Nutrition and Cognition in Older Persons

Home , Memory improvement, Nutrition and cognition

Nutrition and Aging: I.H. Rosenberg; A. Sastre (eds), Nestle´ Nutrition Workshop Series Clinical & Performance Program, Vol. 6, pp. 121–134, Nestec Ltd.; Vevey/S. Karger AG, Basel,  2002.

John E. Morley

GRECC, St. Louis VA Medical Center, and Division of Geriatric Medicine, Saint Louis University, St. Louis, Mo., USA

The concept that ‘we are what we eat’ is by no means a new one and appears to be particularly true when one examines the effect of food intake on cognitive function. Even in the case of mild protein energy malnutrition, poor nutritional state is associated with a decline in cognitive function [1]. Food intake, or the lack thereof, can modulate thought processes in multiple ways (Table 1). This chapter will focus on a number of mechanisms that appear to play a role in modulating cognition in older persons.

Modulation of Memory by Gastrointestinal Peptide Release

Cholecystokinin (CCK) has been shown to enhance memory retention [2]. It produces this effect by stimulating ascending ﬁbers in the vagus nerve (Fig. 1). These then send messages to the nucleus tractus solitarius and from there to the amygdala and the hippocampus [3]. When mice are fed immediately after learning a task, they demonstrate improved memory [2]. This enhanced retention can be abolished by utilizing a CCK antagonist. Circulating CCK levels are elevated in older persons and increase to a greater degree following fat administration [4]. CCK levels are elevated to a greater degree in malnourished compared to healthy older individuals [5]. Food intake improves cognition in humans [6]. It would seem possible that utilizing ﬁnger food high in fat (a potent CCK releaser) may be useful to reinforce positive behaviors in older persons with early deterioration in cognition. A number of other gastrointestinal peptides also modulate memory after peripheral administration. These include gastrin releasing peptide [7] and amylin [8]. The potential ability to manipulate this release of gastrointestinal hormones to modulate memory represents a fertile research ground.

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Table 1. Mechanisms by which food can modulate cognition

1. Release of gastrointestinal peptides that can modulate cognition 2. Alterations in gastrointestinal luminal bacteria resulting in increased gut cytokine release 3. Decreased nutritional status leading to impaired immune function, infections and cytokine release 4. Effects of circulating glucose 5. Effects of fasting on brain membrane fatty acid concentration 6. Vitamin deﬁciencies 7. Free radical scavengers 8. ‘Natural’ memory aids 9. Protein toxicity 10. Food-drug interactions

⇑Memory

Nucleus tractus Amygdala solitarius

Ascending vagus

CCK

Fat

Fig. 1. The mechanism by which cholecystokinin (CCK) enhances memory.

Cytokines and Cognition

Cytokines, such as interleukin-2, have been demonstrated to produce cognitive impairment and delirium after administration to humans [9]. There are three possible mechanisms by which cytokines may have their release

122 Nutrition and Cognition in Older Persons altered by food. Probiotics and biotics alter the gut flora often reducing local gastrointestinal cytokine release and decreasing the possibility that infectious bacteria enter the circulation. Starvation increases the ability of bacteria to translocate from the gastrointestinal lumen into the systemic circulation. Persons with malnutrition have a decrease in the immune system making them more prone to developing systemic infections and cytokine release. It has been suggested that cytokines produce their effects on the central nervous system indirectly similar to CCK by stimulating the ascending fibers of the vagus [10]. Recently we have studied the mechanism(s) by which interleukin-1 (IL-1) produced impaired memory retention. Direct administration of IL-1 into the septum results in impaired retention. Utilizing both mouse and human antibodies and hIL-1, we were able to demonstrate that intraperitoneally administered IL-1 produces its effects both by stimulating ascending nerve fibers and releasing itself in the septum and by a direct effect after it has crossed the blood brain membrane. Cytokine modulation of cognition following food ingestion represents another mechanism worthy of further exploration.

