Maternal antibodies and ASD risk for the offspring

ASDresearchinitiative asked me to comment on the new papers from UC Davis, so now that I’m back from a grueling trip to E Africa (for lectures and touring), I should get back to work…

In one paper, Melissa Bauman, David Amaral and colleagues report a follow up to their prior work, further showing that when pregnant monkeys are injected with antibodies taken from human mothers of autistic children, the monkey offspring display a couple of abnormal behaviors, including unusual social interactions. Such behaviors are not observed in the offspring of pregnant monkeys  given antibodies taken from human mothers of neurotypical kids. While the behavioral differences between the two sets of monkey offspring are convincing, they do not include some of the cardinal signs of human autism such as stereotyped/repetitive behavior, which was reported in their prior paper on this model. However, the type of antibodies injected in this new experiment is different from the type used in the prior work. The antibodies used in the new work are known to be a subset of the various auto-immune antibodies that recognize antigens in fetal monkey brains.  Overall, these results support the hypothesis that some mothers of autistic children generate antibodies against the fetal brain and that these antibodies cross the placenta and alter fetal brain development. In fact, the investigators showed that the brains of the animals with altered behavior do display some differences from the controls when analyzed by MRI.

In an independent set of experiments that will be published very soon, Melissa, David and I found that activating the pregnant monkey immune system, using the same technique that we used in mice, results in offspring with a series of autism-like behaviors, including repetitive behaviors, a deficit in verbalizations and a highly abnormal type of social interaction. A subsequent paper will also show an autism-like abnormality in eye tracking – not looking at faces as much as controls. Could these two models be related – maternal antibodies and maternal immune activation (MIA)? It is indeed possible that MIA stimulates the production of antibodies. However, I favor a mechanism in which MIA induces the cytokine IL-6, which we find alters placental endocrine function and also directly activates subsets of fetal brain cells.

A second, and related new paper from UC Davis by Judy van de Water and colleagues follows up their prior work on characterizing the antibodies found in the blood of mothers of autistic children. The new paper identifies the proteins to which these antibodies bind in extracts of monkey fetal brain. Interestingly, many of these protein antigens are known to have functions in brain development. However, most of these proteins are thought to reside in the cytoplasm, so it remains to be shown how the maternal antibodies would access them in living cells in the fetal brain. Further animal studies will presumably get at this question. It will also be interesting to find out when these antibodies are generated during pregnancy, and whether they are present in subsequent pregnancies in the same mother that involve neurotypical or autistic offspring. The latter point is important because van de Water et al. propose that the presence of combinations of several of these antibodies could be used as a diagnostic biomarker for an autistic outcome of a pregnancy. In fact, they have formed a company to develop such a diagnostic.

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Positive sides to autism

In LA Times article, Temple Grandin sees the advantages that she and others with autism bring to society.

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Important message from the Director of the National Institute of Mental Health

Thanks to ADResearchInitiative blog for the tip on this message.

On another note, our family is off to E Africa for 3 weeks to give lectures (me, viruses and mental health; wife Carolyn, special education) in Uganda, Kenya and Tanzania. We are also looking forward to touring national parks, including tracking mountain gorillas in Biwindi. So I’ll be out of touch till July, but may come back with some interesting stories.

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The President speaks at a mental health conference at the White House

This conference received virtually no press coverage at all.

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Are common bacterial infections making children mentally ill?

“A feverish debate” – Excellent new article on PANDAS etc by Alison Motluck.

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Dietary salt, inflammation and mental illness?

In the past few decades there has been a marked increase in autoimmune disease. This has been correlated with the increased population of the Western diet and processed foods. The latter contain far more salt than homemade foods. Now, two recent papers in Nature provide compelling evidence that a modest increase in salt in the diet of a mouse model of multiple sclerosis strongly increases the symptoms (earlier onset and more severe disease), and induce a pro-inflammatory state. The authors of one paper suggest that, “…clinical trials with severe curtailment of salt intake for individuals at risk for developing autoimmune disease are required.” Given the inflammatory component in mental illness, might this also apply to these disorders?

On the other hand, it has become apparent that changing to a very low salt diet does not lessen the heart attacks or strokes in people at risk, although the American Heart Association is not convinced about the newer data. Nonetheless, there is no necessary connection between heart disease and mental illness studies.

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flu during pregnancy & bipolar in offspring

Readers of this book and blog are well aware that influenza infection during pregnancy increases the risk for schizophrenia and autism in the offspring. Now Alan Brown and colleagues at Columbia Univ expand that risk to bipolar disorder (BD). The new paper provides evidence that the risk for BD increases nearly 4-fold, with nearly a 6-fold increase for a BD subtype with psychotic features. These numbers are similar to the 3-7-fold increase for schizophrenia risk that Brown found found previously. While the most significant risk for a schizophrenia outcome was associated with infection during the first half of pregnancy (primarily late first and early second trimester; not third), the increased risk for BD in the offspring appears to be associated with infection at any time during pregnancy. There is a very slightly increased risk for infection during the 2nd or 3rd trimesters. Thus, it is possible that the timing of the infection may influence the outcome, although genetic background and the intensity of the infection could also play a role.

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