Dipeptidyl peptidase (DPP) IV and autism: supporting opioid-excess?

Serum levels of dipeptidyl peptidase (DPP) IV were found to be lower in children with autism compared to asymptomatic controls according to the study by Shahid Bashira & Laila AL-Ayadhi [1]. Based on analysis by ELISA, researchers concluded that "alterations in the plasma level of DPP IV play a role in the pathophysiology of autism".

A sailor went to sea, sea, sea... @ Wikipedia 

Anyone who has followed the autism research scene for any length of time might have already heard about DPP-IV and autism. The paper by Hunter and colleagues [2] (open-access here) and subsequent response [3] highlights some of the discussions in this area relating to the use of the opioid-excess hypothesis [4] as a means to potentially explain some autism. The idea stemming from some earlier work (see here) being that a defect in the functioning of DPP-IV with regards to its ability to degrade proline-rich proteins such as gliadin (gluten) might account for the build-up of gluten derived opioid peptides suggested as part of the opioid-excess theory. Earlier accounts of issues with DPP-IV in relation to the classic gluten-related autoimmune condition coeliac disease (see here for an overview) kinda set the tone [5] for some analysis with autism in mind. Indeed, at least one trial of enzyme-based therapy has also talked about the potential involvement of DPP-IV in some cases of autism [6].

The Bashira paper did not specifically set out to look at the relationship between DPP-IV and dietary elements potentially linked to autism. Instead their focus seemed to be on the involvement of this peptidase in brain physiology and "its possible link to neuroinflammation in autism". DPP-IV has, for example, been discussed with cerebral ischemia in mind as per the results from Röhnert and colleagues [7] although I hasten to add that I am not equating autism and brain ischemia.

I personally feel that quite a bit more research effort is needed in the area of DPP-IV. Lower plasma levels of DPP-IV have been noted in cases of other conditions such as depression [8]. The recent results from Simone Peters and colleagues [9] which talked about "Short-term exposure to gluten specifically induced current feelings of depression" in their cohort (see this post) could fit well with the reduction in gluten peptide degrading abilities potentially present as a consequence of something like lower DPP-IV levels. Indeed, one might also speculate that the suggestion of non-coeliac gluten sensitivity (NCGS) may actually reflect involvement of opioid peptides on the basis of such a correlation...

I'm also taken back to some work by Vojdani and colleagues [10] which talked about anti-CD26 autoantibodies being present in a "significant percentage of children with autism". CD26, a surface glycoprotein used synonymously with DPP-IV, was suggested to show involvement as a function of "dietary peptides, bacterial toxins and xenobiotics bind[ing] to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with autism". Their follow-up study [11] further added to the literature in this area and how "Dysfunctional membrane peptidases and autoantibody production may result in neuroimmune dysregulation and autoimmunity" in relation to autism. Autoimmunity and autism y'say?

As per the cycles of scientific research, where research areas fall in and out of favour, it does appear that there is a resurgence of interest in elements of the opioid-excess theory with a specific focus on the role of food-derived peptides in relation to at least some autism. The Roy review looking at naltrexone for autism (see here) is one element given the opioid antagonistic effects of this pharmaceutic. The Sokolov paper (with its flaws) looking at beta-casomorphin - the opioid peptide derived from the casein protein - in relation to autism is another. The Trivedi paper (see here) on exogenous opioid peptides and DNA methylation levels adds to the research bundle. Dare I even mention the camel milk and autism connection also being made in the research literature too as a function of different milks and different protein/peptide configurations?

Music to close. Epic by Faith No More.

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[1] Bashir S. & AL-Ayadhi L. Alterations in plasma dipeptidyl peptidase IV in autism: A pilot study. Neurology, Psychiatry and Brain Research. 2014; 20: 41-44.

[2] Hunter LC. et al. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2003 Feb;45(2):121-8.

[3] Shattock P. et al. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2004 May;46(5):357.

[4] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[5] Smith MW. & Phillips AD. Abnormal expression of dipeptidylpeptidase IV activity in enterocyte brush-border membranes of children suffering from coeliac disease. Exp Physiol. 1990 Jul;75(4):613-6.

[6] Brudnak MA. et al. Enzyme-based therapy for autism spectrum disorders -- is it worth another look? Med Hypotheses. 2002 May;58(5):422-8.

[7] Röhnert P. et al. Dipeptidyl peptidase IV, aminopeptidase N and DPIV/APN-like proteases in cerebral ischemia. J Neuroinflammation. 2012 Feb 28;9:44.

[8] Maes M. et al. Alterations in plasma dipeptidyl peptidase IV enzyme activity in depression and schizophrenia: effects of antidepressants and antipsychotic drugs. Acta Psychiatr Scand. 1996 Jan;93(1):1-8.

[9] Peters SL. et al. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity - an exploratory clinical study. Aliment Pharmacol Ther. 2014 May;39(10):1104-12.

[10] Vojdani A. et al. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99.

[11] Vojdani A. et al. Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease. Clin Diagn Lab Immunol. 2004 May;11(3):515-24.

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Bashir, S., & AL-Ayadhi, L. (2014). Alterations in plasma dipeptidyl peptidase IV in autism: A pilot study Neurology, Psychiatry and Brain Research, 20 (2), 41-44 DOI: 10.1016/j.npbr.2014.03.001

Immunological effects from risperidone treatment in autism

The findings from Jai Eun Choi and colleagues [1] suggesting that use of the antipsychotic risperidone may impact on levels of certain cytokines - messenger cells of the immune system - in some cases of autism spectrum disorder (ASD) grabbed my attention recently. I've always been pretty interested in the complexity of the immune system when it comes to something like autism (see here) as well as the various examples of how many of the medications used to 'manage' aspects of autism appear to have quite a few more biological effects over and above those listed on the patient information leaflet. Think melatonin for example, and what a molecular handyperson this pharmaceutic has turned out to be (see here).

