDMA) test, urine specific gravity Hypothyroidism Lymphoplasmacytic adenitis, idiopathic Total T4, Thyroid stimulating hormone (TSH) atrophy (dogs) Hypernatremia Hyperaldosteronism (cats), adipsia, Serum sodium diabetes insipidus Hyponatremia Hyperadrenocorticism, GI or renal losses, Serum sodium cardiac or hepatic insufficiency Hypercalcemia Paraneoplastic, osteolytic lesions, Ionized calcium hyperparathyroidism, renal insufficiency Hypocalcemia Hypoparathyroidism, nutritional secondary Ionized calcium hyperparathyroidism, renal insufficiency 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. for a complete urinalysis with urine cytology, urine relapse or onset of separation-related problems. protein:creatinine ratio, and urine culture. MRI Noise fear can occur later in life, and continue to should be considered prior to establishing a pre- worsen over time until it becomes a concern to sumptive diagnosis of CDS, and CSF analysis may the owner. also be appropriate. Elevated cell count or protein Anxiety is the feeling of unease or apprehen- level suggests an inflammatory process, and cytology sion that an undesirable or unsafe situation may may identify infectious agents, viral inclusions, or occur. It can lead both to increased and decreased neoplastic cells (Nelson and Couto, 2014) (Fig. 15.5). activity levels, as well as altered interactions with owners (either due to change in activity level, or to attention-seeking behaviors). Fear and anxiety 15.2.3 Comorbidity with affective disorders may also contribute to aggression toward both Of great concern from a welfare perspective is the humans and other pets. Cats may inappropri- comorbidity between CDS and a number of affec- ately eliminate or urine mark as a result of anxi- tive disorders related to abnormal levels of fear or ety, and both dogs and cats can lose sphincter anxiety. This directly impacts one of the Five control as a result of spiking fear or anxiety Freedoms, namely freedom from fear and distress. (Landsberg et al., 2012). Other causes of fear and anxiety are also behavio- Chronically anxious pets may exhibit impaired ral rule outs for CDS. Although most behavior memory, learning ability, or ability to perform pre- problems manifest in younger animals, a change in viously learned behaviors (Landsberg and Araujo, environment, schedule, or medical status may increase 2005). Hypervigilant animals may show altered baseline level of stress or anxiety. Aggression may sleep–wake cycles (Ohl et al., 2008), which is a manifest toward a trigger, such as a child or common presenting complaint in cases of CDS another pet, that was only recently introduced to (Landsberg et al., 2011, 2013). Repetitive pacing as the family. In other cases, the geriatric dog or cat a displacement behavior caused by anxiety may itself is newly introduced to the household, and occur throughout the day but be most noticeable to may have an unknown history. Changes in schedule owners in the evening or at night (Landsberg and or a move to a new environment may cause a Denenberg, 2009; Landsberg et al., 2011). 220 J. Wilhelmy and G. Landsberg
Complaint and history compatible with CDS VetBooks.ir Physical, orthopedic and ophthalmological examinations Normal Abnormal Neurological examination Normal Abnormal H&B, BP, BGx2, Pursue relevant BAST, NH3 findings Normal Abnormal Additional tests Advanced imaging Alternative Normal Abnormal diagnosis CSF Brain atrophy only Treatment Treatment success Normal Abnormal Rule out Diagnosis does not neurodegenerative explain clinical diseases signs on its own or failure of treatment Presumptive diagnosis of CDS H&B, hematology and biochemistry; BP, blood pressure; BGx2, blood glucose X 2; BAST’ bile acid , stimulation test; NH3, ammonia; CSF, cerebrospinal fluid; CDS, cognitive dysfunction syndrome Fig. 15.5. Algorithm for the diagnosis of canine dysfunction syndrome. (Reprinted by permission from Springer Nature: Springer; Canine and Feline Dementia: Molecular Basis, Diagnostics and Therapy by Gary Landsberg, Aladár Maďari, Norbert Žilka [eds.]; © 2017.) A learned component may also exist for some vocalization. Cats and more rarely dogs exhibiting behavior problems. Although not always the incit- inappropriate elimination may develop a learned ing cause, attention or food given by the owner substrate or location preference, due to the self- may reinforce some behaviors, such as excessive reinforcing nature of voiding bladder or bowels Cognitive and Emotional Disorders in the Aging Pet 221
