Therapeutic Options for Cognitive Decline in Senior Pets
Many treatment options are now available for pets with age-related cognitive dysfunction, including drugs, nutritional supplements, and diets. This article describes the theory, evidence of efficacy, and potential neuroprotective effects of products used to treat cognitive dysfunction. Cognitive dysfunction is a diagnosis of exclusion, because many painful conditions and health problems may present with similar signs. Practitioners must, therefore, actively question owners of senior pets in order to diagnose cognitive dysfunction and to assess the pet’s general health and well-being.
Introduction
The aging process is associated with progressive and probably irreversible changes that affect behavior.1–3 Any lesion or disease that affects the forebrain, including the limbus and hippocampus, can affect learning and memory circuits and, consequently, behavior. Similarly, impairment of circulation to the central nervous system (e.g., anemia, hypertension) can also cause similar effects. Diseases of virtually all organ systems, tumors, immune-mediated diseases, infections, and endocrinopathies are increasingly common in older pets and can cause alterations in the way a pet behaves. Painful conditions can also lead to a wide range of behavioral signs, such as fear, irritability, aggression, decreased mobility, and altered responses to stimuli. In some cases, behavioral signs may precede other clinical signs and may be the first or only indication of pain or illness.
Regular and thorough evaluation of any change in behavior is essential for the early detection of disease, sensory decline, pain, and cognitive dysfunction. Early detection provides the best opportunity for minimizing discomfort, slowing the progression, and possibly resolving the disease condition. In the spring of 2005, the AAHA Senior Care Task Force published recommendations for annual wellness screening for middle-aged pets and biannual screening for senior pets (defined as the last 25% of predicted life span).4 In addition to physical examinations and laboratory tests, a critical component of the senior care guidelines is the questioning of pet owners to determine if any changes have occurred in their pet’s health or behavior. Most of these changes cannot be detected during the veterinary visit, as they may be intermittent, subtle, and only noticeable to the primary caregivers. In one study of dogs 11 to 16 years of age that had no underlying medical illness, owners were asked to report any behavioral signs that might be consistent with cognitive dysfunction.5 Twenty-eight percent of 11- to 12-year-old dogs and 68% of 15- to 16-year-old dogs showed at least one sign.5 In another study, it was found that 75% of owners of dogs >7 years of age reported one or more behavioral sign consistent with cognitive dysfunction; however, only 12% of owners voluntarily reported the signs to their veterinarians.a The use of a behavioral screening questionnaire can be an important tool in providing a comprehensive senior care program. Other sources of information can be found in veterinary textbooks and client handouts from various sources.1
Cognitive Dysfunction and Brain Aging
Following adequate screening of the pet for behavioral signs by the veterinarian, a diagnosis of cognitive dysfunction syndrome is reached by exclusion of other underlying medical problems. Cognitive dysfunction syndrome is a neurodegenerative disorder of senior dogs and cats, characterized by gradual cognitive decline. It is presumably caused by age-dependent brain pathology.1–3 Several changes have been identified in the brains of older dogs and cats, including reduced brain mass, increased cerebral ventricle size, meningeal calcification, demyelination, glial changes, increased lipofuscin and apoptic bodies, neuroaxonal degeneration, reduced numbers of neurons, increased markers of oxidative stress, and accumulation of beta-amyloid.6,7 Because many of these changes are similar to those seen with early Alzheimer’s disease and senility in humans, the dog has been studied intensively as a model for human brain aging.8,9 Both oxidative damage and beta-amyloid pathology increase with age and have been correlated with cognitive dysfunction.8,10,11