Could it be magic... @ Wikipedia 

The Choi paper worked on the assumption that use of risperidone and other antipsychotics have previously been shown to correlate with changes to serum levels of certain cytokines as per examples of work in the area of schizophrenia [2] and here [3]. Some of this research even hinted that part of the reason why antipsychotics might 'work' in some cases of schizophrenia was to do with their potential effect on "the inflammatory-like situation" present [4]. Certainly it's been noted before on this blog how inflammation may very well play some role when it comes to psychiatry (see here) particularly in light of some of the research on the various inflammatory markers (see here) accepting the chicken-and-egg question of what comes first: inflammation or symptoms?

Anyhow, based on a small-ish sample (n=45), Choi et al looked at plasma levels of "27 different cytokines" both before risperidone treatment was introduced and after 8 weeks on the drug. Interestingly the words 'responders' and 'nonresponders' were included in the analyses undertaken to look for any changes/trends following antipsychotic use (something which I think more studies should head towards). As it happens, "2 of the 27 plasma cytokines showed statistically significant decreases in median levels" - eotaxin and monocyte chemoattractant protein-1 (MCP-1). Further, when those responders and non-responders were separated out "the median values of interleukin (IL)-5 were significantly higher (p=0.005) in the overall responder group than in nonresponders".

Obviously one has to be a little bit guarded about the conclusions reached from this fairly small and fairly short study. Whilst risperidone does have a place in the medicines cabinet for some people with autism (see here), paediatric use (as was the case in the Choi study) is not without risks as per a recent entry on the SFARI website (see here). The guidance from NICE here in the UK (well, England at least) also mentioned how cautious physicians must be when using antipsychotics "for behaviour that challenges" with autism in mind.

I was quite interested in the Choi findings particularly that of the elevations in IL-5 in the responder group. I'm no expert on IL-5 but some light reading around the topic (see here) seems to imply that elevations of this cytokine are probably not going to be a great thing from the point of view of their involvement in the activation of eosinophils [5]. I've talked before on this blog about some of the work looking at eosinophils and autism (see here) and some potentially interesting correlations with other research (see here). I'd perhaps like to see more about this correlation in future studies particularly building on other findings in relation to IL-5 and autism [6] (open-access here) including as part of being a risk factor for offspring autism [7] (open-access here).

Insofar as the eotaxin and MCP-1 findings, well, again there is probably a lot more work to do on these compounds as a function of their mention in other autism research [8] (open-access here). The paper by Paul Ashwood [9] (who incidentally was an author on the Choi paper) looking at Fragile X syndrome (FXS) with and without autism also caught my eye: "significant differences were observed between the FXS group with autism and the FXS without autism for IL-6, eotaxin, MCP-1" as another avenue for further study.

So then... somewhere the drinks are free (or should that be all-inclusive).

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[1] Choi JE. et al. Change in Plasma Cytokine Levels During Risperidone Treatment in Children with Autism. J Child Adolesc Psychopharmacol. 2014 May 14.

[2] Zhang XY. et al. Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry. 2004 Jul;65(7):940-7.

[3] Kim DJ. et al. Effect of risperidone on serum cytokines. Int J Neurosci. 2001;111(1-2):11-9.

[4] Cazzullo CL. et al. Cytokine profiles in schizophrenic patients treated with risperidone: a 3-month follow-up study. Prog Neuropsychopharmacol Biol Psychiatry. 2002 Jan;26(1):33-9.

[5] Takatsu K. & Nakajima H. IL-5 and eosinophilia. Curr Opin Immunol. 2008 Jun;20(3):288-94.

[6] Suzuki K. et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS One. 2011;6(5):e20470.

[7] Goines PE. et al. Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study. Mol Autism. 2011 Aug 2;2:13.

[8] Ashwood P. et al. Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol. 2011 Mar;232(1-2):196-9.

[9] Ashwood P. et al. Plasma cytokine profiles in Fragile X subjects: is there a role for cytokines in the pathogenesis? Brain Behav Immun. 2010 Aug;24(6):898-902.

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Choi JE, Widjaja F, Careaga M, Bent S, Ashwood P, & Hendren RL (2014). Change in Plasma Cytokine Levels During Risperidone Treatment in Children with Autism. Journal of child and adolescent psychopharmacology PMID: 24828014

Ketogenic diet and the valproate mouse model of autism

A brief entry today and yet another blog post that starts with a quote (sorry)... "The offspring exposed to VPA [valproic acid] prenatally demonstrated a significant decrease in the number of play initiations/attacks and this was reversed with the KD [ketogenic diet]".

Gloucester Old Spot @ Wikipedia 

That finding reported in the paper by Ahn and colleagues [1] continues my interest in all-things related to prenatal VPA exposure and the reported effects on some offspring (see here). The added bonus of including some discussion about how the use of a ketogenic diet might reverse some of the effects of VPA exposure (in rats at least) is also worthwhile mentioning.

A couple of pointers perhaps...

