Giving Up Gluten, and the Paleo Diet Fad
Medscape: Why do you feel that gluten is particularly detrimental to our brain health?
Dr. Perlmutter: Gluten-containing foods stimulate inflammatory reactions in a significant number of individuals, well beyond the 1.8% of the population that has celiac disease. This may lead to increased bowel permeability and even increased blood/brain barrier permeability, as described by Dr. Alessio Fasano (formerly at the University of Maryland, now at Harvard). The mechanism deals with the expression of the protein zonulin brought on by gluten exposure. What is so compelling about this newer research is the fact that this reaction to gluten may occur in all humans.
This may explain to some degree the array of neurologic issues now correlated with gluten sensitivity in nonceliac patients, as described by Dr. Anna Sapone and colleagues. So we have to look at gluten sensitivity in a new light, recognizing that its manifestations may extend well beyond the gut. Writing in the Journal of Neurology, Neurosurgery & Psychiatry, Dr. Marios Hadjivassilou stated, "That gluten sensitivity is regarded as principally a disease of the small bowel is a historical misconception. Gluten sensitivity can be primarily and at times exclusively a neurological disease."
That said, many people shop the gluten-free aisle of the grocery store, thinking that those gluten-free breads, pastas, pizza doughs, crackers, and so on are much better because they're gluten-free. The bottom line is these are still powerful sources of carbohydrates.
Even fruit is a source of aggressive carbohydrate in the human diet. Take a simple 12-ounce glass of freshly squeezed orange juice -- what could be better, right? As a matter of fact, that's about 34-36 grams of pure carbohydrates. That's 9 teaspoons of pure sugar with breakfast before your breakfast cereal has even arrived.
My recommendation is to try to keep the total carbohydrates per day to 60-80 grams. If you have 2 glasses of orange juice, you've already consumed 72 grams of pure carbohydrate.
It's really fundamentally important that we address this mechanism of glycation of proteins as being a cornerstone of brain degeneration pathology, and recognize that beta-amyloid itself is a protein that can become glycated and as such can become a powerful nexus for the production of free radicals in inflammation.
We have watched with dismay over the past several years the failure of the drugs designed to rid the brain of beta-amyloid. Most recently, as published in NEJM, a higher dosage of the experimental drug semagacestat was associated with increased cognitive decline of individuals compared with placebo.
Medscape: How does your diet compare with the paleo diet -- the idea that we should be following the presumed diet of Paleolithic humans?
Dr. Perlmutter: They are very similar. It's basically focused on very low carbohydrates and the aggressive addition of good fats: by all means, avoiding modified fats, trans fats, and hydrogenated modified fats, but welcoming back to the table such things as extra virgin olive oil, nuts, seeds, and grass-fed beef (not typical beef).
My diet is not a big beef, go out and eat a lot of meat, kind of diet. When Drs. Campbell and Campbell published The China Study  about the possible health consequences of eating meat, their report was valid because by and large, the type of meat that people are eating is derived from animals that have been fed genetically modified corn and soy and high levels of omega-6 fatty acids, which are proinflammatory. Therefore, clearly the idea that there's a relationship between that type of meat consumption and cardiovascular disease, and even cancer, is valid.
We're talking about specifically small amounts of grass-fed beef and wild fish. We're moving the meat, chicken, and fish away from being the centerpiece of the meal to being the side dish, the garnish. Lots of above-ground leafy green vegetables, colorful vegetables, and welcoming back good fats, because that's what the brain is desperate for.
Medscape: So, it's in line with a review published by the American Society for Nutrition last year, as well as other recent data suggesting that a little saturated fat, particularly from free-range red meat, might not be so bad for our brain health and may protect against anxiety and depression?
Dr. Perlmutter: Absolutely. And not just from grass-fed beef, but from the dreaded egg as well. There is no relationship in the current peer-reviewed literature between egg consumption and cardiovascular risk -- none whatsoever. Yet, there is still the ubiquitous egg-white omelet on every restaurant menu that you can find.
Diet Isn't Everything
Medscape: There are a lot of data on other lifestyle factors with benefits in dementia -- physical activity and mental and social stimulation in particular. How much weight do you give these nondietary factors?
Dr. Perlmutter: We were all over exercise in Grain Brain. One of the notions that I think is very, very empowering and compelling is the idea of neurogenesis -- that humans retain the ability to grow new neurons in the hippocampus throughout our entire lifetime. We can enhance our ability for this activity through the process of epigenetics.
