Age-associated Cognitive Dysfunction
As our pets age, behavioral changes associated with aging of the brain often become evident. Cats and dogs may exhibit changes in sleep patterns, in interactions with other animals or with humans, problems with housetraining, and other symptoms. These changes have been correlated with changes in the brain that appear similar to those seen in human who exhibit signs of Alzheimer’s or other forms of dementia, and it is believed that some of the same mechanisms may lead to the age-associated behaviors seen in our pets.
Once the symptoms reach a sufficient level of severity, and if we have ruled out other detectable medical problems that can affect behavior, we can tentatively classify individual animals as having cognitive dysfunction. There is not established preventative for this syndrome, and the only licensed therapy, a medication called selegiline, is not widely viewed as very effective. So research is ongoing to learn more about the causes of cognitive dysfunction in pets and to develop interventions to prevent or treat it. Many products are also on the market claiming to have some preventative or therapeutic benefit, but as I have discussed in previous articles, there is not robust evidence for any particular approach. (1, 2, 3)
I recently ran across a research article looking at another combination of nutritional supplements intended to have an effect of age-associated cognitive dysfunction, and I thought this would be a good opportunity to revisit the subject.
Yuanlong Pan, Joseph A. Araujo, Joey Burrows, Christina de River, Asa Gore, Sandeep Bhatnagar and Norton W. Milgram. Cognitive enhancement in middle-aged and old cats with dietary supplementation with a nutrient blend containing fish oil, B vitamins,antioxidants and arginine. British Journal of Nutrition (2013), 110, 40–49.
The authors present the combination supplement they are investigating as a potential preventative for age-associated cognitive decline, arguing that given the multiple pathologies of the aging brain a single substance is unlikely to have a significant effect. The specific ingredients were chosen on the basis of theoretical arguments about the proposed mechanism for pathologic changes in the brain with aging and experimental or epidemiologic evidence, primarily in humans, suggesting the particular ingredients might have value.
We have consequently developed a blend of nutrients, referred to as the brain protection blend (BPB), which were selected based on their ability to minimise [sic] or eliminate the risk factors associated with brain ageing and dementia. The BPB includes fish oil, arginine, B vitamins and selected antioxidants. Fish oil containing DHA and EPA was selected to prevent and correct DHA deficiency and offer anti-inflammatory benefits. Arginine was selected to enhance NO synthesis, which has been linked to circulation, blood pressure control and cognition. B vitamins prevent and correct any B vitamin deficiency and minimise [sic] the risk of high homocysteine. Antioxidants, including vitamins E and C and Se, offer protection against oxidative damage and inflammation-induced damage in both brain tissue and blood vessels.
The rationale for choosing these ingredients is reasonable, though as I will discuss below there is not strong evidence of actual clinically meaningful effects for any of them in any species.
The design of the study involved two groups of cats (16 in each) who were fed identical diets except for the “brain protection blend” given to one group. The cats were studies over a period of about 7-11 months, and a number of behavioral tests were administered at different time points. The groups were constituted in such a way that baseline performance on one of the tests, and overall experience with the testing method, were evenly distributed between groups. Though this is a pretty small sample size, the methodology was generally sound and the long duration of the study was a strength.
Of the cognitive tests administered, only one was given at the beginning and again at the end of the study. The others were only given once, which makes it impossible to assess whether the supplement prevented a decline in performance compared to the control group. It is unclear why the investigators conducted the study this way when they seemed to be suggesting that their major hypothesis was that the supplement would prevent loss of cognitive function with aging.
The authors also measured some proxy markers for the effect of the specific components of the supplement. For example they measured vitamin B12, folic acid, fatty acids composition of red blood cells, and total antioxidant activity, each of which would be expected to be influenced by the supplement used.
The results did show some difference in behavior between the groups on three of the four tests used. For the one test that was given twice, both groups actually improved in performance. The control group showed a 2.8% improvement, which was not statistically significant, while the treatment group showed a 10.4% improvement, which was.
The biochemical measurements showed that the fish oil supplementation did increase the levels of n-3 fatty acids and decrease the level of n-6 fatty acids as expected. Folic acid levels were also slightly higher in the treatment group at the end of the study. There was, however, no change in B12 levels or total antioxidant status in either group. And neither group showed any deficiency in any measured nutrient.
Existing Evidence for the Supplement Components
As I said earlier, the choice of specific ingredients was based on some existing evidence, however there isn’t a very strong case that any of these components have a clinically meaningful effect on cognitive function in humans or animals.
For B vitamins, recent reviews have found that deficiency status is associated with a risk of lower cognitive function in humans in some studies. However, this effect is not consistent in all studies, and it does not appear that B12 levels are associated with dementia in individuals without a measurable B12 deficiency or that B12 supplementation is beneficial in individuals with adequate B12 levels to begin with. The relationship between B12 deficiency and cognitive dysfunction is also influenced by genetic variables in the human studies that have not been assessed in cats. So as is often the case, a vitamin deficiency clearly has negative effects, but that doesn’t automatically mean that supplementation above normal levels has benefits. In this study, the cats were not B12 deficient, so a benefit from additional supplementation would not be expected based on extrapolation from the data in humans.(4, 5, 6)
For fish oils, the most recent Cochrane review of the literature in humans concluded, “Direct evidence on the effect of omega?3 PUFA on incident dementia is lacking. The available trials showed no benefit of omega?3 PUFA supplementation on cognitive function in cognitively healthy older people.”(7) Another review focusing specifically on Alzheimer’s also found little evidence of benefit from fish oil supplementation. (8) However, one review focusing on a specific kind of cognitive dysfunction, vascular dementia, did find some indication in the human research of a benefit to fatty acid supplementation. (9) So while this study showed that supplementation did affect the levels of different kinds of fatty acids in the cats, it isn’t clear whether or not this should be expected to have a clinically meaningful effect on brain function in this population.
