Successful brain aging in dogs

Because of advances in care and diet, more animals are living to an older age. We focus a lot on ensuring that our patients' bodies age successfully by emphasizing the same things human physicians tell us — maintain a healthy weight, treat arthritides and monitor for systemic illness associated with specific organ-system compromise that becomes more common with age. We humans also worry about the health of our brains, fearing the debilitating effects of tauopathies such as Alzheimer's disease. Should we be concerned for the health of the brains of our canine companions?

Continuing research suggests that the answer to this question is an unambiguous "Yes!" Over the past generation, we have changed the way we view animals in general. It's now the exceptional person who has grown up on a farm, and we have come to acknowledge the basic and deep role of the human-animal bond in the daily lives of our clients. Clients who have invested in the veterinary care necessary to see their cats or dogs into middle age are prepared to do everything possible not just to extend the lives of their pets, but also to ensure that their pets' brains are as healthy as possible. The relationship these clients value is both behavioral and emotional, and it is this very relationship that pathological brain aging steals. It is incumbent on modern veterinary medicine to do everything possible to thwart that theft of relationship.

Consoling clients that older pets had a good life and advising euthanasia is out of date. The fear that this is the advice that veterinarians will give may keep many clients from seeking help when their older pets begin to fail behaviorally. Instead, if we encourage clients to anticipate change and intervene as early as possible, these pets and the humans who love them can have many years of additional quality life together.

How do we recognize brain aging in dogs?

While humans are afflicted by numerous tauopathies, each of which may have defining cognitive or anatomical dimension, emphasis in dogs has been placed on a relatively nonspecific diagnosis of canine cognitive dysfunction (CD), sometimes also called cognitive dysfunction syndrome. In dogs, CD is usually diagnosed because of a history of disorientation, alterations in social and interactive behaviors, changes in locomotor behavior and sleep cycles and what is often called loss of housetraining. In early-onset CD, animals may have only slightly altered sleep cycles and appear more anxious. Alterations in social and interactive behaviors may manifest early in the condition as an increased neediness but can change to a form of aloof disengagement in social interactions with all species.

Estimates from numerous studies suggest that at least 25 percent of dogs older than 10 show one of these signs associated with brain aging, and that by 15 years, more than 60 percent of dogs are affected to some extent.

What happens to cause deleterious brain aging changes?

If we understand what happens at the cellular and molecular level as brains age, the path to preventing or treating pathological brain aging will become clearer. There are three main contributors to problematic, age-related brain changes: oxidative changes associated with processes like free-radical formation; formation of lesions, including those composed of amyloid; and shifts in oxygen and energy availability. All of these factors interact to compromise brain function.

Oxidative damage

Aging is associated with increased expression of genes associated with stress and inflammation. Changes in gene expression are key to understanding why we and our pets may have difficulty learning with advancing age. As a result of these changes, neuronal loss occurs in the hippocampus — the section of the brain primarily involved in associational learning. This loss of neurons is associated with decreased expression of genes that affect the ability of neurons to send and receive signals.

Anything that causes inflammation or damage to neurons — oxidative assaults, illness, trauma — affects the neurochemicals that allow neurons to talk to each other. To maintain efficient channels of communication between neurons, efficient and numerous connections must exist. These connections are maintained by use because recalling and making molecular memory trigger a second messenger system that ultimately stimulates an important neurotrophic factor called brain-derived neurotrophic factor (BDNF). BDNF, which stimulates cytosolic response element-binding protein (CREB), has three principal functions: 1) to enhance growth of serotoninergic (5-HT) and norepinephrinergic (NE) neurons, 2) to protect these neurons from neurotoxic damage and 3) to help in remodeling neuronal receptors. By stimulating CREB, which facilitates protein transcription, BDNF plays a crucial role in making and repairing all components of neurons.

Amyloid

Like humans, when canine neurons begin to suffer from oxidative assaults, amyloid deposition may occur. Dogs develop plaques composed of beta-amyloid that are like those seen in humans. When amyloid deposition is extensive, it physically disrupts communication between neurons, worsening the processes discussed previously.

