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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Placentas and autism

Several people have inquired about a new paper tying abnormalities in the placenta with an autism outcome in the offspring. This work involved a collaboration between Cheryl Walker and colleagues at UC Davis and Harvey Kliman at Yale in which they analyzed 217 placentas. Those placentas that came from families at high risk for having an autistic child were more likely to have abnormal cell growths called trophoblast inclusions. The at-risk placentas had as many as 15 inclusions while control placentas had no more than 2 such abnormalities. At-risk here means that the family already had a child with autism, which increases the risk 9-fold for the second child to have autism, although that risk is still relatively small (2-7% have autism). Unfortunately, it will be at least a year before we find out how many of the placentas with high numbers of inclusions actually gave rise to autistic children. Kliman had already published a much smaller study in 2006 that indicated that children with autism were 3 times more likely than controls to have inclusions in their placentas.

Elaine Hsiao and I recently reviewed the literature on the placenta and mental disorders, and discussed  findings that the placenta is immune activated by maternal infection/immune activation in mouse models. This activation results in altered endocrine function in the placenta. In our own work, we did not see any gross morphological changes in the placenta, however. Surprisingly, Fatemi and colleagues did report morphological changes in the placenta following maternal flu infection in mice. Histology changes in the placenta were also reported following LPS challenge (to mimic bacterial infection) 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 leading to an autistic outcome. It would be really important if maternal infection is tapping into a general mechanism for increasing ASD risk. It may be, of course, that the inclusions are a sign of general placental stress or immune activation, and could be caused by a variety of stressful conditions, and would therefore not be specific to an autism outcome. It will be interesting to determine which types of conditions lead to the formation of inclusions.

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My new favorite drug?

I’ve written here before that the cholesterol-lowering medications, the statins, have positive effects on a variety of brain diseases and injuries in a variety of animal models (Alzheimer’s, Parkinson’s, stroke), with relatively few side effects. The thought is that they do this by lowering cholesterol, and cholesterol is quite relevant not only for hypertension and cardiac disease, but also for Alzheimer’s disease, for instance. Statins also have anti-inflammatory effects [see my post of Jan 28], which could be due to lowering cholesterol, and possibly by other pathways. Nonetheless, it is said that some 20% of patients cannot tolerate statin side effects, which brings me to the topic of this post. A new protein (PCSK9)(quite a mellifluous name) has recently been found to naturally lower LDL-cholesterol, apparently its normal function. Amazingly, rare individuals with mutations in the gene for PCSK9, which completely disable it, have extremely low LDL-cholesterol levels. Moreover, the people have an 88% lower risk of developing heart disease compared to normal folks. (Recall that cardiovascular disease is the number 1 cause of death worldwide) Equally encouraging is the finding that the rare folks with complete absence of PCSK9 appear to be very healthy – meaning that drugs that block PCSK9 are predicted to have no side effects! Many pharmaceutical companies have jumped on this lead and Regeneron and Amgen have each tested antibodies directed against PCSK9 in phase II clinical trials, and report very effective lowering of LDL-cholesterol levels. Large phase III trials have already begun.

What I’d like to see now are tests of such PCSK9 antibodies in mouse models of brain disorders where inflammation is involved. What I have found so far is that blocking PCSK9 in cell culture reduces the death of several types of neurons. On the other hand, knocking down PCSK9 levels in zebrafish embryos leads to their death, which does not happen in the humans without the normal PCSK9 gene, of course. In addition, there is a bit of evidence that blocking PCSK9 protects against inflammation in macrophages, which is very encouraging also.

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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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Pure cure for autism?

An impressive new paper is just out from Robert Naviaux, Susan Powell and colleagues at UC San Diego. They use our mouse model of the autism and schizophrenia risk factor, maternal immune activation during pregnancy, to show that a drug that blocks purinergic receptors, suramin, is able to correct a wide variety of abnormalities found in human autism. A key finding is that this treatment works in mature, 6 week-old mice – that is, the treatment does not have to be initiated during early development. “Purinergic” is a term for nucleotides such as ATP, and receptors for ATP are found on the surfaces of cells throughout the body. Moreover, ATP is a transmitter used at many different types of synapses in the brain. Tying this into the theme of this blog are many observations that ATP signaling modulates immune responses and chronic inflammation, as well as anti-viral signaling, microglial activation, gut motility and permeability, and sensitivity to food allergens. Suramin inhibits purinergic signaling and has been used for treating African Sleeping Sickness (Trypanosomiasis) since the early 1900s. Treating the offspring of maternal immune activated mice weekly with suramin normalizes their social behavior, motor coordination, body temperature, mitochondrial respiratory function and other metabolic measures. Most impressively, this treatment also corrects a neuropathology that we found in this model, and which is also common in human autism.