Effects of Circulating Glucose

Hypoglycemia is well established as a cause of delirium. On the other hand, continuously elevated glucose levels also are associated with cognitive impairment [11, 12]. This appears to be a direct glucotoxic effect as in mice made diabetic with streptozotocin, a single injection of insulin restores their impaired performance on retention tests to normal [13]. In addition, three studies in older humans found that improved glucose control resulted in improved cognitive ability [14–16]. In addition to this, long-term poorly controlled diabetes results in permanent cognitive dysfunction secondary to vascular dementia [17]. Increases in glucose within the normal range, such as occur during a glucose tolerance test, improve memory in animals [18], young [19] and older [20] humans. Patients with dementia of the Alzheimer’s type appear to have abnormalities of glucose metabolism [21]. Raising the glucose levels in these patients improves cognition [22]. This effect appears to be predominantly due to the increase in insulin levels produced by elevating glucose levels [23].

Fat and the Neuronal Cell Membranes

There is increasing evidence that fatty acid ratios in the diet can modulate the production of neurotransmitters, neuropeptides, enzymes and neuronal membrane composition [24]. In infants, some studies have suggested that dietary supplementation of long-chain polyunsaturated fatty acids may enhance cognitive function [25, 26].

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↑Amyloid precursor protein

↑β-Amyloid

↓∆9-Desaturase

↓Unsaturated fatty acids

↓Membrane fluid

↓Neurotransmitter function

↓ Fig. 2. Pathophysiology of the cognitive defects due Cognition to β-amyloid overproduction. Based on studies in the SAMP8 mouse.

In the Rotterdam Study the effect of food intake on the development of dementia was studied in 5,386 nondemented persons 55 years and older [27]. Dementia was associated with total fat (RR2.4), saturated fat (RR1.9) and cholesterol (RR1.7) intake. Fish consumption was inversely related to incident dementia (RR0.4). In a smaller group of elderly people in Spain lower intakes of saturated fat and cholesterol were found in persons with a normal MiniMental Status Examination [28]. The Italian Longitudinal Study on Aging examined the relationship of dietary macronutrients to cognitive function in 5,632 subjects aged 65–84 years [29]. In this study, high monounsaturated fatty acid intake was protective against age-related cognitive decline. These data are supported by a study in rats that demonstrated that a diet with high concentrations of saturated fatty acids impaired a wide range of learning and memory functions [30]. Yamomoto et al. [31] reported that a diet high in α-linolenate (18:3 n − 3) increased survival time and learning

124 Nutrition and Cognition in Older Persons ability in older rats. Sardine oil which increases brain levels of docosahexanoic acid enhanced membrane ﬂuidity and maze-learning ability in mice [32]. Dietary docosahexanoic acid increased levels of hippocampal acetylcholine and improved passive avoidance response in stroke-prone spontaneously hypertensive rats [33]. The SAMP8 mouse develops early impairment in acquisition and learning [34]. This impairment is related to overproduction of β-amyloid [35, 36]. Activity of 9-desaturase is reduced by nearly 50% with age in these mice [37]. This is due to a speciﬁc decrease in mRNA. The decline in 9-desaturase is accompanied by the expected decline in the brain levels of unsaturated fatty acids. Dietary supplement with perilla oil (rich in α-linolenate) resulted in improved learning ability in the SAMP8 mouse [38]. Figure 2 provides a schema by which β-amyloid overproduction appears to result in cognitive decline. Yehuda et al. [39] provided a short-term supplementation to 100 patients with Alzheimer’s disease with a compound containing a 1:4 ratio of n − 3 and n − 7 fatty acids. Patients showed improvements in mood, cooperation, appetite, sleep, ability to navigate at home and short-term memory. Not all patients demonstrated a response. Overall these studies strongly support a role of membrane mobility in the development of age-related cognitive decline and in dementia. Dietary intervention appears to hold the potential to reverse these defects.

