Impulsivity and uric acid

A few years back I posted about an interesting body of research on purine metabolism in relation to the autism spectrum disorders (ASDs) and how some work from the likes of Mary Coleman and Ted Page had reported high levels of uric acid to be coincidentally present in cases of ASD.

The gout @ Wikipedia  

As with other research angles, the initial interest in this finding of hyperuricosuria - elevated urinary uric acid - and autism did not seem to last. Just like the dusty research doll that is sulphation (sulfation) and autism, uric acid came to find itself under the autism research bed listening to the tune of 'when somebody loved me'. Sulphation, I might add with autism in mind, has started to see something of a renaissance recently but only a small one (see here).

Enter then an intriguing paper by Angelina Sutin and colleagues* reporting on an association between elevated levels of uric acid and impulsivity as a trait in both human and mice. As per another recent paper which was discussed on this blog on ADHD and solar intensity, the publishing journal was Biological Psychiatry which is fast becoming a real favourite journal of mine. Reading through Dr Sutin's profile page it is interesting to note that she has some interest in how personality might be associated with physical and mental health. Her latest paper therefore continues this interesting theme.

A few details from the Sutin paper are in order:

• This was a study drawing on both human and mouse model data to ascertain whether the findings of elevated uric acid in behavioural and psychiatric conditions "characterized by high impulsivity" might actually be specifically related to the impulsivity trait.
• Human participants (N=6883) derived from two cohorts - SardiNIA and the Baltimore Longitudinal Study of Aging - completed the Revised NEO Personality Inventory which aims to characterise the Big Five personality traits (openness, conscientiousness, extraversion, agreeableness, neuroticism) via self-report.
• They also provided fasting blood samples which were screened for uric acid both at time of schedule completion and at follow-up (some 3-5 years later).
• A second study was also reported looking at the behaviour of mice "urate oxidase null" = bred to show elevations in uric acid, compared with wild-type controls. 
• Results: lots of them, but a few of the more interesting findings included (i) impulsiveness and excitement seeking individuals were more likely to have higher levels of uric acid (albeit mediated by factors such as BMI and smoking which themselves pose some interesting questions), and (ii) "homozygous urate oxidase-deficient mice" (high uric acid) showed a lot more exploratory and "emotional" behaviour. 
• In short, the two experiments reported "supports the hypothesis that impulsivity is associated with higher levels of uric acid".
• Another quote from the paper sums up where this kind of research could potentially lead: "The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention".

Very interesting stuff I'm sure you'll agree. Indeed the participant numbers for the human part of the study are certainly impressive and indeed across the two geographically distinct cohorts too, even more impressive.

But with my science-hat on, lets take a step back and point out some important limitations of this work. First and foremost is the assumption that the personality trait impulsivity measured by only one personality inventory is the only potential correlate here, at least among the human participants. It isn't. And indeed one should always be mindful that just because investigators test for something like a personality trait or a specific cognitive skill or even a specific condition/state/disease does not mean they have excluded all other potentially important variables** (indeed if this is even possible). Next is the assumption that self-report responses on a five-point Likert scale are going to be true and honest. No-one can be totally assured of that, particularly if responses are to some of the more less desirable personality traits that we would all like to put to one side. Finally is the interpretation of a mouse model of high uric acid showing the impulsivity trait based on their novelty-seeking and exploratory behaviours during field tests. I've talked mouse models before with autism in mind and how behavioural animal models are always subject to some degree of interpretation until such time that we can talk to the animals (and they talk back).

Having said all that I do find myself still very interested in the Sutin findings in terms of how the work was done, the results obtained and where it could lead. Without giving anything that looks or sounds like medical or clinical advice, one has to wonder (as the authors have done) whether 'adjusting' levels of uric acid might have a knock-on effect on certain behaviours particularly where uric acid might be seen in more behaviourally or psychiatrically defined conditions. I'm not saying everyone should be taking something like allopurinol or anything like that but perhaps further investigation is at least warranted.

