Assessing brain aging in cats

Cats are more common as pets in North America than dogs are, and, on average, they live longer. Indeed, the aged and aging cat population is increasing, but cats have been relatively neglected in the animal brain-aging debate.

Because cats can be naturally independent, we may resort to neglecting their behaviors and cognitive well-being. Thus, we may not be adequately addressing the emotional needs of young and middle-aged cats, and we may need to rethink how we assess brain aging in them.

What we know about cats' brains

Since the 1970s, cats have been the subject of much basic neuroscience research. For example, early studies used cats as models for human seizure activity and damage or lesions.

Interestingly, early studies showed cats with septal lesions experienced dramatic increases in social awareness (based on how much time they spent watching cats with whom they were housed).1 Those with amygdaloid lesions doubled their baseline activities.

These findings may be relevant to aging cats given what we know about the distribution of beta-amyloid and neprilysin, an enzyme that degrades beta-amyloid, in cat brains.2 The distribution of these compounds is regionally sensitive.

Amyloid distribution is most common in the cerebral cortex and the hippocampus, and there is one report of amyloid distribution in the distal olfactory neurons of aged dogs (no equivalent study exists for cats).

Neprilysin distribution appears relatively high in the striatum, globus pallidus and substantia nigra. In contrast, its distribution is low in the cerebral cortex. Neprilysin activity is greatest in the thalamus/striatum followed, in order, by the cerebral cortex (in which executive function and implementation of learning occurs), the hippocampus (where much associational learning occurs) and the white matter.

Not all brain lesions are the same. The conventional wisdom holds that cats may form amyloid plaques but do not appear to develop the neurofibrillary tangles and plaques common in Alzheimer's disease. Beta-amyloid plaques can vary in type and length of termini they express, and these are found in different types of lesions. An early study of three older cats and 20 older dogs found plaques in their brains that contained residues of 42 amino acid (beta-amyloid42) but not 40 (beta-amyloid40), which is commonly found in a subset of human neuritic plaques and cerebrovascular deposits.3 Amyloid lesions appear in the brains of cats at about 10 years of age. In one study assessing 19 cats aged 16 weeks to 14 years, all expressed amyloid precursor protein constitutively in neurons and blood vessels.4 Staining for beta-amyloid was most pronounced in the deep cortical areas of the anterior/midcerebrum of cats older than 10 years. Clearly, amyloid deposition can affect brain function in cats.

Other physiological factors that can affect brain function

Feline cardiovascular changes that can occur with aging (e.g., anemia, decreased cardiac output and perfusion, systemic hypertension, changes in viscosity) may predispose some cats to, or worsen, brain aging.5 Older cats can experience infarcts of periventricular vessels. Any such pathology will worsen risks associated with reactive oxygen species such as free radicals (e.g., hydrogen peroxide, superoxide, nitric oxide). While these compounds are the normal detritus of mitochondrial metabolism, with advancing age, they are not removed as well by endogenous antioxidants (e.g., superoxide dismutase) and free radical scavengers (e.g., vitamins A, C and E) because their production becomes overwhelming. Such changes provide a good environment for the development of tauopathies, including those associated with amyloid deposition. When taken as a whole, these neuropathologic changes put feline brains at the risk of multiplicative assaults.

Like people, aging cats experience changes in how they digest and use food. Mean energy requirements do not decrease in aging cats; in fact, they actually may increase. Digestive efficiency changes; that is, older cats may not digest proteins or fats as well as they did when young.6 As a result, geriatric cats (those older than 11 years) may often be underweight despite the problem with obesity in the overall cat population.

The behavioral effects of age-related brain changes

Before we can assess behavioral effects of brain aging, it's helpful to have some estimate of the range of cat behaviors over time in a controlled situation.

A study published in 1987 that focused on groups of research colony cats aged 1 to 3, 5 to 9 and 11 to 16 years assessed locomotor activity, plank walking, reactivity and spatial-reversal learning.7 This study produced some surprising findings. Cats in the oldest group were relatively insensitive to habituation in locomotor sessions, but younger cats habituated quickly. As a result, older cats did not change activity between or within sessions to the extent that younger cats did. Younger cats seemed to decide if the task wasn't novel, it wasn't worth doing. This may mean older cats have an altered sensitivity to environmental stimuli, but they also made fewer mistakes in walking planks than did the youngest cats and showed no differences in neurobiological assessment when compared with the other two age groups.

