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2010-02-12 Robert Krikorian PhD Memory and Cognitive Improvement With Grapejuice

An Interview With Robert Krikorian PhD

February 12, 2010, By Kirkham R. Hamilton, PA-C
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KIRK HAMILTON: Hi, my name is Kirk Hamilton, your host of Staying Healthy Today, and our mission is simple: To provide you credible usable health information from interviews and our educational resources to help you Stay and Be Well in the busy modern world. Please take a few moments before or after listening to this interview to browse through the Prescription2000.com website, the home of Staying Healthy Today Radio, for our free educational services.

Today's show topic is "Memory And Cognitive Improvement With Daily Grape Juice Intake, And Other Natural Approaches To Memory And Cognition."

Our guest today is Dr. Robert Krikorian, who earned a bachelor's of arts degree and a masters in philosophy from Boston University. He then attended the University of Cincinnati from 1977 to 1984, where he earned his masters and his doctorate degree in clinical psychology. He completed an internship in the Department of Psychiatry from 1980 to 1981, and a fellowship in neuropsychology from 1981 to 1983. He is currently associate professor of clinical psychiatry and the Director of the Division of
Psychology at the University of Cincinnati. He is also the Director of the Cognitive Disorder Center. Dr. Krikorian has research interests on the role of phytoestrogens and exercise on cognitive function of menopausal women and the elderly respectively. His recent article entitled "Concord Grape Juice Supplementation Improves Memory Function In Older Adults With Mild Cognitive Impairment" was published in the British Journal of Nutrition, 2009, and that's where I would like to start our discussion today.

Welcome Dr. Krikorian, and thank you so much for being on the show today.

DR. ROBERT KRIKORIAN: Hello. Thank you.

KIRK HAMILTON: I've reviewed your paper and I've done an interview with you. Your paper was "Concord Grape Juice Supplementation Improves Memory Function In Older Adults With Mild Cognitive Impairment," and I guess my first question would be before that, when did you become interested in nutrition as far as memory and cognitive performance goes?

DR. ROBERT KRIKORIAN: A number of years ago, actually about the time my research interest moved into the area of age-related memory changes and dementia and then I particularly got interested in, I guess I would say, non-pharmaceutical approaches or non-drug approaches to prevention. I think it's - I think we really don't apply enough effort to prevention and it's indeed much easier to prevent a disease especially a disease like Alzheimer's than it is to cure it. And based on my knowledge of metabolism and the benefits of proper nutrition I was drawn to that kind of work.

KIRK HAMILTON: What would be the biochemical theory that you're working on to prevent cognitive decline? Just in general.

DR. ROBERT KRIKORIAN: Well, I'm speaking a little bit out of school. I'm a neuropsychologist, not a biologist or a biochemist. But all fruits and vegetables contain different varieties of a large class called polyphenols. And there are 4,000 or more polyphenols and there are essentially - one can think of them as defense mechanism or constituents of plants that help with defense against sun radiation or predators, that is small animals that might consume the plant at the wrong time in the plant's development. It turns out that berries are enriched with different varieties of polyphenols and in grapes and also in blueberries, there are groups of polyphenols called anthocyanins and proanthocyanidins and with respect to grapes, Concord grape that is, there is a 10 to 15 year history of human work with supplementation in people with cardiovascular disease showing improvement in blood pressure and inflammatory markers and that sort of thing. And then there was one animal study that was done by some colleagues of mine in Boston at Tufts University that demonstrated memory enhancement with moderate term supplementation in old rodents with Concord grape juice.

KIRK HAMILTON: So the polyphenol concept would be a protection against deterioration it would seem to me, versus let's say giving a precursor to a neurotransmitter making something work better. Is that the first hypothesis?

DR. ROBERT KRIKORIAN: Well it turns out, it's actually relatively complicated and not entirely understood. But polyphenols, different varieties do different things, but the anthocyanins and the ones that are enriched in berries seem to do a number of things. They have anti-inflammatory effects so they reduce inflammation which is very important in most age-related diseases including Alzheimer's disease. They have antioxidant effects, but in addition with respect to anthocyanins there has been demonstration that they improve the resilience of neurons, brain cells, to certain kinds of insults like radiation and toxins. They have been shown to actually modify, in a beneficial way, signaling between nerve cells, specifically in memory centers in the brain and in addition, they most recently have been shown to have beneficial effects on metabolism that is enhancing the action of insulin and insulin receptors and even acting like insulin in the body. So there are a variety of effects. It's not clear which combination of those is having the effect on memory, but it is likely that actually it's more than one I would guess.

