Canine cognitive dysfunction

Bronwyn Riggs, VMD, DACVIM (Neurology)
Massachusetts Veterinary Referral Hospital, Woburn, MA
Posted on 2016-09-27
 

With advances in veterinary medicine, we are more and more commonly seeing our pets living to a greater age than has been reported historically. Current estimates in the companion animal population indicate that there are more than 50 million senior and geriatric dogs over the age of 7 years.¹ As such, advanced age in our pets and their associated illnesses have become a very important aspect in who and what we treat in our roles as general practitioners and specialists, alike.

A longer life span brings age-related degenerative changes in a number of organ systems. As with all species, the brain also undergoes degenerative changes with age, resulting in impairment of memory and learning. The term canine cognitive dysfunction syndrome is used in veterinary literature to describe the progressive neurodegenerative disorder of senior dogs that is characterized by a gradual decline in cognitive function, as it pertains to learning, memory, perception, and awareness.²

Signalment & clinical signs

Categories of behavioral changes seen with cognitive dysfunction have been given the acronym “DISHA” by Dr. Landsberg in his studies on cognitive dysfunction in cats and dogs. This includes changes seen with spatial disorientation and confusion, altered social relationships, altered sleep-wake cycles (or night waking), altered learning and memory (resulting in house soiling or loss of learned commands and trained tasks), purposeless, repetitive, or decreased activity, perception and/or responsiveness, or increased anxiety or restlessness.³

Many of the common behavioral presenting complaints in senior pets are related to anxiety, especially separation anxiety, phobias, excessive vocalization, aggression and waking at night. Disruption of nighttime rest is detrimental to the elderly and debilitated patient, not to mention the family caring for their pet. As such, it is one of the most common presenting complaints for behavior problems in senior dogs.²

In a VIN database search for behavior problems in 50 senior dogs aged 9-17 years old, 62% of them had signs consistent with CDS with most demonstrating signs of anxiety, night waking, and vocalization.³ Naturally, these are the behaviors that are likely to have the greatest impact on the dog-human bond.

Cognitive dysfunction is reported to arise with increasing frequency beginning at the age of 11 years of age. Evidence suggests that a decline in cognitive function may occur much earlier than typically reported in the clinic, likely because of limited diagnostic measures available.² Initial signs may be subtle and relatively innocuous, but may progress to a point where they have a significant impact on the pet’s quality of life and owner’s ability to continue to care for the pet.

Diagnosis

Obtaining an accurate history is of the utmost importance in screening for the presence of clinical signs and progression of disease. In client-owned pets, there are a number of questionnaires that have been developed by various institutions. In general, these questionnaires provide a rating scale to measure severity of confusion, repetitive activity, recognition of familiar people and pets, avoidance of petting, and ability to find food, as well as changes over a designated period of time. Unfortunately, these questionnaires tend to be subjective and only provide a measure of global brain dysfunction. In addition, they tend to be insensitive to the early and subtle changes in learning and memory associated with pathological aging.¹

In the laboratory setting, neuropsychological tests can provide a more quantitative and objective measure of cognitive function directly, without the need for questionnaires. Despite being labor intensive, they tend to be more sensitive in identifying early signs of cognitive impairment.¹

Cognitive dysfunction in dogs tends to be a diagnosis of exclusion. As such, it is important to screen for a broad scope of medical problems that may be causing or contributing to a dog’s behavioral changes. MRIs are useful for screening for a myriad of changes that can be seen within the brain associated with age, including cortical atrophy, ventricular dilation, and thinning of the subcortical white matter. In addition, diffuse and scattered T2-weighted hyperintensities can oftentimes be seen within the internal capsule. This is thought to be caused by Wallerian degeneration, demyelination, and accompanying gliosis.⁴

Pathophysiology

The neurobiology of aging is not specific to any one species. Dogs naturally accumulate several types of neuropathology that can parallel and even be consistent with a number of human-related diseases. In 1956, Braumühl reported Alzheimer-like senile plaques in aged dogs. These plaques are made up of β-amyloid (Aβ) protein which is produced by the sequential cleavage of the amyloid precursor protein by beta-secretase and gamma-secretase. Cleavage by gamma-secretase results in differing lengths of β-amyloid protein, with the 42 amino acid form making up most of the insoluble deposits found in brains with Alzheimer’s disease.⁴