These findings may impact how we should assess older cats. Because older cats are willing and able to perform certain tasks repeatedly, it does not mean that ongoing aging of the brain is not taking place. Other similar findings of this research were also interesting in this regard.

For example, older cats were more reactive to auditory stimuli than were younger cats, and they sustained their responses longer. The oldest cats (aged 11 to 16 years) actually performed better on a spatial-reversal learning task than did their younger counterparts. Older cats made fewer errors and learned to reverse faster, although they did not appear to maintain learning between tasks. The oldest cats seemed to have some short-term memory deficits but appeared to view each trial of the specific task as a new learning experience, as determined by a test for randomness in their first few sets of responses (the cats in the two younger groups did not show this randomness in response). Furthermore, these older cats learned from their incorrect responses.

Note that all of the cats tested came from breeding colonies, so they may have had more complex cognitive and experiential lives than do most people's pets. If that's true, it should give us pause. This experimental report may suggest that problem-solving activity early and throughout life would benefit pet cats.

Clinical reports based on client interviews have suggested that 29 percent of pet cats 11 to 14 years old express at least one geriatric-onset behavior problem, and that by 15 years of age, this is true for 50 percent of pet cats.8 Assessment of behavioral change in any species is not trivial because behavior is the integrating component that reflects the whole of any animal. In older cats, the most commonly reported behavioral changes include alteration in social interactions with humans or other animals, overall activity (including changes in quality of activity from that which was previously directed to that which is now aimless), sleep-wake cycles, grooming, feeding and interest in food, learning and generalized behavioral responses and increases in amount and changes in quality of vocalization.

Owners recognize many veterinary problems in their pets because of a change in behavior at some level, and classes of behavioral change can be both nonspecific signs and specific indicators of underlying neurocognitive change. Teasing apart these two can be challenging, especially in a cat that we may not have watched closely and that may remain more of a mystery to the average human than the comparatively transparent dog.

There are few standardized behavioral tests of cognitive function for either pet dogs or cats. However, some of the behavioral tests designed in the 1990s9 to assess cognitive function in cats affected by feline immunodeficiency virus (FIV) infection may have some promise for laboratory studies of aging cats and, better yet, may be sufficiently portable to make at-home or in-hospital testing possible. Factors that may confound our interpretation of such tests and client histories may include the presence of arthritis (which can impede movement), pain from any source, endocrine disease (including hyperthyroidism), renal or hepatic disease and failure, primary neurologic disease, gingival disease (some behavioral tests require the apprehension of food), blindness, deafness or infectious conditions (e.g., FIV) that affect nervous tissue.

Pharmacologic options to help older cats

Several medications licensed for treating cognitive dysfunction, or cognitive dysfunction syndrome—a catch-all diagnosis for the behavioral manifestations of brain aging—in dogs are available. But none of these treatments has been licensed for use in cats. Controlled studies also are lacking.

The available medications focus on promoting more efficient neurochemical signaling (e.g., selegiline, an MAO-B inhibitor), improved blood flow (e.g., nicergoline and propentofylline) or some combination of these two modalities. Anecdotal extralabel use of selegiline, nicergoline and propentofylline has been recommended in cats, generally at reduced dosages from those recommended in dogs. Dosages (oral per day) in cats are as follows:

• Selegiline: 0.25 to 1.0 mg/kg

• Nicergoline: 0.25 to 0.5 mg/kg

• Propentofylline: 12.5 mg/cat.

Once started, if a beneficial effect is noted, treatment is likely to be necessary for life.

For age-related anxiety and distress, treatment with commonly used behavioral medications (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants) may not only help but may be essential. When used correctly, these medications help maintain neuron integrity through second messenger stimulation of neurotrophic factors.

Polyunsaturated fatty acids may play a role in cats as they do in dogs, and there is slight but growing evidence that supplementation with omega-3 and omega-6 fatty acids may prevent some damage by reactive oxygen species. Certainly, there is evidence that they help maintain neuron integrity across species. Phosphatidylserine has been shown to have some beneficial effect in aging dogs, but data are sparse and even sparser in cats. Phosphatidylserine is one of the components of a version of Aktivait (Vet Plus, United Kingdom; available only online in the United States) now being marketed for cats. A number of companies are currently developing foods that may enhance brain health in cats and dogs.

