Thursday, September 30, 2010


I'll get back to Alzheimer's Dementia and fats. But I'm left-handed, and it is more interesting for me to multitask than to stay on one topic in a particularly organized fashion. I have a right-handed accountant for that sort of thing. Ooh, a butterfly fluttered by the window! Pretty!

Ahem. Magnesium is another one of those minerals that our ancestors got lots of, but now we don't. Eaton, Eaton, and Konner figure that an average hunter-gatherer intake is 700mg daily. The RDA is 350mg, and the average US intake is 250mg (Update - these numbers are from "Primal Body, Primal Mind" page 42 - paperback version, and Gedgaudas cites the following paper as the source, but as MM rightly points out, there is no magnesium in this paper!  Sorry to mislead - I had double checked the same source for my zinc posts a few months ago and the numbers were correct, right from the paper, so I didn't bother to double check the magnesium numbers.  Oops!  Fortunately in the internet age everything is double-checked for me.  I have no clue where Nora Gedgaudas obtained the magnesium numbers for her table in the book)(1)(This is an Eaton paper before the addition of the marrow and all the organ meats into the equation, looks like, so one might think the magnesium would be even higher). Who cares? Well, your cells, for one. Magnesium is involved in a lot of cell transport activities, in addition to making energy aerobically or anaerobically. Your bones are a major reservoir for magnesium, and magnesium is the counter-ion for calcium and potassium in muscle cells, including the heart. If your magnesium is too low, your heart could go pitter-patter in some unfortunate ways (2). Ion regulation is everything with respect to how muscles contract and nerves send signals. In the brain, potassium and sodium balance each other. In the heart and other muscles, magnesium pulls some of the load.

That doesn't mean that magnesium is entirely unimportant in the brain. Au contraire! In fact, there is an intriguing article entitled Rapid recovery from major depression using magnesium treatment, published in Medical Hypothesis in 2006. Medical Hypothesis seems like a great way to get rampant speculation into the PubMed database. Fortunately, I don't need to publish in Medical Hypothesis, as I can engage in rampant speculation in my blog, readily accessible to Google. Anyway, this article was written by George and Karen Eby, who seem to run a nutrition research facility out of an office warehouse in Austin, Texas. They might sell zinc supplements for the common cold, but I haven't looked closely enough to say for sure. I must admit to being a zinc fan.

But back to magnesium! Magnesium is an old home remedy for all that ails you, including anxiety, apathy, depression, headaches, insecurity, irritability, restlessness, talkativeness, and sulkiness. In 1968, Wacker and Parisi reported that magnesium deficiency could cause depression, behavioral disturbances, headaches, muscle cramps, seizures, ataxia, psychosis, and irritability - reversible with magnesium repletion.

Stress is the bad guy here, in addition to our woeful diets. As is the case with zinc, stress causes us to waste our magnesium like crazy.

Let's look at Eby's case studies from his paper:

A 59 y/o "hypomanic-depressive male", with a long history of treatable mild depression, developed anxiety, suicidal thoughts, and insomnia after a year of extreme personal stress and crappy diet ("fast food"). Lithium and a number of antidepressants did nothing for him. 300mg magnesium glycinate (and later taurinate) was given with every meal. His sleep was immediately restored, and his anxiety and depression were greatly reduced, though he sometimes needed to wake up in the middle of the night to take a magnesium pill to keep his "feeling of wellness." A 500mg calcium pill would cause depression within one hour, extinguished by the ingestion of 400mg magnesium.

A 23 year-old woman with a previous traumatic brain injury became depressed after extreme stress with work, a diet of fast food, "constant noise," and poor academic performance. After one week of magnesium treatment, she became free of depression, and her short term memory and IQ returned.

A 35 year-old woman with a history of post-partum depression was pregnant with her fourth child. She took 200mg magnesium glycinate with each meal. She did not develop any complications of pregnancy and did not have depression with her fourth child, who was "healthy, full weight, and quiet."

A 40 year-old "irritable, anxious, extremely talkative, moderately depressed" smoking, alchohol-drinking, cocaine using male took 125mg magnesium taurinate at each meal and bedtime, and found his symptoms were gone within a week, and his cravings for tobacco, cocaine, and alcohol disappeared. His "ravenous appetite was supressed, and ... beneficial weight loss ensued."

Interesting, anyway. No one mentioned magnesium (or zinc) during my psychiatry residency, that I recall. Eby has the same questions I do - why is depression increasing? His answer is magnesium deficiency. Prior to the development of widespread grain refining capability, whole grains were a decent source of magnesium (minus all that phytic acid, of course). Average American intake in 1905 was 400mg daily, and only 1% of Americans had depression prior to the age of 75. In 1955, white bread (nearly devoid of magnesium) was the norm, and 6% of Americans had depression before the age of 24. In addition, eating too much calcium interferes with the absorption of magnesium, setting the stage for magnesium deficiency. In Paleolithic times, we drank a lot of magnesium with our natural mineral water, but modern water treatment systems tend to remove the magnesium. Go San Pellegrino!

Magnesium is not readily available in a normal multivitamin, as it is too bulky to fit into the small pills. Therefore you have to go a little out of your way to supplement. Most supplements are also magnesium oxide, which isn't biologically available to the human body. Magnesium glutamate and aspartate can worsen depression (recall that glutamate and aspartate are thought to be neurotoxic in excess). I know, nutrition can be a tricky business.

Next up will be more about the different magnesium supplements, more about magnesium and the brain, and the side effects of robust magnesium supplementation! Yee haw!

Monday, September 27, 2010

Alzheimer's and Omega 3s

Let's continue on our journey deconstructing and reverse engineering psychiatry from an evolutionary medicine perspective. That is, I assume the correct answer and see how the many pieces fit. There is a danger from this approach - if the main hypothesis is incorrect, I might be wasting a lot of time. But I'm having a bit of fun in the process, and it's quite remarkable just how many connections can be made using the intuitive evolutionary framework to lay out the data.

To date there are a large number of studies covering the topic of dementia and omega 3 fatty acids (1)(2). There are a couple of reasons omega 3s have been so thoroughly studied, and if you have the stamina, I'll take you through a bit of molecular biology.

First off, inflammation and Alzheimer's are linked, and omega 3s are basically anti-inflammatory. DHA is modified by phospholipases to become neuroprotectin 1 (your neurons' superhero - neuroprotectin!) Alzheimer's patients have lower phospholipase activity in brain tissue, CSF, and in platelets. All sorts of inflammatory stressors (lack of oxygen, exposure to amyloid, and IL-1b) cause the up regulation of phospholipase, leading to the formation of neuroprotectin from DHA, which then reverses the inflammatory cascade. Perfect negative feedback inhibition - which works best no doubt if the omega 3s and 6s are balanced in a more evolutionary style diet.

Secondly, an imbalance of AA (derived from omega 6) vs DHA (omega 3) may be critical to the formation of amyloid plaques in the first place. Amyloid precursor protein has to be cut in particular ways to make the toxic fragments that eventually aggregate into amyloid plaques. It seems that if brain cell membranes are rich in DHA, the squiggles and wiggles of DHA hide and protect the bad cleavage sites on amyloid precursor protein. AA squiggles and wiggles seem to expose the bad cleavage sites, making it easier to make plaque from amyloid precursor protein. DHA also seems not only to make it physically harder to cut amyloid precursor protein in the bad way, but DHA also chemically cripples the action of the amyloid-creating enzyme, gamma secretase. All this in addition to reducing the inflammatory action of plaque once DHA is formed into neuroprotectin!

So what about those studies of omega 3 and dementia? 17 reasonably good cross-sectional, epidemiological, and prospective cohort studies have been done over the years. Some of better quality than others, of course. 2/3 used food frequency questionnaires, the other 1/3 lab measurements of fatty acid ratios (from serum or plasma). Overall, the studies followed some 24,000 or so people in Japan, the US, Canada, and Europe, both those with dementia and regular population cohorts.

Results time! Some studies found no correlations, but for the most part, diets high in fish were associated with less dementia. Diets high in omega 6, saturated fat, total fat, and cholesterol were associated with more dementia. The association was especially strong for those people without the genetic predisposition for Alzheimer's - people without the ApoE4 allele. (ApoE is short for apolipoprotein E, by the way - yes, just like high density lipoprotein (HDL) and low density lipoprotein (LDL), apolipoproteins carry around fat and cholesterol, but in the brains. More about this in a later post).

