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David Perlmutter, MD: The Dynamic Brain

Interview by Craig Gustafson

Facilitated by The Institute for Functional Medicine Annual International Conference, to be held June 1 to 3, 2017, in
Los Angeles, California.

David Perlmutter, MD, is a board-certified neurologist and fellow of the American College of Nutrition. He received his MD degree from the University of Miami School of Medicine, where he was awarded the Leonard G. Rowntree Research Award. He has published extensively in peer-reviewed scientific journals, including JAMA Neurology, Neurosurgery, and the Journal of Applied Nutrition, and he is a frequent lecturer at symposia sponsored by such medical institutions as Columbia University, Scripps Institute, New York University, and Harvard University. He serves as an associate professor at the University of Miami Miller School of Medicine.
Dr Perlmutter has been interviewed on many nationally syndicated television programs, including 20/20, Larry King Live, CNN, Fox News, Fox and Friends, The Today Show, The Oprah Winfrey Show, TheDr Oz Show, and the CBS Early Show. He is the recipient of the Linus Pauling Award for his innovative approaches to neurological disorders. He is also the recipient of the 2006 National Nutritional Foods Association Clinician of the Year Award and was awarded the Humanitarian of the Year award from the American College of Nutrition in 2010. In 2015, Dr Perlmutter was awarded both the Media Award from the American College of Nutrition and the Healthy Living Award from the Invisible Disabilities Association.
Dr Perlmutter is a 4-time New York Times bestselling author, and his books have been published in 27 languages. His 2013 bestseller , Grain Brain: The Surprising Truth About Wheat, Carbs, and Sugar,1 has more than 1 million copies in print. Other New York Times bestsellers include Brain Maker: The Power of Gut Microbes to Heal and Protect Your Brain—For Life,2 and his latest book, The Grain Brain Whole Life Plan,3 published in November 2016.

Integrative Medicine: A Clinician's Journal (IMCJ): This year's Annual International Conference is focused on the dynamic brain and neuroplasticity, so let's start off with: When did the modern theory of neuroplasticity become verified by the literature?

Dr Perlmutter: The first real landmark work came from  Donald Hebb, PhD, a Canadian researcher. He was puzzling over what it is that allows brain cells to connect. He is the one who, 68 years ago, postulated that some factor is operative when nerve cells communicate with each other that allows them ultimately to connect. He proposed the theory that, paraphrased, states: "Neurons that fire together wire together." Basically, the more that you do something, the more it will ultimately form a more indelible relationship between neurons and neural networks.

IMCJ: Then if this groundbreaking work was done more than 60 years ago, why has clinical practice been so slow to catch up with the accepted evidence?

Dr Perlmutter: I think that clinical practice really focuses on interventional types of things: "What can we do to make things better?" for example. I think that Dr Hebb, being a psychologist, was more involved in the research, trying to understand how it is that neurons ultimately connect in what is now called Hebbian learning. He wrote a book back in 1949 called The Organization of Behavior, and, in that, he proposed this theory whereby these factors conspire to allow neurons to connect to each other.
Your question, I think, deals with clinical interventions to perhaps enhance that process and understanding how that activity might influence cognition, for example. I think that has been only a relatively recent development, which, to a significant degree, parallels the science of neurogenesis, the growth of new brain cells. Interestingly, the same trophic factors are involved in both neuroplasticity, the connection of neurons, and the development of new neurons, which we call neurogenesis.
Certainly what is getting the most attention these days is brain-derived neurotrophic factor, or BDNF, as at least one of the components of the nervous system that enhances the activity both of the genesis of new brain cells, as well as the way that they connect. These days, certainly, the person who is well-deserving of the title the "father of neuroplasticity" is Michael Merzenich, PhD. And he is, in fact, one of the speakers at The Institute for Functional Medicine conference this year.

IMCJ: You mentioned that neurogenesis as being a more recent concept. How did the validation of that theory change the game for neurology?