Cholesterol and Cognition

In vitro, in cell cultures, cholesterol can modulate the production of β- amyloid [40, 41] and hypercholesterolemia accelerates the β-amyloid pathology in a transgenic mouse model [42]. Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons [43]. Sparks [44] found that dietary cholesterol induced Alzheimer-like β-amyloid immunoreactivity in the rabbit brain. Studies examining the effect of cholesterol lowering in middle age support the concept that this will result in decreased atherosclerosis and decreased vascular dementia [45]. The direct effects of cholesterol-lowering agents on cognition are less clear. Two studies failed to show an effect of cholesterol- lowering agents on cognition [46, 47] while two showed deleterious effects [48, 49].

Vitamins

Vitamin deficiencies were among the first clearly recognized causes of delirium. Thus pellagra (nicotinic and deficiency) is characterized by

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Table 2. Effects of vitamin administration on cognition

Reference Treatment Outcome

Eastley et al. [51] Vitamin B12 Improvement in mild cognitive impairment patients on verbal fluency test Hassing et al. [52] Folic acid Improvement in impairment of word recall and object recall Deijen et al. [53] Vitamin B6 Improvement in long-term memory Smidt et al. [54] Thiamine Improvement in cognitive function Wilkinson et al. [55] Thiamine Improved cognition dermatitis on the sun-exposed skin and dementia; thiamine deficiency results in Wernicke’s encephalopathy with delirium, sixth nerve palsy and coma, and vitamin B12 deficiency leads to dementia and megaloblastic anemia. Decreases in vitamin levels are associated with poorer cognitive function [50]. Studies with single vitamin replacement have been shown to result in improved cognition [51–55] (Table 2). Excess vitamin A can lead to hypercalcemia with associated delirium and/or depression.

Oxidative Stress

Free radicals represent one mechanism by which neurons may be damaged. Persons with dementia have lesions in their brains that include damage to DNA, lipid peroxidation, advanced glycated end products and protein oxidation, and are suggestive of free radical damage [56]. β-Amyloid toxicity is eliminated by free radical scavengers [57]. Patients with Alzheimer’s disease have mitochondrial abnormalities which can result in enhanced production of free radicals.

Free Radicals

Vitamin E has been demonstrated to block β-amyloid-induced neuronal damage in cell culture [58]. Vitamin E improves memory in animal models of dementia [59]. In a randomized study in which subjects received α- tocopheral (2,000 IU daily) there was evidence that vitamin E might delay the development of dementia and functional deterioration [60]. However, this ﬁnding required adjustment for the baseline values, creating a questionable statistical outcome. α-Lipoic acid, a potent free radical scavenger that enters the mitochondria, has been shown to markedly improve learning and retention in the SAMP8 mouse [Farr SA and Morley JE, unpublished observations]. Anecdotally we

126 Nutrition and Cognition in Older Persons have seen dramatic improvement in the MiniMental Status Examination in persons with Alzheimer’s disease receiving between 600 and 900 mg of α-lipoic acid a day.

Herbs

The best studied herbal medicine for cognition is ginkgo biloba. Ginkgo biloba extract (EGb 761) has been shown to prevent β-amyloid-induced cell death in hippocampal neurons [61]. Two meta-analyses of the effects of gingko biloba in humans suggest a small, but signiﬁcant, effect in persons with early dementia [62, 63]. Alternatively, van Dongen et al. [64] failed to ﬁnd an effect of gingko in dementia. In a year-long study using EGb 761, Lebars et al. [65] found improvement of 1.4 points over the placebo group in the active group on the Alzheimer’s Disease Assessment Scale–Cognitive subscale. Overall, these studies suggest a small effect of ginkgo on cognition.

Conclusion

There are multiple ways in which nutrition can modulate cognition in older persons. In general, the effect size is small. Studies to determine optimum nutrition for older persons with mild cognitive impairment are clearly needed.

