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Preventing and treating cognitive dysfunction in senior pets (Proceedings)
Even if a medical problem is diagnosed it can be a challenge to determine whether the problem is causing or contributing to the signs in which case a therapeutic trial might prove useful.
Behavior problems in senior pets
Even if a medical problem is diagnosed it can be a challenge to determine whether the problem is causing or contributing to the signs in which case a therapeutic trial might prove useful. In addition, an extensive history is required to determine if there are environmental factors (e.g. schedule changes, new member of the household, new pet, moving), relationship issues and owner responses (consequences) that might play a role in the cause or progression of the problem. This is of particular concern in the older pet which may be more sensitive and less adaptable to change.
Behavioral signs such as changes in activity levels, altered responses to stimuli, altered social interactions, anxiety, altered sleep-wake cycles, housesoiling, confusion or memory deficits may arise as a result of brain aging (e.g. cognitive dysfunction syndrome or CDS). In some cases, behavioral signs may precede other clinical signs, and may be the first or only indication of pain or illness. Therefore, monitoring for behavior changes in senior pets is essential for the early detection of disease, sensory decline and cognitive dysfunction, but is also an important welfare concern for the prompt recognition and treatment of discomfort and pain.
The case distribution of veterinary behaviorists provides some insight into the more serious behavior problems in senior pets. In one study of 62 dogs aged 9 years or older, separation anxiety was seen in 29% of cases followed by aggression towards people (27%); housesoiling (23%); excessive vocalization (21%); phobias (19%); waking at night (8%), compulsive or repetitive behaviors (5%); and intraspecies aggression (5%). In senior cats, the primary complaint of 83 cats at 3 behavior referral practices was housesoiling (73%), followed by intraspecies aggression (10%), aggression to people (6%), excessive vocalization (6%), restlessness (6%) and overgrooming (4%). However, these cases do not represent the more tolerable or less serious behavior changes of older pets that would not necessitate referral. To identify some of these complaints, the VIN database was searched for behavior problems of 50 senior dogs (aged 9 to 17) and 100 senior cats (aged 12 to 22 years). In the dogs, there were 37 cases with multiple signs of anxiety (fear, vocalization, salivation, destructive, hypervigilant); 18 with separation anxiety; "wandering"; 11 night anxiety or waking; 9 noise phobias; 7 vocalizing; 2 with stereotypies; and 2 aggressive. Thirty-one dogs had signs consistent with the traditional categories of CDS commonly referred to as DISH (disorientation, interactions with family members, sleep wake cycles, and housesoiling). In the cat cases, 61 were vocalizing excessively (31 at night); 27 had inappropriate elimination; 22 were disoriented; 19 were wandering; 18 were restless; 6 were irritable or aggressive; 4 were fearful or hiding and 3 were more "clingy" with owners. While medical problems had been ruled out in many cases, cerebral disease, hypertension, sensory decline, pain, metabolic or endocrine disease, anemia, neoplasia, drugs or even infectious agents (e.g. FIV) first needed to be ruled out.
While these studies examined the problems that were serious enough for the owners to seek behavioral guidance, some of most common behavioral signs that arise in senior pets require a more pro-active approach on the part of the practitioner as often go unreported.
Senior care guidelines
In 2005, the AAHA senior care task force published guidelines which included annual wellness examinations and laboratory screening for middle aged pets and biannual screening for senior pets (defined as the last 25% of predicted lifespan).4 In addition, a critical component of the guidelines is the importance of questioning pet owners to determine if any changes have occurred in their pet's health or behavior and to advise them on the importance of promptly reporting any new changes. Early detection provides an opportunity for early diagnosis and treatment so that complications might be prevented, further decline might be slowed, longevity might be increased and welfare issues are promptly addressed.