• Rats, Sprague-Dawley mother rats, were given VPA or saline (as a control) during pregnancy and their pups (VPA-exposed vs. controls) were subjected to measures looking at "juvenile play behavior" and eventually "mitochondrial bioenergetic analysis" as a function of the use of a ketogenic or standard diet.
• Results: "Prenatal VPA exposure also disrupted the pattern of play responses". Not a great surprise there given everything else that has been linked to VPA exposure in-utero. But.. use of the ketogenic diet "was able to modify complex social behaviors and mitochondrial respiration". As noted previously, the reduction in play initiations made by the VPA exposed mice was to some degree rescued following use of the ketogenic diet.

Yes, I know that this was a study of rats, and whilst useful, rats are rats not humans. But I am nevertheless intrigued by the suggestion that something like a ketogenic diet - more typically indicated for some types of treatment resistant epilepsy - might to some degree, affect the behaviour and physiology of animals exposed to a traditional anticonvulsant like valproate during the nine months that made them. Does anyone else find that a little ironic? Also throw in mention of the words 'autism spectrum disorder' alongside that animal VPA exposure model alongside the ketogenic diet (see here) and I'm sure there's some more research to be done in this area.

Mode of action? I dunno. I will draw your attention to some interesting work on carnitine homoeostasis as a function of valproate administration [2] which might be relevant. Carnitine plays a role in mitochondrial function [3] and there is some suggestion that a ketogenic diet might help maintain carnitine levels in the presence of VPA [4]. Whether this applies to brain structures or neurochemistry potentially already affected by prenatal exposure to VPA is a question not yet asked or answered. Bearing in mind the gastrointestinal (GI) effects also noted in VPA exposure models (see here) I might also be inclined to 'look to the bowels' in terms of any potential effects from the ketogenic diet in that organ too.

Music to close and I was taken aback by the performance from Pumeza at the opening to the 2014 Commonwealth Games and her version of Freedom Come All Ye...

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[1] Ahn Y. et al. The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder. Dev Neurosci. 2014 Jul 8.

[2] Morand R. et al. Effect of short- and long-term treatment with valproate on carnitine homeostasis in humans. Ther Drug Monit. 2012 Aug;34(4):406-14.

[3] Zammit VA. et al. Carnitine, mitochondrial function and therapy. Adv Drug Deliv Rev. 2009 Nov 30;61(14):1353-62.

[4] Coppola G. et al. Plasma free carnitine in epilepsy children, adolescents and young adults treated with old and new antiepileptic drugs with or without ketogenic diet. Brain Dev. 2006 Jul;28(6):358-65.

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Ahn Y, Narous M, Tobias R, Rho JM, & Mychasiuk R (2014). The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder. Developmental neuroscience PMID: 25011527

Prenatal and neonatal blood mercury levels and autism

Acknowledging that some topics have the ability to furrow brows when it comes to autism research, mercury and autism is becoming something of a frequent talking point on this blog as a function of a whole slew of articles appearing in the peer-reviewed domain. If I were to [very tentatively] summarise the collected literature so far, it would be to say something like:

Mosaic of mercury @ Wikipedia 

(i) there is quite a bit more research to be done on some sources of mercury being 'linked' to cases of autism i.e. air pollution, fish consumption (see here),
and
(ii) the body burden of mercury for some on the autism spectrum is elevated (see here) compared to other groups and potentially linked to "a decreased ability to excrete mercury due to a combination of lowered reduced glutathione, emergence of oxidative stress, and excessive use of oral antibiotics" according to the review by Francesca Gorini and colleagues [1] (open-access).

I know some people may not like hearing that summary but that's my interpretation of the various reviews and meta-analyses conducted so far. I should add that I'm not though passing any specific comment on whether mercury 'causes' autism bearing in mind what we know about the developmental consequences of exposure.

The paper by Vincent Yau and colleagues [2] looking at maternal serum and infant newborn bloodspot levels of mercury adds to that literature with their conclusion: "levels of total mercury in serum collected from mothers during mid-pregnancy and from newborn bloodspots were not significantly associated with risk of ASD [autism spectrum disorder]". I believe we had seen this data presented before at the 2011 IMFAR conference too (see here).

A few details first:

• Based on data obtained from the EMA (Early Markers of Autism) study, a cohort "identified from the California Department of Developmental Services (DDS)" records, mid-pregnancy maternal serum samples and the wonderful resource that is the neonatal bloodspots related to some 84 children diagnosed with an ASD were analysed for total mercury content (inorganic and organic mercury). Blinded results were compared with 159 population controls (asymptomatic) and 49 children diagnosed with a learning (intellectual) disability or developmental delay.
• ICP mass spectrometry was the name of the analytical game, which as I've talked about before, is one of the methods of choice when it comes to the analysis of the metallome. Archived blood spot samples were subject to laser ablation as a function of their mounting. 
• Results: "Maternal serum and infant blood mercury levels were significantly correlated among all study groups". In other words, maternal mercury burden seemed to be associated with neonatal offspring burden (albeit with a correlation coefficient ~0.4 which is OK but not exactly great).
• Further: "Results for mercury levels in newborn blood samples were similar" across the groups. Ergo, at birth, levels of total mercury from neonatal bloodspots "were not significantly associated with risk of ASD". That's not to say that there weren't some differences in average levels of blood mercury levels across the groups, just that such differences were not deemed to elevate the risk of ASD overall.

Like quite a lot of the science in this area, there are several ways you could interpret these results. You could, for example say that the maternal burden of mercury during pregnancy was not associated with offspring risk of autism. You could also say that 'at or shortly after birth' (remember those words), blood mercury levels do not seem to correlate with the risk of autism. Therefore mercury is not a factor in relation to autism as per other results in this area [3]. You could say those things, as you might for several other variables supposedly related to autism... vitamin D for example? (see here and then see here).