KIRK HAMILTON: Why did you choose Concord grape juice versus pomegranate juice versus blueberry juice?

DR. ROBERT KRIKORIAN: As I said, I had colleagues who had performed a study, an animal study with Concord grape juice, and then beyond that it was a matter of funding. I mean Welch's Foods was interested in funding a proposal that I submitted to them to do this initial study. Actually, subsequently we got some support also to look at blueberry juice and that study has been completed and published as well.

KIRK HAMILTON: So I think one thing I brought up in our written interview was that 100%, there are a lot of juices out there that are a mixed bag of things that say grape juice on it. So you were very emphatic about getting 100% juice, correct?

DR. ROBERT KRIKORIAN: Right. And also Welch's wanted us to use their product so we - so the experimental juice in this study was what a person could buy on the grocery shelf. It's 100% Concord grape juice.

KIRK HAMILTON: And you came up with two and a half cups a day. Is that a - were you looking for a polyphenol count in there or what?

DR. ROBERT KRIKORIAN: Well, not specifically. Actually there was a range between, I believe it was 15 and 21 ounces a day that was consumed according to weight. So people of different weights were prescribed either 15, 18 or 21 ounces. We based that on some of the prior research that had been done with individuals with cardiovascular disease.

KIRK HAMILTON: Well two and a half cups seems like, you know an elderly person could easily get that down in a day.

DR. ROBERT KRIKORIAN: Right. And we - the daily prescription was divided between three meals, the morning, midday and evening meals. So they took the juice with meals and it wasn't - it wasn't a large amount in any given time.

KIRK HAMILTON: Were there any kind of blood tests that you did to follow markers of inflammation or anything like that?

DR. ROBERT KRIKORIAN: We didn't look at inflammation in this study. We did look at glucose and insulin. And there was actually an elevation of insulin in the grape juice subject as opposed to the placebo which was a little startling and unexpected. We got the opposite effect actually in the blueberry juice study. But the numbers were very small in both studies so it's not clear to me that - this is something that we are going to pursue in future studies, but it's not clear to me that this finding will hold up but it needs to be looked at. It's provocative.

KIRK HAMILTON: Now is there - I know obviously if you have hyperinsulinemia that's a risk factor for type 2 diabetes and insulin resistance, etc., etc, and insulin is an inflammatory hormone in general. But is there an advantage as far as brain chemistry goes to having a little elevated insulin?

DR. ROBERT KRIKORIAN: No. No. And actually if one has hyperinsulinemia, what that really means is elevated abnormally high insulin levels in the periphery. Insulin, most nearly all the insulin that is utilized in the brain needs to be transported from the periphery to the brain across the blood-brain barrier, and there's a receptor mediated transport system for that. And - or transport mechanism. And with peripheral hyperinsulinemia as you might imagine the receptors tend to wear out or become toxified by over exposure to insulin and there's a saturation effect. And so actually what happens, or can happen is that the condition of peripheral hyperinsulinemia and central hypoinsulinemia, and that's a very bad situation because insulin is important in a number of ways in addition to helping to get glucose into the neurons and the tissue in the brain. It's important in regulating inflammatory mediators like cytokines and actually beta amyloid which is a neurodegenerative factor, and in addition insulin itself is important in memory processing in the neural events that are important to - in neuroplasticity and encoding new memories. And so given all of these multiple benefits of having normal amounts of insulin in the brain, having too much or too little is not good and it's more likely in the context of older adults with hyperinsulinemia that the person would have too little insulin.

KIRK HAMILTON: Tell us a little about the study you did, just an overview, and what were the results of the study.

DR. ROBERT KRIKORIAN: We randomly assigned older adults with a condition known as MCI, mild cognitive impairment, which means older adults with memory decline that's measurable, it's significant, it's certainly not dementia but it's more impairment than would be expectable for that age. And we enrolled the subjects as I said to either 12 weeks of daily consumption of 15 to 21 ounces of purple grape juice, 100% Concord grape juice, or to a placebo beverage that looks like, tastes like and even smells like grape juice. And then we did memory testing prior to the intervention and at the end of the intervention. And what we found, the primary finding was improvement in a verbal memory measure and then we also had trends that were non-statistically significant effects, but there were improvements in the right direction, so to speak, indicating benefit with respect to another verbal memory measure and a spatial memory measure.

KIRK HAMILTON: Let's go from there. So grape juice would appear, 100% grape juice, to be something that's reasonable for an aging person's diet. Is that fair enough to say?

DR. ROBERT KRIKORIAN: Yes.

