Boosting canine cognition

Getty ImagesAging dogs demonstrate cognitive impairments and neuropathology that closely model human aging, dementia and Alzheimer's disease, says Bill Milgram, PhD, professor emeritus at the University of Toronto's Department of Pharmacology and cofounder of CanCog Technologies in Toronto.1-4

“Most dramatically, older dogs lose their ability to learn, and the more difficult the task, the greater the impairment,” Milgram says. “The ability to learn a complex problem deteriorates in dogs before they lose their ability to remember. These changes may not be readily apparent to pet owners or veterinarians, who may simply see signs of confusion and forgetfulness.”

Another sign of cognitive impairment in canine aging is a deficit in executive function, such as decision-making, planning and organizing behavior. A good test for this decline is “reversal” learning, in which a dog is first trained to respond to one object and to avoid another, and then, after the dog has reliably learned the correct responses, the trainer changes the rules. When the first response is no longer the correct response, the dog has to make a different decision. Aged dogs learn reversal learning more slowly than young dogs.

Compared with younger dogs, older dogs are also deficient in complex discrimination learning, visuospatial learning, memory, and allocentric spatial function. They also experience age-related decline in higher-order cognitive abilities. Older dogs commit more errors doing behavioral tasks, require a longer training period and show reduced memory capacity.2-4

To identify the benchmarks of canine cognitive decline, veterinarians typically use various behavioral tests, or neuropsychological tests, similar in design to those used to study aging in primates and humans.

Although the exact cause of cognitive decline is unknown, older dogs' brains do offer some clues. Researchers have observed such changes as increased markers of oxidative stress, reduced brain mass, reduction of cerebral volume, alteration of cerebral vasculature, increased ventricular size, meningeal calcification, demyelination, glial changes, a reduction in neurons, neuroaxonal degeneration and an increase in apoptotic bodies and deposition of amyloid-beta plaque.1-4

Canine cognitive dysfunction syndrome

Some dogs also experience an aging syndrome called cognitive dysfunction syndrome (CDS), which is typically characterized by the emergence of a specific set of behavioral signs. These signs can include inappropriate housesoiling, alterations in activity levels, reduced interaction with family members or other pets, alterations in sleep-wake cycles, changes in learned behaviors, disorientation and wandering. Diagnosing CDS in dogs is difficult because it is primarily dependent on the pet owner reporting the appropriate signs.4,5

“CDS is different from the type of cognitive-neurophysiological testing that we've done, looking at cognitive decline in dogs,” Milgram says. “They're not the same thing. Canine CDS encompasses a range of different functions, not all of which are aspects of cognition. For example, decreased behavioral activity is considered to be a sign of CDS. While activity generally does decrease with age, some of our cognitively impaired animals actually become more active, yet they are showing other signs of cognitive impairment. That's one example of how the two conditions would differ.”

Correlates of cognitive decline

Recent studies using the anticholinergic drug scopolamine and the novel acetylcholinesterase inhibitor phenserine suggest some cholinergic involvement in cognitive decline. Aged dogs were found to be more sensitive to the impairing effects of scopolamine than young dogs, suggesting a decrease in cholinergic tone with increasing age. Dogs administered phenserine showed improved learning and memory. It was shown that cholinergic decline could result in memory impairment, but this may be secondary to deficits in attention or encoding of new information.1

Other studies have assessed various interventions to combat mental impairment. A study in aging beagle dogs, for example, used two interventions: 1) dietary fortification with a broad spectrum of antioxidants and mitochondrial cofactors and 2) a program of behavioral enrichment that included cognitive enrichment, environmental enrichment and extra programmed exercise.3  

The mixture of antioxidants included dl-alpha-tocopheryl acetate (100 vs. 1,000 ppm), L-carnitine (< 20 ppm vs. ~250 ppm), dl-alpha-lipoic acid (<20 ppm vs. ~120 ppm), ascorbic acid (< 30 ppm vs. ~80 ppm), and 1 percent inclusions of each of the following (one-to-one exchange for corn): spinach flakes, tomato pumice, grape pumice, carrot granules and citrus pulp. The three-year study compared young and old dogs receiving the two diets.

