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Canine Cognitive Dysfunction

Introduction

Cognition is defined as; the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses. As we age our cognitive ability declines naturally, however some individuals may experience a rate of decline much greater than expected. This is known as cognitive dysfunction.

Cognitive dysfunction is apparent in a number of species, including; humans, dogs and cats. In dogs, canine cognitive dysfunction (CCD) can be responsible for alterations in normal behaviour, for example, the dog may be less active or show changes in their social interactions with human family members.

CCD is more likely to affect older dogs (just as human cognitive dysfunction, also known as dementia, is more likely to affect older individuals). The clinical signs of CCD can start to develop from 8 years of age, with the likelihood of developing CCD increasing with age. In a study by Neilson et al which looked at male and female dogs aged between 11 to 16, 28% of dogs aged 11 to 12 were diagnosed with mild CCD, whilst 10% were diagnosed with severe CCD. In the 15 to 16 year age bracket this increased to a 68% diagnosis rate for mild CCD and a 35% diagnosis rate for severe CCD.

Clinical Signs of Cognitive Dysfunction in Dogs

The initial signs of CCD can be very mild and thus easy to miss, however the symptoms will gradually develop over time. As the clinical signs can become apparent from as early as eight years of age, it is vital that you begin to regularly monitor your dog’s cognitive function by completing behavioural questionnaires. These questionnaires will be available from your vet. Using a questionnaire will allow for early diagnosis of CCD and thus prompt intervention.

The clinical signs of CCD typically fall in to the following categories, mainly associated with memory and learning:

  • Activity e.g.Increased or decreased movement, restlessness or wandering
  • Disorientation e.g. Decreased recognition of familiar people, pets or places
  • Interaction Changes e.g. Decreased interest in interaction or play
  • Sleep Pattern Alterations e.g. Restless sleep, crepuscular (dawn/dusk) sleeping activity
  • Loss of House Training e.g. Increased house soiling, or no signal of wanting to go outdoors

If a dog is displaying any abnormalities in the above categories, it is worth visiting your vet to rule out any differential diagnoses. For example, if your dog is displaying decreased activity it might not be CCD but instead something such as osteoarthritis. However, whilst it is important to rule out differential diagnoses, it is possible for CCD to coexist with other diseases.

Pathology of Canine Cognitive Dysfunction

Cognitive dysfunction is a reduction in the mental ability of an individual beyond what is expected for that age. There are a number of factors which can cause this decrease in cognitive function:

  • Increased oxidative damage of brain tissue by free radicals, correlated with a decrease in antioxidant levels
  • Development of ß-amyloid plaques in the cortical regions of the brain
  • Impaired glucose metabolism in the brain
  • Decreased frontal lobe volume

Dogs with CCD also show reduced cerebral blood flow and reduced dopamine levels in the brain.

Free radicals are harmful chemicals produced on a daily basis by the body. As dogs age, the amount of free radicals produced increases but the amount of antioxidants (free radical neutralising molecules) decreases. An Increased level of free radicals leads to increased amounts of cellular injury and decreased glucose metabolism by neurones.

Unregulated free radicals can react with mitochondria, DNA, lipids and proteins resulting in alterations to enzymes, receptors and ion channels, organelle loss and eventually apoptosis (Montuschi, P 2007). The mitochondria are essential for neuronal defence and repair (Liu, J 2008), damage to them leads to impaired electron transport, decreased energy production and increased production of free radicals resulting in an escalating cycle of destruction (Wei, YH 1998).

Neuropathology of Canine Cognitive Dysfunction

Different structures in the brain undergo different aging processes:

  • Meninges become thick and calcified (Osella, MC 2008)
  • Blood vessels become harder (arteriosclerosis) and show decreased perfusion (Milgram, NW 2004). There is also increased likelihood of haemorrhage surrounding the blood vessels (perivascular haemorrhage) (Landsberg, GM 2010).
  • Ventricles become dilated (Osella, MC 2008).
  • Neurones and glial cells demyelinate (Hu, YS 2010; Hill, AS 2004), their membrane function alters and they are more likely to undergo apoptosis. The axon structure undergoes degeneration and fatty deposits (lipofuscin) build up on the neurons (Salvin HE 2010).
  • Neurotransmitters and receptors decrease in abundance.

Treating Canine Cognitive Dysfunction

Treating CCD often involves a three-pronged approached; utilising pharmaceuticals and nutraceuticals and combining them with mental and behavioural support.