Finally, on a similar note to the Sutin study I also recently came across a study by Soto-Insuga and colleagues*** which reported some very preliminary findings from treating iron deficiency in cases of attention-deficit hyperactivity disorder (ADHD). To quote: "Treatment with iron supplements can be an effective alternative to treat patients with ADHD and iron deficiency, especially the inattentive subtype". By 'treatment' I take it to mean that not only were the authors resolving the iron deficiency but also in specific cases of ADHD identified by that inattentive subtype**** they were talking about the management of behavioural symptoms too.

Example evidence that the psychosomatic or somatopsychological relationship should definitely remain near the top of the research agenda?

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* Sutin AR. et al. Impulsivity is associated with uric acid: evidence from humans and mice. Biol Psychiatry. April 2013.

** Cerecero P. et al. Association between serum uric acid levels and cardiovascular risk among university workers from the State of Mexico: a nested case--control study. BMC Public Health 2013; 13: 415.

*** Soto-Insuga V. et al. Role of iron in the treatment of attention deficit-hyperactivity disorder. An Pediatr (Barc). April 2013.

**** Solanto MV. The predominantly inattentive subtype of attention-deficit/hyperactivity disorder. CNS Spectr. 2000; 5: 45-51.

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Sutin AR, Cutler RG, Camandola S, Uda M, Feldman NH, Cucca F, Zonderman AB, Mattson MP, Ferrucci L, Schlessinger D, & Terracciano A (2013). Impulsivity is Associated with Uric Acid: Evidence from Humans and Mice. Biological psychiatry PMID: 23582268

More on urinary metabolomics in autism research

The -omics. Y'know all those new-fangled disciplines which have sprung up to describe how sciences look at genes, bacteria, etc. We used to call it plain old scientific analysis, but now depending on what your sample medium or technology or your target species is, its been rebranded and repackaged as an -omic.

Shepherdess @ Wikipedia  

I've talked about a few of the -omics quite a bit on this blog and their relationship to systems biology; ranging from microbiomics (studying bacteria) to epigenomics (chemical modifications of the genome) to metallomics (metals affecting cellular functions). I've even invented a new -omic: psychobacteriomics.

Indeed in my other life I'm currently helping out on an article talking about one of the 'next big' -omic things: lipidomics. I'm just waiting for the science of Paulomics to emerge and discover just what makes me tick.

Anyhow, the reason for the -omics chatter is due to my stumbling across an interesting couple of papers from Patrick Emond and colleagues* and by the same authorship group, Sylvie Marcel and colleagues** and their description of findings based on the science of metabolomics. Aside from the metabolomics link (which ties into some of my own research interest or at least that of the people I work with) I was always going to be interested in these papers because of some of the authorship group on the papers and their work on a favourite autism assessment schedule of mine***.

So, metabolomics - think low molecular weight metabolites and where we look for them (blood, saliva, urine, CSF) - and how there may be good reason for looking at group differences and similarities across different peoples and different conditions. I might point out that this is not the first time urinary metabolomics - the sample medium described - has been discussed on this blog as per the Ming findings and Yap findings with autism in mind. I want to also direct you to the Yang findings on the appliance of metabolomics to schizophrenia which were really rather interesting and are still crying out for independent replication.

The Emond paper briefly:

• The tools of the trade were gas chromatography - mass spectrometry (GC-MS), which were applied to urine samples received from 26 children diagnosed with an autism spectrum disorder (ASD) and compared with 24 asymptomatic controls.
• Analysis of the samples was followed by some nifty statistics to help identify any potential discriminating metabolites between the groups and bingo, a few compounds of interest were reported on.
• Results: "The relative concentrations of the succinate and glycolate were higher" in the autism group. 
• But, "hippurate, 3-hydroxyphenylacetate, vanillylhydracrylate, 3-hydroxyhippurate, 4-hydroxyphenyl-2-hydroxyacetate, 1H-indole-3-acetate, phosphate, palmitate, stearate, and 3-methyladipate were lower" in the autism group.

