Guest article by Joel Stone DVM, PhD
I have spent more time with my dog, Jenna, over the years than I have with my wife and kids. Part of the reason is that as a veterinarian, I am lucky enough to be able to bring her to work with me every day. She currently is 13 years old. We know each other so well, that most the time she knows what I want her to do before I ask her. However, I have started to see aging changes over the past year that includes a low level of cognitive dysfunction. In her case, this includes mild disorientation and changes in social interactions and activity levels. Of course, I am getting older myself and I wouldn’t be surprised if my wife said the same thing about me! In truth, Jenna and I have grown old together. Unfortunately, the tempo at which dogs grow older is much faster than for humans. We all want to stay young, and as a veterinarian and a “pet-parent” for a dog that I dread the day I have to say good-bye, I thought it might be good to talk about what we can do to treat cognitive dysfunction.
What is Cognitive Dysfunction Syndrome? From a neurologic and anatomical perspective, the pathology in dogs and cats shares some characteristics with human Alzheimer’s disease, 1,2specifically B-amyloid accumulation, phosphorylation, and nerve loss in regions of the brain.2-5The most common signs of cognitive dysfunction syndrome in dogs include house soiling (in a previously house-trained dog), and an increase or decrease in social interactions.6 Dogs can show signs of anxiety or fear (eg. agitation), which may be a result of disorientation. Older dogs should be screened for cognitive dysfunction syndrome at annual veterinary visits.
What promotes cognitive health as pets age? Like in humans, environmental enrichment, mental stimulation, and diet promote cognitive health as pets age. There are no approved drugs for the prevention of cognitive dysfunction syndrome, and only one drug has been approved for dogs to treat cognitive dysfunction syndrome, once clinical signs have been detected.7
Selegiline is the only FDA-approved drug for treatment of cognitive dysfunction syndrome. It is only approved for use in dogs, although use in cats has been described.8 Selegiline is a monoamino oxidase inhibitor (MAOI) that specifically inhibits monoamine oxidase-B. In clinical trials, selegiline was shown to improve sleeping, housetraining, and activity in dogs.9 It has also been shown to improve spatial memory and have positive effects on learning and attention.10 It is important to note that improvement in clinical signs may take giving one tablet once a day for 6-8 weeks. As with most drugs, some dogs had adverse effects including vomiting, diarrhea, hyperactivity/restlessness, ataxia and disorientation as reported in the clinical trials.11
Some nutraceuticals have been used to treat cognitive dysfunction syndrome. The following discussion is limited to those that are available in the United States and that have been studied in dogs and cats.
α-Casozepine is derived from α S1-casein in milk. Though the mechanism of action is not completely understood, α-casozepine appears to have efficacy in anxiety paradigms in cats and dogs12,13; in dogs, however, it was evaluated for equivalence against selegiline.13
α-Casozepine (Zylkene) may be useful in alleviating signs of anxiety that accompany cognitive dysfunction syndrome.
Antioxidants & Phospholipids
Oxidative stress appears to have a role in cognitive disorders by causing damage to proteins and lipids in the brain. Vitamins E and B and resveratrol have antioxidant properties and have been incorporated into supplement combinations and diets. Phospholipids (eg, phosphatidylserine) have also been included for their role in cell signaling. Products that contain a mixture of antioxidants and phospholipids (eg, phosphatidylserine) are available. One such product has been evaluated in an open-label trial with a small number (n = 8) of dogs with cognitive dysfunction syndrome.14 Although positive effects were shown on signs of cognitive dysfunction syndrome,14 results should be followed with a larger, controlled trial. This product was also shown to improve performance in a memory task in a placebo-controlled study of laboratory beagles.15 Other supplement combinations are available outside the United States, one of which includes antioxidants, phosphatidylserine, and omega-3 fatty acids and has been shown to improve scores for house soiling, owner recognition, and number of hours awake during the day.16
S-adenosyl-L-methionine tosylate (NOVIFIT) may help maintain cell membranes and regulate cellular functions. It has been evaluated for use in treating depression, osteoarthritis, and liver disease.17 NOVIFIT (NoviSAMe) has also been shown to selectively improve performance on tasks of executive function in laboratory-housed dogs and cats with cognitive dysfunction syndrome.18 In cats, treatment was most successful in earlier stages of cognitive decline as compared with later stages.18
Apoaequorin* is a calcium-binding protein derived from jelly-fish. It is believed to have calcium-buffering effects that protect against cell death. When assessed for effects on attention and memory in laboratory-housed dogs, apoaequorin showed favorable results against both placebo and selegiline for select cognitive tasks, particularly selective attention.19
Two prescription diets have been labeled to support cognitive health in dogs, including:
Hills Canine b/d (hillsvet.com) and Purina Pro Plan Veterinary Diets NeuroCare (purina.com).
Hill’s Canine b/d contains supplements of antioxidants, mitochondrial cofactors, and omega-3 fatty acids. Aged dogs fed this diet for 6 months showed improved performance (ie, fewer errors) on an oddity discrimination task as compared with aged dogs fed a control diet.20 Purina Pro Plan Veterinary Diets NeuroCare is supplemented with antioxidants, omega-3 fatty acids, and medium chain triglyceride vegetable oil. This diet was studied in a randomized controlled trial and was shown to improve signs of cognitive dysfunction syndrome in dogs following a 90-day feeding period, relative to baseline.21 In another study, dogs fed a diet supplemented with arginine, B vitamins, fish oil, and antioxidants performed better in tests of memory and discrimination.22 These specific diets are available for dogs, whereas supplementation has been incorporated into the diets of senior and geriatric cats. No veterinary diet has been specifically labeled to support cognitive function in cats. However, there is evidence that middle-aged cats fed a diet supplemented with antioxidants, arginine, B vitamins, and fish oil performed better in a series of cognitive tests as compared with cats fed a non-supplemented control diet.23
Dr. Joel Stone is a practicing veterinarian in Colorado, a former research scientist, and the inventor of Better Breath™ for Pets—a revolutionary product that treats and prevents periodontal disease and bad breath in dogs and cats. Email Dr. Stone at [email protected] or visit getbetterbreath.com to learn more!