Unless veterinarians are proactive in asking owners about these signs, they often go unreported, presumably because they are thought to be insignificant or untreatable. In one study of dogs aged 11-16 that had no medical signs, 28% of 11-12 year-old dogs and 68% of 15 to 16 year old dogs showed at least one sign of DISH (CDS). In a more recent study, 124 dogs over 7 years of age were evaluated and 22 were eliminated due to possible medical factors. Of the remaining dogs, 42 had alterations in one category and 33 had signs in 2 or more categories.6 In a study commissioned by Hills Pet Nutrition, 75% of owners of dogs over 7 years of age indicated that their pet had one or more signs when asked, but only 12% reported the signs to their veterinarians. In a prospective study of aged cats presented to veterinary clinics for routine annual care, 154 owners of cats aged 11 and older were asked to report any signs of cognitive dysfunction. After eliminating 19 cats with medical problems, 35% of the cats were diagnosed with CDS; 28% of 95 cats aged 11 to 15, and 50% of 46 cats over 15 years.
It is therefore the role of the veterinarian and staff to inform the clients of the importance of reporting these signs. Questionnaires, such as the ones available in the Handbook of Behavior Problems of the Dog and Cat can be used to quickly and extensively screen for problems at each visit. Handouts such as Senior Moments from AAHA, the handouts on the Lifelearn Client on line handouts (lifelearncliented.com) or those available from commercial companies that market products for senior pets can also be used to educate owners about the importance of regular geriatric evaluations.
Causes of behavioral signs in senior pets
Cognitive dysfunction in senior pets
CDS a neurodegenerative disorder of senior dogs and cats that is characterized by gradual cognitive decline and increasing brain pathology. Elderly dogs are less able to perform a variety of cognitive tasks including discrimination, oddity, reversal, and spatial memory compared to younger dogs. Based on clinical signs alone, CDS has been traditionally diagnosed in dogs at 11 years and older. However, dogs show impairment in the spatial memory task as early as 6 to 8 years of age.13 These functions are considered to be highly dependent on the frontal lobe, which shows atrophy and beta amyloid accumulation prior to other brain areas. Laboratory studies have also been able to demonstrate altered sleep wake cycles, increased stereotypy and decreased social contact with humans in dogs with cognitive impairment.
To diagnose CDS, veterinarians must rely on owner history. Only with careful questioning is it likely that signs would be detectable in the earliest stages of development. The diagnosis was initially based on clinical signs represented by the acronym DISH or a) Disorientation b) Altered Interactions with people or other pets c) Altered sleep-wake cycles and d) Housesoiling. In addition, since activity may initially decline and over time become restless or repetitive in pets with CDS, an A for activity has been added to the acronym (DISHA). However, while a decline in learning and memory may arguably be the most important hallmark of cognitive decline this is not adequately captured when one looks only at the DISHA signs. This is because the average pet may appear minimally challenged in its learning and memory tasks such as name recognition or housetraining, while laboratory testing can demonstrate changes many years earlier. In those dogs that are trained to a higher level of performance (e.g. assistance dogs, explosive or drug detection, performance dogs) signs of learning or memory loss might be identified at an earlier age. Studies of humans with Alzheimer's disease (AD) and other forms of age related dementia have found that anxiety, night time waking and agitation may be associated with frontal lobe dysfunction. This may be analogous to the restlessness, pacing and night waking seen in elderly pets. In addition, many of the problems presented to behaviorists and many of the problems reported in the VIN survey seem to indicate that agitation and anxiety may also be a sign of CDS. Alterations in self-hygiene, appetite and responsiveness to stimuli may also be associated with CDS. In France the term confusional syndrome is used to describe cognitive disorders such as disorientation, loss of previously learned behaviors and altered sleep-wake cycles. A depressed mood is also described including lethargy, changes in appetite, decreased activity and decreased interest in interactions with family members and other pets, which may progress to a chronic state of anxiety.1
Once signs are identified any disease possible medical causes or contributing factors must be ruled out. The aging process is associated with progressive and irreversible changes that can affect behavior. Any disease that affects the central nervous system or its circulation can affect behavior as can extracranial causes of neurological signs (e.g. metabolic or endocrine disorders). Pain, dental disease, sensory decline, and neuropathies can also affect the way in which a pet responds to a stimulus. In addition, any disease process affecting elimination can cause housesoiling.