But you might also consider the bank of research which has reported elevated levels of mercury in various biofluids and tissues particularly focused on slightly older infants and children with autism as illustrative of something potentially important: increasing exposure to mercury with age. Take for example the paper by Majewska and colleagues [4] and their findings reporting: "Autistic children significantly differed from healthy peers in the concentrations of mercury in hair: younger autistics had lower levels, while older - higher levels than their respective controls". The results from Hertz-Picciotto and colleagues [4] (open-access here) also implied that behaviour might play a role in blood mercury levels: "Interestingly, although few children had Hg amalgams, those who did and who also either chewed gum or had bruxism appeared to have experienced sufficient release of inorganic Hg to be measurable in blood". I say this noting that not every child with autism has mercury amalgams, as neither do they all partake in teeth grinding.

The Yau results make an important contribution to the issue of mercury and autism in terms of maternal contribution and mercury load at birth. As part of some further investigations, and bearing in mind that participants in the EMA initiative might also be involved in other State initiatives (beincharge!), I would like to see further follow-up of participants and if and how their mercury load might have changed as they matured. Analysis of other parameters mentioned in that Gorini review paper - such as glutathione measures for example - might also offer some important accompanying data on whether excretion factors are part of the issue here and what might be done to help relieve any excess burden of the troublesome heavy metal that is mercury. Oh, and given that genetic factors might also play some role in mercury accumulation as per the findings by Llop and colleagues [5] (open-access), there may also be more research to do here too...

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[1] Gorini F. et al. The Role of Heavy Metal Pollution in Neurobehavioral Disorders: a Focus on Autism. Review Journal of Autism and Developmental Disorders. 2014. June 27.

[2] Yau VM. et al. Prenatal and neonatal peripheral blood mercury levels and autism spectrum disorders. Environ Res. 2014 Jun 27;133C:294-303. 

[3] van Wijngaarden E. et al. Autism spectrum disorder phenotypes and prenatal exposure to methylmercury. Epidemiology. 2013 Sep;24(5):651-9. 

[4] Hertz-Picciotto I. et al. Blood mercury concentrations in CHARGE Study children with and without autism. Environ Health Perspect. 2010 Jan;118(1):161-6.

[5] Llop S. et al. Polymorphisms in ABC transporter genes and concentrations of mercury in newborns--evidence from two Mediterranean birth cohorts. PLoS One. 2014 May 15;9(5):e97172. 

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Yau VM, Green PG, Alaimo CP, Yoshida CK, Lutsky M, Windham GC, Delorenze G, Kharrazi M, Grether JK, & Croen LA (2014). Prenatal and neonatal peripheral blood mercury levels and autism spectrum disorders. Environmental research, 133C, 294-303 PMID: 24981828

p-cresol and autism: in need of further research

"These results confirm the elevation of urinary p-cresol in a sizable set of small autistic children and spur interest into biomarker roles for p-cresol and p-cresylsulfate in autism".

The peasant dance @ Wikipedia 

That was the primary conclusion from the paper by Gabriele and colleagues [1] looking at "three components of urinary p-cresol, namely p-cresylsulfate, p-cresylglucuronate and free p-cresol" in samples from 33 participants diagnosed with an autism spectrum disorder (ASD) compared with matched asymptomatic controls. The confirmation bit of that quote refers to the fact that members of this authorship group have previously reported on elevated urinary p-cresol in cases of autism [2] which was talked about in the very first proper research-based post on this blog (see here).

Before proceeding, perhaps it might be worth my while going through a few descriptive details. p-cresol (para-cresol) otherwise known as 4-methylphenol is a compound of some note in terms of the various ways and means one arrives at this organic aromatic compound. The solvent toluene is eventually metabolised into p-cresol, as is the amino acid tyrosine in the presence of strains of the anaerobic bacterium Clostridium difficile [3] for example. That being said, there are quite a few other ways in which one might come into contact with this compound.

According to the paper by Vanholder and colleagues [4] there is quite a bit of evidence to suggest that whilst p-cresol and its metabolites are compounds found in some quantity in just about everyone, under certain circumstances, elevations in amount may not be particularly desirable [5] particularly when it comes to renal functions. Indeed, quite a bit of the focus has been on the conjugated derivative p-cresylsulfate (formed through O-sulfonation) when it comes to toxicity [6]. I'll come back to this issue shortly.

A few points on the Gabriele paper might be useful:

• Based on a small participant group comprising 33 participants of various ages on the autism spectrum and 33 sex- and age-matched asymptomatic controls, levels of free p-cresol and it's two metabolites were measured via HPLC with fluorescence detection.
• All metabolites were "significantly elevated" in ASD cases compared to controls.
• "This increase was limited to ASD children ≤8 [less than or equal to 8] years". Also: "Urinary levels of p-cresol and p-cresylsulfate were associated with stereotypic, compulsive/repetitive behaviors (p < 0.05), although not with overall autism severity".

I probably don't need to say it, but when it comes to talk about biomarkers and autism, I do tend to be a little restrained about the promise of any results. Think back to my recent post on organic acids as biomarkers for autism (see here) and just about all the caveats talked about then in terms of heterogeneity and comorbidity come into play here too. That also this and other results from this group are based on HPLC with either UV (ultraviolet) or fluorescence detection could also be considered problematic as a function of the many and varied components found in urine and how without mass spectrometry or NMR, assigning labels to compounds is slightly problematic. Think casomorphins as another example...

