Older dogs and cats are the most rapidly growing segment in many veterinary clinic populations. In part, this is because better and more sophisticated treatment for primary medical conditions has lead to longer-living pets. Many of these older animals will be affected by non-specific signs associated with cognitive aging. The proportion of dogs and cats with cognitive decline will increase as they age (e.g., clients will note behavioral changes for more 16-year-old dogs than for those 10 years old). Changes in non-specific behavioral signs associated with aging may not accurately reflect the degree of true cognitive change or "dementia" that the pet is experiencing, but these signs are excellent indicators of client distress. Client distress potentially leads to euthanasia of the pet. We can now do better.
Common client complaints and signs of cognitive decline: The most common changes noted by clients are:
1. Disorientation. The dog or cat seems to get lost in the house, in his or her room, or confused when outside. The pet may become increasingly distressed within each episode of disorientation early on in the progression of the cognitive changes, and less so as the changes become more pronounced.
2. Alterations in social and environmental interactions. As cognitive decline progresses affected dogs and cats interact less with their canine and feline housemates, play less, overall, ignored favored toys, and withdraw from clients, often refusing interaction with them. If forced to interact, dogs and cats can become completely withdrawn, or agitated and more distressed, possibly to the extent of becoming aggressive as a means to decrease interaction. When greeted, affected pets appear not to recognize clients. This profound alteration in client interaction and affect is the change that most distresses clients.
3. Changes in diel/sleep-wake cycle. Affected dogs and cats may no longer exhibit standard sleep-wake cycles, instead, pacing +/- vocalization during the night. Cats sleep often during the day as a normal behavior, so these changes may be most noticeable for dogs. Increased vocalization that is repetitive and monotonic is the most common complaint of clients with aging cats. The most distressing aspect of changes in diel for the clients is that they cannot comfort their pets when they pace and vocalize. Early in the progression of the condition diel changes may only be manifest as increases in time spent sleeping, which, unfortunately, may be considered a "normal" aging change.
4. Changes in elimination behaviors. Clients often described cognitive changes associated with eliminative behaviors as "a loss of housetraining." It is likely that changes in memory and learning associated with true housetraining (e.g., the ability to inhibit elimination unless provided with an appropriate substrate) are affected as a result of cognitive changes, but it is important to note that these dogs are not incontinent. The pets either appear to "forget" to eliminate when taken to their normal locations and substrates, and then eliminate anywhere they are when the need is urgent, or they have reduced inhibition and will eliminate wherever they are once they reach a certain threshold stimulus. The extent to which cognition is involved in inhibition of volitional behaviors is largely unexplored in dogs and cats but appears to be important in humans.
Accordingly, cognitive dysfunction is best defined by the following conditions: a change in interactive, elimination, or navigational behaviors, attendant with aging, that are explicitly not due to primary failure of any organ system, and that are not consistent with the definitional criteria for any anxiety disorder. Organ system dysfunction that could contribute to the non-specific signs discussed are found in Table 1. The minimum recommended database required to exclude any of these systemic conditions is found in Table 2.
It should be obvious that physical ability, or lack thereof, could confound how the client perceives the extent to which the complaint is behavioral or physical. A check sheet should be completed by clients at every annual visit. This way, not only will the clients watch for signs that may be early indicators of impending cognitive decline, but the physical contribution to the cognitive changes will be assessed in a routine manner along with the behavioral component. By having the clients complete such check sheets each time the dog or cat is seen, changes will be noted in a more accurate manner than one that depends on the client's memory, alone. This check sheet can also be used to assess whether the animal has improved post-treatment.
Changes in neurochemistry. It should be noted that the diagnosis of cognitive dysfunction or decline is a phenotypic one based on how the behaviors look. This does not imply that any specific underlying neurocellular mechanism is responsible for the changes noted. Recent advances have indicated that afflicted dogs may have variable amounts of cellular and neurochemical changes that are, themselves, rooted in different molecular processes. Age-related declines are generally associated with vulnerability of the cholinergic neurons. Such vulnerability could be the level of the cholinergic neuron, itself, the neurotrophic support system, cytoskeleton alteration, target loss, and vascular dysfunction. We know so much about canine behavioral changes that occur with age because dogs are good neuroanatomical and neurobehavioral models for humans because the non-specific behavioral changes associated with aging are shared by humans and dogs.