The acronym DISHA has been used to describe the signs associated with clinical cognitive dysfunction, and it represents disorientation, alterations in the way the dog interacts with stimuli (e.g., people, other pets), house soiling, or activity level changes.1,2 These signs do not entirely encompass all of the changes that may occur as a result of brain aging, however. An increase in anxiety, altered responsiveness to stimuli, and deficits in learning and memory are also commonly documented. While learning ability and memory are arguably two of the most important criteria for early detection of cognitive decline, these are difficult parameters to assess in pet dogs—except, perhaps, in those dogs trained to a higher level of performance, such as agility-trained dogs, therapy dogs (e.g., guide dogs for the blind), or working dogs (e.g., drugs/explosives detection). On the other hand, standardized cognitive tests have been developed in the laboratory that provide unbiased quantitative measures in dogs of declining cognitive function as they age, and they provide a means of examining the link between cognitive decline and brain pathology.9,12–15 One example is the oddity discrimination task, in which the dog is presented with three objects covering three wells.12 Two of the objects are identical, and food is placed in the well under the dissimilar object. The dog is then given the opportunity to displace one of the objects with its nose and is rewarded when it displaces the odd object. This test assesses a dog’s ability to learn a complex problem and is highly sensitive to age when object similarity is increased.12 For assessing memory, dogs can be tested on tasks that evaluate their ability to recall the location of a food reward after a delay of ≥5 seconds (i.e., delayed, non-matching to position task).13
Based on clinical signs alone, cognitive dysfunction has been traditionally diagnosed in dogs ≥11 years of age. Dogs may show impairment in the delayed, nonmatching tasks as early as 6 to 8 years of age.14 In the laboratory, dogs also demonstrate early impairment in high-level cognitive functions (executive functions), which can be measured by switching rules (reversal).15 For example, if dogs initially are trained to associate food with the larger of two objects, and then they are required to respond to a smaller object, aged dogs typically commit more errors than young dogs when learning that the object-food association has been altered. A task that involves switching rules is referred to as a reversal learning task. Both of these tasks (i.e., delayed, nonmatching and reversal learning) are considered highly dependent on the frontal lobe, which shows atrophy and beta amyloid accumulation earlier than other areas of the brain.16 Laboratory studies have also demonstrated altered sleep cycles, increased stereotypy, and decreased social contact with humans in aged dogs with cognitive impairment, as well as a progressive decline in cognitive abilities in dogs over time.17,18
Treatment Options
While controlled clinical trials are invaluable in determining the efficacy of therapeutics on cognitive dysfunction in pets, the standardized neuropsychological tests discussed above provide more objective and sensitive measures of improvement, because they can measure fine changes in memory and learning and do not rely on subjective owner assessments. Many of the products that have been shown to be effective in the treatment of cognitive dysfunction and may potentially slow the progress of the disease have been studied in the laboratory as well as through clinical trials.
Many recent therapeutic options for both pets and humans have focused on a synergistic combination of ingredients rather than monotherapy. Combinations of antioxidants, certain fatty acids, essential minerals, vitamins, metabolic cofactors, and trophic nutrients may be effective in contributing to brain cell health and memory preservation.19–21 Because oxidative damage is considered to be one of the main factors in age-related decline of dogs, this multimodal, synergistic approach has become a focus of therapeutic intervention for the treatment of cognitive dysfunction in dogs, and many of the ingredients studied have been selected for their ability to scavenge or prevent the production of oxygen-free radicals.8,22,23 One study, however, suggested the most significant effect on health and life span in dogs can be achieved through weight (caloric intake) control.24
Nonpharmaceutical Approaches
Dietary Therapy