Environmental intervention

What we lack in products for aging cats can be redressed by creativity in behavioral and environmental intervention. To be maximally effective, we must retrain ourselves to stimulate cats at young ages and to keep them stimulated throughout their lives. Kittens don't actually age out of their charming, active and clownish selves. These behaviors become more complex and less obvious to us, so we cease to interact in the same way. We need to change this.

Cats, like all other aging mammals, have improved cognitive function if they are stimulated. Meal feeding for cats may be mandatory for those with certain health conditions, but if the animal is healthy, we should consider feeding them with puzzle balls or boards, mazes or anything that encourages cats to hunt, move around and use their brains. Remember the colony cat experiments from the 1980s: Older cats were happy to problem-solve, and, once rewarded, they learned how to do so every day for each test.

Conditioning for cats is important. Indeed, old cats that can walk planks and mazes have good muscle tone. Range-of-motion exercises, massage, aquatic treadmills (for cats that will tolerate them) and water beds (which can help with balance and epaxial muscle stimulation) are underexploited in feline stimulation.

Additionally, cats have an exquisite sense of smell. The health of olfactory neurons may be improved by encouraging cats to use their sense of smell. For example, routinely dragging a sardine on a string through the grass for the cat to track may help maintain neuron health and interest. There are creative adaptations of this paradigm for even the smallest apartment.

Cats that enjoy the outdoors as youngsters do not have to give that up as oldsters. Several buggies, carriages and bicycle accoutrements are available that allow people to transport pets. And even if older pets no longer can see the beach or hear the surf, they surely can feel and smell the air. The tactile and olfactory stimulation of other pets also likely plays an underestimated role for aging cats. Providing cats with soft surfaces to rub against and bedding of varying textures and temperatures (through judicious placement of warm gel inserts) can encourage cats to move and explore. If stimulation is important, we need to exploit all aspects of it, providing no distress is involved.

Final thoughts

If we want cats to age successfully, we must plan for it when they are kittens. All of the interventions that will render healthier cognitive abilities as a cat ages will, in turn, improve the animal's welfare and the quality of its intellectual life, regardless of age.

Dr. Overall, faculty member at the University of Pennsylvania, has given hundreds of national and international presentations on behavioral medicine. She is diplomate of the American College of Veterinary Behavior (ACVB) and is board certified by the Animal Behavior Society (ABS) as an Applied Animal Behaviorist.

REFERENCES

1. Glendenning KK. Effects of septal and amygdaloid lesions on social behavior of the cat. J Comp Physiol Psychol 1972;80(2):199-207.

2. Takeuchi Y, Uetsuka K, Murayama M, et al. Complementary distributions of amyloid-beta and neprilysin in the brains of dogs and cats. Vet Pathol 2008;45(4):455-466.

3. Cummings BJ, Satou T, Head E, et al. Diffuse plaques contain C-terminal A beta 42 and not A beta 40: evidence from cats and dogs. Neurobiol Aging 1996;17(4):653-659.

4. Gunn-Moore DA, McVee J, Bradshaw JM, et al. Ageing changes in cat brains demonstrated by beta-amyloid and AT8-immunoreactive phosphorylated tau deposits. J Feline Med Surg 2006;8(4):234-242.

5. Gunn-Moore DA, Moffat K, Christie L-A, et al. Cognitive dysfunction and the neurobiology of aging in cats. J Small Anim Pract 2007;48:546-553.

6. Fahey GC Jr, Barry KA, Swanson KS. Age-related changes in nutrient utilization by companion animals. Annu Rev Nutr 2008;28:425-445.

7. Levine MS, Lloyd RL, Fisher RS, et al. Sensory motor and cognitive alterations in aged cats. Neurobiol Aging 1987;8(3):253-263.

8. Neilson JC, Hart BL, Cliff KD, et al. Prevalence of behavioral changes associated with age-related cognitive impairment in dogs. J Am Vet Med Assoc 2001;218(11):1787-1791.

9. Steigerwald ES, Sarter M, March P, et al. Effects of feline immunodeficiency virus on cognition and behavioral function in cats. J Acquir Immune Defic Syndr Hum Retrovirol 1999;20(5):411-419.