Shifts in oxygen and energy availability for the brain

Glucose is considered the common brain energy currency, but it is not stored. The stored form of glucose is glycogen. Glycogen is found mainly in astrocytes, and the amount of glycogen available is affected by glucose concentration and by neurotransmitter presence and function. During hypoglycemia, glycogen is converted to lactate via pyruvate (glucose > pyruvate > lactate). The lactate is then transferred to adjacent neurons. This conversion and transfer allow the neurons to use a source of aerobic fuel.

The use of lactate in hypoglycemic events can extend axon functions for 20 or more minutes — a long time for a neuron. Astrocytic glycogen is also converted to lactate during periods of intense neural activity, demonstrating the role of astrocytes as bankers of energy-conversion compounds. Most lactate used as an energy source is thought to come from glycogenic processes because lactate, itself, is too large a molecule to pass through the blood-brain barrier.

Ketone bodies and fatty acids have also been proposed as alternate energy sources because of their modulating effects on hypoglycemia. Beta-hydroxybutyrate (beta-OHB), in particular, may be useful for protecting hippocampal neurons from toxicity. In a placebo-controlled, double-blind study in people, mildly impaired patients with Alzheimer's disease who were supplemented with medium-chain triglycerides (MCTs) showed improvement in a number of cognitive test measures, and such improvement correlated with beta-OHB increases.1 Note that this result depended on the apolipoprotein E (APOE) genotype since only patients without an APOE-epsilon4 allele responded to acute elevation of beta-OHB.

The role for adequate provisioning of brain energy is not separate from that of protecting against beta-amyloid lesions. In a study of eight 9- to 11-year-old beagles (four control, four treatment), supplementation with MCT at a dosage of 2 g/kg/day resulted in improved mitochondrial function, which was most pronounced in the parietal lobe.2 Steady-state levels of amyloid precursor protein (APP) also decreased in the parietal lobe after short-term supplementation, leading to the conclusion that short-term MCT supplementation can improve brain energy metabolism and also decrease APP levels in old dogs.

Polyunsaturated fatty acids (PUFAs) may also play an interactive role in neuronal integrity and energy available to the brain. The long-chain PUFAs commonly shown to be involved in neuronal integrity and development of the nervous system include arachidonic acid (ARA), docosahexaenoic acid (DHA) and eicosahexanoic acid (EHA). All of these PUFAs are essential for early brain development. ARA is thought to maintain hippocampal cell membrane fluidity and protect cells in the hippocampus from oxidative stress.

DHA may encourage development stage-specific associational learning, although the data are mixed. Supplementation with DHA and EPA affects concentration of these substances in rat brains, but their distribution is not uniform. Diets deficient in alpha-linoleic acid especially cause decreases of DHA in the frontal cortex — the part of the brain responsible for complex learning and integration of information and executive function. In dogs, low DHA concentrations during gestation or lactation depress the retinal sensitivity of puppies, which can have profound and complex behavioral outcomes. The current data support the need for DHA for optimal neurologic development in puppies, and there are hints that it may improve both early and long-term cognitive abilities, but the data are scant.

Age-related cognitive decline in dogs may be associated with decreases in omega-3 PUFAs in the brain.3 Because MCTs increase fatty acid oxidation, they may increase omega-3 PUFAs in the brain via metabolism of adipose tissue. In a two-month study of eight beagles (four controls, four treatment) fed an MCT-enriched diet, enrichment was shown to result in increases in brain phospholipid and total lipid concentrations.

Conclusion

We and our dogs will age and die, but we do not have to go gently into that good night. Instead, by judicious and smart use of diet, medication and exercise as I will discuss in Part 2 of this article, we can extend quality of life for ourselves and for the dogs who love us.

Dr. Overall, faculty member at the University of Pennsylvania, has given hundreds of national and international presentations on behavioral medicine. She is a 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. Reger MA, Henderson ST, Hale C, et al. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging 2004;25(3):311-314.

2. Studzinski CM, MacKay WA, Beckett TL, et al. Induction of ketosis may improve mitochondrial function and decrease steady-state amyloid-beta precursor protein (APP) levels in the aged dog. Brain Res 2008;1226:209-217.

3. Taha AY, Henderson ST, Burnham WM. Dietary enrichment with medium chain triglycerides (AC-1203) elevates polyunsaturated fatty acids in the parietal cortex of aged dogs: implications for treating age-related cognitive decline. Neurochem Res 2009;34(9):1619-1625.