If you have children you may recall the tale of Goldilocks and the three bears.  They were Momma Bear, Poppa Bear and Baby Bear.  The take home lesson from the story, at least regarding porridge, was that the best temperature was not too hot, not too cold, but just right.  Neurons have similar needs when it comes to glucose and insulin levels.  I refer to this "just right" concept as the "Goldilocks Principle."  The major fuel the brain burns is sugar, or more precisely glucose.  The body can make glucose and we can consume it, or foods containing it, in our diet.  White bread is an example of a food source of glucose.  The starch in the white bread is a large molecule composed of long strands of single glucose molecules linked together side to side.  These links, or chemical bonds, holding the glucose together must be broken apart during the digestive process.  When this occurs, the glucose is able to be absorbed.  Not only is it absorbed, it is rapidly absorbed.  More rapidly than the body can use it.  This allows it to build up in the blood stream.  As a matter of fact, if you are aware of the glycemic index of food (a quantitative scale that categorizes the impact various foods have on the blood sugar level), white bread sets the upper standard at 100.  To put this in perspective, white table sugar comes in at about 60.

When the blood sugar skyrockets upward, it sends a signal to the pancreas, an organ in the back of the abdomen behind the stomach, to release insulin into the circulation.  One of the functions of insulin is to allow the body to clear glucose from the bloodstream thus preventing the buildup of high blood sugar levels.  Other foods that contribute to this blood sugar surge are refined carbohydrates such as cakes, cookies, desserts, and soda.  These are staples in the average diet of most Americans.  When consumed throughout the day, this type of diet produces a roller coaster effect on blood glucose and insulin levels.  High, then low, then high, then low and so on cyclically over and over throughout the day.  From the brain's perspective it is exposed to blood sugar levels of 150, then 60, then 140, then 65, and so on.  The reason for the very low, sometimes too low, sugar levels, is that after insulin clears most of the glucose from the blood it is  itself cleared more slowly and thus 'hangs around' for awhile.  This allows it to drive down blood sugar levels below normal.  You might have experienced this a couple of hours after a meal when you felt jittery, dizzy, or mentally woozy.  Welcome to the world of hypoglycemia (blood sugar that is too low).  Since the most potent stimulus for appetite is a low, or falling, blood sugar level you feel quite hungry.  If refined carbs are eaten, they initiate the cycle again.  This is the typical dietary roller coaster based upon an inability to feel satisfied and not hungry for prolonged intervals.  You have just eaten and are hungry again.  If you have been here before, you now know why.

These recurrent surges of glucose are bad for the brain.  Since the brain isn't able to store glucose in any meaningful amount, it depends on a stable, continuous supply.  When we become hypoglycemic, neurons are not able to maintain the high energy levels they depend on for optimal functioning.  When glucose and insulin  levels are elevated two things happen.  To protect themselves from these extremes, neurons tend to become 'resistant' to the action of insulin, and insulin levels in the brain fall.  This is exactly what is observed in the brains of patients suffering from Alzheimer's disease, and to a lesser extent, in persons with failing memories.  To prevent this, our goal should be to maintain a persistent and stable blood glucose and insulin level.  This is determined by dietary means.  It requires the avoidance of refined carbohydrates including fructose and HFCS (high fructose corn syrup, or all corn syrup, for that matter) and trans fats (partially hydrogenated oils, usually corn oil, safflower oil, or cottonseed oil).  Good foods for the brain include those with lean protein and essential omega 3 fatty acids such as eggs, cold water fish, walnuts, and flax and pumpkin seeds.  Non-starchy fruits and veggies such as berries of all types, avocados, olives, spinach, colorful bell peppers and so forth are also at the top of the list.  In addition, I love spices of all sorts.  They contain wonderful nutrients and literally no calories and include turmeric, sage, ginger, rosemary, and cinnamon to name a few.  It is necessary to avoid excessive calories.  A lean body is usually the home of a happy brain.  If you build your diet based upon these guidelines, you will be doing your brain (and body) a big favor!

It is a little-known fact that nerve cells (or neurons as they are called) share more similarities with the cells in the pancreas that make insulin (the pancreatic islet cells called beta cells) than any other cell type in the body.  As it turns out, this is no small  coincidence.  For one thing, they both synthesize and secrete compounds that send signals to other cells.  In the brain these compounds perform like hormones that act over short distances and are called neurotransmitters.  Examples are serotonin (the feel-good compound), dopamine (the focusing compound), norepinephrine (the alerting compound) and many others.  In the pancreas, insulin (the blood-sugar controlling hormone) is synthesized, stored and secreted into the blood when called upon to control blood sugar levels.  Another recent discovery is that in the brain there are receptors (unique docking proteins located in the membranes encapsulating nerve cells) that bind and are activated by insulin.  Even more recently it was discovered that certain neurons in the brain are actually able to synthesize and secrete insulin, which appears to be identical to the insulin produced in the pancreas.  That this occurs is not controversial.  However, what is uncertain is what exactly insulin does in the brain. 