Elevated levels of urinary p-cresol are also not a feature of every metabolomic study looking at autism. In their review of all-things p-cresol and autism, Persico & Napolioni [7] talked about how the results from Yap and colleagues [8] reported "blunted and not increased levels of p-cresylsulfate in autistic patients". The Yap study did utilise (1)H NMR spectroscopy and so did not suffer the same analytical shortcomings as the more recent trials. That all being said, I don't want to come down too hard on the latest results from Gabriele and colleagues. They got what they got and now put their results out for further inspection and hopefully, independent verification.

I am also wondering whether the paper by Clayton and colleagues [9] might also be relevant in this case. Dr Clayton, who some might remember from other work talked about on this blog (see here), discussed how "in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen [paracetamol]". Sulphation capacity when it comes to autism is already something of a research interest (see here) which when added to a growing body of work looking at paracetamol use during pregnancy and possible links to offspring development (see here) might indicate some other interesting investigations to be done. I wonder if perhaps even the sulphation depleting metabolism of something like p-cresol might actually be the more important part of such investigations to autism research?

Music to close, and are you a troublemaker?

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[1] Gabriele S. et al. Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study. Biomarkers. 2014 Jul 10:1-8.

[2] Altieri L. et al. Urinary p-cresol is elevated in small children with severe autism spectrum disorder. Biomarkers. 2011 May;16(3):252-60.

[3] Dawson LF. et al. The analysis of para-cresol production and tolerance in Clostridium difficile 027 and 012 strains. BMC Microbiology 2011, 11:86

[4] Vanholder R. et al. p-cresol: a toxin revealing many neglected but relevant aspects of uraemic toxicity. Nephrol Dial Transplant. 1999 Dec;14(12):2813-5.

[5] Liabeuf S. et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant. 2010 Apr;25(4):1183-91.

[6] Vanholder R. et al. The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate: A Systematic Review. J Am Soc Nephrol. 2014 May 8. [Epub ahead of print]

[7] Persico AM. & Napolioni V. Urinary p-cresol in autism spectrum disorder. Neurotoxicol Teratol. 2013 Mar-Apr;36:82-90.

[8] Yap IK. et al. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010 Jun 4;9(6):2996-3004.

[9] Clayton TA. et al. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14728-33.



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Gabriele S, Sacco R, Cerullo S, Neri C, Urbani A, Tripi G, Malvy J, Barthelemy C, Bonnet-Brihault F, & Persico AM (2014). Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals, 1-8 PMID: 25010144

Prenatal valproate exposure and brains

The paper by Amanda Wood and colleagues [1] (open-access) makes a potentially very important contribution to the growing literature looking at how prenatal exposure to sodium valproate (VPA) may affect some children. Authors reported on: "regional structural cortical brain changes in humans exposed to VPA in utero" and specifically, increased cortical thickness in the left inferior frontal gyrus.

Lightning and lava @ Oliver Spalt @ Wikipedia 

In case you need any background on the story behind pregnancy exposure to VPA, I would direct you to a few previous posts where the topic has been covered on this blog (see here and see here) with an autism slant. You might also read my small contribution to a more formal article on this topic here.

Outside of any reported elevated risk of offspring autism or autistic traits associated with prenatal VPA exposure, I'm also minded to bring in some interesting work on intestinal inflammation being reported in a VPA mouse model (see here) to further highlight that important gut-brain axis which I seem to be a little obsessed with.

The Wood paper is open-access and has some accompanying media coverage but a few pointers might be useful...

• Following other work by the authors on this topic [2] the idea behind this latest research was to apply the science of neuroimaging to a participant group comprising 16 children exposed to VPA in-utero compared with age- and sex-matched children not exposed to such pharmaceutics prenatally.
• MRI scans were taken and analysed and "whole brain group differences" assessed. 
• Results: well, as discussed, there were some findings in terms of cortical thickness but also specifically with language skills in mind. To quote again: "Asymmetry of cortical thickness in the inferior frontal lobes was seen in controls but not cases". I understand that this finding might have some relevance to language processing [3] although set my non-expert stall out on such matters. As per that previous link [2] and other evidence [4], language functions in VPA exposed children tend to poorer compared to controls and to those exposed to other anti-convulsant medication during the nine months that made us. This last point on different medications potentially carrying different risk profiles [5] is something equally interesting.

Allowing for the relatively small participant groups studied and the lack of any other research parameter such as looking at accompanying brain chemistry which may be important [6], the Wood paper offers some intriguing insights into how pregnancy VPA use might affect infant brain development. The very important detail of analysis being based on real human children and not rat offspring also invites some further examination of previous results based on rodents [7]. Rats are rats, children are children.

I'm going to leave you with a quote from the authors about their study: "VPA remains an important medication for people with epilepsy. What this study really tells us is that further research is required so that all women with epilepsy can make informed decisions about their medication use during pregnancy". I couldn't agree more, and as per the Treating for Two initiative, I'm not the only one.

Music then... HRH Gaga and Just Dance.

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[1] Wood AG. et al. Altered cortical thickness following prenatal sodium valproate exposure. Annals of Clinical and Translational Neurology. 2014. July 3. doi: 10.1002/acn3.74

[2] Nadebaum C. et al. Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology. 2011 Feb 22;76(8):719-26.

[3] Powell HWR. et al. Hemispheric asymmetries in language-related pathways: A combined functional MRI and tractography study. NeuroImage. 2006; 32: 388-399.

[4] Shallcross R. et al. In utero exposure to levetiracetam vs valproate: development and language at 3 years of age. Neurology. 2014 Jan 21;82(3):213-21.