The overall trend was enough to cause researchers to try prospective controlled trials with omega 3 supplementation in dementia. 6 have been done to date. The first one, in 2004, was badly designed at the beginning. 20 Alzheimer's patients were treated with 500 mg of the omega 3 EPA. Since EPA is not an important fatty acid in the brain as far as we know, there was no effect in cognitive decline between the supplement arm and the placebo arm of the studies. In Japan in 2006, 240mg of AA+DHA was compared to 240mg of olive oil daily for 90 days. The mild cognitive impairment group with the PUFAs showed some improvement, whereas the olive oil group had no improvement.

Also in 2006, a large (204 subjects) double blind randomized controlled trial was done with 1.7 grams DHA and 0.6 grams EPA or placebo for 6 months, followed by an additional 6 months of "open label" where everyone got the omega 3 treatment. Overall, there was no difference between the two groups, except one subgroup of mild cognitive impairment did better on the omega3s. Another small study in 2008 had similar results.

In 2009, 485 cognitively normal elderly folks were randomized to 900 mg DHA a day or placebo for 6 months. The treatment arm doubled their plasma DHA levels and showed improvement in some of the learning and memory tests (but not in the main study objective, the "global battery score") while the controls didn't improve. A second trial of 402 subjects with mild to moderate Alzheimer's dementia and 2 grams of DHA vs placebo did not meet the primary objective despite healthy increases in serum and CSF levels of DHA in the treatment arm.

Whew. So here we have science. Plausible molecular mechanism, followed by epidemiological studies, followed by randomized controlled trials. Overall, the science tells us that omega 3 is probably protective against amyloid and helpful in memory. Why? Because non-demented and mildly demented individuals benefited, while the more severe cases did not. In my last Alzheimer's post, I discussed how amyloid builds up over decades, and amyloid-zapping interventions in the end stage is like dousing a fire just after the house is burned down. Theoretically, omega 3s should have some benefit at the inflammatory stage too - I wonder what the outcome in more severe cases would be if the omega 6s and 3s where held to an evolutionary ratio of 2:1 or 1:2 or 1:1?

In general we are not talking about mega doses here. In the epidemiological studies, DHA intakes of 180mg a day correlated with a 40% reduction in dementia. Average Western diet intake is 80mg a day. Fatty fish three times a week or so would do the trick.

There are two schools of thought about getting the 3/6 ratios correct in the paleosphere. One way is to let time be on your side, avoid excess omega 6, and supplement prudently with Omega 3. DHA is easily oxidized, so you would want to supplement with oil you can taste - in fish, for example, or teaspoons. Another way is to take in high amounts of omega 3 to more or less wash out the omega 6. This method might make more sense if you are in a more desperate situation - mild cognitive impairment already, active heart disease, bad autoimmune stuff going on. The risk is that high amounts of PUFAs are tough on the liver and are bad to combine with sugar and alcohol, and likely cancer promoting. My perspective - if you can get away with it, take it slow. But compared to a number of other medical treatments for our various diseases of civilization, even higher doses of PUFAs for a short term is likely safer and possibly more beneficial.

(did this post on the iPad so I'm adding references later, when I get a moment at the bigger computer! - Done!)

Saturday, September 25, 2010

Your Brain on Omega 3s

Nitty gritty time. I've been touting the benefits of omega 3 fatty acids from the beginning of the blog, but I haven't really gone into exactly what those marine-animal derived PUFAs are doing up there, and why they are so important. Fortunately, one of the papers I'm reading for the Alzheimer's series has an excellent discussion. (1)

If you recall, the brain has a heck of a lot of cell membranes, and cell membranes are made out of fat. The fat content of the brain is a little different than the rest of the body - the only PUFAs allowed into the healthy brain in any appreciable amount are the omega 3 DHA and the omega 6 derived (or obtained directly from animal foods) arachidonic acid (AA). In addition, while AA is found in equal amounts all over the brain, DHA is found predominately in the gray matter. That's where our thinking takes place.

Let me explain a bit about the actual structure of these molecules, and that may clarify some things. It will be helpful for you to consume some wild-caught salmon before reading this as the DHA helps the transcription factors of your hippocampus in the process of making new memories.

Saturated fats and cholesterol make rather boring cell membranes all on their own. Their structure is pretty straight, and they line up rather like this:


PUFAs have unsaturated bonds, which make them rather kinky. Add some PUFAs to a cell membrane and you suddenly get this:


The unsaturated bonds break up the structure a bit, and molecular biologists call this "increasing membrane fluidity." Important membrane proteins, such as ion channels, depend on the presence of PUFAs to be incorporated correctly into the membrane. If all is well, the PUFAs serve as part of "lipid rafts" that are required for transport of protein and signals through the membranes, the formation of synapses, and maintaining the integrity of the neuronal membranes. Lipid rafts. Whee!!

We can make a bit of DHA from ALA (an omega 3 found in plants, such as flax), but the process is horribly inefficient. Otherwise, DHA is made by photosynthetic algae eaten by krill or fish or oysters, etc. - which we eventually consume. We cannot make DHA ourselves in useful amounts. The amount and ratios of PUFAs in our brain are dependent upon what we consume in our diet.

AA is important in the brain - it initiates and maintains the inflammatory cascade, which is a critical function. But AA is a different kinky shape than DHA and the overall membrane functioning is quite different if we have a ton of AA compared to DHA. The paper notes here that "it is intriguing that the dramatic increase in the prevalence of [Alzheimer's disease] in the last century not only parallels the increase in average lifespan, but also an increase from 2 to more than 20 of the ratio of omega 6 to omega 3 PUFAs in the average Western diet."

Our brains are designed to run on fish oil. We really shouldn't be operating the all-important noggin too far outside the design specs, or nasty things tend to happen.

In the next couple of posts we will explore a bit more about DHA vs AA in the pathology of Alzheimer's, and also figure out why the randomized controlled trials of omega 3 fatty acids in dementia have, so far, been a bust.

(PS - Dr. BG had a couple of recent blog posts on the topic of our fish-eating ancestors - similar points to mine though made with considerably more flair!) 

Thursday, September 23, 2010

ADHD, Food Additives, and Histamine

I'll get back to the wild world of Alzheimer's research in a day or two.  My September issue of the Green Journal arrived via USPS this afternoon, and of course this paper caught my eye:

"The Role of Histamine Degradation Gene Polymorphisms in Moderating the Effects of Food Additives on Children's ADHD Symptoms."

A colleague rolled her eyes at me when I squeaked while reading the title.  But do you know how many diet-related articles are published in my specialty journal (the oldest specialty journal in publication, by the way) every year?  Maybe one or two.  And I've laid out the groundwork for evaluating this study.  If you didn't read them the first time around, maybe take a moment now to go back to the archives to look at Hyperactivity and Diet and A Closer Look at Tartrazine.   The recap is that some food additives have been shown to worsen the symptoms in ADHD (or hyperactivity) in some children, but other children seem to be impervious.

ADHD in children is diagnosed when kids have symptoms of inattention, impulsivity, and hyperactivity, to the point where severe problems interfere with daily functioning.  The disorder is highly inherited, and a few genes have been found in some families that seem to explain the symptoms - the dopamine transporter genes and dopamine receptor genes, among others.  Issues with these genes make sense for the symptoms you would see in ADHD - dopamine is the neurotransmitter, in our frontal lobes, especially, that is responsible for helping us pay attention and keeping us from saying things we shouldn't.  If our dopamine system doesn't work efficiently, then you could see how someone could have ADHD.

But what in the world does this have to do with food dyes?  Azo food dyes like yellow number five are known to cause allergic reactions in susceptible people, typically hives.  That means artificial food colorings may result in the release of histamine, a chemical we let loose during an allergic reaction.  The theory the researchers are working with here is that exposure to food dyes may cause some kids to release histamine, maybe not to a degree to where there is a full-on allergic reaction and hives, but where it could possibly affect behavior or impulsivity.  Since the H3 receptor is prevalent in the human brain, histamine could certainly have a behavioral effect.

Researchers took the same kids who were involved in the Southampton study and checked the their genes for dopamine transporter, dopamine receptor, COMT, and ADRA2A genetic polymorphisms.  All these genes have been associated with select groups of families with ADHD.  In addition, the researchers tested for differences in the histamine N-methyltransferase (HNMT) genes to check out the histamine hypothesis.  An efficiently functioning HNMT system means you clear histamine from the body in a timely manner.  If your gene codes for a protein that is less efficient, you might be more vulnerable to allergy and other histamine-mediated problems.  These kids were a random community sample and didn't necessarily have ADHD, and had gone through a double-blind crossover placebo controlled trial of two mixes of food dyes and preservatives and a control.  The kids' behavior overall worsened significantly in the eyes of the parents and independent observers during the weeks they drank the additive-laden juice compared to the additive-free control juice.  But, once again, individual reactions to the hyper juice were highly variable.  Individual reactions were checked against the individual genotype to see if any connections could be made.