Changes in brain pathology that aged dogs share with aged humans with a diagnosis of one form of human dementia (Alzheimer's disease) include (1) thickening of the meninges and dilation of the ventricles, (2) age-related gliosis, (3) vascular changes, (4) diffuse plaques, and (5) amyloid deposition. Dogs do not seem to form the true neurofibrillary tangles that humans form.
Most of what we know about neurochemistry in these conditions is the result of correlational studies examining correlation. For example, in most neurodegenerative disorders, activity of the enzyme monoamine oxidase B (MAO-B) is elevated and levels of achetylcholine are either primarily or secondarily lowered. In the case of Alzheimer's disease and canine cognitive dysfunction, the increased activity of MAO-B appears to correlate with depletion of dopamine and loss or decreased activity of dopaminergic neurons. However, the primary MAO receptor in dogs appears to be of the subclass A, not B, a paradox that is unresolved.
One mechanistic hypothesis is a neuroregulatory one. Because of the increased activity of MAO-B, dopaminergic neurons are unable to maintain production and so undergo some atresia. Normal dopaminergic function is essential for basal ganglia function. Degeneration of dopaminergic neurons is invariably associated with motor and cognitive defects. In part, this decreased metabolism may be responsible for further cellular deterioration and apoptosis/programmed cell death. Bombardment with highly reactive free radicals can both induce and augment this effect. Free radicals increase with cellular degeneration, which may then cause DNA fragmentation, which further worsens the functioning of cells. In fact, enzymes called capsases are increased in and around amyloid containing plaques and tangles, and may be essential in encouraging DNA fragmentation and in promoting degeneration of mitochondrial and endoplasmic reticulum products. All of these processes are capable of leading to cellular apoptosis. Free radical production accentuates this process. Compounds that thwart free radical production or destroy them hinder programmed cell death and may augment cognitive function. The newer foods and supplements for aging dogs are intended to redress the pathology associated with free radical production and apoptosis.
Drugs that either are or could potentially be useful: There are numerous drugs - and the list is always growing for humans - that may be affective in the treatment of cognitive decline. There is only one drug, selegiline (Anipryl® Pfizer), with a label for canine cognitive dysfunction in the United States. It is important to remember that all other use is extra-label, and that for some of the medications discussed canine and feline dosages have not been investigated. Once treatment with any of these cognitive enhancers has begun, it is likely to be lifelong. Because most of these medications are metabolized through renal and hepatic cycles, appropriate pre- and post-medication biochemical evaluation is warranted.
1. Selegiline (starting dose for dogs: 0.5-1 mg / kg po q. 24 h; starting dose for cats: 0.25-0.5 mg / kg po q. 24 h): This is a selective inhibitor of MAO-B receptors (e.g., an MAO-I). MAO-Is that affect the B receptor enhance the degradation of phenylethylamine, norepinephrine, dopamine and tyramine but have little effect on serotonin. Selegiline exerts its effect both by blocking this degradation and inhibiting the re-uptake or recycling of neurotransmitters in the synaptic cleft, resulting in an increased amount of neurotransmitter in the cleft and increased saturation of the post-synaptic receptors, primarily on dopamine receptors. These actions are thought to be both neuroprotective and directly stimulatory for neuron function, in part because dopamine is a precursor to norepinephrine.
2. Nicergoline: This compound is an ergoline derivative that has alpha-1 adrenergic blocking effects. Accordingly, one of its main effects is to augment cranial and brain blood flow and distribution. Because of the feedback effects on neuronal metabolism, nicergoline, like selegiline, may have a neuro-protective effect. Nicergoline's neuroprotective effects may be more direct: it inhibits lipid peroxide formation, inhibits lipid peroxidation, and may act as a scavenger of free radicals.