Dr Perlmutter: There was a huge reluctance to accept the fact that growth of new brain cells could occur in humans. There are many reasons that that was the case, but at the time, it was ultimately discovered and published by Peter Eriksson, MD, PhD.4 This idea—published in November 1998 in the journal Nature Medicine, volume 4, issue 11—had been well proven in rodents and in primates. But there was almost a religious rejection of the notion that we could grow new brain cells as humans.
Dr Eriksson, working with Fred Gage, PhD, at the Salk Institute in California, in a very clever way was able to demonstrate neurogenesis in humans. There were a group of patients being followed who had squamous cell carcinoma of the face. They were being given a chemical that marks cells in division, BRDU, bromodeoxyuridine, which labels cells during the process of mitosis—which is obviously upregulated in cancer.
Several of these patients died, and Dr Gage and Dr Eriksson looked at their brains, specifically at the area where neurogenesis had been found in primates—the hippocampus, the brain's memory center. Lo and behold, they found cells labeled with BRDU in humans of various ages—well into adulthood—showing active genesis of new cells, essentially stem cells being formed in the hippocampus. This was revolutionary.
As a matter of fact, he wanted to publish this breakthrough finding but was rejected by multiple peer-reviewed journals, again, who just basically dug in their feet because they could not accept this change in paradigm; that neurogenesis does occur in humans. Ultimately, he not only demonstrated that neurogenesis is occurring in humans, but that these newly formed neurons actually develop and differentiate into fully functional neurons, by doing a special type of staining called TUJ staining. This was landmark, groundbreaking research that went directly against the teachings that formed many of my contemporaries' training in terms of medical school and in residency—this notion that brain cells are terminally differentiated and we do not gain any new population of brain cells. Nothing could be further from the truth.
Now we fully understand that, and we have come to the point where we do get right back to the clinical arena and recognize that this process, this incredible process of neurogenesis, can be enhanced by making simple lifestyle changes. That is the part that really lends itself wonderfully to those of us who are working with patients and trying to change their ability to influence their health destiny as it relates to their brains.

IMCJ: With regard to neurogenesis, you mentioned the hippocampus, in particular. I was recently reading an article that referred to a study where they compared cab drivers versus bus drivers…

Dr Perlmutter: Exactly, and they found significant differences in that these individuals did appear to be both laying down and retrieving information and there were clearly brain changes associated with that. Right?

IMCJ: Right, and they found that the taxi drivers had larger hippocampi than the bus drivers that they attributed to the fact that the taxi drivers had to learn the entire city and divine what the specific route was going to be for a given fare at a given time of the day, versus the bus drivers who had a set route that they drove consistently.

Dr Perlmutter: That is right. The study that you are referring to was published, actually, in a journal that is called Hippocampus. The study was done in London. It was published, actually, quite a while ago, in 2006,5 and they did indeed demonstrate that there were patterns—changes in the patterns of hippocampal gray matter seen in taxi drivers. It really brings to mind the question, "Now what is happening?" Because none of us is really in a position of needing to learn directions anymore because we have apps, like Waze and Google Maps, that basically take the guesswork out. We do not have to remember phone numbers, addresses, or how to get anywhere anymore because your iPhone is going to tell you where to go. I think that clearly there are changes that might not necessarily be positive now that we have off-loaded so much of our brain power.

IMCJ: What potential do these theories of neuroplasticity and neurogenesis hold as a clinical tool to support health and well-being?

Dr Perlmutter: I think it is a question that needs a lot of attention because, in the recent work of Kirk Erikson, PhD, they demonstrated what we have known for a long time—that physical exercise has a dramatic effect in terms of upregulating the transcription of BDNF, relating to increased serum level of BDNF, increased size of the hippocampus, and improved cognitive function to the extent that his recent publication and editorial that followed it indicated that people who regularly engage in aerobic exercise may have as much as a 50% reduced risk for developing Alzheimer's disease.
That is profound in the context of (1) the fact that we have no meaningful treatment for that disease, (2) that
5.4 million Americans are already affected by that, and (3) that the number is projected to triple by the year 2050. Here is a powerful intervention that costs nothing and nobody is talking about. What we see on the evening news are commercials for medications, cholinesterase-inhibiting medications or NMDA-receptor antagonists that do not work. That is what people think they need to do: Basically live their lives, come what may, and then hope that medical science has developed a cure for this disease, which we now recognize is highly preventable between engaging in aerobic exercise on a daily basis and keeping your blood sugar low or not becoming a type 2 diabetic. These 2 factors alone have a profound effect in terms of lowering an individual's risk for becoming an Alzheimer's patient regardless of their APOE status.