Of the 297 kids, about half were three years old, and the other half were eight and nine.  Among the three year-olds, certain histamine and dopamine gene polymorphisms were associated with higher baseline hyperactivity - prior to drinking any hyper juice.  That is to be expected if the genetic theory is sound.  Among the 8/9 year-olds, there wasn't a connection found.

But what about when we added the additives?  Overall, the three year-olds had significant reactions to the hyper juice (more Mix A than Mix B) if they lacked certain alleles of the histamine N-methyltransferase (HNMT) gene.  There seemed to be no differences in the reactions depending on the dopamine or other checked genotypes.   In the 8/9 year-olds, the results were quite similar.  Not too much difference when dopamine may be off, but a significant difference depending on the HNMT gene allele. 

The study was relatively short term, and obviously should be replicated before we jump up and down too much.  But genetic differences in our histamine systems may explain why some kids react very badly to azo food dyes, and others don't seem to bat an eye.   And this would mean that ADHD, in some people, is very likely a food allergy.  Those kids might also be vulnerable to environmental allergies that affect the histamine system.  There is also some evidence that methylphenidate (ritalin) and atomoxetine (strattera), medications used for ADHD, work not only via dopamine but also via histamine interactions.

The editorial in the same issue says it all:  "The links are clear, and the paper is a watershed, although still falling far short of definitive proof.  As with every breakthrough, more questions emerge than are answered...[the Southampton study didn't separate preservatives from additives which is an issue, as removing preservatives has economic and food safety issues] but there is no cost to health or safety in giving up artificial food colors.  It certainly appears that over and above this set of studies, the cumulative evidence is sufficient for society to demand adherence to the precautionary principle and to... restrict the use of artificial dyes, at least in foods that target children."

From the conservative American Journal of Psychiatry, that is a clarion call.  Amen.

Wednesday, September 22, 2010

Alzheimer's Pathology and the Dementia-Free Kitavans

Over the last two posts I explored the theory that hyperglycemia might be one of the predisposing factors for developing Alzheimer's dementia.  The epidemiological studies looked pretty solid (though we know that a strict reliance on epidemiology can cause us to do ridiculous things, such as eating boneless skinless chicken breasts or, even worse, veggie burgers).  At least there was a plausible biochemical mechanism - high levels of insulin could interfere with the enzyme that clears away amyloid in the brain, thus allowing amyloid to build up into plaques.  Unfortunately, the smaller studies and autopsy studies Dr. Steve Parker linked in the comments seemed to show no link between Alzheimer's and diabetes.

The best hypothesis I could come up with, from the data of the papers from those posts, was that perhaps a combination of the genetic predisposition to Alzheimer's (carrying the ApoE4 allele) and diabetes could put one at higher risk.  People with ApoE4 seem to have lower amounts of enzyme to clear away amyloid in the first place, so add lots of insulin, and you've got plaque city.  But hyperglycemia alone wasn't going to explain it - though everyone agrees that hyperglycemia is rotten for the brain.

So what does cause Alzheimer's?  Truth be told, a whole cascade of things played out over decades (1).  Beta-amyloid peptide is definitely a key player, but it certainly isn't the only one.  It all begins with amyloid aggregating in vulnerable areas of the brain (called plaques - and this takes years and years), followed by accumulations of tau protein (called tangles).  The plaques and tangles (when I was in residency, there was a holy war going on between different sects of brain researchers about which was more important - plaques or tangles) seem to interact with inflammatory cells in a way that the accumulated plaques and tangles finally trigger diffuse brain toxicity and neuronal death.  At the beginning, measuring amyloid can predict problems even before someone experiences the first clinical stage of Alzheimer's called "mild cognitive impairment" (MCI).  The cognitive decline seems to be triggered when tau protein increases.  So, to recap - long symptomless amyloid buildup, tau takeover, inflammation and neuron destruction.  Boom.  Alzheimer's dementia.

Researchers looking just at amyloid ran into problems.  For example, there has long been interest in developing a vaccine against amyloid - sounds awesome, right?  Zap out Alzheimer's with our own immune system!  However, by the time the amyloid has accumulated to Alzheimer's proportions, it's very unlikely that a vaccine could reverse the course of the disease.  Vaccine trials (and trials of other drugs that lower amyloid production) even showed reversal of plaque build-up at autopsy, but the patients were still demented despite zapping the plaques.   If you wanted to stop Alzheimer's by targeting amyloid, you would need to start decades earlier, and no one wants to take an experimental preventative anti-amyloid medicine without a safety track record for a lifetime  (or at least I don't!).  However, this brings up the interesting hypothesis that low-carbers, paleo diet enthusiasts, Kitavans, or anyone who avoids hyperglycemia could be preventing amyloid build-up at this long prodromal stage, thus possibly reducing risk of later Alzheimer's.

But... there are types of frontal temporal dementias in humans that involve just tau protein, no amyloid required.  Any treatment or hypothesis that is focused on amyloid is missing a big part of the picture (sorry, plaque researchers!).  If you are looking to combat Alzheimer's at later stages of the disease (mild cognitive impairment and beyond) you need to fight brain inflammation and tau protein tangle accumulation.

The brain inflammation is, in part, mediated by oxidative damage (free radical ions roaming around and taking out proteins, fats, and brain DNA).  This has been known for quite a while, leading to lots of research into vitamin E (a known antioxidant) as an Alzheimer's preventative.  It works great in certain types of mutant mice, but was lousy in experimental trials of humans with MCI or Alzheimer's.  But vitamin E may not be quite specific enough, and lots of alpha-tocopherol (vitamin E) might even deplete our own self-made antioxidant gamma-tocopherol - meaning too much oral vitamin E could be pro-oxidant.  Oops! 

Here's where it gets very interesting for the Kitavans and for certain evolutionary-minded psychiatrists.  The inflammation in Alzheimer's dementia is linked to eicosanoid production (2).   The actual process is dizzyingly complicated, with certain inflammatory markers (such as IL-1beta and complement protein) being pro-plaque and tangle in certain models of the disease, and anti-plaque and tangle at other times.  Seems that complement can lead the immune system to chew up plaques and tangles in an appropriate inflammatory response, whereas in Alzheimer's brains late into the disease, complement reactions are way out of proportion and likely worsen the problem, inviting a bunch of inflammatory fighting forces to the decimated neural battleground.  But, if you recall, the evolutionary medicine theory is that our inflammatory cascade is all out of whack due to the horrible Western dietary imbalance between the inflammatory and anti-inflammatory eicosanoid precursers, omega 6 and omega 3 polyunsaturated acids. 

Well, if one is too afraid of Unilever and saturated fat to ask people to decrease their omega 6 consumption, one could do something chemically similar by trying to treat Alzheimer's with NSAIDs (naproxen, ibuprofen and the like).   The Anti-inflammatory Prevention Trial (ADAPT) looked at first to be a failure and was halted early over safety concerns.  But, something very interesting happened several years after the naproxen treatment was halted (about two years into the study)(3).  Apparently the treatment group had significant reduction in conversion to Alzheimer's Disease 1.5 years after the naproxen was stopped.  AND measurements of the treatment group's CSF at the same time showed 40% reduction of the tau/amyloid ratio.  That's good, as increasing tau/amyloid ratio is one of the markers of accelerating  cognitive decline in Alzheimer's.   Other studies have shown a reduction in dementia with long term use of ibuprofen (especially in ApoE4 carriers).

Now, since long-term NSAID use can kill your kidneys, cause ulcers and possibly heart attacks, it's not a great strategy for a primary population-based treatment of Alzheimer's.  I prefer the Kitavan approach - balance out those omega 3s and omega 6s.  (I'll go into the use of omega 3s as treatment and prevention of Alzheimer's in the next post). 

One more thing about those Kitavans - island living may not be particularly stressful.  Chronic expression of the inflammatory cytokine IL-1 can interfere in the regulation of the HPA axis, resulting in the unfortunate elevation of glucocorticoids, like cortisol.  As we've discussed before, long-term excess cortisol is bad for the brain.  Interestingly, many Alzheimer's patients have too much cortisol (called hypercortisolism) that is not fully explained by damage to the hippocampus (4).  In Alzheimer's, the excess cortisol may contribute to insulin resistance and problems with energy regulation in the brain.  And, as we know, energy is everything when it comes to helping out a sick brain.