Pharmaceuticals

Selegiline Hydrochloride is the only licensed drug available for treatment of CCD. It is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B). Because MAO-B is responsible for the metabolism of dopamine, its inhibition by Selegiline increases dopamine concentrations. Selegiline Hydrochloride has also been shown to reduce glial cell damage, promote synthesis of nerve growth factors and to a minor extent, reduce free radical damage.

There are side effects associated with selegiline hydrochloride use however. Due to the fact selegiline is metabolised to L-amphetamine and L-methamphetamine it shares similar side effects with these sympathomimetic stimulants.

Side effects range from minor dizziness and nausea to more serve heart arrhythmia and respiratory difficulties.

Nutraceuticals  

Treating CCD is a long term process and many people can be concerned with continually administering pharmaceuticals to their pets. As an alternative to pharmaceuticals, many owners are turning to nutraceuticals such as AKTIVAIT® from VetPlus. AKTIVAIT® is a synergistic combination of nutrients, antioxidants and mitochondrial co-factors which has been demonstrated to be of benefit for cognitive dysfunction (Heath, Sarah 2007). AKTIVAIT® is available to treat both canine and feline cognitive dysfunctions.

How AKTIVAIT® Works

AKTIVAIT® contains a number of ingredients which act together synergistically to alleviate CCD. Ingredients include:

  • Docosahexaenoic Acid (DHA) – Reduces neuronal inflammation and apoptosis. DHA is also responsible for increasing neuronal levels of phosphatidylserine
  • N-Acetyl Cysteine (NAC) – A primary precursor to glutathione a crucial endogenous antioxidant which protects neurones from oxidative damage. NAC levels decrease significantly with age
  • L-Carnitine & Acetyl L-Carnitine – Essential in the transport of long chain fatty acids. L-Carnitine enhances mitochondrial function whilst Acetyl L-Carnitine acts synergistically with α-lipoic acid to improve brain function, memory and activity levels by helping to reduce mitochondrial damage and increase mitochondrial numbers
  • Phosphatidylserine – Regulates the fluidity of neuronal membranes. It enhances transmembrane transport, ion channel function and enhances neurotransmitter release. Phosphatidylserine also protects cholinergic neurons and pyramid cells of the hippocampus from apoptosis and loss of dendritic spine. It also increases nerve growth factor synthesis and release, thus stimulating neuron sprouting and growth. Phosphatidylserine stands out as an essential brain nutrient (Osella, MC 2008).
  • Coenzyme Q10A lipid soluble antioxidant which helps to maintain antioxidant defences by regenerating vitamin E. Coenzyme Q10 is essential for electron transport in the mitochondria, while deficiency impairs ATP production and leads to oxidative stress. Supplementation with Coenzyme Q10 has been shown to delay brain atrophy and to protect against cognitive decline.
  • Selenium – An antioxidant which can help prevent cognitive decline and oxidative damage
  • Vitamin E & Vitamin C – Antioxidants which have a synergistic benefit in protecting mitochondria from age-associated oxidative damage and it has been shown that in cases of CCD, vitamin E levels in the brain are significantly reduced.
  • α-Lipoic Acid – A powerful mitochondrial antioxidant capable of regenerating most other antioxidants. α-lipoic acid protects cortical neurons from β-amyloid and hydrogen peroxide induced cytotoxicity and reduces lipofuscin levels. Synergistic antioxidant effects have been demonstrated with vitamin E, Coenzyme Q10 and Acetyl L-Carnitine. α-lipoic acid has been reported as toxic in cats and as such, is not included in AKTIVAIT® Cat.

In clinical trials, it was indicated that AKTIVAIT® has a clear, beneficial effect on aspects of behaviour associated with CCD (Heath, Sarah 2007).

Given that cognitive dysfunction is a progressive and irreversible condition it it recommended to start supplementation when any tell-tale behaviour signs are identified and all differential diagnoses have been ruled out (Neilson JC 2001; Heath, Sarah 2007).

Mental and Behavioural Support

Providing mental stimulation and environmental enrichment for dogs with CCD can help to improve cognitive function (Milgram, NW 2004) and has been shown to enhance neurogenesis and decrease brain pathology (Hu YS 2010).

Dogs with CCD will be suffering from memory and learning impairments; it is important not to get angry with the dog as this can cause further anxiety. Instead help your dog to relearn commands, use large visual or audio cues to aid navigation and discrimination. Any training stimulation should be given in short bursts as dogs with CCD have a limited concentration span.