Aging and its effect on the brain
With increasing age there is a reduction in brain mass including cerebral and basal ganglia atrophy, an increase in ventricular size, meningeal calcification, demyelination, glial changes (including an increase in the size and number of astrocytes), increasing amounts of lipofuscin and apoptic bodies, neuroaxonal degeneration and a reduction in neurons. There is also an increased accumulation of diffuse beta amyloid plaques and perivascular infiltrates in dogs, cats and humans. In dogs and cats the plaques are diffuse and lack a central core while in humans beta amyloid distribution may progress to neuritic plaques and neurofibrillary tangles (NFT). No evidence for NFT has been found in aged dogs or cats. However in cats, staining for hyperphosphorylated tau has been demonstrated, indicating a possible pre-tangle formation in cats. Numerous vascular and perivascular changes have also been identified in older dogs, including microhemmorhage or infarcts in periventricular vessels. Arteriosclerosis may also be seen in the older dog or cat due to fibrosis of vessel walls, endothelial proliferation, mineralization, and beta amyloid deposition. This angiopathy may compromise blood flow and glucose utilization. With age, there may also be a depletion of catecholamine neurotransmitters, an increase in monoamine oxidase B (MAOB) activity as well as a decline in the cholinergic system.
a) Beta-amyloid: Studies have shown that beta amyloid is undetectable in young dogs and is most extensive in the oldest canines. In dogs, errors in learning were strongly associated with increased amounts of beta amyloid deposition. Although the exact role of beta amyloid is yet to be determined, it is neurotoxic and can lead to compromised neuronal function, degeneration of synapses, cell loss, depletion of neurotransmitters and is correlated with the severity of cognitive dysfunction.
b) Reactive oxygen species (ROS): A small amount of oxygen that is used by the mitochondria for normal, aerobic, energy production is converted to ROS or toxic free radicals such as hydrogen peroxide, superoxide and nitric oxide within the mitochondria. As mitochondria age, they produce relatively more free radicals and less energy.30 Increased MAOB activity may also result in increased liberation of free radicals. Normally the body's antioxidant defenses including enzymes such as superoxide dismutase, catalase, and glutathione peroxidase and free radical scavengers such as vitamins A, C, and E, eliminate free radicals. With increasing age, the net effect of increased production and decreased clearance leads to an increase in ROS which react with DNA, lipids, and proteins leading to cell damage, dysfunction, mutation, neoplasia and cell death. The brain is particularly susceptible to the toxicity of free radicals.
c) Vascular insufficiency: There may also be a link between vascular insufficiency, decreased perfusion and the signs of brain aging.
Treatment of cognitive dysfunction
Many age related disease processes cannot be resolved; however, it may be possible to slow the decline of the disease (e.g. diet) or control the clinical signs (e.g. pain management). However, even if the cause of the problem can be resolved, the behavior may persist because of learning and conditioning.
In addition, owners must be made aware of the limitations that might be placed on improving the behavior of a senior pet. Therefore owners may need to implement varying forms of environmental management such as improved lighting in litter areas, larger litter boxes with lower sides, ramps for improved mobility, more frequent trips outdoors for elimination, paper training or doggy diapers, or even separation of pets from stimuli to which they are fearful or aggressive.
If cognition is impaired, diet or drugs might be useful in improving signs, slowing the progress of CDS and making the pets more amenable to behavioral management. Studies have also shown that continued enrichment in the form of training, play, exercise and novel toys can help to maintain cognitive function (i.e. use it or lose it). Keeping up a regular, predictable daily routine may help to reduce anxiety, and maintain temporal orientation. Making gradual changes to the pet's household or routine can also help the senior pet adapt better. As sensory acuity, sensory processing and cognitive function decline, adding new odor, tactile, and sound cues) might help the pet better navigate its environment and maintain some degree of environmental familiarity and comfort.