Dr. Stone holds a Ph.D. in Comparative Medicine from the University of California, San Diego and a Doctor of Veterinary Medicine (DVM) degree from Colorado State University.
1. Landsberg G, Hunthausen W, Ackerman L. The effects of aging on behavior in senior pets. In: Behavior Problems of the Dog and Cat. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2013:211-236.
2. Head E. Neurobiology of the aging dog. Age (Dordr). 2011;33(3):485-496.
3. Zhang C, Hua T, Zhu Z, Luo X. Age-related changes of structures in cerebellar cortex of cat. J Biosci. 2006;31(1):55-60.
4. Zhang C, Zhu Q, Hua T. Effects of ageing on dendritic arborizations, dendritic spines and somatic configurations of cerebellar Purkinje cells of old cat. Pak J Zool. 2011;43(6):1191-1196.
5. Chambers JK, Tokuda T, Uchida K, et al. The domestic cat as a natural animal model of Alzheimer’s disease. Acta Neuropathol Com. 2015;3:78.
6. Landsberg GM, Deporter T, Araujo J. Clinical signs and management of anxiety, sleeplessness, and cognitive dysfunction in the senior pet. Vet Clin North Am Small Anim Pract. 2011;41(3):565-590.
7. U.S. Food & Drug Administration. Application number 141-080 (Anipryl). US FDA website. https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/141- 080. Accessed November 6, 2018.
8. Landsberg G. Therapeutic options for cognitive decline in senior pets. J Am Anim Hosp Assoc. 2006;42(6):407-413.
9. Knoll J. (L-)Deprenyl (selegiline), a catecholaminergic activity enhancer (CAE) substance acting in the brain. Pharmacol Toxicol. 1998;82(2):57-66.
10. Ruehl WW, Bruyette DS, DePaoli A, et al. Canine cognitive dysfunc-tion as a model for human age- related cognitive decline, dementia and Alzheimer’s disease: clinical presentation, cognitive testing, pathology and response to 1-deprenyl therapy. Prog Brain Res. 1995;106:217-225.
11. Anipryl [package insert]. Kalamazoo, MI: Zoetis; 2013.
12. Beata C, Beaumont-Graff E, Coll V, et al. Effect of alpha-casozepine (Zylkene) on anxiety in cats. J Vet Behav Clin Appl Res. 2007;2(2):40-46.
13. Beata C, Beaumont-Graff E, Diaz C, et al. Effects of alpha-casozepine (Zylkene) versus selegiline hydrochloride (Selgian, Anipryl) on anxiety disorders in dogs. J Vet Behav Clin Appl Res. 2007;2(5):175- 183.
14. Osella MC, Re G, Odore R, et al. Canine cognitive dysfunction syndrome: prevalence, clinical signs and treatment with a neuroprotective nutraceutical. Appl Anim Behav Sci. 2007;105(4):297-310.
15. Araujo JA, Landsberg GM, Milgram NW, Miolo A. Improvement of short-term memory performance in aged beagles by a nutraceutical supplement containing phosphatidylserine, Ginkgo biloba, vitamin E, and pyridoxine. Can Vet J. 2008;49(4):379-385.
16. Heath SE, Barabas S, Craze PG. Nutritional supplementation in cases of canine cognitive dysfunction—a clinical trial. Appl Anim Behav Sci. 2007;105(4):284-296.
17. Sharma A, Gerbarg P, Bottiglieri T, et al. S-adenosylmethionine
(SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry. 2017;78(6):e656-e667.
18. Araujo JA, Faubert ML, Brooks ML, Landsberg GM, Lobprise H. NOVIFIT (NoviSAMe) tablets improve executive function in aged dogs and cats: implications for treatment of cognitive dysfunction syndrome. Intern J Appl Res Vet Med. 2012;10(1):90-98.
19. Milgram NW, Landsberg G, Merrick D, Underwood MY. A novel mechanism for cognitive enhancement in aged dogs with the use of a calcium-buffering protein. J Vet Behav Clin Appl Res. 2015;10(3):217-222.
20. Milgram NW, Zicker SC, Head E, et al. Dietary enrichment counteracts age-associated cognitive dysfunction in canines. Neurobiol Aging. 2002;23(5):737-745.
21. Landsberg G, Pan Y, Mougeot I, et al. Efficacy of a therapeutic diet on dogs with signs of cognitive dysfunction syndrome. In: Proceedings of the 11th International Veterinary Behaviour Meeting. 2017;114.
22. Pan Y, Kennedy AD, Jönsson TJ, Milgram NW. Cognitive enhancement in old dogs from dietary supplementation with a nutrient blend containing arginine, antioxidants, B vitamins, and fish oil. Br J Nutr. 2018;119(3):349-358.23. Pan Y, Araujo JA, Burrows J, et al. Cognitive enhancement in middle-aged and old cats with dietary supplementation with a nutrient blend containing fish oil, B vitamins, antioxidants, and arginine.