IMCJ: What role might environmental toxins play in Alzheimer's risk?

Dr Perlmutter: We are just beginning to look at why that might be an event. When you understand the Functional Medicine Matrix, you realize it is sort of like a carousel and that you can jump onto that carousel at multiple points. We have genetic predisposition, we have early life factors, and we have triggering events. Many of these triggering events, I think, are things that people are becoming much more aware of.
For example, a new understanding is that even the air we breathe might significantly increase a person's risk for cognitive decline and even full-blown Alzheimer's disease. A study6 that was published just in January of this year in the journal Science looked at the risk for developing dementia in relationship to how close somebody lived to a busy street. When you live near a busy street, you are exposed to what are called PM2.5. What that means in scientific jargon is particle size of around 2.5 micrometers or less. These are things that are strongly associated with oxidative stress and we know that these particles are associated with other inflammatory issues like asthma, lung cancer, and coronary artery disease. Now new research indicates that through multiple mechanisms, these same particles are associated with a dramatically increased risk for developing dementia.
The Lancet reported a study7 indicating that those people who live within 50 meters of a major roadway have a 10-fold increased risk of dementia compared with those people who live at least 150 meters away from a busy roadway. This was looking at a population of around
6.6 million subjects, basically all of those living in Ontario, Canada. It was a really incredible study that builds on Harvard research that looked at the Framingham data and showed significant shrinkage or decline in brain volumes, again, in individuals who have had this PM2.5 exposure. We add this to the list that includes exposure to environmental mercury, other heavy metals, and now the very air that we breathe as being a potent environmental risk factor for cognitive decline and risk for dementia. I would say, "Who knew?" but we had to suspect that.

IMCJ: Earlier you mentioned that at the moment there is not a recognized cure for Alzheimer's, but there has been some significant progress in mild cognitive impairment and moderate cognitive impairment and the ability to actually reverse that, hasn't there?

Dr Perlmutter: Well, not from a pharmaceutical perspective, no, there has not. By and large, pharmaceutical approaches have focused on 3 areas: NMDA receptor antagonism, anticholinesterase therapy based on the so-called acetylcholine hypothesis that deficiencies of acetylcholine lead to brain degeneration—which I think we all recognize now is basically absurd—and, third, the notion that the approximate cause of cognitive decline in the Alzheimer's brain or even prior to the diagnosis is this accumulation of beta-amyloid plaque.
I think we now recognize that this is not a disease that is caused by a single variable. Multiple issues conspire to ultimately lead to the decline in cognitive function that we then call dementia. Now, reversing that is, in fact, possible, but not by pharmaceutical means as yet. Dale Bredesen, MD,8 and his work published in the journal, Aging in 2014, demonstrated actual reversal of full-blown Alzheimer's disease in 9 of 10 patients, not by providing one intervention, but by using, ultimately, as many as 36 different leverage points including change in diet, increase in aerobic activity, optimizing vitamins and nutrients including vitamin D and DHA, going on a gluten-free diet, and stress reduction. Multiple factors allowed those patients to actually recover, many of whom were able to return to gainful employment.
Now, as it relates to mild cognitive impairment, there are multiple studies that demonstrate significant improvement in cognitive function just by introducing an exercise regimen to the extent that the Mayo Clinic proceedings several years ago indicated—that physical exercise should be considered as a therapeutic prescription in the treatment of cognitive decline. It is really taking us, I think, significantly away from this notion of looking for and needing a pill, but, rather, recognizing that there are some lifestyle issues that are critically important.
Again, what the Mayo Clinic published was the idea that moderate-intensity physical exercise should be considered as a prescription for lowering risk for cognitive decline and slowing cognitive decline across the age spectrum. That was published in the Mayo Clinic Proceedings back in September of 2011.9 When there is an Alzheimer's drug or a drug that has utility in treating mild cognitive impairment, to get back to your question, I am going to be thrilled. That will be wonderful. However, this should be a very inclusive approach as opposed to being an approach that just focuses on monotherapy. I think that even Dr Bredesen's approach does, in fact, welcome the utility of pharmaceuticals as part of a more wide-ranging spectrum in dealing with, and even averting, brain-function decline.