KIRK HAMILTON: Okay. And obviously if there was other juices like 100% pomegranate juice or blueberry juice, that might be reasonable as well?

DR. ROBERT KRIKORIAN: Uh-huh.

KIRK HAMILTON: Or eat the whole fruits. So how about - can you tell me what you would think of as a memory preventive diet that you would recommend as people get older?

DR. ROBERT KRIKORIAN: Uh, yes. I would recommend first of all thinking about eliminating the negative things. I would recommend eliminating as much as possible, and entirely if the person can do it, if they have enough willpower and conscientiousness, to eliminate all processed carbohydrates. So in terms of carbohydrate consumption eating only fruits and vegetables and not consuming grain products of any sort and certainly not sweets of any sort.

KIRK HAMILTON: Run that by me again so I understand you right. So you said processed grains obviously. You mean whole grains? You wouldn't recommend eating whole grains?

DR. ROBERT KRIKORIAN: Yes. Whole grains aren't a good, be it relative to fruits and vegetables. If you look at the carbohydrate concentration of whole grains, its orders of magnitude greater than you would get in a vegetable or fruit and even in whole grains where fiber is touted, the fiber concentration is still lower than in fruits and vegetables. In addition, grains tend to contain anti-nutrients, phytates and lectins, and again I am a little bit out of my depth here, but lectins have been demonstrated to - they're proteins that - and again they're defenses and we didn't evolved in a context or an environment where we - where humans consume these. But these are defenses that are able to get through the digestive system intact, these whole proteins. And they can stimulate the immune system or irritate the immune system in inappropriate ways. And just nutritionally, calorie per calorie, they're not as good a bet as fruits and vegetables. In addition to their higher carbohydrate concentration, so you're taking a bigger metabolic hit with even whole grains than you would be with celery or lettuces as an example or berries.

KIRK HAMILTON: Somehow that doesn't resonate with me. We can agree to disagree on that. I mean if you study, let's look at the Okinawan centenarians. Okay, they even eat white rice. Alright, and soba noodles and things like that. So I - that one we can disagree on, I guess.

DR. ROBERT KRIKORIAN: Well, Okinawans are very healthy and they do eat some rice but they also probably eat, the cohort you're talking about , the very healthy ones who have been described in the books by --

KIRK HAMILTON: Willcox and Willcox.

DR. ROBERT KRIKORIAN: Yes. Their calorie consumption is reduced relative to other Japanese and people that eat a Western diet of course. So that may - their longevity - that may overcome the negative effect of any particular dietary component.

KIRK HAMILTON: Alright. Well that's a unique one that I probably disagree with, but I'm glad you brought it up and made me think.

So how about protein? What is your schtick on protein and memory and aging?

DR. ROBERT KRIKORIAN: I think protein is good. I think what people in general think of as a high protein diet is probably more like an adequate protein diet. If you do some reading or research with respect to what Paleolithic humans consumed in terms of protein it was probably along the lines of 25 to 35, maybe 40% of calories. And if one doesn't have kidney disease, protein is not a problem and provides a lot of benefit especially with respect to muscle mass and -

KIRK HAMILTON: Let me ask you this. Why would you go to a Paleolithic - I mean this is just for the sake of argument. Paleolithic people didn't live very long. Now, it's not - I'm not saying that's because of their diet obviously. It's because of trauma, whatever. Why wouldn't we go and study aging cultures that are living a long time such as the Okinawans centenarians, such as Sardinians in Italy, such as the Nicoyans in Costa Rica, and such as Blue Zone people and look at what they eat because I don't get a high protein diet there or high animal protein.

DR. ROBERT KRIKORIAN: Well you may not, and I think it's important to look at contemporary cultures but if you - you should be looking at contemporary primitive cultures. And I don't believe any of the ones you mentioned are primitive cultures. If you look at the primitive cultures, the protein intake obviously varies and I'm not saying that high protein is essential for longevity or good health, but I do believe it's a good thing to do. I don't think there's one essential for health, but I think high protein is certainly not detrimental and provides a lot of benefit. And when I say high, I'm saying high relative to estimates that are generally made, you know for what it is 0.6 grams of protein per kilogram body weight, thinks like that. I think that's relatively low.

KIRK HAMILTON: Alright. Well another area we might have a little disagreement on, but maybe we're not as far apart as I think.

Let's go to some micronutrients. Do you recommend any specific micronutrients? I interviewed Dr. Shea not to look ago on this very topic and you know you have a product that has let's say SAMe in it, N-acetylcysteine, acetylcarnitine and the homocysteine lowering nutrients of B6, B12, folic acid. Do you recommend anything yet, or is that just something you steer away from?