References

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Discussion

Dr. Roberts: You have suggested a deluge of factors that might be important, but if you had to design the ideal diet for testing, what would it look like? Dr. Morley: It would be a diet that had a lot of fish oil and a fair amount of α-lipoic acid in it, plus a small amount of carbohydrate so it would have a poor glycemic index rather than a good one. These three things are based on what we have seen, and we have such a diet which is going into testing now. The α-lipoic might be wrong but it works very well on animals. Dr. Meydani: Someyearsagowedidastudyinananimalmodelofamyloidosis where we fed animals fish oil compared with corn oil and saturated fat [1]. We could show that amyloid deposition was significantly decreased in the animals that had fish oil, and at the time we hypothesized that the effect was through macrophages and a reduction in cytokine production. In the studies where you looked at fish oil and other

130 Nutrition and Cognition in Older Persons types of fat, was the fish oil given in the context of a low-fat diet or a high-fat diet? With a high-fat diet we had high levels of amyloid in our model. Dr. Morley: They were given a normal-fat mouse diet, not a low-fat diet. We are very convinced from our studies that what we are doing is altering the membrane mobility. We have a lot of data showing that neurotransmitter binding and the activation of the neurotransmitters within the cells are both markedly decreased when β-amyloid is high; when we bring it down and alter the fatty acid concentration in the membrane, the animal goes back to behaving like a 4-month-old rather than a 12-month-old. We may be wrong but makes sense and that fits with other published data, particularly from Yehuda’s [2] group in Israel. Dr. Folstein: In the studies where you have caused altered memory, have you looked at the brain? What is going on there, and why is the memory changing? Dr. Morley: Our theory is that we are altering membrane fluidity. We have a large amount of data, both in vivo and in vitro, showing alterations in neurotransmitter function as opposed to binding sites. There are small changes in binding sites but large changes in the function of agents such as arecoline. Alterations in memory are mirrored by alterations in arecoline function, so I think what we are looking at is an alteration in membrane mobility – the ability of the membrane to transduce a neurotransmitter and produce its effect within the cells. Dr. Folstein: You are speaking as if the problem is primarily at a neuronal level, but there is evidence that the important changes are not at neuronal level but in the white matter. Dr. Morley: They may be, but most probably aren’t. However, I think we have many models of dementia and what I presented is the story I like the best as it fits our own data. I really wanted to make it clear that there is no one answer; that is why I reviewed each of these areas, otherwise you would have just got my story. We have a lifetime of work and I will be demented long before we know most of the answers. Dr. Meydani: In relation to fish oil, are there any studies showing differences in memory and cognitive function in Eskimos versus Western populations? Dr. Morley: One of the things I avoided carefully was making any ethnic or racial comparisons. There will be substantial differences in the prevalence of malnutrition, in education level, and so on, and you would have to control for all of those, so it would not be reasonable to compare Eskimos with a ‘Western’ population. A better comparison was made in the Rotterdam study [3], in a homogeneous population where a lot of people were eating fish. Dr. Cottrell: In drug-resistant epilepsy we are now using vagal pacemakers. These seem to work quite effectively in some epileptic patients. If the vagus nerve has an influence on memory, do you know any trials on Alzheimer’s disease using vagal pacemakers? Dr. Morley: No, I don’t. Dr. Cottrell: It might be worth a trial I suppose. Also, do you know of any electrophysiological studies of the effect of CCK on neurons? It is now known that in vertebrates peptides act directly on ion channels. It would be interesting to look at the effect on long-term potentiation. Dr. Morley: There is a huge literature on CCK and electrophysiological changes within the central nervous system. Much of the work has been done in the hypothalamus rather than in the hippocampus, because of the feeding effects. There are one or two studies on long-term potentiation, though I think that’s an inadequate proxy for memory – it sometimes works and it sometimes doesn’t when you compare long-term potentiation with memory, which we’ve done many times. However, I think there are at least two studies showing effects of CCK on long-term potentiation within the hippocampus [4, 5], though it’s not something we went into in any great detail.