IMCJ: You mentioned that Dr Bredesen's approach has 36 different access points in the protocol. If I understand it correctly, there is a tipping point. A patient incorporates enough of the access points and there will be a point at which things begin to go the other way. So a given patient does not have to adhere to all 36 access points.

Dr Perlmutter: That is right. Beyond that, there is some degree of personalization of the program by, really, all of us who are involved in Functional Medicine. That is "What might that person specifically need based upon his or her biometrics, his or her genetic predisposition?" for example. I think, again, one of the primary tenets here is to not lock into a specific recipe for a specific medical problem. Be very open to the notion that these protocols need to be very malleable and very much personalized with reference to the uniqueness of the individual patient.

IMCJ: Is there a difference between approaches for remission of conditions or repair of an injury versus something that is more targeted toward prevention and wellness?

Dr Perlmutter: I was once criticized online by somebody indicating that I have extrapolated between those 2 ideas: that prevention versus intervention should be considered very different approaches. I tend to reject that because I think that we are trying to undo these processes and target these mechanisms preemptively in the preventative protocol and interventionally when dealing with established diseases. However, the processes are, in fact, the same.
Ultimately, from a broad mechanistic perspective, they are inflammatory and mediated through the action of oxyradicals and nitrogen radicals. Oxidative stress and inflammation are indeed the cornerstone mechanisms that can be targeted in both a preventive scheme and also from an interventional perspective once disease has manifested. Having said that, we need to take a step back and ask, "What is it in our physiology that enhances this feed-forward inflammation and oxidative stress that ultimately leads to the penultimate event in neurodegeneration and mitochondrial dysfunction and/or failure?" The ultimate event, of course, being what is induced by this mitochondrial dysfunction, and that is apoptosis or actual loss of brain cells.
We can get to that endpoint through multiple channels, and I think we've got to address what those common channels are that both lead to disease and also help to propagate it once it has manifested. That takes us back to lifestyle issues. We know that, for example, glycation of proteins is a seminal event in initiating both oxidative stress as well as inflammation. This relates, then, back to diet and other lifestyle issues. It is why, for example, type 2 diabetes is associated with as much as a quadrupling of the risk for developing Alzheimer's disease. That is, by and large, a preventable condition based upon lifestyle choices. It is why we focus so heavily on diet and on lab parameters like hemoglobin A1c, fasting insulin, fasting blood sugar, and fructosamine as giving us some sense as to where this individual might be on the risk scale.
We see strong correlations that demonstrate, for example, a very powerful relationship between a person's A1c and the degree of atrophy of their hippocampus. That is a powerful relationship published in the Journal of Neurology.10 When we see that information, it tells us that doing our very best to control blood sugar is going to go a long way to keeping the brain from degenerating. There are multiple other mechanisms that are involved with sugar metabolism that have a role to play in the brain, not the least of which is the role of insulin, but, that said, I think that my opinion is: We can certainly explain this dramatic increase in Alzheimer's incidents based upon a correlation with increased incidents of type 2 diabetes.
As an Alzheimer's preventative approach, it is incumbent to keep blood sugar levels in a range that is good for the body and good for the brain. I think that the so-called normal levels of blood sugar need to be reassessed through the lens of what is an optimal level. We let people get away with a blood sugar of 100 when clearly we see published in the New England Journal of Medicine in September of 2014 an article aptly entitled "Glucose Level and Risk for Dementia" demonstrating that even a level of 100, which is considered normal, is already associated with increased risk for developing dementia.11 We need to really revise that and pay close attention to those biomarkers because they have implications not just for the development of type 2 diabetes, but for inflammatory diseases across the spectrum, which do, in fact, include Alzheimer's as well as coronary artery disease, obviously diabetes, and even cancer.

