Friday, 1 August 2014

Restricted and repetitive behaviours disappeared? More optimal outcome and autism

Today I'm bringing to your attention the paper by Eva Troyb and colleagues [1] and the quite dramatic assertion: "Reports of current behavior indicated that RRB's [restricted and repetitive behaviors] had almost totally disappeared in the OO [optimal outcomes] group". RRBs just in case you might not know include quite an array of behaviours, some of which might not be considered 'disabling' such as the presence of certain circumscribed interests. Others, such as an insistence of sameness and the presence of often rigid routines, can have a rather more profound effect on quality of life.
Where's my hat? @ Wikipedia 

For those who might not know, optimal outcome in relation to cases of autism spectrum disorder (ASD) refers to the idea that for some (emphasis on some) diagnosed as being on the autism spectrum, the label of autism or ASD is not as immutable as was once thought. The latest Troyb paper adds to a growing body of literature in this area coincidentally talked about in this piece appearing recently in the New York Times.

I've covered this emerging area of work for some time on this blog and so present a brief history so far...

  • beginning with the concept of differing developmental trajectories being present across the very heterogeneous autism spectrum (see here),
  • then there was the publication of the paper by Deborah Fein and colleagues [2] first discussing optimal outcome and autism (see here),
  • further research on the nature of optimal outcome followed and how it might impact on some of the psychology associated with autism (see here),
  • optimal outcome, by any other name, was described by other independent research groups (see here),
  • and then focus shifted to a possible role for intervention as being associated with optimal outcome (see here).

I might add that whilst I have indicated the Fein paper was the first to describe optimal outcome in respect of ASD, there have been some rumblings down the ages in the autism research peer-reviewed literature about remission of core symptoms. Take for example the paper by Gajzago & Prior [3] from 1974 reporting on 2 children "thought to be classical cases of Kanner syndrome" who went on to be "functioning adequately both intellectually and socially and are progressing normally at local schools". Mention of the word 'recovery' in the title of that paper, sandwiched in between quotation marks, hints at how delicate a subject symptom remission was even in those times.

I will, as I always seem to do on this topic, reiterate that when talking about optimal outcome and autism we are not talking about some universal concept occurring across the entire autism spectrum. For the majority of those diagnosed as being on the autism spectrum, their strengths and difficulties are a lifelong feature albeit fluctuating and changing/adapting as a consequence of factors like maturation, the presence of comorbidity and the environment they find themselves in. The group which do seem to fit into the concept of optimal outcome however, represent an important part of that autism spectrum insofar as increasing our knowledge about just how heterogeneous a condition autism really is [4] and how, far from being a singular condition, autism is perhaps better reflected in the description of the more plural autisms (see here). 

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[1] Troyb E. et al. Restricted and Repetitive Behaviors in Individuals with a History of ASDs Who Have Achieved Optimal Outcomes. J Autism Dev Disord. 2014 Jul 17. [Epub ahead of print]

[2] Fein D. et al. Optimal outcome in individuals with a history of autism. J Child Psychol Psychiatry. 2013 Feb;54(2):195-205.

[3] Gajzago C & Prior M. Two Cases of "Recovery" in Kanner Syndrome. Arch Gen Psychiatry. 1974;31(2):264-268.

[4] Kohane IS. An Autism Case History to Review the Systematic Analysis of Large-Scale Data to Refine the Diagnosis and Treatment of Neuropsychiatric Disorders. Biol Psychiatry. 2014 Jun 12. pii: S0006-3223(14)00422-3. 

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ResearchBlogging.org Troyb E, Orinstein A, Tyson K, Eigsti IM, Naigles L, & Fein D (2014). Restricted and Repetitive Behaviors in Individuals with a History of ASDs Who Have Achieved Optimal Outcomes. Journal of autism and developmental disorders PMID: 25030967

Thursday, 31 July 2014

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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ResearchBlogging.org 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

Wednesday, 30 July 2014

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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ResearchBlogging.org 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

Tuesday, 29 July 2014

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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ResearchBlogging.org 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

Monday, 28 July 2014

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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ResearchBlogging.org 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

Friday, 25 July 2014

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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ResearchBlogging.org 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

Thursday, 24 July 2014

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...


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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ResearchBlogging.org 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