[5] Vajda FJE. et al. The teratogenicity of the newer antiepileptic drugs – an update. Acta Neurol Scand. 2014. July 18

[6] Almeida LE. et al. Increased BDNF expression in fetal brain in the valproic acid model of autism. Mol Cell Neurosci. 2014 Mar;59:57-62.

[7] Mychasiuk R. et al. Effects of rat prenatal exposure to valproic acid on behaviour and neuro-anatomy. Dev Neurosci. 2012;34(2-3):268-76.

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Wood, A., Chen, J., Barton, S., Nadebaum, C., Anderson, V., Catroppa, C., Reutens, D., O'Brien, T., & Vajda, F. (2014). Altered cortical thickness following prenatal sodium valproate exposure Annals of Clinical and Translational Neurology DOI: 10.1002/acn3.74

Trauma and PTSD raise risk of autoimmune disorders?

I admit to some head scratching when I first read the paper by Aoife O’Donovan and colleagues [1] reporting that among war veterans of the Iraq and Afghanistan campaigns, "trauma exposure and PTSD [post-traumatic stress disorder] may increase risk of autoimmune disorders".

It wasn't that I didn't believe the results, but rather that the idea that a physical event with a psychological consequence could impact on a somatic condition with an autoimmune element to it seemed to open up some new avenues particularly pertinent to this blog and its focus on psychology and biology intersecting. That there may be consequences for other conditions from the O'Donovan findings was something else that piqued my interest.

Sunset in Rio @ BBC 1

Anyway, a few details first:

• A retrospective study based on the analysis of several thousands of medical records of US troops deployed into active theatre in Iraq or Afghanistan was the study starting point. The idea being that outside of PTSD being "associated with endocrine and immune abnormalities" [2] there may be more to see when it comes to autoimmune disease - conditions characterised by a breakdown in the immune system distinguishing self from other. The types of autoimmune disorder included for study ranged from inflammatory bowel disease (IBD) to lupus erythematosus.
• From an initial cohort of 666,269 veterans, 203,766 (30%) were diagnosed with PTSD and just shy of 20% were diagnosed with a psychiatric disorder other than PTSD. Comparing those with PTSD with those without, authors reported a "significantly higher adjusted relative risk (ARR) for diagnosis with any of the autoimmune disorders alone or in combination compared to veterans with no psychiatric diagnoses... and compared to veterans diagnosed with psychiatric disorders other than PTSD".
• Both men and women with PTSD seemed to be equally affected by autoimmune disorders. Military sexual trauma exposure was also "independently associated with increased risk in both men and women" of autoimmune disorders.

The first thing that struck me about the O'Donovan findings was the observation that nearly a third of all veterans were diagnosed with PTSD. I've talked before about concepts like shell shock and how thousands of troops suffered psychological trauma during the First World War (see here). In the modern era where trench warfare has to some extent been overtaken by the digital battlefield, it appears that the psychological harms of war still persist and still inflict a terrible burden.

As intrigued as I was about the PTSD - autoimmune disorder connection included in the O'Donovan paper, a quick trawl through some of the other research in this area tells me this is not the first time that such an association has been made. The results from Boscarino [3] hinted that "chronic sufferers of PTSD may be at risk for autoimmune diseases" based on an analysis of Vietnam war veterans. The comparison between veterans who operated in different theatres of conflict (Iraq/Afghanistan vs. Vietnam) also to some degree negates any individual geographical effect from the war zone itself as influencing the results. The paper by Zung and colleagues [4] looking at paediatric type 1 diabetes frequency and psychological stress associated with the 2006 Lebanon War concluded that war trauma might play a role in the increased numbers of cases situated near the conflict. One wonders what the outcome of current events might be too. Such data also implies that age and occupation (i.e. a military career) are not going to be able to account for the PTSD - autoimmunity link either.

So then to the question of what mechanism might be driving this association. Outside of the general area of immune response and something like inflammation [5], the paper by Sommershof and colleagues [6] reported data pointing to a "profoundly altered composition of the peripheral T cell compartment [which] might cause a state of compromised immune responsiveness" in relation to traumatic stress and physical health. I'm no expert on T cells but I gather that they do play an important role in the issue of autoimmunity [7] (open-access) so perhaps there is more research to do there. O'Donovan et al also list "lifestyle factors" as also influencing the trauma exposure / PTSD - autoimmune disease relationship which brings into play a whole host of issues ranging from drug and/or alcohol abuse to less extreme environmental factors. I'd also be minded to suggest that culturally-related issues might also play a role in any relationship as per studies like the one from Whealin and colleagues [8] talking about "risk and resilience correlates of PTSD" as a function of ethnicity. I might also draw your attention to the important paper by Alessio Fasano on gut permeability and autoimmune disease [9] which might very well link PTSD to other physiological events as per other descriptions [10].

Whichever way you look at the O'Donovan paper, their findings present some stark facts about caring for war veterans. They also emphasise how war really can be hell.

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[1] O'Donovan A. et al. Elevated Risk For Autoimmune Disorders In Iraq And Afghanistan Veterans With Posttraumatic Stress Disorder. Biological Psychiatry. 2014. June 28.

[2] Pace TW. & Heim CM. A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun. 2011 Jan;25(1):6-13.

[3] Boscarino JA. Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies. Ann N Y Acad Sci. 2004 Dec;1032:141-53.

[4] Zung A. et al. Increase in the incidence of type 1 diabetes in Israeli children following the Second Lebanon War. Pediatr Diabetes. 2012 Jun;13(4):326-33.