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Dr. Taylor: You commented on nutrients that are mainly lipid soluble because you were concentrating on membrane. What are the effects of the aqueous antioxidants such as vitamin C? Dr. Morley: The data on vitamin C that I am aware of are all epidemiological. I don’t know of any interventional studies with vitamin C, other than Linus Pauling’s. I haven’t seen any studies at all on vitamin C and memory, though I might have missed them. Dr. Gutiérrez: Are you aware of any study looking at the effect of hypercholesterolemia in elderly people? What is the expected effect on cognition in this particular group? You mentioned that statin treatment could have a deleterious effect. Dr. Morley: The effect may be deleterious. There are as far as I know no studies on statins in Alzheimer’s disease. That is soon to be totally changed as an NIH sponsored study is about to begin. I think the outcome is likely to fit with our expectations – that these people will be worse off on statins. When people on statins come to see us with early dementia, we tend to stop them. This at least makes the relatives happy, though it may only be because they have one less drug to remember. We have little evidence to suggest that lowering plasma cholesterol in useful in early dementia. On the other hand I think there is good evidence that in people with hypercholesterolemia lowering cholesterol early on will stop them developing vascular dementia. I think the data support taking statins at least until you become demented, and at that stage they should probably be stopped. It looks as though there may be an ideal level of cholesterol. If you can get your cholesterol into that ideal level it will have a beneficial effect. What that ideal level is for an 80-year-old, I have no idea. I think that is one of the areas we should be looking at very carefully, not only for memory but also for vascular disease. Dr. Hirsch: Do you know if there are differences in memory loss between obese and non-obese elderly people? Obese individuals have increased cytokines and that could be an additional factor. Dr. Morley: There are some studies in obese animals. Obese animals don’t learn as well as non-obese animals, but this could be an artifact of the training mechanisms used, which sometimes involve food rewards or may rely on the animals’ mobility in some way. So I’m not certain that the memory deficit is a real one. One dietary restriction study showed that with moderate dietary restriction – about 20% – there was an improvement in outcome in a couple of memory tests in rats that were around 20 months of age [6, 7]. Am I right, Dr. Weindruch? Dr. Weindruch: There are around 10 such studies in mice or rats subjected to life-prolonging energy restriction. I recall that about seven of those studies report that age-associated changes in learning and behavior are attenuated in calorically restricted animals. Dr. Malnoe: You showed a reduction of 9-desaturase with aging. We know that the products of 9-desaturase are mainly oleic acid and palmitoleic acid. A good source of oleic acid is olive oil, so I wonder if anybody has looked at the effect of olive oil on memory in a mouse model, or any other model. Dr. Morley: I don’t know of any data on that but it makes a lot of sense. I don’t think it is any different from using fish oil or any of the other ways of making those changes. Dr. Ferry: Would you comment on the relative antagonism between CCK8, which enhances memory after dietary intake, and CCK4 which is a principal factor in anorexia and reduced dietary intake in elderly people? Dr. Morley: CCK8 switches off a meal. So our study of CCK8 has been predominantly from the point of view of its being an anorectic agent. The problem is that almost all the neurotransmitters that alter feeding also alter memory, and they don’t often have a positive effect on memory. So the reality is that if you develop a great CCK

