More evidence of immune involvement in autism and schizophrenia, and implications for therapy

Given that many studies have provided evidence that infection in  pregnant women is associated with increased risk for autism and schizophrenia in the offspring, Alan Brown and his colleagues in Finland measured the levels of C-reactive protein (CRP), an established biomarker of inflammation, in maternal serum. This was done in a large national birth cohort of 1.2 million, with an extensive serum biobank and national psychiatric registries consisting of virtually all treated autism cases in the population. They found that elevated maternal CRP levels are significantly associated with autism in offspring. This adds to the  findings in earlier posts here showing that elevated cytokines in amniotic fluid or maternal serum are also associated with increased risk for autism in the offspring.

Adding to the evidence of immune dysregulation in schizophrenia, a new meta-analysis of the literature (by Mark Rapaport and colleagues at Cedars-Sinai Medical Center) reports that CRP levels are significantly increased in schizophrenia patients. Consistent with this, Paul Tooney in Sydney finds that blood cells from schizophrenia patients display changes in gene expression related to inflammation and immunity, and most importantly, these changes are ameliorated following anti-psychotic medication.  I’ve noted here previously that such drugs have anti-inflammatory actions in studies of cultured cells. Tatiana Falcone and colleagues at the Cleveland Clinic report that pediatric patients hospitalized with a first episode of psychosis display elevated blood levels of cytokines.

Minocycline is a tetracycline antibiotic that has been tested for a wide variety  disorders because it has a good safety profile and it has a plethora of positive effects on cultured cells and in animal models. I follow the literature on this drug because it has anti-inflammtory properties. There are a number of papers showing that minocycline has positive effects in mouse models of fragile X syndrome (FXS), and a small, open label, add-on (added to usual medications) study in FXS patients showed significant improvement in symptoms. Thus, it is of interest that Randi Hagerman’s group at UC Davis now reports results of a randomized, double-blind, placebo-controlled trial of minocycline in children and adolescents with FXS. They find a 3 month treatment results in modest but global improvement in symptoms. Moreover, a large, 1 year add-on trial of minocyline in England, Brazil and Pakistan found amelioration of negative symptoms in schizophrenia.

Another promising FXS treatment was just reported by Susumu Tonegawa of MIT and collaborators at Afraxis, Inc. in La Jolla. They developed a new inhibitor of PAK, an enzyme that plays a role in the remodeling of synaptic connections. In adult  FXS mice, this inhibitor can reverse all of the abnormal behaviors tested, and corrects the altered synaptic connections. These are remarkable results because they were found in adult mice, a short time after a subcutaneous injection of the inhibitor. It will be interesting to follow the future studies of this approach, and how it compares to ongoing FXS human trials.

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7 Responses to More evidence of immune involvement in autism and schizophrenia, and implications for therapy

  1. passionlessdrone says:

    HI Paul Patterson –

    I would think that this kind of finding is going to prove particularly problematic for the idea that autism rates have been stable. We have been recklessly embracing lifestyles characterized by increased inflammation for a while now (at least in the first world), and once we accept the fact that you don’t get to tinker around with the gestational environment without changing things up from a neurodevelopmental standpoint, we must then accept that *some* amount of the increase is non-imaginary.

    I would note that there was a mixed/negative minocycline study with an autism population by the same group; I do wonder if the reason that benefits were observed in the FXS group, but not the autism group is a function of the degenerative nature of FXS compared to straight autism. Guessing even deeper, perhaps the microglial activation profile in FXS is different than autism, and alleviating that problem in one group shows benefit, while in the other, the changes caused by an altered microglial profile during development cannot be undone, even though the neuroimmune environment showed evidence of change.

    – pD

  2. Cyrus Grisham says:

    HI Paul Patterson,

    I found an interesting article about microglia called “The brain eating itself” ( http://www.theaggie.org/2013/04/25/the-brain-eating-itself/ ). I also found that using NAC for my negative symptoms of schizophrenia helps me a lot. NAC seems to have an positve effect on the immune system. Now I’m wondering why it’s helping…

    • phpatterson says:

      Very interesting Cyrus. Yes, NAC has anti-inflammatory effects in mouse models. Plus, there is a report of a positive effect in a clinical trial of schizophrenia – see J Clinical Psychiatry 72:7, 2011.

      • Hi Paul Patterson & Cyrus Grisham –

        NAC is some great stuff!

        It has a double blind, placebo controlled study in autism showing positive effects. You don’t see that too often!

        A randomized controlled pilot trial of oral N-acetylcysteine in children with autism (Biol Psychiatry. 2012 Jun 1;71(11):956-61. doi: 10.1016/)

        Also, there are animal models that indicate is could be useful as a preventative tool in cases of maternal immune activation; i.e.,

        Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation (Hippocampus. 2008;18(6):602-9. doi: 10.1002)

        Which is exciting, exciting stuff. Of course, it’s also a bit terrifying, because I’m sure that ‘preventing deficits’ isn’t *all* it’s doing up in there, but even still, very nice.

        I’ve struggled for a while trying to detangle the threads between oxidative stress, immune response, and how altering one seems to change the other, but my mental model keeps falling apart before I can see it. 😦

        – pD

  3. Hi Paul

    A new paper out from Yale focuses on trophoblast inclusions and autism risk.

    http://news.yale.edu/2013/04/25/autism-risk-spotted-birth-abnormal-placentas

    Seems to be some pretty impressive research. I also had a look at an earlier Yale paper – Placental Trophoblast Inclusions in Autism Spectrum Disorder – Anderson et al

    http://medicine.yale.edu/obgyn/kliman/autism/asd/607_152587_ASD%20Placenta%20Biol%20Psych.pdf

    What caught my eye was the discussion surrounding (5-Hydroxytryptamine,5-HT) in Autism / Schizophrenia and whether there is a strong relationship to your research surrounding maternal immune activation ?

    Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT₂A and mGlu₂ receptors in the adult offspring.

    http://www.ncbi.nlm.nih.gov/pubmed/21289196

    I suppose the nuts and bolts question to start with is – Would influenza or other viral / bacterial infection be strongly associated with the trophoblast inclusions found in ‘autism placentas’ ?

    regards

    • phpatterson says:

      Excellent question. In fact our paper (Hsiao & Patterson, Brain Behav Immun 2012) demonstrated that the placenta is immune activated by maternal infection/immune activation in the mouse model. This resulted in altered endocrine function in the placenta. We did not see any gross morphological changes in the placenta, however. Surprisingly, Fatemi did report such morphological changes in the placenta following maternal flu infection in mice. Histology changes in the placenta were also reported following LPS challenge during pregnancy. The most intriguing part of the Yale findings in the human study is that maternal infection would have only occurred in a minority of those cases, so the placental changes must have been caused by other factors, and so placental pathology may be a common mechanism. It would be really important if maternal infection is tapping into a general mechanism for increasing ASD risk. I’ll write a post about this once I get hold of the Yale paper. Cheers, PHP

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