[5] Tursich M. et al. Association of trauma exposure with proinflammatory activity: a transdiagnostic meta-analysis. Translational Psychiatry. 2014. July 22.

[6] Sommershof A. et al. Substantial reduction of naïve and regulatory T cells following traumatic stress. Brain Behav Immun. 2009 Nov;23(8):1117-24.

[7] Dejaco C. et al. Imbalance of regulatory T cells in human autoimmune diseases. Immunology. Mar 2006; 117: 289–300.

[8] Whealin JM. et al. Evaluating PTSD prevalence and resilience factors in a predominantly Asian American and Pacific Islander sample of Iraq and Afghanistan Veterans. J Affect Disord. 2013 Sep 25;150(3):1062-8.

[9] Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012 Feb;42(1):71-8

[10] Berk M. et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 Sep 12;11:200.

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O’Donovan, A., Cohen, B., Seal, K., Bertenthal, D., Margaretten, M., Nishimi, K., & Neylan, T. (2014). Elevated Risk For Autoimmune Disorders In Iraq And Afghanistan Veterans With Posttraumatic Stress Disorder Biological Psychiatry DOI: 10.1016/j.biopsych.2014.06.015

Medical comorbidities in autism

A very quick micropost to direct you to the second version of the document: 'Medical comorbidities in autism spectrum disorders' published by Treating Autism, a group based here in Blighty.

Covering a fair chunk of the peer-reviewed science examining the various medical comorbidities which seems to crop up with some regularity when a diagnosis of autism spectrum disorder (ASD) is made, this free document (complete with a 6 page reference list) is pretty comprehensive.

The message is quite a clear one: under-diagnosis of medical comorbidity and the prospect of barriers to accessing appropriate healthcare represent significant challenges to those diagnosed on the autism spectrum. Hence, receipt of a diagnosis of autism "should represent the beginning of medical investigation and assessment, not the end".

Congratulations go to all those who contributed to this document and in particular, Natasa, for her hard-work in bringing this important primer to fruition. So, please, disseminate far and wide...

Common variation and the genetics of autism

The paper by Trent Gaugler and colleagues [1] reporting that the genetic architecture of the autism spectrum disorders (ASDs) seems in the most part to be due to "common variation" over and above "rare variants or spontaneous glitches" adds to the quite voluminous literature in this area.

Everything in proportion? @ Wikipedia 

Based on an analysis of "a unique epidemiological sample from Sweden" researchers looked at DNA variations in some 3000 individuals with autism and asymptomatic controls. They were able to model their findings "based mostly on combined effects of multiple genes and non-shared environmental factors" including some "synthesis of results from other studies".

Their results: "Most genetic risk for autism comes from common inherited gene variations that can be found in many individuals without the disorder" as per one write-up of the study results. Spontaneous mutations - those so-called de novo mutations which seem to be of growing interest to autism research - were reported to only 'modestly' increase risk of the condition (2.6% of the total risk). About 40% of the risk was unaccounted for, but combined with those common inherited gene variations, made up about 90% of the total risk or liability for ASD.

Quite a lot of the discussion about these results has focused on the issue of tiny genetic effects which many people not on the autism spectrum have present in their genome adding up into something with "substantial impact" when present together. Other research has hinted at similar things as for example, in the paper by St Pourcain and colleagues [2] looking at the genetics of social communication issues.

Whilst I do think that the Gaugler paper is an important one, I am minded to suggest a few words of caution. First and foremost is the reliance on observed genetic variation in the current paper. Although no expert in genetics, my very basic knowledge is that such variations are structural in nature as per issues like single-nucleotide polymorphisms (SNPs). The presence of such mutations (which we all have by the way, dotted around our genomic landscape) whilst of interest, don't actually though tell you an awful lot about the function of particular genes as a consequence of those point mutations unless further studies are conducted. Genes for example expressing protein can be affected by such mutations but, as we've come to realise in the past few decades, gene expression is also to some degree affected by other variables, as per the rise and rise of the science of epigenetics and the focus on non-structural effects on the genome. It's beyond the scope of this post to go too heavily into epigenetics and autism, but the research forays so far have provided some interesting data on issues like DNA methylation and autism (see here) and potential knock-on effects (see here). Importantly, structural variations might not necessarily be the same, or have the same effects, as epigenetic variations although the two may work synergistically.

Second, and I hate to bang on about this, but autism or ASD does not normally appear in some sort of diagnostic vacuum. As per the Gillberg work on the ESSENCE of autism (see here) or the 'big data' studies from the likes of Kohane and colleagues (see here), not only is autism an extremely heterogeneous condition in terms of presentation, but also a condition more than likely to co-exist alongside some heightened risk of certain comorbidity. It's all well and good saying that cumulative common genetic variants raise the risk of autism but, as per other biomarker discussions, we might very well replace the word autism with something like attention-deficit hyperactivity disorder (ADHD) or epilepsy or even something more somatic along the lines of the various work looking at autoimmune conditions appearing alongside autism. In short, genetic risk might be related to other things outside of just autism or its individual traits, and as I was reminded recently: "correlation is not the same as causation" (thanks Natasa). Oh, and then there is the RDoC initiative to consider...

Finally, it is a glaring omission in quite a bit of the coverage of this paper that the 41% of risk "unaccounted for" does not receive more interest than it has. I don't want to speculate on what might be included in the array of factors involved in this category (outside of my previous chatter on possible epigenetic factors) but will again draw your attention to other work on the old genetics-environment relationship with autism in mind and the question of heritability (see here and see here). That also one media piece talking about the Gaugler study is quoted as saying: "On their own, none of these common variants will have sufficient impact to cause autism" is an important detail which implies both cumulative effects and possibly the input of some external force(s). And those effects may very well cross the nature-nuture debate in some instances as per the results from Mitchell and colleagues talked about in a previous post.