Sometimes it is easier to determine what biological role a compound plays when investigators analyze the circumstances when it is absent.  A rodent study addressed this very issue for insulin.  This experiment suggested that Alzheimer's disease may be caused by a deficiency in brain insulin.  Suzanne de la Monte and colleagues at Brown University in Providence, Rhode Island, had previously shown that insulin was produced in the brain.  She believed it was vital for the survival of neurons.  When they analyzed the brains of post-mortem Alzheimer's patients, they identified reduced concentrations of insulin in their brains.  Based upon these observations, they created a rodent model that mimicked the human condition by causing a fall of insulin levels in the brains of these rodents.   They subsequently documented the death of insulin producing neurons and the delayed development of dementia as determined by performance on the Morris Water Maze test that was administered to the rodents.  Death and degeneration of neurons were not the only findings they observed.  There were also increased concentrations of phosphorylated tau proteins in the brain.  In Alzheimer patients the level of phosphorylated tau proteins parallels the cognitive deterioration.  An enzyme that contributes to the density of phosphorylated tau proteins is GSK (Glycogen Synthase Kinase).  It is under the control of insulin.  With low insulin levels its activity increases and the number of phosphorylated tau proteins increases.  These striking findings suggest that insulin deficiency in the brain may trigger Alzheimer's disease.  The nexus between neurodegeneration and insulin deficiency raises the possibility that Alzheimer's disease is a brain-specific neuroendocrine disorder.  For this reason de la Monte has suggested an alternative name for this disorder-Type III diabetes.  Type I and Type II diabetes result when the body can't produce enough insulin or is resistant to its actions.  She describes Type III diabetes as a brain-specific form incorporating features of both Type I and Type II diabetes where insulin secreting neurons die and other neurons become resistant to the actions of insulin.

That this novel reformulation of Alzheimer's disease is not so far fetched is suggested by the rodent experiments already mentioned as well as human studies documenting the beneficial impact on mental acuity of pharmaceuticals designed to enhance insulin sensitivity  in patients with Alzheimer's disease.  What is even more remarkable is that this suggests that other non-pharmaceutical interventions able to improve insulin sensitivity might well be able to lower the risk of developing Alzheimer's.  Such interventions include  common lifestyle choices entirely under our control such as diet, exercise, smoking, excessive drinking and engaging in a mentally challenging lifestyle. 

It seems intuitive that if the brain burns glucose, that more would be better for brain health and functioning.  In the long-term this is clearly not the case because high glucose levels are a potent factor contributing to brain shrinkage, or atrophy, and the development of insulin resistance-a condition that predisposes to low brain insulin levels with the possible complications we have previously discussed.   What is clear is that ongoing high levels of mental acuity rely on a stable, moderate supply of glucose.  Not too much and not too little.  What determines this is almost entirely under our control and something that will be discussed in the next article.   This is important because disorders such as insulin resistance, pre-diabetes and frank diabetes increase the likelihood of memory and mental problems such as Alzheimer's disease two to four fold.

Any student of the brain and its anatomy is abundantly aware of the seemingly impossible terminology used to identify each of its hills and valleys-hypothalamus, subiculum, insula, fornix, putamen, and others too numerous to list.  Two that are of interest for this discussion are the cuneus and the hippocampus.  They are not visible from the surface of the brain, but are tucked safely along its inner surface.  Although they are separated geographically, they both participate in a vital mental function-memory.  These discrete regions communicate with each other via a deep band of fibers (the long processes called axons that connect nerve cells).  Because we use our memory constantly there is never a moment when these nerve cells are inactive.  As a matter of fact, the brain constitutes 2% of the body weight and consumes 20% of the energy so, on average, it requires 10X the energy  the remainder of the body gets by on. 

Glucose is the primary fuel used by nerve cells to produce all this energy.  When we notice ourselves becoming hypoglycemic, we sense that our brain is not functioning on all cylinders and experience "brain fog."  That is because the brain doesn't really store an appreciable amount of glucose and thus requires a stable continuous supply to get the job done.  There are even brain scans that are able to generate pictures demonstrating how much sugar each area of the brain is consuming.  This type of scan is called a PET scan (for Positron Emission Tomography).  Because of its high metabolic rate, the brain consumes a lot of glucose and this can be seen on a PET scan.  Some of you might be aware of the application of PET scans in cancer diagnosis.  This is useful because most tumors also burn glucose at a rapid rate and hence are easily identified on PET scans.  As chemotherapy  attacks the cancer cells, subsequent scans show less glucose being used by the tumors and correlate with less metabolic activity and subsequent shrinkage.

