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.

Depression 2 - Inflammation Boogaloo

It is well known that symptoms of clinical depression are likely mediated by inflammation in the brain. A number of lines of evidence support this idea, including that depressed people, old and young, have elevated levels of certain inflammatory proteins in the plasma and cerebrospinal fluid. Anti-inflammatory agents treat depression, and pharmacologic agents such as interferon-alpha, that cause depression, also lead to increases in the inflammatory proteins IL-6 and TNF-alpha. In addition, when someone who is depressed responds to antidepressant treatment, these same inflammation markers decrease (1). People with generalized inflammatory syndromes (such as acute viral illness, rheumatoid arthritis, insulin resistance, and cardiovascular disease) have higher rates of depression than the general population too. I also notice in my clinic that people who have had bone surgery tend to get depressed for a few weeks after the operation, more so than people who had other kinds of surgery. I always wonder if sawing through the bones releases an enormous wave of inflammatory cytokines.

There are several suspected mechanisms of how this inflammation leads to depression, many of them very cute. Here's one - the amino acid tryptophan is a precursor to Eli Lilly's second favorite neurotransmitter, serotonin*. Turns out that tryptophan is also the precursor to kynurenic. When the inflammatory cascade is activated, more tryptophan is made into kynurenic, which leaves less tryptophan around to make into Eli Lilly's second favorite neurotransmitter, serotonin. And everyone knows that without serotonin, we're unhappy (and angry). SSRIs work, in part, by undermining the effect of the inflammatory cytokines, pushing more tryptophan to be made into serotonin.

Here's another mechanism - inflammatory cytokines also interfere with the regulation of another neurotransmitter, glutamate. Glutamate is an excitatory neurotransmitter that, if left to go wild, can pound our NMDA receptors in the brain and wreak major havoc. No one wants overexcited NMDA receptors, and clinical depression is one among many nasty brain issues that can be caused by overexcitement. Astrocytes, little clean-up cells in the brain, are supposed to mop up excess glutamate to keep it from going nutso on the NMDA. Turns out inflammatory cytokines interfere with the clean-up process (2). The horse tranquilizer (and club drug) ketamine, when administered IV, can eliminate symptoms of severe depression pretty much immediately in some cases (do NOT try this at home) (3). Ketamine helps the astrocytes mop up glutamate, and it is assumed that this is how ketamine instantly cures depression. Unfortunately, the effects of ketamine don't last, otherwise it would be a nifty psychiatrist's tool, indeed.

Finally, inflammatory cytokines also push the brain from a general environment of happy "neuroplasticity" (mediated finally by our old friend, BDNF) towards an environment of neurotoxicity (sounds bad, and it is!).

In my post on vegetable oils, I made note of a popular theory that a relative imbalance between the consumption of anti-inflammatory omega 3 fatty acids (fish oil) and inflammatory omega 6 fatty acids (vegetable oil, such as corn oil) predisposes us to inflammation. The omega 6 fatty acids are the precursors for many of the nasty, depressing cytokines mentioned above (such as IL-6). Well, an absolute flurry of research has been done in this area in the last decade or so, because omega 3 fish oils would be a nifty, low side effect, cheap treatment for depression, if it worked. Some studies have been disappointing (4)(5). However, the largest study yet, hot off the presses, does show benefit (equal to a prescription antidepressant) for those who have depression, but not concurrent anxiety, at a daily dose of 150mg DHA and about 1000mg EPA. (DHA and EPA are fish oil omega 3 fatty acids).

Well, neat! But adding extra omega 3 is just one half of the omega 6/omega 3 balancing act. What if we decreased dietary omega 6 at the same time? Researchers looked at the blood levels and tissue levels of all the different kinds of fatty acid in this recent paper. Turns out that depressed people had higher amounts of omega-6 fatty acids, but the amounts of monounsaturated fats, saturated fats, and omega 3 fats were about the same between depressed and non-depressed individuals. (Other studies showed a decreased amount of omega 3 and an increased amount of omega 6 (6)).

As far as I know, there haven't been any major studies testing both a dietary decrease in omega 6 and supplementation with omega 3 for depression, but it would be an interesting intervention. Dr. Guyenet uses the work of Dr. Lands to make a case that reducing omega 6 PUFAs to less than 4% of calories would be a great way to reduce overall inflammation, and lots of Western disease. Hunter gatherers, such as the Kitavans, consume less than 1% of calories from omega 6 fatty acids. Right now, in the US, about 7% of our calories are omega 6 PUFAs.

In summary - inflammation is depressing! Fish oil may make it better, but avoiding corn/safflower/sunflower/soybean oil (theoretically) makes it all better still, and is the natural state for which we are evolved.

*Eli Lilly's favorite neurotransmitter is, of course, dopamine.