132 Nutrition and Cognition in Older Persons antagonist that makes people eat more, they may also not remember to eat! For those of us working in the field trying to develop drugs for anorexia of aging this is a major problem. Every time you use a drug that enhances food intake you tend to harm other functions. Your point is very well taken. Dr. Endres: Has anybody done studies with polyphenols or alcohol in relation to cognitive function and mood? Dr. Morley: Fundamentally drinking is great for your memory – that is, people who drink a reasonable amount of alcohol, not an excess, tend to have better cognitive function than people who do not drink alcohol. There is a huge literature on this, though none in older people. The only study I have been able to find on alcohol and memory in older people was one involving thiamine supplementation in Irish women. They did extremely well with thiamine replacement, which may have indicated that this cohort was composed of heavy drinkers rather than moderate drinkers. There is evidence that alcohol taken in moderation improves bones, improves muscle, improves cardiovascular function, and it also appears to improve cognitive function. Dr. Gutiérrez: Do you think it is really alcohol or something else present in wine, for example, like flavonoids, that has a positive effect on cognitive impairment? Dr. Morley: It seems that all kinds of alcohol produce positive effects, not just red wine. There are enough data now to suggest that any kind of alcohol is good for you. That makes me think that it most probably is not going to be a particular contaminant in alcohol. Dr. Weindruch: I thought it might be useful to alert people to the emerging epidemiological literature relating low energy intakes to a lower risk of Alzheimer’s disease and Parkinson’s disease. Papers have been published on this from groups in New York City (Dr. R. Mayeux) and Case Western Reserve University (Dr. M. Smith). Dr. Morley: There does appear to be a most healthy point in the body mass index. When you get old, a very low body mass index is also a disaster as far as cognition is concerned, as judged by nursing home patients. The problem is finding the right part of the U-shaped curve. Dr. Rosenberg: I certainly agree with your observation that the short-term effects on memory of the nutritional manipulations you have talked about are going to be small, and the literature is quite consistent in that regard. But if one takes the long view, one is now talking about the potential impact of nutritional or dietary changes for preventing memory loss, or even for preventing dementia. It is clear that there are evolving studies that indicate that dietary change over periods of time may affect the cognitive decline that is so much a feature of aging. We have some recent data from the Framingham study clearly showing that homocysteine levels 10 years before the onset of dementia predict a higher risk of it occurring. Would you comment on this aspect of nutrition and memory – not so much the short-term effects of diet and nutrients, but what are the elements of diet that you think are the most important in preventing dementia or cognitive decline? Dr. Morley: The homocysteine story is a very good one and will be covered by Dr. Folstein. I think the problem with homocysteine is how you lower it. Certainly in the USA, where most people are vitamin B12 and folate replete, high doses of these vitamins have no effect on homocysteine at all, even in people with very high homocysteine levels. Also, estrogen deficiency, renal failure, hypothyroidism, and a variety of other factors are known to alter homocysteine. So the problem is, can we actually lower homocysteine in a population where there is a reasonable amount of folate available? If somebody becomes demented and stops eating, which often happens, then the replacement of folate and B12 becomes very important. When we start to look at other factors, the questions become tougher. It is obvious that there is a subset of dementias that are vascular. So if I lived in Japan – where

133 Nutrition and Cognition in Older Persons vascular dementia is a major problem – I could give you a pretty good answer because it is clear that you would need to do the nutritional things that would inhibit the development of vascular dementia. In the USA, however, we are uncertain what triggers β-amyloid production – if indeed that is the central component of some but not all the cases of Alzheimer’s cases – and we have no idea whether diet might inhibit its development. So I would come back to the recommendation of a good regular diet that maintains weight without allowing you to get too skinny. I have a feeling that fish oil is good for you and possibly also vitamin E, but the data are terribly scanty. If there is anything that comes out of my talk as a recommendation it is that somebody needs to fund some large diet/memory studies, particularly in people who have dementia. I also think we should avoid using drugs and try to see what we can achieve by diet, though this may be only a dream. Dr. Jensen: I wonder if your proposed fatty acid intervention is just another example of things coming full circle, because there are very compelling data that α-linolenic acid and some of the long n-3 polyunsaturates are involved in retinol and brain development in neonates and also in cognitive performance [8], so perhaps there is a future market for infant formulas in geriatrics. Dr. Morley: In fact the only human data I could find were very good data in infant formulas. So I think you are right – the things we have learned from infants should be imported into the geriatric field. Dr. Vazquez: Would you recommend nutritional supplementation with antioxidants in healthy people in their 50s who have apo-E polymorphism associated with Alzheimer’s disease? Dr. Morley: I don’t know. Your point is well taken. I would suggest eating more fish, maybe taking an antioxidant, looking at the cholesterol in your diet to avoid developing vascular dementia, and taking care of other risk factors such as hypertension and smoking. It is entirely guesswork at the moment and I don’t want anyone going away from here today saying they heard the answer. What we can suggest is the routes to take to look for the answer. If you are a mouse I can help you, but I am not certain I can if you are a human.

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