A variety of studies have shown that a high intake of fruits and vegetables may decrease the risk of age-related cognitive decline in rodents, dogs, and perhaps humans, through their antioxidant and anti-inflammatory properties.25–27 Dietary therapy was first utilized when a commercial diet became available that was designed to treat cognitive dysfunction in senior dogs.b This particular diet is supplemented with a broad spectrum of antioxidants and mitochondrial cofactors that are intended to improve antioxidant defenses as well as decrease production, increase clearance, and reduce the toxic effects of oxygen-free radicals.28–31 The brain is particularly susceptible to the effects of oxygen-free radicals, because it has a high rate of oxidative metabolism, high lipid content, and limited ability for regeneration.22–28 The diet is supplemented with vitamins E and C and other antioxidants, such as beta carotene, selenium, dl-α-lipoic acid, and a number of flavonoids and carotenoids from fruits and vegetables (e.g., spinach flakes, tomato pomace, grape pomace, carrot granules, citrus pulp). The addition of l-carnitine and dl-α-lipoic acid is intended to enhance mitochondrial function.30,31 The level of omega-3 fatty acids is also increased to promote cell membrane health and provide a potential anti-inflammatory effect.32 The efficacy of this diet was assessed using neuropsychological testing procedures for >2 years, as well as clinical trials.12,33–35
When compared to a nonsupplemented diet, improved performance was seen as early as 2 to 8 weeks and continued through 6 months when assessed with an oddity discrimination learning task. Improvement was maintained through 2 years based on reversal and delayed, nonmatching to position memory tasks.12,33,34 In a 60-day, double-blind clinical trial of 142 dogs, a significantly greater improvement in cognitive signs occurred in the group on the fortified diet than in the control group.35
Environmental Enrichment Therapy
In addition to the effects of the fortified diet, a multiyear longitudinal study also examined the effects of environmental enrichment (e.g., exercise, novel toys, etc.) on dogs in comparison to dogs that had no such enrichment.28,33,34 After following these dogs for >2 years, the control group (i.e., no enrichment, no supplemental diet) showed a dramatic decline in cognitive function, while those in either the supplemental diet or the environmental enrichment groups continued to do better than the control group on discrimination and reversal tasks.28,33,34 The combined effect of the supplemental diet and the enriched environment provided the greatest improvement, particularly in learning and executive function tests.12,28,33,34
Supplemental Therapies
A wide variety of other complementary therapies have been marketed as treatments for cognitive dysfunction. These products may contain a mixture of herbal extracts, vitamins, phospholipids, fatty acids, antioxidants, and mitochondrial cofactors that are believed to act in a synergistic or potentiating manner to slow the progression or improve the clinical signs associated with brain aging. Recently, three clinical trials have reported improvements in clinical signs associated with cognitive dysfunction syndrome in pets using a variety of dietary supplements containing phophatidylserine.36–38 One of these productsc [see Table] is currently distributed in Italy for elderly dogs and cats as a dietary supplement that protects neurons from age-related degeneration. In a recent study, dogs were tested after administration of 60 days of either a placebo or the product, in a crossover design using delayed, nonmatching task on position assessments.39 Performance accuracy was significantly improved in the treated group compared to baseline. In addition, dogs receiving the supplement in the first portion of the study maintained their improved performance.39
Phosphatidylserine is a naturally occurring phospholipid that is a major building block of the cell membrane. Since neurons are highly dependent on their plasma membranes (e.g., for generation and transmission of impulses, synaptic communication, etc.), phosphatidylserine may facilitate membrane-dependent neuronal processes, such as signal transduction, release of secretory vesicles, and maintenance of the internal environment. These neuronal processes may be compromised in the aged brain.40,41 Clinical studies indicate phosphatidylserine improves cognitive function in humans, both during and after treatment, and also improves social interaction, memory retrieval, and activity in both humans and rodents.42,43 Phosphatidylserine may also enhance acetylcholine release, inhibit age-related loss of muscarinic receptors in the rat brain, have neuroprotective effects on cholinergic neurons, and activate the synthesis and release of dopamine.44–47 A decline of cholinergic transmission is considered an important factor in age-related cognitive decline in both dogs and humans.48,49 In dogs and perhaps cats, phosphatidylserine may improve cognitive deficits, memory, orientation, learning, and social behavior, and may have neuroprotective effects.