Selegiline is s selective and irreversible inhibitor of MAOB in the dog.26 It may act by enhancing dopamine and other catecholamines in the cortex and hippocampus. Selegiline has been shown to increase 2-phenylethylamine (PEA) in the dog brain. PEA is a neuromodulator that enhances dopamine and catecholamine function and may itself enhance cognitive function.32 Selegiline may also contribute to a decrease in free radical load in the brain, by inhibiting MAOB, and by increasing free radical clearance by enhancing enzymes such as SOD. The dose is .5 – 1 mg/kg per day. There are no drugs licensed for CDS in cats although there are anecdotal reports of successful use of some of the canine medications (selegiline at .5 to 1 mg/kg per day). Therefore the possibility of improving signs must be weighed against potential risks.
Nutritional and dietary therapy
Another strategy in the treatment of CDS is to use dietary supplements to improve antioxidant defenses and reduce the toxic effects of free radicals. A variety of studies have shown that high intake of fruits and vegetables, and vitamin E and C, have decreased the risk for cognitive decline.
A senior diet (Canine b/d, Hills Pet Nutrition, Topeka, KS) is supplemented with fatty acids, antioxidants (vitamins C and E, beta carotene, selenium, flavonoids and carotenoids), dl-alpha-lipoic diet and l-carnitine which are intended to enhance mitochondrial function.36 The diet improved performance on a number of cognitive tasks when compared to older dogs on a non-supplemented diet, beginning as early as to 2 to 8 weeks after the onset of therapy. After two years, a control group (no enrichment, control diet) showed a dramatic decline in cognitive function, while those in either the enriched diet or the environmental enrichment group alone continued to do better than control. However, the combined effect of the enriched diet plus the enriched environment provided the greatest improvement.
Four clinical trials have reported improvements in clinical signs associated with CDS in dogs using dietary supplements containing phophatidylserine. One such product, Senilife is distributed in North America by CEVA Animal Health. In a recent study dogs were tested after administration of 60 days of either a placebo or the product, in a crossover design using a memory task. Performance accuracy was significantly improved in the treated group compared to baseline and dogs receiving the supplement in the first portion of the study maintained their improved performance. Phosphatidylserine is a membrane phospholipid that may facilitate signal transduction and stimulate the release of acetylcholine and dopamine. In humans with cognitive decline, phosphatidylserine has been reported to improve activity, social interactions, memory and learning, which may be maintained for some time after discontinuation of therapy. Ginkgo biloba is an MAO inhibitor and free radical scavenger which may enhance dopaminergic, serotonergic and cholinergic transmission as well as cerebrovascular blood flow, that has also been reported to improve cognitive function in humans. Vitamin B6 (pyridoxine) is a cofactor in the synthesis of neurotransmitters. Vitamin E may further enhance the effects of gingko biloba as well as neutralize free radicals. Resveratrol may protect against oxidative damage and reduce beta amyloid secretion.
S-adenosyl-l-methionine or SAMe (Novifit, Virbac, Fort Worth, TX) is also now available for the treatment of dogs and cats for CDS. It is dosed at 10-20 mg/kg daily. SAMe is found in all living cells and is formed from methionine and adenosine triphosphate (ATP). It is particularly abundant in the brain and liver SAMe may help to maintain cell membrane fluidity, receptor function and the turnover of monoamine transmitters such as noradrenaline, serotonin and dopamine as well as increase the production of glutathione, a major cell antioxidant. In humans SAMe may also improve cognitive function in elderly patients with dementia. In a recent clinical trial, 36 dogs over 8 years of age with signs of CDS were given either placebo or SAMe tysolate at 18 mg/kg per day. Greater improvement in activity and awareness was reported in the SAMe group after 8 weeks.
Other natural products, many with similar ingredients are also available in the veterinary market but generally lack the scientific evidence to support any claims of efficacy.
In conjunction with drugs for CDS it might be necessary to also consider medications that address specific signs. For example, antidepressants and anxiolytics may be indicated for the pet that is anxious or night waking. Since, SSRIs such as fluoxetine and the anxiolytic buspirone have little or no cardiovascular or anticholinergic effects they might have less potential for side effects in the elderly. Lorazepam, oxazepam and clonazepam have no active intermediate metabolite and might therefore be safer than other benzodiazepines in patients with compromised hepatic function. Natural therapies for anxiety and aiding sleep might also be considered such as melatonin, aromatherapy and pheromones.
References available on request