Deciphering the genetic architecture of autism is still very much a work in progress. This latest contribution to the issue is important not least for the conclusions arrived at with talk of an additive model and it's intersection with common genetic mutations present in the general population. That being said, I still want to see more from the discipline. I'd like to see a more comprehensive analysis taking into account both genetic and epigenetic factors crossing environmental contributions too. I'd also like to see more focus on smaller groups on the autism spectrum as a function of things like developmental trajectory (see here) or response to certain interventions (see here). And for those who seem to be using this work as a hammer against environment being related to cases of autism, just remember, there may be many, many routes towards a clinical diagnosis...

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[1] Gaugler T. et al. Most genetic risk for autism resides with common variation. Nature Genetics. 2014. July 20.

[2] St Pourcain B. et al. Common variation contributes to the genetic architecture of social communication traits. Mol Autism. 2013 Sep 18;4(1):34.

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Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, & Buxbaum JD (2014). Most genetic risk for autism resides with common variation. Nature genetics PMID: 25038753

Autism and asthma yet again

"Asthma is approximately 35 % more common in autistic children".

Pipe down @ Wikipedia 

That was the finding reported by Stanley Kotey and colleagues [1] based on their analysis of the 2007 National Survey of Children's Health (NSCH) dataset, a resource looking at "the physical and emotional health of children ages 0-17 years of age" resident in the United States. I don't intend to dwell too much on the Kotey findings aside from pointing out: (a) the reported prevalence of autism came in at 1.8% which is not a million miles away from the latest US estimate made by the CDC and, (b) although the unadjusted odds ratio (OR) for asthma in cases of autism was 1.35 (CI: 1.18-1.55), the adjusted OR taking into account factors such as "age, gender, body mass index, race, brain injury, secondhand smoke and socio-economic status" dropped down to 1.19... so perhaps it was more accurate to conclude that asthma is approximately 20% more common in kids with autism. Oh and that OR and relative risk might not necessarily be one and the same [2].

The NSCH is a valuable resource which provides snapshots for lots of different aspects of child health and wellbeing (see here). A quick trawl of the sections pertinent to an autism and/or asthma diagnosis (see section 2 here) reveals how information about diagnosis is arrived at. I was taken by the fact that questioning about an autism spectrum disorder (ASD) diagnosis was "applicable for ages 2-17 years only" which perhaps ties into some of the issues raised in other papers when it comes to early diagnosis.

Asthma and autism is a topic not totally unfamiliar to this blog (see here). The quite recent paper from Tsai and colleagues [3] covered in a previous post (see here) detailing how asthma might be a risk factor for autism puts the Kotey findings into some potential context albeit not necessarily with the same directional association. The paper from Chen and colleagues [4] likewise also discussed in another post (see here) also implicates comorbidity (ADHD in that case) as a potential confounding variable bearing in mind the estimated rates of ADHD in cases of autism (see here).

When it comes to the hows and whys of any relationship between asthma and autism, a rather large void starts to appear outside of any link just being due to coincidence [5]. "[The] Autism-secondhand smoke interaction was insignificant" kinda suggests that tobacco smoke filled houses and cars were probably not a primary reason for any connection. Given what is known about asthma - a chronic lung condition characterised by inflammation of the airways - one might look to something like immune function as being a commonality between the conditions especially in light of recent meta-analyses with autism in mind. A couple of years back I did a sort of focus on some of the work from Kevin Becker (see here) including his paper on the hygiene hypothesis [6] (open-access here). I'm not necessarily saying that this is the primary connector, merely that the interaction between immune functions and environment might have some role to play. I might add that all the recent chatter on air pollution and autism (see here and see here and most recently here) might also be something to look at with further assiduity. Oh, and one might also think about certain medicines as perhaps being important to this relationship too (see here).

I would close with a last sentence from Kotey et al: "screening may be an efficient approach to reduce risk of morbidity due to asthma". In other words, asthma is yet another comorbidity for which a diagnosis of autism seemingly carries no protection, and the onus is on professionals to reduce any further health inequality...

So: Ben E King and Stand By Me. "Chopper! Sic'em, boy!"

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[1] Kotey S. et al. Co-occurrence of Autism and Asthma in a Nationally-Representative Sample of Children in the United States. J Autism Dev Disord. 2014 Jul 6.

[2] Davies HT. et al. When can odds ratios mislead? BMJ. 1998 Mar 28;316(7136):989-91.

[3] Tsai PH. et al. Increased risk of autism spectrum disorder among early life asthma patients: An 8-year nationwide population-based prospective study. Research in Autism Spectrum Disorders. 2014; 8: 381-386.

[4] Chen MH. et al. Asthma and attention-deficit/hyperactivity disorder: a nationwide population-based prospective cohort study. J Child Psychol Psychiatry. 2013 Nov;54(11):1208-14.

[5] Mrozek-Budzyn D. et al. The frequency and risk factors of allergy and asthma in children with autism--case-control study. Przegl Epidemiol. 2013;67(4):675-9, 761-4.

[6] Becker KG. Autism, asthma, inflammation, and the hygiene hypothesis. Med Hypotheses. 2007;69(4):731-40.

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Kotey, S., Ertel, K., & Whitcomb, B. (2014). Co-occurrence of Autism and Asthma in a Nationally-Representative Sample of Children in the United States Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-014-2174-y