The boring thing about evolutionary medicine is that we have the same prescription for every problem.  Stop sucking down vast quantities of omega 6.  Eat a diet that won't promote obesity and hyperglycemia.  Get plenty of sleep and lots of play to avoid excess stress.  And who knows, we just might, eventually, prove that government panel wrong, as the Kitavans already have.  So maybe not boring at all, just completely intuitive, relatively simple, and AWESOME.

(picture of neurofibrillary tangle of hyperphosphorylated tau protein lifted from wikipedia)

Sunday, September 19, 2010

Alzheimer's and Hyperglycemia 2

So we know what Gary Taubes thinks.  Since Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health (Vintage) came out, there has been quite a bit more research into the topic of metabolic syndrome and the risk for Alzheimer's dementia.  I'm going to list some of the papers and the results to show what we're looking at here (there are a TON of studies, so I'm trying to pick a few studies on either side of the issue here):

J Am Geriatr Soc. 2010 Mar;58(3):487-92.  Metabolic syndrome and risk of dementia in older adults.
Forti P, Pisacane N, Rietti E, Lucicesare A, Olivelli V, Mariani E, Mecocci P, Ravaglia G.  Conclusion: MetS measured in late life is not associated with risk of dementia. After age 75, persons with MetS may even be at lower risk for AD.

J Am Geriatr Soc. 2002 Jan;50(1):41-8.Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study. Di Carlo A, Baldereschi M, Amaducci L, Lepore V, Bracco L, Maggi S, Bonaiuto S, Perissinotto E, Scarlato G, Farchi G, Inzitari D; ILSA Working Group.  Conclusion: Incidence of dementia in Italy paralleled that in most industrialized countries. About 150,000 new cases per year are expected. A significant gender effect was evidenced for major dementia subtypes. The burden of VaD, especially in men, offers opportunities for prevention.

Biochim Biophys Acta. 2009 May;1792(5):432-43. Epub 2008 Dec 16.(Pre)diabetes, brain aging, and cognition. S Roriz-Filho J, Sá-Roriz TM, Rosset I, Camozzato AL, Santos AC, Chaves ML, Moriguti JC, Roriz-Cruz M. Abstract: Cognitive dysfunction and dementia have recently been proven to be common (and underrecognized) complications of diabetes mellitus (DM). In fact, several studies have evidenced that phenotypes associated with obesity and/or alterations on insulin homeostasis are at increased risk for developing cognitive decline and dementia, including not only vascular dementia, but also Alzheimer's disease (AD). These phenotypes include prediabetes, diabetes, and the metabolic syndrome. Both types 1 and 2 diabetes are also important risk factors for decreased performance in several neuropsychological functions. Chronic hyperglycemia and hyperinsulinemia primarily stimulates the formation of Advanced Glucose Endproducts (AGEs), which leads to an overproduction of Reactive Oxygen Species (ROS). Protein glycation and increased oxidative stress are the two main mechanisms involved in biological aging, both being also probably related to the etiopathogeny of AD. AD patients were found to have lower than normal cerebrospinal fluid levels of insulin. Besides its traditional glucoregulatory importance, insulin has significant neurothrophic properties in the brain. How can clinical hyperinsulinism be a risk factor for AD whereas lab experiments evidence insulin to be an important neurothrophic factor? These two apparent paradoxal findings may be reconciliated by evoking the concept of insulin resistance. Whereas insulin is clearly neurothrophic at moderate concentrations, too much insulin in the brain may be associated with reduced amyloid-beta (Abeta) clearance due to competition for their common and main depurative mechanism - the Insulin-Degrading Enzyme (IDE). Since IDE is much more selective for insulin than for Abeta, brain hyperinsulinism may deprive Abeta of its main clearance mechanism. Hyperglycemia and hyperinsulinemia seems to accelerate brain aging also by inducing tau hyperphosphorylation and amyloid oligomerization, as well as by leading to widespread brain microangiopathy. In fact, diabetes subjects are more prone to develop extense and earlier-than-usual leukoaraiosis (White Matter High-Intensity Lesions - WMHL). WMHL are usually present at different degrees in brain scans of elderly people. People with more advanced WMHL are at increased risk for executive dysfunction, cognitive impairment and dementia. Clinical phenotypes associated with insulin resistance possibly represent true clinical models for brain and systemic aging.

Biol Psychiatry. 2010 Mar 15;67(6):505-12. Epub 2009 Apr 9. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Profenno LA, Porsteinsson AP, Faraone SV.  (* Emily's note:  This is a paper that ended up in my physical mailbox earlier this year, leading me to be enthusiastic about the diabetes/Alzheimer's link yesterday*).  Conclusion: Obesity and diabetes significantly and independently increase risk for AD. Though the level of risk is less than that with the APOE4 allele, the high prevalence of these disorders may result in substantial increases in future incidence of AD. Physiological changes common to obesity and diabetes plausibly promote AD.

Neurology. 2008 Sep 30;71(14):1065-71. Epub 2008 Apr 9.Impaired insulin secretion increases the risk of Alzheimer disease.Rönnemaa E, Zethelius B, Sundelöf J, Sundström J, Degerman-Gunnarsson M, Berne C, Lannfelt L, Kilander L.  Conclusion: In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.

Diabetologia. 2009 Aug;52(8):1504-10. Epub 2009 May 20. Glucose metabolism and the risk of Alzheimer's disease and dementia: a population-based 12 year follow-up study in 71-year-old men. Rönnemaa E, Zethelius B, Sundelöf J, Sundström J, Degerman-Gunnarsson M, Lannfelt L, Berne C, Kilander L.  Conclusion: In this community-based study, low early insulin response was associated with increased risk of subsequent Alzheimer's disease, whereas low insulin sensitivity was not. Vascular dementia was not related to early insulin response. We suggest that glucometabolic disturbances are linked differentially to the pathogenesis of these two main dementia subtypes.

Diabetologia. 2009 Jun;52(6):1031-9. Epub 2009 Mar 12.Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study. Xu WL, von Strauss E, Qiu CX, Winblad B, Fratiglioni L.  Conclusion: Uncontrolled diabetes increases the risk of Alzheimer's disease and VaD. Our findings suggest a direct link between glucose dysregulation and neurodegeneration.

Neurology. 2010 Aug 31;75(9):764-70. Epub 2010 Aug 25.Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T. RESULTS: Higher levels of 2-hour post-load plasma glucose, fasting insulin, and HOMA-IR were associated with increased risk for NPs after adjustment for age, sex, systolic blood pressure, total cholesterol, body mass index, habitual smoking, regular exercise, and cerebrovascular disease. However, there were no relationships between diabetes-related factors and NFTs. Regarding the effects of APOE genotype on the risk of AD pathology, the coexistence of hyperglycemia and APOE epsilon4 increased the risk for NP formation. A similar enhancement was observed for hyperinsulinemia and high HOMA-IR. CONCLUSION: The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE epsilon4.

Neuropathol Appl Neurobiol. 2009 Feb;35(1):60-8. Epub 2008 Mar 10.Beta-amyloid deposition in brains of subjects with diabetes.Alafuzoff I, Aho L, Helisalmi S, Mannermaa A, Soininen H.  Conclusion:  We conclude that the hypothesis that hyperinsulinaemia would significantly elevate the Abeta load and thus increase the extent of AD pathology cannot be supported. Our result challenges the claim that DM is a direct risk factor of developing AD. Thus further studies on pathological lesions in demented diabetics should be conducted.

* * * 

 So what have we got?  Italians who seem to be protected from dementia by metabolic syndrome.  Finnish diabetics whose brains don't seem to have an increase in beta-amyloid plaques despite insulin-degrading enzyme issues, directly disproving Gary Taubes' theory.  Brazilians who found the opposite of the Finns, proving Gary Taubes' theory. Meta-analysis showing independently increased factors for dementia with obesity and diabetes.  Insulin resistance showing increased risk of Alzheimer's 35 years later. 


It's complicated.  That's all right.  There are thin type II diabetics and obese type II diabetics, after all.