3. Galantamine: Galantamine is a new acetylcholinesterase inhibitor that potentiates pre-synaptic nicotinic cholinergic neurotransmission.
4. Clomipramine (Clomicalm®: Novartis)(starting dose for dogs: 2 mg/kg po q. 12 h, or 1 mg / kg po q. 12 h x 2 weeks, then 2 mg / kg po q. 12 h x two weeks, then 3 mg / kg po q. 12 h as maintenance dosage; starting dose for cats: 0.5 mg / kg po q 24h): As a relatively specific tricyclic antidepressant (TCA) that has two functioning metabolites, one that acts as another TCA that primarily affects norepinephrine and another that acts as a specific selective serotonin re-uptake inhibitor (SSRI), clomipramine augments the functioning of both serotonin (particularly with respect to the pre- and post-synaptic 5-HT1A subtype receptors) and norepinephrine. By blocking the re-uptake of these neurotransmitters clomipramine may alter neuronal metabolism, and through these changes exert a cryo-protective effect. TCAs and SSRIs may also exert some of their beneficial effect in conditions involving cognitive change by decreasing the anxiety attendant with the development of these conditions. Because of the association of old-age onset separation anxiety and the potential advent of cognitive dysfunction, treatment with clomipramine may be a rational first step when the diagnosis is unclear.
Behavioral interventions that may prove useful: By the time cognitive decline is fully advanced and the patient manifests debility within each of the non-specific sign groups, intense, active behavior modification is unlikely to be helpful precisely because its success depends on an intact cognitive system. The earlier behavioral, pharmacological and dietary intervention are accomplished, the more likely that the dog or cat will experience improvement. That said, at present the course of this condition can be slowed, not aborted.
Behavior modification designed to teach the dog or cat to sit or lie down and relax can act as a rule structure for affected animals. If during regular times of the day the clients pay attention to their dog or cat in specific and routine ways, the animals will have a rule structure that provides some degree of predictability and expectations about interactions. Such predictability decreases anxiety. Additionally, regular interaction, particularly if it involves some cognitive stimulation (eg, requiring the pet to sit for a treat) will help stimulate neuron function. Stimulation of neuronal function that involves second messenger systems and new protein translation has been associated with increased mental flexibility and decreased cognitive decline in humans. Routine interaction can be as simple as daily massage, including gentle extension and manipulation of all joints or gentle grooming.
Playing games For animals that have always played games, adapting the games to their changing physical needs but continuing to play them may be essential for mental well-being. In an unpublished study conducted by Dr. N.W. Milgram's group at the University of Toronto, the biggest improvement in cognitive function was seen for aged dogs who had both some biochemical intervention and environmental enrichment. As our pets slow down, we tend to ignore playing with them. This is wrong: it is exactly at this time that they need more creative games, possibly including food puzzles, that rely more on brains than on brawn.
Because pets also become compromised by arthritis or changes in visual and auditory acuity concomitantly with age-associated behavioral/cognitive changes, it is critical that we address the physical changes with the intent to ameliorate any decrement in behavioral function that they may cause. Dogs that used to enjoy running, may enjoy swimming, and pools that have therapeutic swimming programs for dogs are now more readily available. Dogs and cats with arthritis may be more willing to interact or go with the people on car trips if they do not have to jump into the car or go up or down stairs. Ramps are an easy and - depending on their design - mentally stimulating solution. Dogs and cats may more easily sit or lie down and offer a paw or "high fives" for their dinner if their dinner is easy to eat. Elevated dinner dishes can accomplish this. It should go without saying - but likely doesn't - that appropriate pain control for arthritic and other physically debilitating changes is an essential part of any pet's well-being.
The behavioral and environmental solutions for changes brought on by aging are limited only by the client's imagination and willingness to meet their pet's needs. When they have done this, aging can be a graceful segue from youth and middle-age. Such an approach allows the clients to keep their pets in a humane manner, which may make the inevitable loss of the pet kinder, more rational, and a lot easier to accept, than were the client to euthanize the pet for the behavioral signs that the client finds so disturbing.