The accumulation of Aβ plaques in the brains of dogs does not seem to begin until about 8 years of age. Thus, cognition may decline prior to Aβ plaque accumulation, implying that cognitive impairment may be more tightly coupled to the production of toxic soluble assembly states of Aβ. Alternatively, other pathologies may be contributing to cognitive decline, such as cerebrovascular dysfunction, progressive oxidative damage, and synaptic dysfunction.5 What has been established is that the extent of Aβ plaque deposition in the dog brain is linked to the severity of cognitive deficits.⁴

In humans, Alzheimer’s disease is one of the most common neurodegenerative disorders and is characterized by an initial decline in episodic memory followed by progressive decline across multiple cognitive domains. This results in behavioral changes that impair social function and eventually results in death.³

Classical diagnosis of Alzheimer’s disease has relied on post-mortem confirmation of two hallmark pathologies: senile plaques and neurofibrillary tangles. Other brain changes are also documented, such as neuronal loss, cortical atrophy, alterations in neurochemical systems such as the cholinergic, glutaminergic, dopaminergic, and GABAergic neurotransmitter systems, and reduced neuronal and synaptic function. Risk factors associated with the development of Alzheimer’s disease include genetic, metabolic, and nutritional influences, all of which are likely equally relevant to our aging pet population. Clinical Alzheimer’s is considered a late stage of disease progression, which explains the limited clinical success of therapeutic interventions.³

The exact role of β-amyloid accumulation in the development of cognitive dysfunction is yet to be determined. What we do know is that it is neurotoxic and can lead to compromised neuronal function, degeneration of synapses, cell loss, and depletion of neurotransmitters. We also know that it is correlated with the severity of dysfunction. In dogs, errors in learning tests, including discrimination, reversal, and spatial learning, were strongly associated with increased amounts of β-amyloid deposition, indicating a correlation between cognitive dysfunction and the extent of β-amyloid accumulation, but a causative role has not been directly established.²

Differences from the human pathology in our canine counterparts exist in a lack of dense core plaques as seen in Alzheimer’s disease. Instead, a more diffuse subtype occurs, suggesting that canine plaques are less mature than those seen in Alzheimer’s disease. Along these lines, dogs do not show such extensive cognitive impairments (ability to eat is retained) as is seen in people, which suggests that the disease progression in pets is more comparable to earlier stages of Alzheimer progression.⁴

Oxidative damage and mitochondrial dysfunction is another mechanism by which aging occurs within the brain. With this, a small amount of oxygen that is used by the mitochondria for normal aerobic energy production is converted to reactive oxygen species (ROS). As mitochondria age, they become less efficient and produce more free radicals and less energy. Increased monoamine oxidase (MAO) activity may also result in increased liberation of oxygen free radicals.²

Normally, antioxidant defenses, including enzymes like superoxide dismutase (SOD), catalase, glutathione peroxidase and free radical scavengers eliminate free radicals. If the balance of detoxification and production is tipped in favor of overproduction, as can occur with aging, the excess of free radicals can react with DNA, lipids, and proteins, leading to cell damage, dysfunction, mutation, neoplasia, and cell death. The brain is particularly susceptible to the toxic effects of free radicals because of its large metabolic needs.⁴

White matter hyperintensities (WMH) are a frequent finding on MRIs of geriatric dogs and elderly people. It has been well established that WMH are associated with cognitive decline in people. It is felt that cognitive impairments in WMH are related to ischemic interruptions of frontal subcortical circuits or disruption of cholinergic pathways that traverse the subcortical white matter.⁶

The term, leukoaraiosis has been developed as a purely descriptive term to avoid making assumptions about the underlying pathology of WMH. Although leukoaraiosis initially was intended to encompass all aspects of white matter change, with time, the term has been used within a different clinical context from that of inflammatory disorders (leukodystrophies). Instead, it is now reserved for lesions with presumed ischemic and age-related origins.⁷

With the thought that ischemia may be the route to pathologic changes seen with leukoaraiosis, we are seeing this term used in the context of vascular dementia more and more. Simply put, vascular dementia is a term that describes dementia caused by problems in the supply of blood to the brain. Vascular lesions can be the result of focal lesions, such as lacunar infarcts and/or diffuse cerebrovascular disease, as in small vessel disease.