But the overall theory isn't as straightforward as Taubes insulin-degrading enzyme being too busy to clean up the amyloid too, though the overall theory is simple in concept - hyperglycemia speeds up aging.  It's like our metabolisms in fast-forward.  Anatomic brain differences have been shown in patients with diabetes (type I and II) consistent with non-diabetic patients > 80 years old.  Also shrinkage of the hippocampus and the amygdala (these are also found to be shrunk in type II DM).  Patient with uncontrolled type II diabetes have worse cognitive function and memory.  Patients with more diabetic complications (suggesting poorer glycemic control) also have more cognitive difficulty.  Studies of the "oldest old" (>85 years) don't seem to show a difference between diabetic and non-diabetic populations, though.  Though at that point almost everyone starts losing weight (possibly improving diabetic control).  Alzheimer's disease is the cause of dementia in 82.5-91% of type II diabetics - which is greater than the general population.  (1)   But insulin degrading enzyme (IDE) is still important - patients with the genetic predisposition for Alzheimer's have decreased expression of IDE in the hippocampus.  Since one of the above studies showed a special link between diabetes and ApoE (in the Japanese), it does make one ponder.  The meta-analysis from Biological Psychiatry makes for interesting reading too - suggesting that diabetes is, indeed, an independent risk factor.

All in all, the primary sources certainly give one less of a warm and fuzzy feeling than the secondary ones.  That is to be expected.  But there's no harm in keeping one's fasting insulin levels low.  And perhaps a lot to be gained.

Saturday, September 18, 2010

Alzheimer's and Hyperglycemia

courtesy wikipedia

The theory that Alzheimer's dementia is in part caused by metabolic syndrome is fairly well known in the paleoblogosphere and literature. I touch upon it now more for the sake of completeness than to try to explore anything new and mind-blowing - at least for the first part of the series. Also, I always learn a bit more about neurobiology when I dig a little into these subjects. As much as I love and appreciate my several regular readers, much of this blog is a selfish endeavor.

Today, though, I'll start with one of my favorite secondary sources: Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health (Vintage) by Gary Taubes. He has a whole chapter on dementia, cancer, and aging - pages 204-225 if you are following along in the hard copy - which I bought directly after seeing Mr. Taubes interviewed on the Colbert Report back in 2007. If it weren't for watching that interview, I might have tried counting calories or something really silly rather than consulting a paleolithic-friendly nutritionist in order to lose the last of the baby weight at the beginning of this year, and then none of this would have happened. So thank you, Stephan Colbert. I just put a big hunk of pastured butter to melt into my local-grown vegetable soup (simmered with grassfed cow marrow bones), and I owe it all to you.

Here's the theory. Hypertension, atherosclerosis, smoking, and apo E4 increase the risk of cardiovascular disease, vascular dementia (obviously - vascular dementia is generally thought to be caused my multiple and increasing stepwise vascular insults to the brain, like little strokes or clots) and Alzheimer's dementia (which is associated with excess tau and amyloid protein build-up in the brain, like a fish tank that never gets cleaned). Folks with type 2 diabetes have twice the risk of developing Alzheimer's, and diabetics on insulin therapy have four times the risk.

There's a protein called insulin-degrading enzyme that does just what you might expect. It clears out insulin in the brain. It also clears out excess amyloid (at least in test tubes), so one can imagine if it were super-busy with the insulin, amyloid might get left cluttering up the joint. Unlucky mice with no insulin-degrading enzyme get dementia, and elderly people get increased amyloid in their cerebral spinal fluid when insulin is injected into their veins.

The obvious conclusion is that once wants low insulin levels so that your insulin-degrading enzyme can keep itself busy with the pesky amyloid, leaving none to form plaques. One way to achieve that is a low carbohydrate diet. Even the high-carbohydrate Kitavans, though, had exceedingly low fasting insulin levels (1), so a paleolithic-style diet will seem to do the trick if you don't have metabolic syndrome to begin with, whether low or high carb. If you have a bit of high blood pressure and some tub about the waist, you might want to skip the squash and go straight for the meat and butter. But forget the refined carbohydrates. They do not love your brain.

Is Alzheimer's disease increasing? Yes, absolutely. Wouldn't it be nice if we could do something about it? The National Institutes of Health convened a panel earlier this year, who determined there is no reliable way to prevent Alzheimer's. I can see myself at the back of the room, frantically waving my hand. "The Kitavans have no dementia!" I would say. Would there be raised eyebrows? Puzzlement? A security team called to escort me off the premises?

Evolutionary medicine can sometimes be very lonely.

Thursday, September 16, 2010

Borderline Personality Disorder and Glutamate

If you recall from Love and Opium, I discussed how borderline personality disorder possibly stems from attachment problems combined with temperamental sensitivity plus opiate receptor issues.  And in other posts, I've discussed the basic idea that excess glutamate is Evil in our poor brains.

Well, a new article in the Archives of General Psychiatry brings it all together!  Amazing what happens when you pay attention.

Let's review.  Borderline Personality Disorder is a disruption of healthful coping skills, leading to impulsive behavior, inability to contain emotion properly, and difficulty controlling anger.  This disorder affects 2% of the population and 20% of psychiatric inpatients, so chances are you know someone who suffers from it.

So is this all psychological, or are there actual neurological correlates in the brain?  Yes, that is a silly question because OF COURSE there are neurological correlates in the brain.  It comes down to dysregulation in the fronto-limbic network.  The limbic region of the brain controls emotion, the frontal region is rather like the policeman in your head that tells you that your hysterical internal observations about your Aunt Gertie's Awful Hat are NOT appropriate to share at the present time and place.  So if your fronto-limbinc network is out of whack, you can be impulsive, easily angered, and too sensitive.

So the Archives, in true form, goes into excruciating detail about all the fMRI and other imaging studies that have failed to show any conclusive correlations to borderline personality disorder.  Don't worry!  I want to keep my few dozen fans!  So let's skip to the good stuff.  Fronto-limbic function in borderline personality disorder was found to be especially dysregulated with respect to remembering "unresolved negative life events."

I've no doubt Kurt Harris, M.D. knows more about these types of imaging studies, but the next thing our intrepid borderline personality disorder researchers did was get a Proton Magnetic Resonance Spectroscopy (MRS) scan of their borderline patients.  MRS apparently allows one to follow the metabolism of all sorts of interesting neurotransmitter characters, including glutamate, while the scanned subject is still alive and thinking.

Thirty female patients diagnosed with borderline personality disorder were scanned and tested alongside thirty female matched controls.  And, not surprisingly, differences were found.  Patients were higher with respect to anxiety, depression, impulsivity, and dissociation ("out of body" sorts of feelings, or numbness of response to intense emotions).  And on the brain imaging studies, borderline patients had significantly higher amounts of glutamate (the excitatory, and, in excess, neurotoxic neurotransmitter) in the anterior cingulate cortex (ACC) than the controls.  Since the ACC is the heart of our ability to contain our impulses, having too much glutamate on board could presumably short circuit our ability to restrain ourselves.

Abnormal levels of frontal glutamate have also been found in studies of depression, schizophrenia, and ADHD.  And glutamate dysregulation has also been found to be a problem with dissociation symptoms in general.  The difference is, insurance companies will pay when I record a diagnosis as major depression, schizophrenia, or ADHD (all considered "organic" disorders), whereas they might not if I made the mistake of coding a patients' primary problem as borderline personality disorder (considered "psychological" and not organic).

And men, if you  are looking for male data here, you are a bit out of luck.  Turns out all relevant MRS studies of borderline personality disorder have included only women.

Insurance companies - it is ALL organic.  Psychology is expressed within the confines of the neurochemistry of the organism.  And, eventually, all of it will have to be paid for, one way or another.

Tuesday, September 14, 2010

Schizophrenia Round-up and Back to School

Today I went back to school.  Every fall, I help teach the introduction to psychiatry class for the second year medical students at my institution.  I work with a small group, teaching basic interviewing and write-up skills.  Today was a large lecture, though, so I got to be in the audience, thumbing through this month's stack of journals while the students were Introduced to Psychiatry.  

There are a few interesting papers in the Archives of General Psychiatry this month, which isn't always the case.  The Archives tends to have really tedious genetic polymorphism and functional MRI studies out the wazoo.  You get paper headings like "Reduced brain white matter integrity in trichotillomania." Which, believe me, is not even as interesting as it sounds.  Still, the Archives is an excellent journal and they don't accept horrible studies, just boring ones.