IMCJ: It really is amazing that we allow that threshold to be so high.

Dr Perlmutter: Well, we look at normal ranges that are developed from large numbers of people. Our norms are an extrapolation of averages. That does not take lab work and bring it into the clinical arena in terms of what is best. It is time that we look not at normal levels but at optimal levels. Then, from an interventional perspective with an established patient, someone who already is manifesting disease—what then should we do based upon just the simple notion of blood sugar being detrimental to the brain? And that is a far more aggressive approach. By placing that patient on a ketogenic diet, powering the brain with fat as opposed to carbs, the result is far more efficient production of ATP, far less production of free radicals associated with oxidative phosphorylation, and, ultimately, amping up of the body's production and availability of beta-hydroxybutyrate. This is far more than a cellular fuel, but actually a messenger molecule stimulating G-protein receptors that augment antioxidant protection, reduce inflammation, and also act as what we call a histone deacetylase inhibitor, which has some very powerful effects in a positive way in terms of viability and preservation of brain cells.

IMCJ: In the very first interview I ever did in this field, I talked to a gentleman about insulin sensitivity, glycation, and related issues. He said, "Even at the blood glucose level of 90, you have got damage going on in your body. It's just not good."

Dr Perlmutter: Well, that is right. We have seen well beyond cognitive impairment, even Parkinson's disease, which is considered a motor event, be profoundly affected by the intervention of placing people on a hyperketonemia diet—actually pushing them into ketosis. This is not news. The first report of this was published way back in 2005 in the Journal of Neurology.12 What we know is that in Parkinson's, for example, the mitochondrial defect is in what we call complex one of the electron transport chain. It is why, for example, coenzyme Q10, which can bypass that defect, has been so heavily investigated.
We also know that ketone metabolism, using ketones as a mitochondrial fuel, might actually bypass that mitochondrial defect. The first study done back in 2005 was actually very small. It involved only 5 patients, Parkinson's patients on medication, and they were placed on a very strongly ketogenic diet for a 28-day period. They measured a bunch of parameters that make up what is called the Unified Parkinson's Disease Rating Scale. That is a common scale used by neurologists to measure how a Parkinson's patient is doing, looking at things like mentation and mood, activities of daily living, motor function, and whether there are any complications from the treatment that they might be receiving.
The study was really quite dramatic because it demonstrated improvements pretty much across the board—dramatic improvements—in these parameters, especially in terms of motor function. Over the brief study—28 days—the participants achieved an average reduction of 43% in their UPDRS or Unified Parkinson's Disease Rating Scale rating with one patient having an 81% decline on the UPDRS scale, which is far better than what you can typically achieve with medication. This was just by placing them on a diet that cut their carbs, cut their sugar, and favored healthful fat.
Now, these days we would want to amp that up, of course, by adding coconut oil and MCT oil, and being very strict on the carbs. It is so unfortunate that there is still such a reluctance to embrace anything nutritional. Here this was published in the Journal of Neurology, which is arguably the most well-respected neurology journal on the planet. It is actually the journal published by the American Academy of Neurology. This was 12 years ago, and no one has paid any attention to it since that time. But now we are seeing all kinds of work that is really starting to popularize ketosis. A recent comprehensive book by Thomas Seyfried, PhD,13 looking at the metabolic basis of cancer, is one example. We are really seeing a lot of new information that is going to be difficult for mainstream medicine to turn its back on.

IMCJ: What topic will you be focusing on in your presentation at the conference?

Dr Perlmutter: Well, my opening key note is going to take a very broad overview of where we are in the neurosciences today, the challenges we face in terms of the sheer numbers across multiple disease spectrums, and what the notion of prevention is all about as it relates to the brain. I am then going to introduce, by way of their presentation, each of the speakers and talk about what they are going to present and how their specific topic uniquely fits into the Functional Medicine Matrix. Then I am going to explore a little bit further the notion of neurogenesis and neuroplasticity and ultimately a talk about how just thought in and of itself, even without action is able to change the brain in terms of its network and also in terms of its functionality. I am doing a workshop, as well, which is where I will do more discussion about the role of the microbiome.