One form of small vessel vascular dementia that causes damage to brain white matter is known as Binswanger’s disease, or subcortical leukoencephalopathy. Binswanger’s disease is a type of subcortical vascular dementia caused by white matter atrophy but with the distinction of necessitating subcortical dementia to differentiate it from other causes of leukoaraiosis.⁸

Clinical signs are comparable to what we see in our patient population, as it is associated with difficulties in the processing of information, executive function, and mood disturbance. In humans, this becomes especially apparent as it affects their ability to adapt to complex situations where more than one cognitive process is at play. Other areas that are also affected include gait control and bladder instability.⁶

Pathology associated with Biswanger’s disease involves white matter changes, including myelin loss (pallor), enlargement of perivascular spaces, gliosis, and axonal loss. Changes to the blood vessels involve hyaline thickening and arteriosclerosis leading to lipohyalinosis and ultimately fibrinoid necrosis, all of which contributes to reduced blood flow and ischemia.⁸

Hypertension is strongly associated with white matter disease and is the only definite modifiable risk factor for leukoaraiosis and Binswanger’s disease. Aggressive blood pressure management therefore appears to be the only way to prevent the onset and progression of these disease processes and their potential complications. Unfortunately, once established, pathologic changes are irreversible.⁹

Leukoaraiosis and/or Binswanger’s disease have yet to be expressly explored within veterinary research and literature. That being said, MRI characteristics and some of the histopathologic changes seen in these disease processes have been reported independently of one another.

Treatment

Currently, there are no definitive treatments for reversing or “curing” a decline in cognitive function. Rather, management of this condition is reliant on behavioral modification techniques, environmental enrichment, targeted nutrition, and medications that may slow the progression of disease and improve quality of life of the pet and family. Of utmost importance is ensuring that any underlying medical problems be addressed. Unfortunately, even in the face of a resolved medical problem, the behavior may persist due to learning and conditioning.²

Mental stimulation is essential in maintaining quality of life and continued enrichment can help maintain cognitive function. This is analogous to human studies in which education, brain exercise, and physical exercise has been found to delay onset of dementia.¹⁰

As sensory, motor, and cognitive function declines, new odor, tactile, and/or sound cues may help a pet better navigate its environment and maintain some degree of environmental familiarity and comfort.3 Similarly, maintaining a regular, predictable daily routine and providing the pet with control to engage in positive interactions may help reduce stress and anxiety and maintain temporal orientation. On the other hand, inconsistency in the environment can cause stress and negatively impact health and behavioral well-being.²

Studies have shown that mental stimulation can help maintain cognitive function and even slow cognitive decline. Therefore, enrichment should focus on positive social interactions and new and varied opportunities for exploration, interactive games, and stimulating ways to obtain food, toys, and treats.³

Some diets and supplements have been shown to improve antioxidant defense thereby reducing the negative effects of free radicals. Canine b/d is said to improve signs and slow progress of cognitive decline as early as 2-8 weeks after starting therapy. It is supplemented with a combination of fatty acids, antioxidants, as well as DL-α-lipoic acid and L-carnitine, which are intended to enhance mitochondrial function. Trials with the b/d diet showed that a combined effect of supplemented diet and environmental enrichment provided the greatest benefit and when started prior to onset of behavioral signs, cognitive health may be extended.³

Medium chain triglycerides (MCTs) are converted to ketone bodies by the liver. Given that a decline in cerebral glucose metabolism and reduced energy metabolism are associated with cognitive decline, it is thought that MCT-induced ketone bodies may provide an alternate energy source that can be used by the brain. Additionally, MCTs are thought to improve mitochondrial function, increasing polyunsaturated fatty acids in the brain, and decreasing amyloid precursor protein in the parietal cortex of aged dogs. For this reason, it has been approved as a medical dietary supplement for patients with Alzheimer’s Disease.³

Phosphatidylserine is a membrane phospholipid that constitutes a major building block of the cell membrane. Because neurons are highly dependent on their plasma membranes, phosphatidylserine may facilitate the activities of the neuron that are dependent on the cell membrane, such as signal transduction, release of secretory vesicles, and maintenance of the internal environment.³

Selegiline is a selective and irreversible inhibitor of monoamine oxidase B. As such, it has many potential neuroprotective qualities, including reducing free radical production and/or increasing enzymes that scavenge free radicals, such as superoxide dismutase and catalase. In addition, it may increase brain 2-phenylethylamine, which is a neuromodulator that enhances dopamine and catecholamine function in the cortex and hippocampus and may itself enhance cognitive function.³