The first interesting one is "Modification of Cognitive Performance in Schizophrenia by Complexin 2 Gene Polymorphisms." (I know, it sounds really boring!  But give it a chance.)  Turns out this group in Germany put together a database of genetic data for schizophrenia research.  23 different research centers compiled the genetic data of 1071 patients with schizophrenia and 1079 controls.  Then they threw the DNA into their big machines, and out pops loads of data.  Over 3000 phenotypic data points for each patient!  There's a specific gene, complexin 2, which codes for a type of protein that regulates how synaptic signaling happens in the brain.  Specifically, complexin 1 and 2 control the release of the soluble-N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE).  Differences in the complexin 2 proteins and mRNA have been noted in previous autopsy studies of schizophrenics, so the genes were an obvious place to look.  In those autopsy studies, a significant decrease in complexin 2 was found in regions of the brain that are specifically damaged in schizophrenia (like the dorsolateral prefrontal cortex and the hippocampus).  This same protein/gene expression was found to be decreased in studies of bipolar disorder, Alzheimer's, and Huntington's disease, but in different parts of the brain more affected by those other disorders.   All of the disorders, though , have symptoms of cognitive impairment, meaning in the advanced stages of each disease, you just can't think as clearly as you once did.  And, sure enough, when they traced the schizophrenia patients who had certain types of poorly expressed complexin 2 gene, they tended to have more cognitive impairment than the other schizophrenia patients

Okay, that's not particularly interesting, at least from an evolutionary medicine standpoint.  Except I couldn't help but notice all those disorders up there (except bipolar disorder) are ones I've discussed in the blog who have some evidence to link them to wheat or to metabolic syndrome.  Mice with knocked out complexin 2 genes have a few issues, but apparently not cognitive ones.  Until you take those mice and deprive them of their mothers.  Then the complexin 2 knockout mice get mouse dementia, of sorts.   It's the genetic difference plus the stress that seems to cause the disease.  Good old two-hit hypothesis.

Next up is one that will warm the cockles of your sun-worshiping hearts.   "Neonatal Vitamin D Status and Risk of Schizophrenia: A Population-Based Case Control Study."  Thank you, Netherlands, who apparently keeps dried blood samples from all the babies born there.  The researchers took 424 individuals with schizophrenia and 424 sex and age matched controls, and pulled their blood samples from the big bank 'o blood, and figured out each neonate's vitamin D levels.

Vitamin D is a big suspect in schizophrenia for the following reasons - Vitamin D undoubtedly plays a role in the development of the brain.  People born in winter and spring have higher risk for developing schizophrenia, and the farther you are born from the equator, the more likely your birth month will be a factor.  Immigrants with dark skin who move to northern countries also have children with higher rates of schizophrenia.  In addition, city kids are more likely to develop schizophrenia compared to country kids.   This study is the first time someone was able to go back and directly check the vitamin D levels from neonatal blood of people who later get schizophrenia.

The average level of vitamin D (measured as 25 (OH) vitamin D3) varied widely from winter to summer, with babies born in March (cases and controls) having the lowest levels, around 26 (deficient), and babies born in August having an average level of nearly 50 (which is good).  One caveat - the actual level may be misleading.  The level might degrade over time, and these samples were up to 27 years old when tested.  However, since there were matched controls of the same age for each patient, it was presumed that the degradation would be the same for both sets of data.     

But now the key results - babies born with a vitamin D level of 46.5 had the lowest risk for schizophrenia (again, that might not be the actual level, measured so many years later).  The babies within the lowest two quintiles (the lowest 40%) of vitamin D levels had significantly increased risk.  Surprisingly, babies in the highest quintile, with the highest vitamin D levels, had higher risk too.  The researchers were able to go back and check for all sorts of variables which might confound things - UV light therapy at birth for high bilirubin might affect vitamin D levels, for example, admission to the NICU, age, sex, etc. etc. and nothing seemed to change the overall U-shaped data curve, with the "sweet spot" between the 3rd and 4th quintiles of vitamin D levels.  Now the researchers wisely emphasized caution when considering these results - it's an observational study, and there can be plenty of confounders nobody thought of.  However, if the cause-effect relationship holds true, the researchers suggest that mere vitamin D supplementation in dark-skinned immigrants in northern countries could reduce the incidence of schizophrenia in those populations by "a staggering 87%."

A third study in this same issue is called "Birth Weight, Schizophrenia, and Adult Mental Disorder," where the researchers did pretty much what you might think, but on a very large scale.  They followed 1.49 million single babies born in Sweden and Denmark between 1973 and 1986.  Both countries have "comprehensive national registers of psychiatric treatment."  In 2002 (Sweden) and 2005 (Denmark), these countries had 5,445 registered cases of schizophrenia and 57,455 cases of "any adult psychiatric disorder."  (My first thought - 5445 cases of schizophrenia seems low out of 1.49 million, and it is only 0.37 %.  There should be around 14,900 cases as the worldwide prevalence is right around 1%.  Just something to keep in mind!) 

The results - birth weight of less than 2500 grams (5 pounds, 8 ounces) in these babies translated into a higher risk for schizophrenia, and the risk actually decreases (for schizophrenia) as the birth weights go up.  The heavier the kiddos were, the lower the risk, all the way up to >4500g (that's 9 pounds, 15 ounces).  Low birth weight also translated into a higher risk for all mental disorders, including an aggregate "all diagnoses" group and for each subgroup of  substance abuse,  mood disorders (like major depression and bipolar disorder), and anxiety disorders.  And, indeed, in the subgroups, the higher the birth weight (all the way up to the megababy 10 pounder and above group), the lower the risk.

Interesting!  Obviously, very low birth weight is associated with all sorts of issues - premature delivery, infection, brain hemorrhages - any or all of these could have stress on the baby's forming brain.  It is interesting that the heavy babies had lower risk than the so-called normal weight babies.  I actually would have expected another "U-shaped" curve here.  But no!  Still, there could be huge confounders. High birth weights are associated with gestational diabetes, but I'm not sure how common that was in Sweden and Denmark back in the 70s and 80s, so maybe it wouldn't be as much of a factor as I would have thought.  

One of those confounding factors could actually be vitamin D!  This study showed maternal vitamin D intake associated with birth weight (low vitamin D = lower average birth weight), and it was postulated that adequate vitamin D intake protects moms from infections.  This study is a little more interesting - white women with a vitamin D level from 60-80 had the lowest risk of having small for gestational age babies, but there was no relationship between vitamin D levels and birth weight in black women.  And, of course Don Matesz blogged today about this study, showing that pregnant women who took 4000 IU vitamin D daily had a lower risk of preterm birth.

All told, several interesting findings this month.  Don't get vitamin D deficient!  But try not to go nuts with the supplementation either.  Levels are best!  Ask your doctor, or go to Grassroots Health to order a home test.  I tend to aim for a level of 50, but perhaps pregnant women would want to go just a bit higher (Caucasian women may want to aim for that 60-80 range).  Be sure you are getting your K2 also!  I always use pastured butter, but I also have a vitamin D supplement that comes with K2 in it. 

Believe it or not, there is another blog-worthy study in this month's Archives, but I will save it for later in the week.  See you then!

Sunday, September 12, 2010

Autism 4 - Inflammation Speculation

Charles Ives (insurance specialist and modern composer) wrote The Alcotts (right click to open in new tab) somewhere around 1911.  It's his most accessible work, as he was one of the first experimenters with polytonal music - you'll hear some, but not too many, of the clashing polytones in this piece.  He composed many melodies from the early 1900s right up until 1927, when one day he came downstairs and said he could compose no more.  "Nothing sounds right."

And so we come round again to autism.  The heartbreaking disorder where, in 30% of cases (1), children seem to be developing normally, only to regress and lose speech and language development somewhere between 18 and 36 months.  It seems that in most children, the disorder is detectable very early with differences in gaze and response to social stimuli (2).  The reason no one has been able to find a specific pathological cause or cure is because it is multifactorial - it seems that a combination of genetic, environmental, neurological, and inflammatory factors contribute to the development of autism.  Today I would like to focus specifically on the inflammation.

The best evidence of the actual inflammatory damage comes from the work of some neurologists and pathologists at Johns Hopkins.  They were able to examine the brains (post-mortem) of several children and adults with autistic disorders, and also the CSF obtained via spinal tap from autistic children and normal controls (3).  They found that the most striking differences between autistic and normal brains were loss of the purkinje cell layer in the cerebellum, and marked activation of the microglia, which are cells in the central nervous system which mediate the inflammatory response.  In the CSF, the researchers found elevations of many pro-inflammatory cytokines and chemoattractants for macrophages - cells that are called into action to eat and destroy invaders.  Other studies have shown that autism is possibly an autoimmune disease of some kind (4).   Only this one seems to work on susceptible developing brains, leading to the devastating consequences we are all too familiar with.

In the evolutionary medicine paradigm, autoimmune disorders are diseases of civilization, caused by our highly inflammatory diets and stressful lifestyles.  And, indeed, this theory brings together the possible "bad guys" we've discussed already, gluten, casein (which may be a bad guy only in the context of gluten exposure also), and insufficient vitamin D. (Hat tip again to Jamie, who pointed out this study he saw first in a comment on Whole Health Source, where a high fiber diet seemed to reduce the plasma half-life of vitamin D.  The fiber used in the study was wheat fiber.)