A study published in Proceedings of the National Academy of Sciences in 2011 showed that we can actively modify the gene for the production of brain-derived neurotrophic factor (BDNF) with simple exercise. The investigators looked at 120 elderly nondemented individuals over a 1-year period who either stretched or did aerobics. They measured 3 variables: serum BDNF levels, memory function, and morphometric analysis of hippocampal size on MRI before and after the intervention period. After 1 year, the group that did the aerobic exercise had an increase in hippocampus size by about 1%, improvement of memory function, and higher levels of serum BDNF.
What is so incredible about that is there is no pharmaceutical that can do that. Believe me, you would have probably the world's most valuable pharmaceutical if you could develop a drug that would do that. Plain old physical exercise, nonproprietary. No one owns it. That's why you don't hear about this on the evening news. It's not advertised in our medical journals. Just aerobic exercise improved memory, grew the hippocampus, and raised BDNF levels -- which beyond neurogenesis also stimulates neuroplasticity, which is fundamental for learning. How incredible that you can modify the growth of your brain today by engaging in aerobic exercise! All you need to go out and buy is a pair of sneakers.
The Obama administration just dedicated $33 million to help pharmaceutical companies develop an Alzheimer disease prevention pill, and yet this article has already been published showing preservation of hippocampal size and function -- in fact, regeneration of hippocampal size and function.
A Whole-Grain Gripe
Medscape: What do you say to the fact that many global diets proven to be healthy -- particularly the Mediterranean diet, which is continually shown to be beneficial in numerous medical and mental conditions -- include whole grains? And that many of the world's so-called "blue zones" -- regions in which residents have notably long lifespans -- also include grains in their diets?
Dr. Perlmutter: I think people do tolerate some amount of grains, and that the classic Mediterranean diet is one that has added fat and lower carbs. Of note, an April 2013 article in NEJM  compared a standard US diet with a Mediterranean diet supplemented with extra-virgin olive oil and a Mediterranean diet supplemented with mixed nuts. The investigators looked at 3 endpoints: myocardial infarction, stroke, and death. They had to stop the study halfway through it, at 4.6 years, because the individuals with the highest fat consumption had a 30% lower risk for the endpoints. It was unfair to the rest of the participants.
Can people get away with having some whole grain products? I suspect so. But you have to understand that wheat products represent 20% of our caloric intake in the United States. That's not the way it is around the rest of the world. The Mediterranean diet, for example, does not pound people over the head with soda.
Medscape: How would you respond to your detractors that there just isn't enough evidence to support would could be considered a somewhat extreme change in our country's dietary habits?
Dr. Perlmutter: My response is that the "extreme change in dietary habits," to quote you, is actually what has happened to human nutrition in only the past several centuries. In the early 19th century, Americans consumed just over 6 pounds of sugar each year. That figure now exceeds 100 pounds. And there has been a dramatic reduction in the consumption of healthful fat. Beyond the mechanism of protein glycation, as well as the powerfully detrimental downstream effects of uncontrolled insulin signaling, we haven't even begun to understand the epigenetic consequences related to the effects of these new dietary challenges in terms of maladaptive genetic expression.
So in reality, I am not suggesting a change. I am recommending that we end this grand experiment and return to a diet that isn't evolutionarily discordant.
Medscape: Do you have any final comments for Medscape's audience of clinicians? How do you feel your ideas should be incorporated into patient care?
Dr. Perlmutter: Again, look at A1c in a different way. Rather than simply representing a metric of average blood sugar over a 3- to 4-month period, look at it as a way of modifying your pharmaceutical intervention; look upon it as a marker of what it really is, glycation of protein. That glycation of protein dramatically relates to inflammation and oxidative stress. That's number one.
Second, begin to incorporate a fasting insulin metric as a way of anticipating who's going to then develop elevations of fasting blood sugar and glycation of hemoglobin moving forward. The earliest sign of pancreatic stress is elevation of fasting insulin -- which ideally should be less than 8, not up to 24, which is what is in the so-called normal range.
Third, recognize that vitamin D is a powerful player in terms of brain health. Beyond strong and healthy bones, vitamin D activates more than 900 genes in human physiology, most of which are important for brain health. Low levels of vitamin D correlate with increased risk for multiple sclerosis, dementia, and Parkinson disease. Those are my 3 take-home messages.
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