Human studies have also been done looking at the effect of antioxidant vitamins on cognitive dysfunction in humans. There is some evidence of benefit of Vitamins C and E for reducing the risk of vascular dementia and Alzheimer’s (8, 9) A review of selenium and Alzheimer’s, however, showed no therapeutic benefit and only a theoretical suggestion that the supplement could have preventative benefits. (10)
What Does This Study Show?
The current study did find some differences in performance on cognitive function tests between cats who were fed the supplement and cats who were not. However, there are a number of limitations to our ability to extrapolate from these results to the use of such a supplement in prevention or treatment of cognitive dysfunction.
For one thing, the results of cognitive function tests might or might not reflect any effect on real-world behavior. It isn’t entirely clear that differences on these kinds of laboratory exercises predict benefits in terms of real-life function that would be noticeable to cat owners. Only a study of cats with naturally occurring clinical disease, or a large long-term study looking for differences in the chances of developing such disease, can really tell us if this sort of supplement would be useful in the real world.
It is also not entirely clear what relevance most of the tests have to the main goal of the study, showing that the supplement could potentially prevent age-associated decline in brain function. Since most tests were only administered once, they can’t be used to show a protective benefit. And for the one test done twice, both groups actually improved in function. While the treatment group improved more than the control group, which might indicate some effect of the treatment, neither showed evidence of cognitive decline.
The authors chose to interpret the differences seen as indicating a possible enhancement of cognitive function. This is certainly a possible explanation of the data, though there are reasons why this can only be a tentative conclusion. However, in terms of treating or preventing cognitive dysfunction associated with age, this study can’t provide any direct evidence since it isn’t clear there was any such dysfunction in these cats.
Another possible source of error appeared in the way the cognitive function test data was analyzed. The original intent was to include a failure to respond during a test as a contribution to the error rate for that subject. However, the rate of failure to respond was higher than expected and would have significantly impacted the outcome of several tests. As a result, the authors changed their method of calculating the error rate after the fact, and they ignored response failures. In some cases individual subjects were excluded entirely from the data for specific tests because of failing to respond. The authors mention that five such exclusions were necessary for the treatment group. It isn’t clear from the report if any individuals from the control group were excluded from the analysis for this reason.
This is important because changing the way the main outcome measure is determined after the test has been done introducing a significant risk of bias into any study. And if the subjects who failed to respond were predominantly from the treatment group, this could change the direction of the different in test scores and completely alter the conclusions of the study. While there is no way to know if this is actually the case, this does raise a significant question about the internal validity of these data.
In terms of the biochemical data, it did show that the supplement had the desired effect on fatty acid levels. However, there was no sign of any vitamin deficiency in any of the subjects, so based on the data in humans it is not clear that additional supplementation of B, C, and E vitamins would be likely to have any benefits. And in any case, the blood testing did not show any difference in B12 levels or in total antioxidant status, so it is not clear that these components of the supplement even had any effect at all on the actual levels of these substances in the subjects.
Are There Risks?
As always, there is little chance of an intervention of any kind in medicine having dramatic benefits with no risks. The evidence from human studies suggests most of the ingredients in this supplement had few side effects. Previous studies have found some risks associated with supplementation of Vitamin E and Selenium, including possibly increased risk of some cancers. On the whole, it is likely that the particular supplement studied in this investigation has few clinically significant risks.
Cognitive dysfunction associated with ageing is a significant problem for companion animals, and it appears to have some clinical and biological features similar to some kinds of dementia in humans. There is limited evidence in humans that some nutritional supplements can have benefits in terms of preserving or improving cognitive function, however the data are weak and inconsistent, and often the effect depends on existing deficiency, genetic constitution, and other specific factors. The idea that nutritional supplements might help prevent or treat cognitive dysfunction in cats and dogs is reasonable, but there is little evidence to support the use of any particular supplement, and not much is known about the details of which nutrients might benefit individuals with particular causes of cognitive dysfunction.
The current study provides some support for the hypothesis that some of the nutrients investigated might have some effect on cognitive function in cats. However, the design generally does not allow any conclusion about the prevention or treatment of age-associated cognitive declines since it is not clear if any of the cats had this disorder or if there was deterioration in the control cats not experienced by the cats given the supplement. It is possible that the supplement improved the cats’ ability on some of the tests given in the study, but additional studies accounting for some of the limitations in this project would need to be done to confirm this.
Overall, then, there is little reason to believe that any specific supplement or combination will have dramatic benefits for all or most individuals with age-associated cognitive dysfunction. It may be that some causes of this syndrome can be mitigated by supplements and that this could result in clinically meaningful benefits, however this remains to be demonstrated.