Since its emergence, levetiracetam has also been recognized as a medication that belongs to a class of drugs that are under investigation for their “nootropic”, or cognition enhancing, effects. Along these lines, data is currently emerging, in human medicine, on possible uses of levetiracetam outside the realm of epilepsy, including the treatment of psychiatric disorders, such as anxiety, panic, stress, mood, bipolar, autism, and Tourette’s syndrome. On the veterinary end of things, levetiracetam has been reported, both in the literature and anecdotally, to improve the overall quality of life in geriatric dogs who undergo its use for seizure control.¹¹

Other therapies, including Vivitonin, Adrafinil, melatonin, Benadryl, phenobarbital, and trazodone, buspirone, fluoxetine, as well as several natural productions (suntheanine, honokiol and berberine extracts, alpha casozepine, pheromones, and lavender essential oils) have also been used with varying degrees of success to help with signs associated with cognitive dysfunction in dogs.³

Conclusion

As has been demonstrated, canine cognitive dysfunction is a very important disease process associated with the aging dog, with significant implications for quality of life of the pet and family. It is our hope that with ongoing research, further links between comparable human-related diseases may be made with further advances in treatments gained.
 

References

1. Head, E., Zicker, S. Nutraceuticals, aging, and cognitive dysfunction. Vet Clin Small Anim 2004; 34: 217-228.
2. Landsberg, G., Araujo, J. Behavior problems in geriatric pets. Vet Clin Small Anim 2005; 35: 675-698.
3. Landsberg, G., Nichol, J., Araujo, J. Cognitive dysfunction syndrome – a disease of canine and feline brain aging. Vet Clin Small Anim 2012; 42: 749-768.
4. Vite, C., Head, E. Aging in the canine and feline brain. Vet Clin Small Anim 2014; 44: 1113-1129.
5. Cotman, C., Head, E. The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. Journal of Alzheimer’s Disease 2008; 15: 685-707.
6. Grueter, B., Schulz, U. Age-related cerebral white matter disease (leukoaraiosis): a review. Postgrad Med J 2012; 88: 79-87.
7. O’Sullivan, M. Leukoaraiosis. Pract Neurol 2008; 8: 26-38.
8. Caplan, L. Biswanger’s disease – revisted. Neurol 1995; 45: 626-33.
9. Jung, W., Mun, C., Kim, Y., Park, J., Lee, B., Lee, Y., Moon, E., Jeong, H., Chung, Y. Cortical atrophy, reduced integrity of white matter and cognitive impairment in subcortical vascular dementia of Binswanger type. Psychiatry and Clinical Neurosciences 2014; 68: 821-832.
10. Landsberg, G., DePorter, T., Araujo, J. Clinical signs and management of anxiety, sleeplessness, and cognitive dysfunction in the senior pet. Vet Clin Small Anim 2011; 41: 565-590.
11. Farooq, M., Bhatt, A., Majid, A., Gupta, R., Khasnis, A., Kassab, M. Levetiracetam for managing neurologic and psychiatric disorders. Am J Health-Syst Pharm. 2009; 66: 541-561.

Additional reading

• Azkona, G., Garcia-Belenguer, s., Chacon, G., Rosado, B., Leon, M., Palacio, J. Prevalence and risk factors of behavioral changes associated with age related cognitive impairment in geriatric dogs. JSAP 2009; 50: 87-91.
• Bain, M., Hart, B., Cliff, K., Ruehl, W. Predicting behavioral changes associated with age-related cognitive impairment in dogs. J Am Vet Med Assoc 2001; 218: 1792-1795.
• Hasegawa, D., Yayoshi, N., Fujita, Y., Fujita, M., Orima, H. Measurement of interthalamic adhesion thickness as a criteria for brain atrophy in dogs with and without cognitive dysfunction (dementia). VRU 2005; 46 (6): 452-457.
• Landsberg, G. Therapeutic options for cognitive decline in senior pets. J Am Anim Hosp Assoc 2006; 42: 407-413
• Neilson, J., Hart, B., Cliff, K., Ruehl, W. Prevalence of behavioral changes associated with age-related cognitive impairment in dogs. J Am Vet Med Assoc 2001; 218 (11): 1787-1791.
• Salvin, H., McGreevy, P., Sachdev, P., Valenzuela, M. Under diagnosis of canine cognitive dysfunction: A cross-sectional surgery of older companion dogs. The Veterinary Journal 2010; 184: 277-281.