Epidemiological studies suggest that autoimmune disorders are much more common than normal in families of kids with autism.  In addition, mothers with asthma, psoriasis, and type I diabetes were more likely to have autistic kids.  In fact, mothers diagnosed with asthma or allergies during the second trimester seem to have especially high risk, suggesting that a flare-up of autoimmune disease at a particular stage in fetal development might be causative (4).  Epidemiologists at the Harvard School of Public Health did a meta-analysis of studies of prenatal risk factors and autism (5), and they found higher risk for mothers and fathers of "advanced" age, a two-fold increased risk among mothers with gestational diabetes, and also increased risk among mothers who had bleeding during pregnancy and psychiatric medication use (there are specific studies demonstrating an increased risk with depakote use during pregnancy and autism).

Inflammation, inflammation, inflammation.  Psoriasis is associated with obesity (inflammation), gestational diabetes with insulin resistance and inflammation.  All these diseases of civilization are floating around autism.  All these diseases of civilization with multifactorial causes, genetic susceptibilities, and chronic management in lieu of cure.

What if mothers and young children had sufficient rest, play, vitamin D, and an anti-inflammatory, nutrient-rich diet? (My go-to choice here being a primal or paleo style diet, of course.)  No processed food, no extreme fructose, minimal and balanced omega 3 and 6 fatty acids, and no gluten.

There are too many variables.  The study will probably never be done.  But, as always, our health is in our hands.

Saturday, September 11, 2010

Autism and Vitamin D

Vitamin D researcher Dr. John Cannell is all over this one, so I don't need to reinvent the wheel here.  I'll hit the highlights and link his articles for the full discussion.  His 2007 article (thank you, Jamie, still commenting and sending amazing articles and links from a disaster zone!) may be familiar to some of you from the vitamin D council website, but he printed an updated article available on pubmed central in August of 2010 reviewing all the new research between 2007 and now.  Hooray!

His major points (he has several more, but I'll put up some of the more compelling ones):

1) Autism is increasing, as is vitamin D deficiency, and the autism epidemic came upon us at the same time the major health authorities advised us to eschew the sun.

2) Vitamin D is likely central to brain development as a key helper in neural development and neuroprotection.  In addition, autism is likely mediated by inflammation, and vitamin D is a key player in anti-inflammatory processes.  Also, vitamin D enables glutathione, the "master antioxidant," clear our system of free radicals, and glutathione also acts as a chelating agent to bind toxic heavy metals such as mercury, which kids with autism have a tough time clearing from their systems.

3) Williams syndrome, a chromosomal disease which (among other things) results in abnormally high levels of circulating active vitamin D in early childhood, results in kids who are especially social and overfriendly - rather the opposite of autism symptoms.

4) During pregnancy, boys' brains are bathed in testosterone, and girls' brains in estrogen.  Estrogen is known to have many vitamin D enhancing properties.  This could account for the 4:1 ratio of boys to girls suffering from autism.

5) Studies show autism births occur most often in March, at the end of winter, when vitamin D levels would be lowest.

6) African Americans seem to suffer from a higher rate of autism, and they also have a higher rate of vitamin D deficiency than people with lighter skin.  In Europe, the children of darker-skinned immigrants have higher rates of autism also.

7) Rickets, due to vitamin D deficiency, is characterized by hypotonia (poor muscle tone) and developmental delay, as is autism.

8) Autism seems to be higher among the kids of highly educated women, and they are more likely to follow guidelines for sun restriction for themselves and their children.

All told, it makes for a compelling theory, and Dr. Cannell has a point in that "this theory deserves immediate attempts to disprove it."  My only major issues with it are that rickets is not autism, and that there may not be a new autism epidemic after all, but we are only now recognizing how prevalent the disorder actually has been all this time.  But I could certainly be wrong about that second bit.  And, by all means, let's please give pregnant women guidelines for sufficient vitamin D and get the kids to play outside!  And let's study vitamin D and autism directly.

Dr. Cannell touches on this next part in his 2010 article, and it is part of one of the overriding themes of my blog - we have a lot to learn from history.  If vitamin D deficiency is the cause of autism, then all of this has happened before.  Rickets, characterized mostly by bone growth abnormalities in children, became endemic during the industrial revolution, when people in cities, especially, seemed to spend very little time outdoors, diets were poor, and many children died, as there was no cure.  Eventually, cod liver oil and sunbathing were shown to prevent and improve the disease.

Here is Dr. Cannell's quote:  "If adequate amounts of vitamin D prevent autism, one would expect children with rickets to have an increased risk of autism. To my knowledge, the neuropsychiatric symptoms of rickets have not been studied in the modern era. However, at least two old papers have addressed it, both published before Kanner described autism in 1943. Both papers describe ‘weak mindedness,’‘feeble minds,’‘mental dullness,’ unresponsiveness and developmental delays. Even more intriguing, both papers report that the mental condition in rickets improved with vitamin D."

Those papers, Hallerhan MM. The effect of rickets on the mental development of young children. Arch Psychol. 1938;229:1–67, and Gilmour A. The mental condition in rickets. School Hygiene. 1912;9:6–16, are not available online, but may be worth trying to get a look at (if I can find my library ID.  We are certainly spoiled in the internet age!)

I do happen to have handy a copy of Nutrition and Physical Degeneration, first published in 1939, and here is what he had to say about the state of mental health at the time (1):

"Many of our modern writers have recognized and have emphasized the seriousness of mental and moral degeneration. Laird has made a splendid contribution under the title "The Tail That Wags the Nation,"  in which he states:
    The country's average level of general ability sinks lower with each generation. Should the ballot be restricted to citizens able to take care of themselves? One out of four cannot. . . . The tail is now wagging Washington, and Wall St. and LaSalle Street. . . . Each generation has seen some lowering of the American average level of general ability.
    In Laird's analysis of our present situation he has stressed a very important phase. While emphasizing that the degeneration is not limited to restricted areas, he raises the question as to whether local conditions in certain areas play important roles in the rate and extent to which degeneration has taken place. He says further,
   Although we might cite any one of nearly two dozen states, we will first mention Vermont by name because that is the place studied by the late Dr. Pearce Bailey. "It would be," he wrote, "safe to assume that there are at least 30 defectives per 1000 in Vermont of the eight-year-old mentality type, and 300 per 1000 of backward or retarded persons, persons of distinctly inferior intelligence. In other words, nearly one-third of the whole population of that state is of a type to require some supervision."
The problem of lowered mentality and its place in our modern conception of bodily diseases has not been placed on a physical basis as have the better understood degenerative processes, with their direct relationship to a diseased organ, but has generally been assigned to a realm entirely outside the domain of disease or injury of a special organ or tissue. Edward Lee Thorndike, (8) of Columbia University, says that "thinking is as biological as digestion." This implies that a disturbance in the capacity to think is directly related to a defect in the brain."

* * *

Of course, at the time, they did not have the diagnostic categories to differentiate between the varieties of autism, mental retardation (most commonly due to hypothyroidism at the time), and cerebral palsy. But there they were, recognizing that mental illness was biological, way back in the early part of the century.  Pretty good considering that psychiatry is something of the red-headed stepchild of modern medicine even today.  

It does make you wonder.  This "mental degeneration" of that time period, in part, led to the rise of eugenics, and even Nazis.  In the late 1800s, admissions to mental asylums skyrocketed.   The mental health of the western world seemed to improve after World War II, when bread began to be fortified with B vitamins, and people recognized the importance of at least a small amount of vitamin D.  But anxiety, depression, and "bodily degeneration" is on the rise again with our change to industrial processed food, and maybe autism as well.

In historical novels, a curative practice for what ails you is always to take some time visiting on the seashore.  One would expect to get more sun then, and eat more nutrient-rich seafood.  Sounds like a good plan to me.

Thursday, September 9, 2010

Diet and Autism 2

One of the questions that came up in the comments on my first post of the series was why are researchers (and celebrities) stuck on gluten-free, casein-free diets to treat autism?  The whole idea is based on the idea that the exorphins (dietary opiate proteins) found in gluten and casein somehow cause or exacerbate the neurological issues in autism spectrum disorders (ASDs).  Also, it is well documented that kids with ASDs seem to have more gut and dietary issues than other kids, so a dietary culprit was an obvious place to look.

A weakness to these theories is that we have been eating gluten and casein for a long time (the beta casein A1 is found in about 50% of cows of European descent, which are also the cows who make American, Australian, and New Zealand milk at least), and the autism rates have been (possibly) escalating only recently.  Or have they?