(Pryor et al., 2001). Although punishment may or litter boxes should be available in this location. reduce a behavior’s frequency, it can increase anxi- Additional enrichment can take the form of VetBooks.ir ety and fear, and does not address animal’s underly- operantly conditioned behaviors (ranging from ing motivation (Landsberg et al., 2011). simple tricks to sports such as nose work), play, Finally, even geriatric pets require the freedom to time on walks spent exploring novel environments, express normal behavior. Owners may believe that and food toys or puzzles. Although novelty can be senior pets do not need stimulation, do not respond a source of enrichment, moderation is suggested. to training, or need to be left alone to rest due to Aged dogs and cats, perhaps especially those with physical disease. Although exercise and lifestyle cognitive or sensory deficits, may be less anxious if adjustments may be necessary, enrichment is still their routine and environment is kept structured beneficial and even needed for older pets. Repetitive, and predictable. destructive, or attention-seeking behaviors may stem from lack of stimulation or boredom. 15.3.2 Nutraceuticals Enrichment and the opportunity to practice species- specific behaviors should be provided to pets of A number of supplements have been demonstrated all ages. to benefit patients with cognitive dysfunction. Senilife® (Ceva Animal Health) contains phosphati- dylserine, a cell membrane component postulated to 15.3 Treatment: Addressing Welfare aid in neuronal signal transduction and cholinergic Concerns transmission (Tsakiris and Deconstantinos, 1985; Osella et al., 2007). It additionally contains vitamin 15.3.1 Enrichment B6 (pyridoxine), which may exert a neuroprotective When used in combination with medical and nutri- effect (Dakshinamurti et al., 2003). This supplement tional therapies (discussed below), physical exercise is approved in both dogs and cats, and has been and mental enrichment have been shown to slow shown to improve cognition both in clinical studies the progression of cognitive impairment (Milgram and a laboratory model in dogs (Osella et al., 2007; et al., 2004; Head, 2007; Head et al., 2009). Aged Araujo et al., 2008). dogs trained to run on a treadmill for 10 minutes Aktivait® (VetPlus Ltd.), another supplement con- daily showed acutely improved performance on taining phosphatidylserine, has been shown to sig- both a concurrent discrimination task and a novel nificantly improve social interactions, disorientation, object location task (Snigdha et al., 2014). When and house soiling in dogs with CDS (Heath et al., this exercise regimen was continued, dogs showed 2007). Cholodin®-Fel (MVP Labs) is a supplement improved performance on an object location mem- for senior cats that contains phosphatidylserine and ory task. In humans, exercise is known to benefit pyridoxine. In a preliminary study, 9 of 21 aged cats brain function, and has been shown to delay the treated with this supplement showed lessened confu- onset of cognitive decline associated with sion and improved appetite (Messonier, 2001). Alzheimer’s disease. This may be due to increased Novifit® (Virbac Animal Health) contains growth of neurons and blood vessels, as well as S-adenosylmethionine, which may help maintain cell improvement in this organ’s ability to cope with membrane fluidity and receptor function, regulate oxidative stress (Radak et al., 2007). Enrichment in neurotransmitter levels, and decrease oxidative stress aged dogs protected against neuronal loss in the (Rème et al., 2008; Araujo et al., 2012). A placebo- hippocampus (Siwak-Tapp et al., 2008). controlled trial found clinical improvement in cogni- As previously discussed, such exercise and tively impaired dogs (Rème et al., 2008), and aged enrichment must allow for limits of age and disease beagle dogs showed a trend toward improved rever- in some older patients. However, both dogs and cats sal learning. Aged cats with milder clinical signs also should have the opportunity to perform species- showed fewer reversal learning errors consistent with specific behaviors, such as scratching, perching, improved executive function (Araujo et al., 2012). and hunting behaviors in cats and chewing in dogs. Neutricks™ (Neutricks LLC) contains apoaequorin, Senior pets in particular should be provided with a calcium-buffering protein found in jellyfish that the opportunity to retreat to a quiet location pro- may be neuroprotective. In one laboratory trial, tected from the chaos of children, visitors, and apoaequorin-treated dogs demonstrated improved other pets. Desired resources such as resting spots performance relative to controls on discrimination 222 J. Wilhelmy and G. Landsberg