Mixing stimulation such as above with consistent, moderate exercise and play can help enhance the quality of life for the dog.

Combining behavioural and environmental with the administration of nutraceuticals such as AKTIVAIT® can have a potentially valuable role in maximizing the benefits of therapy in terms of increased quality of life (Heath, Sarah 2007).

References

Bain MJ, Hart BL, Cliff KD, Ruehl WW (2001). Predicting behavioural changes associated with cognitive impairment in dogs. JAVMA; 218 (11) 1792- 1795

Chapman BL and Voith VL (1990). Behavioural problems in old dogs 26 cases (1984-1987) JAVMA; 196: 944- 946

Cummings BJ, Head E, Afagh AJ, Milgram NW, Cotman CW (1996). Beta amyloid accumulation correlates with cognitive dysfunction in the ages canine. Neurobiology of Learning and Memory; 66: 11- 23

Hart BL, Neilson JC, Ruehl WW. Behavioural Changes in Ageing Dogs: A demographic analysis. In: Mills DS, Heath SE, Harrington LJ (1997). Proceedings of the First International Conference on Veterinary Behavioural Medicine; 31- 33

Heath, S.E., Barabas, S. & Craze, P.G. (2007), Nutritional supplementation in cases of canine cognitive dysfunction—A clinical trial, Applied Animal Behaviour Science, vol. 105, no. 4, pp. 284-296.

Hill, A.S., Werner, J.A., Rogers, Q.R., O’Neill, S.L. & Christopher, M.M. (2004), Lipoic acid is 10 times more toxic in cats than reported in humans, dogs or rats, Journal of Animal Physiology and Animal Nutrition, vol. 88, no. 3-4, pp. 150-156.

Hu, Y.S., Xu, P., Pigino, G., Brady, S.T., Larson, J. & Lazarov, O. (2010), Complex environment experience rescues impaired neurogenesis, enhances synaptic plasticity, and attenuates neuropathology in familial Alzheimer’s disease-linked APPswe/PS1DeltaE9 mice, The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol. 24, no. 6, pp. 1667-1681.

Landsberg, GM (2010) An overview of clinical aspects and signs of age related cognitive dysfunction. J Vet Behav 5(3): 153-4

Liu, J. (2008), The Effects and Mechanisms of Mitochondrial Nutrient α-Lipoic Acid on Improving Age-Associated Mitochondrial and Cognitive Dysfunction: An Overview, Neurochemical research, vol. 33, no. 1, pp. 194-203.

Kitani K, Kanai S, Ivy GO, Carillo MC (1998) Assessing the effects of deprenyl on longevity and antioxidant defences in different animal models. Ann NY Acad Sci; 854: 291- 306

Milgram, N.W., Head, E., Zicker, S.C., Ikeda-Douglas, C., Murphey, H., Muggenberg, B.A., Siwak, C.T., Tapp, P.D., Lowry, S.R. & Cotman, C.W. (2004), Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in beagle dogs, Experimental gerontology, vol. 39, no. 5, pp. 753-765.

Montuschi P, Barnes P & Roberts LJ (2007) Insights into oxidative stress: the isoprostanes. Curr Med Chem 14: 703-717

Neilson JC, Hart BL, Cliff KD, Ruehl WW (2002). Prevalence of behavioural changes associated with age-related cognitive impairment in dogs. JAVMA; 218 (11): 1787- 1791

Osella, M.C., Re, G., Badino, P., Bergamasco, L. & Miolo, A. (2008), Phosphatidylserine (PS) as a potential nutraceutical for canine brain aging: A review, Journal of Veterinary Behavior: Clinical Applications and Research, vol. 3, no. 2, pp. 41-51.

Salvin, H.E., McGreevy, P.D., Sachdev, P.S. & Valenzuela, M.J. (2011), The canine cognitive dysfunction rating scale (CCDR): a data-driven and ecologically relevant assessment tool, Veterinary journal (London, England : 1997), vol. 188, no. 3, pp. 331-336.

Tapp PD, Siwak CT, Gao, FQ (2004). Frontal lobe volume , function and β-amyloid pathology in a canine model of aging. J Neuroscience; 24: 8205-8213

Wei, Y.H. (1998), Oxidative stress and mitochondrial DNA mutations in human aging, Proceedings of the Society for Experimental Biology and Medicine.Society for Experimental Biology and Medicine (New York, N.Y.), vol. 217, no. 1, pp. 53-63