Researchers hypothesized that dietary intervention could help combat free radicals and the effect of oxidative stress on the aging brain. The free radical theory of aging associates age-dependent neuropathology with reactive oxygen species formed as by-products of cellular metabolism. Enhanced levels of oxidative damage are observed in both neurodegenerative diseases and in the normal aging canine brain.3

Researchers concluded that “age-related cognitive decline in dogs can be partially ameliorated by a combination of maintenance on an antioxidant-fortified food or a program of behavior enrichment, though the combination of the two proved to be more effective than either alone.”3

An additional study used a different antioxidant “cocktail,” a proprietary nutraceutical supplement (Senilife, Milan, Italy). The supplement was administered as one capsule/5 kg BW/day for a 60-day wash-in, and during an additional 10 days of testing. Each capsule contained 25 mg phosphatidylserine, 50 mg Ginkgo biloba extract (titrated in ginkosides, 24 percent), 20.5 mg pyridoxine, and 33.5 mg d-alpha-tocopheryl acetate (natural vitamin E).4

The results showed that this blend of antioxidants improved canine short-term memory performance when assessed by a delayed-nonmatching-to-position task (see sidebar “Putting memory to the test”). This same antioxidant also has been shown to improve clinical signs of CDS.4

In another dietary intervention study, Milgram and collaborators examined the cognitive effects of supplementation with 5.5 percent medium chain triglycerides (MCTs) over eight months on healthy aged dogs.6 MCTs provide an alternative energy source to the brain as ketones vs. glucose. This study found significantly improved performance in the group receiving the MCT supplement on age-related cognitive function as measured by sequential landmark discrimination learning ability, egocentric visuospatial function and focused attention.6

“We also found that dogs consuming MCTs showed elevated blood levels of beta-hydroxybutryate, a ketone, which probably accounts for the observed benefit, as ketones can provide a source of brain energy distinct from the more ‘normal' source of energy from glucose metabolism,” Milgram says. This fits with a large body of evidence indicating that aging is associated with reduced supply of energy to the brain, partly because of changes in blood flow.

“From the work that we've done, antioxidants alone are not really ‘huge' as far as cognition is concerned,” Milgram notes. “Alone, antioxidants did not have a big impact, but when dogs had both antioxidants and behavioral enrichment, they did better.”

The take-home message from these studies? While antioxidants may be beneficial, they're not the “cure” for aging, at least not yet, says Milgram. “This is a really complicated area, and there are many different kinds of antioxidants and many different pathways where antioxidants can act,” he says. “Moreover, some combinations of antioxidants might be more harmful than helpful. This is an area that still requires quite a bit of research. I think supplementation of diet high in antioxidants should be done, but don't expect it to be a magic bullet.”

Conclusion

Although further studies are needed, nutritional interventions that reduce the development of brain pathology may have important benefits for aged pet dogs, though environmental enrichment has shown to play a significant role. Similar benefits are shown for aging humans. “The dog may well be the best of all possible animal models for human cognitive aging,” Milgram says.

References

1. Araujo JA, Studzinski CM, Milgram NW. Further evidence for the cholinergic hypothesis of aging and dementia from the canine model of aging. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(3):411-422.

2. Chan ADF, Nippak PMD, Murphey H, et al. Visuospatial impairments in aged canines (Canis familiaris): the role of cognitive-behavioral flexibility. Behav Neurosci 2002;116(3):443-454.

3. Milgram NW, Head E, Zicker SC, et al. Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in beagle dogs. Exp Gerontol 2004;39(5):753-765.

4. Araujo JA, Landsberg GM, Milgram NW, et al. Improvement of short-term memory performance in aged beagles by a nutraceutical supplement containing phosphatidylserine, Gingko biloba, vitamin E, and pyridoxine. Can Vet J 2008;49(4):379-385.

5. Araujo JA, Studzinski CM, Head E, et al. Assessment of nutritional interventions for modification of age-associated cognitive decline using a canine model of human aging. Age 2005;27(1):27-37.

6. Pan Y, Larson B, Araujo JA, et al. Dietary supplementation with medium-chain TAG has long-lasting cognition-enhancing effects in aged dogs. Br J Nutr 2010;103(12):1746-1754.