learning and attention tasks, although not a spatial Purina ProPlan Bright Mind or Optiage (Nestle memory task. In another study, apoaequorin was Purina Research) is a diet supplemented with VetBooks.ir found to be superior to selegiline in the treatment of medium-chain triglycerides (MCT). Dogs at even 6 cognitive dysfunction in dogs (Milgram et al., 2015). years of age show significantly reduced cerebral Although this product is available for cats, no glucose metabolism compared with dogs at 1 year evidence-based studies are available. of age, and MCTs provide ketone bodies as an alter- native energy source for aging neurons (London et al., 1983). Compared with controls, dogs fed a 15.3.3 Prescription diets diet supplemented with 5.5% MCT over 8 months The goal of nutritional therapies for cognitive showed significantly better performance in land- decline is to reduce oxidative stress, correct meta- mark one and landmark two discriminations, an bolic changes associated with impaired cognition, egocentric learning and egocentric reversal task, and improve mitochondrial function and neuronal and a variable oddity task (Pan et al., 2010; Pan, signaling (Head et al., 2002, 2009; Milgram et al., 2011). Treated dogs demonstrated elevated levels of 2004; Araujo et al., 2005b; Kidd, 2005; Sullivan and the ketone body β-hydroxybutyrate (Sullivan and Brown, 2005; Scarmeas et al., 2006; Gunn-Moore Brown, 2005; Taha et al., 2009). A double-blinded et al., 2007; Head, 2007; Siwak-Tapp et al., 2008; placebo-controlled clinical trial of ProPlan Veterinary Joseph et al., 2009; Landsberg et al., 2010; Pan et al., Diets Neurocare in dogs with CDS found significant 2010, 2013, 2017; Pop et al., 2010; Pan, 2011; improvement in all categories of DISHAA signs over Dowling and Head, 2012; Fahnestock et al., 2012). a 3-month period. This diet is supplemented with As previously mentioned, dogs fed commercial diets 6.5% MCT and a brain protection blend containing specific to size, breed, age, or health status carried a B vitamins and antioxidants, among other compo- lower risk for CDS than dogs fed low-quality com- nents (Pan et al., 2017). mercial diets or leftovers (Katina et al., 2016). More specific diet-related brain effects were observed in 15.3.4 Prescription pharmacotherapy other studies. For example, aging dogs fed diets rich (Table 15.4) in antioxidants showed improved mitochondrial function (Head et al., 2009) and improved cogni- In North America, selegiline hydrochloride tion, as well as reduced oxidative damage and Aβ (Anipryl®, Zoetis Animal Health) is the only phar- pathology (Dowling and Head, 2012). maceutical that is approved for use in dogs suffering Multiple diets specifically formulated for dogs from CDS. Selegiline is a selective irreversible and cats with cognitive dysfunction have been stud- inhibitor of monoamine oxidase B (MAOB), ied. Prescription Diet b/d Canine (Hill’s Pet although its mechanism of action in dogs is not Nutrition) is supplemented with fatty acids, anti- entirely clear. Concurrent use with other MAO oxidants (vitamins C and E, beta-carotene, sele- inhibitors or serotonergic drugs is contraindicated. nium, flavonoids, carotenoids), and dl-alpha-lipoic Administration results in a number of effects in the acid and l-carnitine. A 3-year longitudinal study of central nervous system: enhanced dopaminergic and 48 beagle dogs aged 8 to 12 years found improve- catecholaminergic function in the cortex and hip- ment in a landmark task within 2 weeks, subse- pocampus, increased release and reduced reuptake quent improvement in oddity discrimination, and of norepinephrine, increased free radical scavenging maintenance of reversal learning. The greatest bene- enzymes, and neuroprotective effects. Its metabo- fit occurred in dogs receiving both the diet and lites l-amphetamine and l-methamphetamine can added behavioral enrichment (Milgram et al., 2004; enhance cognitive function and improve behavior Araujo et al., 2005b; Head, 2007; Head et al., (Milgram et al., 1993, 1995; Ruehl et al., 1996). 2009; Dowling and Head, 2012; Fahnestock et al., When given in laboratory dogs at a dose of 0.5–1 2012). These dogs showed decreased oxidative dam- mg/kg in the morning, selegiline resulted in reduced age, as well as increased brain-derived neurotrophic clinical signs of CDS and improved working memory. factor and neuronal health (Milgram et al., 2004; Although improvement was seen at 2 weeks in some Head, 2007; Head et al., 2009; Pop et al., 2010; dogs, others took up to 2 months to respond (Ruehl Dowling and Head, 2012; Fahnestock et al., 2012). et al., 1995; Head et al., 1996; Campbell et al., 2001). Young dogs fed the diet showed no cognitive Although selegiline’s use in cats is extra-label, improve- changes (Scarmeas et al., 2006). ment in disorientation, vocalization, and decreased Cognitive and Emotional Disorders in the Aging Pet 223