The authors interpret their findings to suggest that there is too much purinergic signaling in the offspring of immune-activated mothers, which could lead to widespread metabolic disorders of the types seen in autism. What has not yet been shown, however, is whether human autism does, in fact, involve elevated purinergic signaling. One would also like to have seen what this treatment does to the other core autism symptoms found in this model: deficits in communication, and increased repetitive behaviors.

The striking improvements induced by weekly injections of suramin raise the question of whether this treatment could be tested immediately in autism subjects. After all, it has been used in humans for another purpose for decades. However, Naviaux has issued this declaration in response to that question: “Suramin is not suitable for long-term treatment of children with autism because of the potential for toxicity.  This was included as an important caveat in the original PLOS One publication.  Dr. Naviaux’s clinical trial will be a single-dose drug trial that is designed to test the general principle of antipurinergic therapy (APT) in autism.  If successful, the trial may point the way to the development of newer and safer drugs.  Neither Dr. Naviaux, the University of California, the Autism Research Institute, nor Autism Speaks endorses the use of suramin as a general treatment for children with autism.”

Not only for drug development, this important study highlights purinergic pathways as a key area for further study in autism pathophysiology.

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TEDx talk: Mind altering microbes

Our just graduated PhD student Elaine Hsiao recently gave a superb 5 minute talk at Caltech’s TEDx event on her work on gut-brain connections related to autism: Mind Altering Microbes. [click on that title to see the talk][click on the empty space below to see her picture; I don’t know why it is not showing up normally]

EYH pic2

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My favorite drug II

Back from cold and rainy refereeing, but followed by exciting 3-2 win by my son’s soccer team, in which he scored the winning goal!

New paper just out from Mark Bear’s group at MIT. They have been at the forefront of identifying pharmacological interventions in mouse models of fragile X syndrome (FXS), and this has led to several current clinical trials, with potential implications for autism, as FXS patients display a number of behavioral symptoms found in autism spectrum disorder, including seizures. Using an Fmr1 mutant (knockout) mouse model of FXS, they now report that the cholesterol lowering drug lovastatin can reduce seizures in these mice. The drug reduces both the number and severity of seizures and associated behaviors induced by a loud noise (audiogenic seizures) when injected intraperitoneally or given orally 48 hours before testing. This study did not come totally out of the blue as some prior work found that other rodent models of epilepsy can respond positively to statin drugs, although conflicting findings were also reported in these models. There is evidence that statins work in these models by reducing inflammation. How does this statin work in the FXS mice? The most obvious possibility is that its effects on fatty acids and cholesterol are responsible, but Bear and colleagues provide evidence that lovastatin reduces Ras-ERK1/2 signaling and the excessive protein synthesis found in the the FXS mice. This is relevant because other methods of reducing ERK signaling also inhibit audiogenic seizures in this model. It will next be important to assess the effects of lovastatin on other autism-related behaviors in these mice. However, the authors also point out that controlling epilepsy in FXS patients is an important goal in itself, and current treatments are not without side effects whereas lovastatin has a known safety profile and is already approved for lowering cholesterol in children.

Statins are not only effective in treating and preventing cardiac disease but they have also shown efficacy in reducing risk for Alzheimer’s disease, reducing pathology in a mouse model of Parkinson’s disease, and they not only reduce the risk of stroke but they aid in functional recovery. At least some of the beneficial effects may be due to the anti-inflammatory effects of statins, which make them all the more attractive in the context of autism. Given their strong safety profile in the many millions of people taking these drugs over decades, these are my favorite drugs.

Note: Suzanne Ayres reminded me of a point made by a recent paper reporting that red blood cells from autistic patients contain less cholesterol than controls.  While this is not the same thing as measuring cholesterol in serum, it does raise the issue of findings in Smith-LemiOpitz syndrome. This congenital disease involves a reduction in cholesterol levels that leads to malformations, many organ pathologies and some autism-like symptoms. Clearly, one does not want to lower cholesterol levels too much!

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