IMCJ: Research in that area, the gut-brain connection, has exploded in recent years.

Dr Perlmutter: That is for sure. It is like we have just come upon this, but, truthfully, medicine has lived in a world of reductionism, of looking upon the body and its constituent parts as basically a machine, as described by Descartes. That is: The brain is the computer and the lungs are the bellows and the heart is the pump. But now we recognize that this integrative view, this holistic view of the human body, is really going to give us the most powerful leverage points to be aggressive and successful in keeping people healthy, but also in reversing disease. We are just beginning to see gut-targeted therapies that have profound effects in terms of brain function as it relates to mood, as it relates to cognition, and even as it relates to motor activity.
Beyond that, we are just beginning to fully appreciate that the mitochondria within each and every neuron—and there are thousands of mitochondria in every nerve cell—are really deeply involved in regulating cellular or neuronal DNA expression. It is a very humbling notion that the mitochondria are actually involved, for example, in regulating the nuclear genes that deal with whether a cell will live or die. Mitochondria regulate the action of what are called caspase enzymes, which are involved in cellular apoptosis.
To a significant degree, we have to look upon the mitochondria as wielding the Sword of Damocles, determining who lives and who dies. We are now understanding—in recent research, published last week—that ultimately autism may be, in fact, a mitochondropathy, a mitochondrial event, and that there may be some influence upon neuronal mitochondria from things going on in the gut whereby, for example, changes in gut bacteria that may have been induced by the herbicide, glyphosate, may ultimately relate to mitochondrial changes within the brain. This correlation could well explain why autism is increasing so dramatically in its incidence worldwide.
For more information on the Institute for Functional Medicine 2017 Annual International Conference, visit http://IFM.org/AIC/.


1. Perlmutter D. Grain Brain: The Surprising Truth About Wheat, Carbs, and Sugar. Boston, MA: Little, Brown and Company; 2013.

2. Perlmutter D. Brain Maker: The Power of Gut Microbes to Heal and Protect Your Brain—For Life. Boston, MA: Little, Brown and Company; 2015.

3. Perlmutter D, Loberg K. The Grain Brain Whole Life Plan. Boston, MA: Little, Brown and Company; 2016.

4. Eriksson PS, Perfilieva E, Björk-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4(11):1313-1317.

5. Maguire EA, Woollett K, Spiers HJ. London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Hippocampus. 2006;16(12):1091-1101.

6. Underwood E. The polluted brain: Evidence builds that dirty air causes Alzheimer's, dementia. Science Magazine Web site. http://www.sciencemag.org/news/2017/01/brain-pollution-evidence-builds-dirty-air-causes-alzheimer-s-dementia. Published January 26, 2017. Accessed March 22, 2017.

7. Chen H, Kwong JC, Copes R, et al. Living near major roads and the incidence of dementia, Parkinson's disease, and multiple sclerosis: A population-based cohort study. Lancet. 2017;389(10070):718-726.

8. Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY). 2014;6(9):707-717.

9. Mayo Clinic. Aerobic exercise may reduce the risk of dementia, researchers say. ScienceDaily Web site. www.sciencedaily.com/releases/2011/09/110907163919.htm. Published September 11, 2011. Accessed March 21, 2017.

10. Kerti L, Witte AV, Winkler A, Grittner U, Rujescu D, Flöel A. Higher glucose levels associated with lower memory and reduced hippocampal microstructure. Neurology. 2013;81(20):1746-1752.

11. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369:540-548.

12. VanItallie TB, Nonas C, Di RA, Boyar K, Hyams K, Heymsfield SB. Treatment of Parkinson disease with diet-induced hyperketonemia: A feasibility study. Neurology. 2005;64:728-730.

13. Seyfried T. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer. Hoboken, NJ: Wiley; 2012.

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