Table 15.4. Drug doses for adjunctive therapy of clinical signs VetBooks.ir Drug Dog dose Cat dose Lorazepam 0.025–0.1 mg/kg sid to prn 0.125–0.25 mg/cat sid–bid Oxazepam 0.2–1.0 mg/kg sid–bid 0.2–0.5 mg/kg sid–bid Fluoxetine 1.0–2.0 mg/kg sid 0.5–1.5 mg/kg sid Sertraline 1–5 mg/kg sid or divided bid 0.5–1.5 mg/kg sid Clonidine 0.01–0.05 mg/kg bid or prn 5–10 μg/kg bid–tid Dexmedetomidine oromucosal gel 125 μg/m2 Propranolol 0.5–2.0 mg/kg bid or prn Buspirone 0.5–2.0 mg/kg bid–tid 0.5–1 mg/kg bid Trazodone 2–5 mg/kg (to 12 mg/kg) prn to tid 25–50 mg/cat sid–bid Gabapentin 10–30 mg/kg bid–tid 5–20 mg/kg sid–tid Selegiline 0.5–1 mg/kg sid in am 0.5–1 mg/kg sid in am sid, once daily; bid, twice daily; tid, three times daily; prn, when needed; am, morning. 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. affection have been reported in cats at a dose of 0.5–1 15.3.5 Symptom-based anxiolysis mg/kg in the morning (Landsberg, 2006; Gunn- Moore et al., 2007; Landsberg et al., 2010; Overall, As previously discussed, dogs and cats suffering 2010). A small study found no evidence of toxicity at from cognitive dysfunction may experience an a dose of up to 10 mg/kg (Ruehl et al., 1996). increase in anxiety. This can result in sleep–wake In some countries in Europe and in Australia, disturbances, cause or exacerbate agitation or propentofylline (Vivitonin®, Karsivan Vet®, MSD aggression, and generally compromise the welfare of Animal Health) is also licensed at a dose of 5 mg/kg both patient and owner. Therefore, symptomatic twice daily for use in dogs showing mental dullness, treatment for night waking and anxiety is often pro- lethargy, and tiredness in the absence of any other ductive. Clomipramine, amitriptyline, and paroxe- identifiable cause. Propentofylline is a xanthine tine should be avoided, as anticholinergic drugs are derivative that may increase oxygenation in the contraindicated. Fluoxetine, sertraline, or buspirone brain and periphery, by means of improving micro- can be considered (Araujo et al., 2005a, 2011a,b; circulation and inhibiting thrombus formation Zhang et al., 2005; Pugliese et al., 2007). Trazodone (Parkinson et al., 1994). However, aged beagle dogs can also be considered, either alone or in combina- treated with propentofylline in a laboratory trial tion with an SSRI or buspirone. Serotonergic drugs showed no change in behavioral activity (Siwak should not be used concurrently with selegiline. et al., 2000). There are anecdotal reports of efficacy Benzodiazepines do carry the risk of exacerbat- at a dose of 12.5 mg per cat twice daily (Gunn-Moore ing cognitive deficits, as well as causing sedation or et al., 2007; Landsberg et al., 2010; Overall 2010). ataxia. However, they can provide anxiolysis, and Also licensed for use in some European coun- importantly mitigate nighttime waking. Lacking tries, nicergoline is an alpha 1 and 2 adrenergic active intermediate metabolites, lorazepam or agonist recommended for use at a dose of 0.5 mg/ oxazepam might be preferred. Adjunctive use of kg once daily. Nicergoline may enhance cerebral propranolol, clonidine, or oromucosal dexmedeto- circulation and neuronal transmission, as well as midine may inhibit release or block the effects of exerting a neuroprotective effect (Penaliggon et al., noradrenaline, exerting anxiolytic effects. 1997; Siwak et al., 2000). Anticholinergic drugs Gabapentin may reduce reactivity, as well as pro- may accelerate cognitive decline, and avoidance in vide analgesia in a painful senior pet (Landsberg aged pets is suggested (Araujo et al., 2005a, et al., 2011). Although not directly beneficial in 2011a,b; Cai et al., 2013; Gray et al., 2015; Cross slowing the progression of CDS in the manner of et al., 2016). Drugs that enhance cholinergic trans- those listed above, other natural products can be mission, such as donepezil and phenserine, might used to directly treat anxiety: pheromones (Adaptil, theoretically improve clinical signs in CDS patients Feliway), l-theanine, alpha-casozepine, l-trypto- (Araujo et al., 2005a). phan, or Phellodendron and Magnolia extracts. 224 J. Wilhelmy and G. Landsberg