Similar findings can be identified on PET scans as we age.  When nerve cells become less efficient at burning glucose, they appear less bright on the scan.  This correlates with lower glucose metabolism and impaired function.  This is typically identified in the brains of persons with Alzheimer's disease.  Initially it develops in localized regions and then as time passes it progresses to involve more and more of the surface of the brain.  Often the first symptoms noticed have to do with a declining memory.  For this reason it is no surprise that PET scans show a fall in glucose metabolism in the areas comprising the cuneus and hippocampus.  This radiologic finding is one method used to confirm the diagnosis of Alzheimer's disease.

An illuminating paper on this topic was published in the Proceedings of the National Academy of Sciences (Volume 101, Number 1, pages 284-289) wherein the researchers used this imaging technique to study the brains of mentally normal, healthy middle-aged persons ranging in age from 20-39 years.  The common factor shared by each of the subjects was the possession of one copy of a certain gene (or more precisely, allele) called the APO E epsilon 4 allele.   This is a risk factor for the development of Alzheimer's disease.

When the brains of these subjects were scanned, the results were remarkable.  As a group, they had a lower glucose metabolic rate in the identical regions that are identified early on during the course of Alzheimer's disease, although not as severe.  Since this usually is seen in people who are in their mid-seventies, it was surprising to find the same, albeit milder, findings in asymptomatic subjects who were more than 40 years younger.   As far as I am aware, this is the earliest abnormality able to predict the subsequent development of Alzheimer's.

As such, it provides evidence that the development of the disorder starts early in life and progresses slowly over decades.  It also gives us a protracted window of time to be proactive in slowing down or even preventing it.  Just as heart disease has risk factors that are able to be modified, so does memory loss and neurodegeneration.  In this instance, impaired ability of the brain to use glucose is the risk factor.  This has been referred to as Type III diabetes by various neuroscientists and researchers in the arena of brain health.  The similarities between Type II diabetes (usually referred to as adult-onset diabetes) and the brain condition referred to as Type III diabetes are remarkable.  They are both metabolic disorders having to do with abnormalities of glucose metabolism, which is something we have a great deal of control over.  I will discuss what this means and why it is important in the next article.

Today is September 4, 2007.  It coincides with the publication of my first book:  The Brain Trust Program.  You can read more about it at  www.DrMccleary.com.  This is also my initial blog entry.  I hope to have many more to share.

I would like to introduce myself.  My name is Larry McCleary.  I am a pediatric neurosurgeon and was acting Chief of Pediatric Neurosurgery at The Children's Hospital in Denver for a number of years.  I did my training at New York University-Bellevue Medical Center in NYC.  I had the pleasure of training with one of the premier pediatric neurosurgeons in the world, Dr. Fred Epstein.  I have retired from that position and now live in Incline Village, Nevada.  While I was doing brain surgery in children I published a number of professional articles in medical journals.  Since that time I have changed my focus from caring for children with sick brains to writing and developing and testing unique nutritional supplement formulations for a variety of conditions.  This path was a logical step that evolved from the fact that I love to read medical literature and dispense it in an understandable format such as the book that was just published, use it to design unique nutritional formulations, or speak about it to reporters, interviewers or general audiences.  As a practicing physician it was my goal to provide optimal care to my patients.  Now I strive to do the same by supplying readers with current insights, beneficial information, and novel nutritional products.

I am also the Doctor for the Shining Stars Foundation.  It is a non-profit organization in Colorado whose mission statement is to provide programs to help children with cancer and other life threatening diseases.  We have had children from all four corners of the country participate.  The web site is www.ShiningStarsFoundation.org.  We are currently in the process of writing a book that chronicles the lives and showcases the spirit of these brave children.  There is also a documentary film being produced that is based on interviews of the kids being conducted by other children going through similar situations.  The kids have said to us again and again that the most powerful tool to help them get through the cancer experience is communication with their peers.  The film is designed to make their experiences available for other children around the world who are fighting a similar battle.

I wish to welcome you to an ongoing discussion of a number of topics I find fascinating and that I hope will strike your fancy as well.  They will involve brain health and other aspects of diet, nutrition, metabolism, science and nutritional supplementation.

Thanks for joining the ride!

Larry McCleary, M D.