Back in 2003, JAMA released a study and editorial on the rates of autism.  At the time, most studies were showing that rates were somewhere around 1 per 1,000 children.  Since previous studies (from the 60s and 70s) usually estimated around 4-5 per 10,000 children, that means a doubling of prevalence from the 1970s to the 1990s and early 2000s.  (There are many issues with trying to put a reliable number together- I recommend you read the editorial I linked as it seems to be a very fair presentation of the data - the main issue being that the definition for autism spectrum disorders widened considerably between 1960 and 1990, which could certainly explain an increase in prevalence in studies without an actual increase in prevalence in the population).   Then a number of very large survey studies were done in 2006-2009, including 78,000 parents in the National Children's Health Study (1), and another multi-site study in the Autism and Developmental Disabilities Monitoring (ADDM) Network (2).  These were all big news last year, as several of these studies came out at the same time, and the rate had jumped to approximately 110 per 10,000 children.  I'll let the second study speak for itself at this point:

"Approximate range: 1:80--1:240 children [males: 1:70; females: 1:315]. The average prevalence of ASDs identified among children aged 8 years increased 57% in 10 sites from the 2002 to the 2006 ADDM surveillance year. Although improved ascertainment accounts for some of the prevalence increases documented in the ADDM sites, a true increase in the risk for children to develop ASD symptoms cannot be ruled out. On average, although delays in identification persisted, ASDs were being diagnosed by community professionals at earlier ages in 2006 than in 2002."

A 57% increase in four years.  That sounds really, really bad.  However, much of this increase was felt to be due to increased awareness, and recognition that early intervention and treatment could help kids with ASDs, so kids were being diagnosed earlier, and the diagnosis would be made more readily so kids could be eligible for early intervention services.  In fact, the latest studies may be the ones that actually have a more realistic estimate of the number of kids affected, and previous studies grossly underestimated the number of cases.  In my opinion, the best evidence that autism may not be increasing at all is a report from the Adult Psychiatric Morbidity Study from the UK in 2007 (3).  They found that approximately 1% of adults living in households have symptoms consistent with ASDs.  Since that is pretty close to the 1 in 110 number we have for today's children, it suggests that the enormous increase in diagnosis in kids may be due to increased outreach and widening of diagnostic categories.  However, a more recent increase can't entirely be ruled out.

In any event - that means that we don't necessarily have to look for something brand spanking new or rapidly changing in our society to explain the increase.  We can take a broader view.  So back to gluten and casein and those pesky exorphins. 

Couple of interesting tidbits.  Really, the theorized mechanism of wheat and casein exorphins causing neurotoxic events that are expressed as our brains develop is quite similar to the same theory in schizophrenia.  It's probably coincidence, but schizophrenia and autism both affect about 1% of the population.  Some of the same genetic chromosomal deletion syndromes are implicated in both autism and schizophrenia.

And, frankly, the exorphin question is an easy one to test, at least indirectly.  We have naltrexone, after all, a readily available, relatively inexpensive opiate blocker in pill form.  Once taken, it will sit on our opiate receptors like a lock on a door, blocking exorphins from casein and gluten just as readily as heroin or morphine, and keep the opiates from activating our opiate receptors.  So if dietary exorphins worsen autism in those of us with vulnerable phenotypes, naltrexone should help.

Fortunately, there are several studies of naltrexone and autism (4)(5)(6).   And, overall, the studies lean towards naltrexone being a useful treatment for some kids.  It seems most effective in decreasing self-injurious behavior (interesting in light of the findings I wrote about in this post, linking alterations in the opiate symptoms and self-injurious behavior), like self-picking, finger-biting, and head-banging.  It also seems to help some kids with improved attention and eye contact, hyperactivity, agitation, stereotyped behaviors, social withdrawal, and temper tantrums. (Naltrexone is not FDA approved for use in autistic disorder in kids, but due to the limitations of therapeutic alternatives, it is mentioned often in review papers as a useful medicine that might be worth giving a try).

Does that mean that dietary exorphins are definitely the cause of the problem, or at least piece of the cause?  Not so fast.  The whole reason scientists studied naltrexone in autism in the first place had nothing to do with wheat or casein.   Turns out a paper in 1979 hypothesized a link between derangements in the opiate systems of autistic children and the symptoms of autism, and later naltrexone studies showed that some kids with autism seem to produce an excess of beta-endorphin (our own, natural opiates).  Theory goes like this - flooding the immature brains of kids with beta-endorphins may delay or hamper maturation in some way, causing the brains of autistic kids to stay in an infantile stage of development, particularly with regards to social interaction and sensory response.  Kids who responded best to naltrexone had the biggest decreases in the amount of their own beta-endorphins.

All right, let's bring it all together.  A large subset of autistic kids seem to have leaky guts (remember - no robust link between the amount of leakiness in the gut and either positive celiac markers OR gastrointestinal symptoms such as diarrhea, bloating, or abdominal pain - you can't tell if a kid has a leaky gut using these kinds of criteria or tests!).  Another subset of autistic kids have elevated levels of their own natural beta-endorphins and seem responsive to an opiate blocker, naltrexone.  Gluten and casein have exorphins (opiates) which can hypothetically wriggle through that leaky gut and may have an effect on the central nervous system.

There, finally, a plausible link between gluten, casein, and autism.  Not as necessarily a cause, and certainly not a cure, but perhaps as an exacerbating factor.  But, before April 2010, the dietary studies were crap.  And too small.  Enter the ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders.  Published in Nutritional Neuroscience in April 2010, this study combined a lot of nice features.  It had a decent sample size - 72 Danish kids with ASDs (established by standard diagnostic criteria), and it was long - two years.  It had a sort of modified cross-over design.  It was honest about being single blind - meaning the researchers (except the nutritionists) didn't know which kids were getting the special diets, but the parents (of course) knew. The kids' urine was tested for any abnormal metabolic byproducts.

Here's what the researchers did - for the first year, they put about half the kids on a gluten-free, casein-free diet and monitored their progress for 8 months.  If the improvements in the kids on the diet were significantly better than the kids off the diet, they would extend the trial and put everyone on the GF-CF diet at 12 months, and monitor them for a total of 24 months (this is what happened in the actual trial - there was significant improvement in the study diet kids, and a worsening in the kids on the standard diet, so everyone was put on the study diet for the last 12 months).  The researches used a battery of different tests, measuring a bunch of different subsets of autistic behaviors and ADHD symptoms at points along the trial.  The results?

"Introducing a gluten-free, casein-free diet had a significant beneficial group effect at 8, 12, and 24 months of intervention on core autistic and related behaviors..."  The improvement was less dramatic after the first 8 months, and could represent a plateau effect.  Attentional and communication symptoms seemed to improve the most.  About half the kids dropped out in the second year, perhaps the kids that didn't benefit.  The researchers note that there aren't long-term safety studies of gluten-free casein-free diets in kids, and that a knowledgeable nutritionist should be consulted.


One last little thing.  The leaky gut study I wrote about extensively in my first post on diet and autism had a very interesting component I didn't mention then.  Some of the kids in that study, turns out, were already on a gluten-free, casein-free diet.  The leakiness of the gut was measured via the IPT test - two sugars, lactulose and mannitol, are given orally to fasting kids, and their urine is collected for the next five hours.  Mannitol is small and absorbed via the cells of the gut, and the amount absorbed reflects the "absorptive capacity of the gut."  Lactulose is too large to be absorbed directly by the cells, so it has to squeeze in between the cells, and if a lot can squeeze through, the gut is "leaky" and the ratio of lactulose to mannitol in the excreted urine goes way up.  A "normal" ratio is less than 0.03, and the higher the number is, the more leaky the gut is.  Control kids in that study had ratio average of 0.023.  In the autistic kids overall, the ratio was an average of 0.041.  But in the autistic kids who were on the gluten-free, casein free diet, the ratio was less than 0.02, and when only data from the autistic kids not on the special diet was used, the average ratio jumped up to approximately 0.055.   And, once again, the leakiness measured in these kids had no relation to GI symptoms or positive celiac marker testing.

The take-away point?  Once again, I think there is enough scientific evidence to suggest that some kids with ASDs will, in fact, benefit from a gluten-free, casein-free diet, and while it is no cure and may not be a part of the original cause (some known teratogens that cause autism seem to work at around 8 weeks gestation (7)), it may be worth a try.  It shouldn't be attempted without some professional nutritional advice, especially in a picky kid.  And it's clearly no holy grail.

Another point - gluten is (once again) creepy.  Gliadin and zonulin do not a good combination make.  No one wants a leaky gut.  Just something to think about.