Ginkgo biloba inhibits monoamine oxidase (MAO) A and B, which increases dopamine levels.50 It is reported to improve cognitive function in humans (and improve short-term retention of spatial memory), to have antioxidant effects, and to enhance cerebral vascular blood flow.51,52 Ginkgo biloba also has phosphatidylserine-like activity, since it also stimulates the cholinergic and serotonergic systems in aged animals.53–55 Ginkgo biloba also may protect neurons against apoptosis induced by beta-amyloid protein, one of the main pathogenic characteristics of age-related cognitive decline in dogs.9,10,56
Vitamin B6 (pyridoxine) is also reported to be a cofactor in the synthesis of neurotransmitters (e.g., serotonin, nor-adrenaline, dopamine), thereby supporting phosphatidylserine in normalizing neurotransmitter levels and synaptic transmission.57 Vitamin E may further enhance the antioxidant effects of ginkgo biloba and may neutralize free radicals, prevent damage to cell membranes, and may be a key ingredient in diets designed for cognitive dysfunction in dogs.28 Vitamin E may also slow the functional deterioration clinically observed in humans with pathological brain aging.58
One commercially available productd also contains essential fatty acids (i.e., docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) and acetyl cysteine, which is a primary precursor to glutathione and coenzyme Q10. Fatty acids and glutathione have been shown to be beneficial in influencing the effects of brain aging in humans.59,60 This product also uses a multimodal approach to improving and attenuating the effects of brain aging on behavior. A number of other natural supplementse,f,g are available for the treatment of cognitive dysfunction in senior pets; however, data to support these claims have been limited so far [see Table].18,61
Pharmacological Options
Selegiline
The first therapeutic agent approved for use in dogs, based on results of both neuropsychological testing (including reversal and spatial memory) and clinical trials, was selegiline.61,62 Selegiline is a selective and irreversible inhibitor of MAO B in the dog.61 Enhancement of dopamine and perhaps other catecholamines in the cortex and hippocampus is presumed to be a primary mode of action.62 In the canine brain, selegiline increases 2-phenylethylamine, which is a neuromodulator that enhances dopamine and catecholamine function and may inherently enhance cognitive function.63 Catecholamine enhancement may lead to improved neuronal impulse transmission. Selegiline may also contribute to a decrease in free radical load in the brain by directly scavenging oxygen-free radicals and enhancing scavenging enzymes such as catalase and superoxide dismutase.64,65 In addition, because MAO B is inhibited, fewer toxic free radicals may be produced. Selegiline may also have neuroprotective effects on dopaminergic, noradrenergic, and cholinergic neurons.66 Selegiline (0.5 to 1 mg/kg per os [PO]) is given each morning and should not be used concurrently with antidepressants, narcotics, and other MAO inhibitors (e.g., amitraz).
Enhancing Cerebral Perfusion
Drugs that putatively enhance cerebral vascular circulation may also potentially improve the signs of cognitive decline, because cerebral perfusion may decrease with age in the dog.67 Nicergoline is an alpha-1 and alpha-2 adrenergic antagonist that is licensed in some countries for the treatment of age-related behavior disorders in dogs.68 It may increase cerebral blood flow, inhibit platelet aggregation, enhance neuronal transmission by increasing dopamine and noradrenaline turnover, and may have neuroprotective effects.68 Propentofylline is licensed for the treatment of dullness and lethargy in senior dogs in a number of European countries. It is purported to inhibit platelet aggregation and thrombus formation, may make red blood cells more pliable, and increases blood flow.69 Testing of propentofylline has been limited primarily to clinical trials. The dose for nicergoline in dogs is 0.25 to 0.5 mg/kg PO q 24 hours (each morning), and for propentofylline the dose is 3 mg/kg PO q 12 hours.
Drugs that may enhance the noradrenergic system, such as adrafinil and modafinil, might be useful in older dogs to improve alertness and help maintain normal sleep-wake cycles (by increasing daytime exploration and activity). The noradrenergic system helps to maintain alertness, wakefulness, attention, memory, and learning; augmentation may be neuroprotective. In laboratory studies on discrimination learning in dogs, adrafinil has been shown to increase locomotion and improve learning, although memory may be impaired at the same dose.70 In a comparable study, adrafinil led to a significant increase in locomotion, while nicergoline and propentofylline had no effect.71 The contradictory effects of adrafinil on learning and memory indicate that cognitive-enhancing therapeutics should be tested using a wide variety of cognitive tests, since the benefit of improving one function at the cost of another may or may not be acceptable, depending on the specific circumstance.
Cholinergic Transmission
Since a decline in cholinergic function in the brain is associated with memory impairment in humans, a major focus of drug therapy for Alzheimer’s disease is the use of drugs that enhance cholinergic transmission. In dogs, disruption of cholinergic transmission has been demonstrated to impair memory as measured by delayed, nonmatching on position tasks.48 Recent studies have also found that middle-aged and senior dogs show greater sensitivity than young dogs to the memory-impairing effects of an anticholinergic drug (i.e., scopolamine) that readily crosses the blood-brain barrier; this response is similar to the sensitivity pattern seen in humans.48,49 Therefore, drugs that augment cholinergic transmission might have clinical applications in dogs with cognitive decline. In one small, placebo-controlled study, an experimental cholinesterase inhibitor, phenserine, was shown to improve both learning and memory in aged dogs.49 To date, the drugs (such as donepezil, tacrine, and gallantamine and rivastigmine) presently licensed for enhancing cholinergic transmission in humans with Alzheimer’s disease have not been tested or proven to be effective in dogs. Possible problems with their use in dogs include the potential for gastrointestinal side effects, the absence of clinical or laboratory dose-response data, potential for toxicity, and differences in drug metabolism.72,73 On the other hand, since the elderly are particularly susceptible to anticholinergic effects, it would be prudent to consider selection of drugs that cause less sedation and have fewer anticholinergic effects for any chronic treatment in dogs and cats.