15.4 Concluding Remarks Araujo, J.A., Faubert, M.L., Brooks, M.L., Landsberg, G.M., Lobprise, H. (2012) NOVIFIT® (NoviSAMe®) Almost every veterinarian has likely heard a client VetBooks.ir Tablets improve executive function in aged dogs and relate, ‘Well, my dog or cat’s behavior has changed, cats: Implications for treatment of cognitive dysfunc- but I think he or she is just getting old.’ Although age tion syndrome. International Journal of Applied is not a disease, diseases associated with aging can Research in Veterinary Medicine 10, 90–98. affect the central nervous system as well as other Azkona, G., Garcia-Belenguer, S., Chacón, G., Rosado, systems of the body. Behavior change can be a mani- B., León, M., et al. (2009) Prevalence and risk factors festation of disease both centrally and peripherally, of behavioural changes associated with age-related cognitive impairment in geriatric dogs. Journal of and it is the job of the veterinarian to tease out Small Animal Practice 50, 87–91. http://dx.doi. contributing causes. A majority of dogs and cats org/10.1111/j.1748-5827.2008.00718.x. reaching a certain age will experience changes in Bain, M.J., Hart, B.L., Cliff, K.D., Ruehl, W.W. (2001) behavior: disorientation, altered social interactions, Predicting behavioral changes associated with age- sleep–wake disturbances, loss of housetraining and related cognitive impairment in dogs. Journal of the other learned behaviors, increased or decreased American Veterinary Medical Association 218, activity levels, and increased anxiety or fear. These 1792–1795. http://dx.doi.org/10.2460/javma.2001. changes can be associated with accumulations of 218.1792. diffuse beta amyloid plaques, as well as distinctive Borghys, H., Van Broeck, B., Dhuyvetter, D., Jacobs, T., macro- and microscopic degeneration, within the de Waepenaert, K., et al. 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16 Mental Health Issues in Farm VetBooks.ir Animals: A Music Mixing Board Model of Behavioral Characteristics Using the Panksepp Emotional System Temple Grandin Department of Animal Science, Colorado State University, Ft. Collins, Colorado, USA 16.1 Introduction reduction in fearfulness in domestic dogs. Zapata et al. (2016) found genetic variations that reduce fear At the time of my contribution to the first edition of that may have contributed to dog domestication. this book in 2005 my research group had conducted Recent studies are showing that temperament or some of the early research that showed that cattle personality in farm animals cannot be completely temperament had an effect on weight gain. Beef explained by determining an animal’s overall fear level. cattle that struggled or moved more while loosely For example, whereas the exit speed test would held in a squeeze chute (chute test) had lower weight measure fear, the chute test measures fear combined gains (Voisinet et al., 1997). Other studies have rep- with another trait (Bruno et al., 2016). In addition, licated this result in cattle and pigs (Benhajali et al., Brazilian researchers evaluated the influence of dif- 2010; Holl et al., 2010). Studies using another type ferent genes while using an electronic chute test to of temperament testing, termed exit speed scoring, measure struggling while held in a squeeze chute (dos found that beef cattle that run out of a squeeze chute Santos et al., 2017). They concluded that tempera- quickly have lower weight gain, poorer reproductive ment is a complex trait that incorporates a variety performance, and higher physiological measures of of different behavioral phenotypes. I hypothesize stress (Burrows and Dillon, 1997; Vetters et al., that standard industry temperament tests mainly 2013; Kasimanickam et al., 2014). measure fear, but in some cases they may also be The above studies served as motivation for the US measuring other emotional traits such as aggression beef cattle industry to include both chute scoring and or separation distress (Grandin and Deesing, 2014), exit scoring in their criteria for selecting breeding which likely differ from fear. animals. Twenty years later, I have observed that this has resulted in improved mental well-being in herds of beef cattle: the animals are much less reactive and 16.3 Panksepp Emotional System calmer when they are handled. In the United States, After reading many papers in the farm animal, pet today’s extensively raised beef cattle are very different – and wildlife literature I came to the conclusion that in emotionality and temperament – than the beef the Panksepp (1998, 2011; Montag and Panksepp, cattle that were raised before chute scoring and exit 2017) basic emotional systems would be the best way speed scoring became a regular industry practice. to explain many conflicting results in scientific studies of farm animal temperament. Different researchers use different terms and the trait of fearfulness is often 16.2 When Fearfulness is Reduced, confused with other behavioral traits. What follows is Other Personality Traits Become Evident an outline of the Panksepp emotional system – with Twenty years of temperament selection has reduced my added explanations – which may provide a good fearfulness in beef cattle. This may be similar to the framework for animal personality traits. © CAB International 2020. Mental Health and Well-being in Animals, 2nd Edition (ed. F. McMillan) 231