DR. ROBERT KRIKORIAN: Well, I do have some particular recommendations that I would make for my patients and also for the general public and that would be vitamin D3 supplementation because I think most people in our culture don't get enough, and the recommendation, the official recommendations aren't high enough based on several publications in the last couple of years. So one or two or even 3000 IUs a day seems to be important. Optimally one would get tested to get blood levels.

KIRK HAMILTON: Can I just interject - is that for cognitive function or is that just general? I mean I'm well aware of vitamin D for general health or -

DR. ROBERT KRIKORIAN: Well for general health is what I'm thinking of. And then also given the Western diet, I think omega-3 fatty acid supplementation is probably a good idea unless one is able to eat cold water fish or some other source consistently. And then for aging people I often recommend a chromium picolinate supplement because chromium is important for insulin receptor function and given the huge importance of metabolic function for dementia and health in general you want to optimize that as much as possible. Beyond that, I think vitamins and minerals and other more exotic supplements can be beneficial but it's a very tricky game and it's not just more is better necessarily so I think one needs to be cautious about recommendations and also treating oneself with those things and the more you - the more I've learned about it the more complexed it seems.

KIRK HAMILTON: Let me ask you about two areas of interest of yours. One is phyto - I guess you're trying to get grants for research on phytoestrogens on cognitive function and also exercise and cognitive function. So if you could spend a few moments maybe talking about phytoestrogens and/or sex hormones in cognitive function in the elderly.

DR. ROBERT KRIKORIAN: Okay. We did - actually we're no longer pursuing that just because we're - we've got other studies going with berry fruits and also very low carbohydrate diets at this point. But we did complete a trial with postmenopausal women using an isoflavone extract looking at neurocognitive outcomes, essentially memory function, and we didn't find a benefit but it's not clear to me that we should write off isoflavones. It's been demonstrated I think, since we did the study, that there seems to be a window of opportunity for intervention around, during the perimenopausal period, that is just before menopause and for the first 12 months or so after the final menstrual cycle. And intervention at that time with estrogenic agents may be beneficial, but delaying intervention for several months or years after that as we did in our study may not be so effective and there' some data with conjugated estrogens - the pharmaceutical forms - that shows a possibility of actual detriment with delayed intervention.

KIRK HAMILTON: Now is this for cognitive function that you're talking about, not overall healthy necessarily?

DR. ROBERT KRIKORIAN: Right, but there's some suggestion that overall health might be adversely affected with delayed intervention.

KIRK HAMILTON: Okay. How about exercise? Tell me about how important it is to exercise and if so what kind in the elderly for mental function and brain function.

DR. ROBERT KRIKORIAN: Exercise is important. I think it's a close second to diet. I feel like diet is the most important factor but exercise and stress control are also important. And I think that my sense is that most people think about endurance conditioning or aerobic conditioning and I think that's a positive thing to do certainly but something that tends to get neglected somewhat is strength training and maintaining muscle mass. And I think that's extremely important. As we age we lose muscle unless we have some sort of resistance training or resistance activity, unless we stress our muscles in what we do and it's been shown that virtually at any age one can build and maintain muscle through exercise and physical activity. So that's my - for aging people that's my primary exercise recommendation. That is to do some sort of resistance activity to build upper body and lower body strength and it's so important to maintain function. One of the major difficulties with older adults is that they have trouble getting around and it's partly related to - and also with falls - and it's partly related to muscle atrophy. But exercise of virtually any type will be good for the brain. There's a lot of animal data and some human data now showing that exercise promotes cognitive function. It stimulates neurogenesis or enhances neurogenesis with the creation of new brain cells. It stimulates blood flow to the brain and it also can be a factor that increases the expression of neurotrophic factors, that is chemicals released in the brain that are important in memory processing and supporting brain cells.

KIRK HAMILTON: That is the perfect closing for us. You know I was going to ask you all your pearls, but I think we've got a lot here. And I want to thank you, Dr. Krikorian, for coming on. This is Dr. Robert Krikorian. He is an associate professor of clinical psychiatry and the Director of the Division of Psychology at the University of Cincinnati.

And again, Dr. Krikorian, thank you for coming on the show today.

DR. ROBERT KRIKORIAN: Oh, thank you. It was a pleasure to talk to you.

KIRK HAMILTON: And I want to thank you, the audience, for listening today on this edition of Staying Healthy Today Radio. And remember until next time, Stay and Be Well.

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