Other Options
Other treatment strategies that have received attention in humans include nonsteroidal anti-inflammatory drugs, statins, N-methyl-D-aspartate receptor (NMDA) antagonists, and hormone replacement therapy. Estrogen may have anti-inflammatory and antioxidative effects and may increase cerebral blood flow. In aged dogs, estrogen-treated females made significantly fewer errors in a size-reversal learning task; however, they made more errors in spatial memory tasks.74 In one study of a small group of dogs, intact, aged male dogs had less evidence of cognitive impairment than neutered dogs.75 Recent studies in humans may support testosterone as being neuroprotective against Alzheimer’s disease.76 If supplementation with testosterone or estrogen is considered, these hormones should be given at physiological levels, since high levels can be toxic.
Treating Cats
No drugs are licensed for the treatment of cognitive dysfunction in cats, although there have been anecdotal successes with some canine medications. The possibility of improving signs in cats must be weighed against the potential risks. Selegiline has been reported to be useful in senior cats for improving clinical signs of cognitive dysfunction, such as disorientation, increased vocalization, decreased affection, and repetitive or restless activity.1–3 In a small, nonplacebo-controlled study of 27 cats about 4 years of age, selegiline was effective in improving a variety of behavioral signs, including productive signs (e.g., aggression, insomnia, bulimia) and deficit signs (e.g., anorexia, increased sleep).76 Except for occasional gastrointestinal upset, no adverse effects were reported. Nicergoline may be given by dissolving a 5-mg tablet in water, giving 25% of the solution, and discarding the rest. If desired, propentofylline may be administered at 12 mg PO q 24 hours. Many of the natural supplements (e.g., Senilife) make label claims for treating cats, but improvement has only been anecdotal, and little or no published data are available.
Treating Specific Clinical Signs
Additional forms of therapy may be considered for pets with specific clinical signs such as increased anxiety and nocturnal wakefulness. Selective serotonin reuptake inhibitors (e.g., fluoxetine) and the anxiolytic, buspirone, have minimal cardiovascular and anticholinergic effects and may be useful for these signs. Lorazepam, oxazepam, and clonazepam have no active intermediate metabolites and are probably safer than other benzodiazepines in animals with compromised hepatic function. Natural therapies for calming the animal, reducing anxiety, or inducing sleep include melatonin, valerian, Bach’s flower remedy, and certain pheromones.h,i
Conclusion
A number of therapeutic agents that may slow or prevent cognitive decline are marketed for the treatment of cognitive dysfunction in pets. While most appear to be useful in theory, many have not been tested; others have been subjected to neuropsychological trials in the laboratory and/or in clinical trials. While combining therapies may be the most appropriate option, drug compatibilities, side effects, and contraindications must be a constant concern. Additionally, it is important to consider a therapy’s cost-benefit ratio, which is often unknown.
United States Marketing Research Summary, Omnibus Study on Aging Pets, November 2000; Hill’s Pet Nutrition, Topeka, KS 66603
Canine B/D; Hill’s Pet Nutrition, Topeka, KS 66603
Senilife; Innovet Italia S.r.l., Milano, Italy
Activait; VetPlus Ltd, Lytham, United Kingdom
Geriactive; Centaur Pharmacy, Guelph, Ontario, Canada
Senior Moment; Nutramax Laboratories, Edgewood, MD 21040
Proneurozone; Animal Health Options, Golden, CO 80403
DAP; Veterinary Products Laboratories, Phoenix, AZ 85013
Feliway; Veterinary Products Laboratories, Phoenix, AZ 85013