The Mavel paper also:

• A slightly different analytical technique based on nuclear magnetic resonance spectroscopy (NMR) applied to urine samples from 30 children with ASD and 28 controls. Indeed quite a specific type of NMR was done (Heteronuclear Single Quantum Coherence, HSQC) which aids in metabolite identification. I'm not sure if the participant groups from this paper overlapped with that of the Emond paper or not.
• Similar statistics and modelling to that in the GC-MS paper were used on the data obtained and differentiation data were presented across the groups.
• Results: findings for a few compounds intersected those reported in the Emond paper (i.e. succinate reported to be present in higher quantities alongside β-alanine, glycine and taurine). Other compounds were reported as being lower: "creatine and 3-methylhistidine concentrations were lower in autistic children than in controls".
• More than that however were the details of the methodology used, and how 2D HSQC NMR might be applied to further larger studies in the autism research field. 

As a bit of a cop-out, I'm not going to go through each compound with a fine-toothed comb. OK, perhaps a little more explanation of some of those metabolites might be in order and in particular the role that gut bacteria may very well have had on them.

Hippurate for example, is an interesting metabolite given its proposed links to all things gut bacterial. Indeed I note on that very interesting paper by Andrew Clayton on gut bacteria and the aromatic amino acids potentially with autism in mind, hippurate and its precursor benzoic acid were mentioned in one of the rat models discussed. That the autism group seemed to show generally lower levels of hippuric acid (hippurate) might potentially imply some involvement of the amino acid glycine (which conjugates with benzoic acid) although I am of course, just speculating. That being said, the glycine finding in the Mavel paper (being higher) might suggest that there is more going on here.

I'll also just mention that the higher levels of urinary taurine were also noted in the Yap paper**** too. Oh and some wondering about whether lower urinary creatine levels might also be tied into the lower urinary creatinine levels that we reported on a few years back (paper is here in case your interested).

I note that in the Emond paper, the authors talk quite a bit about how you treat the urine samples prior to analysis might affect what results you get. Again, it's not something that I really want to get into. Indeed just before you completely switch off, although I know a little bit about sample prep when it comes to things like SPE, I freely admit that the process of oximation (for derivatisation) is a different language for me. I will however say that basing results of ion mass with only one (sometimes no) decimal place, is a short-coming as compared to the power of accurate mass via Time-of-Flight (ToF) spectrometry for example when it comes to authoritative compound assignment, but that's not a criticism.

I am genuinely intrigued over the potential of the -omics when it comes to conditions like autism (sorry, the autisms). The two French papers are another step into that brave new world bearing in mind that chromatographic methods***** also need to be allied with strong detection technology****** (open-access). Assuming science can also start to sort out some of those phenotypes which make up the autism spectrum, this area of work promises so much in terms of insights into pathology and the development of objective diagnostic markers.

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* Emond P. et al. GC-MS-based urine metabolic profiling of autism spectrum disorders. Anal Bioanal Chem. April 2013.

** Mavel S. et al. 1H–13C NMR-based urine metabolic profiling in autism spectrum disorders. Talanta. 2013; 114: 95-102.

*** Barthélémy C. et al. Validation of the Revised Behavior Summarized Evaluation Scale. J Autism Dev Disord. 1997; 27: 139-53.

**** Yap IK. et al. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010; 9: 2996-3004.

***** Zurawicz E. et al. Chromatographic methods in the study of autism. Biomed Chromatogr. April 2013.

****** Wood AG. et al. Mass spectrometry as a tool for studying autism spectrum disorder. Journal of Molecular Psychiatry 2013; 1: 6.

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Emond P, Mavel S, Aïdoud N, Nadal-Desbarats L, Montigny F, Bonnet-Brilhault F, Barthélémy C, Merten M, Sarda P, Laumonnier F, Vourc'h P, Blasco H, & Andres CR (2013). GC-MS-based urine metabolic profiling of autism spectrum disorders. Analytical and bioanalytical chemistry PMID: 23571465



Mavel, S., Nadal-Desbarats, L., Blasco, H., Bonnet-Brilhault, F., Barthélémy, C., Montigny, F., Sarda, P., Laumonnier, F., Vourc′h, P., Andres, C., & Emond, P. (2013). 1H–13C NMR-based urine metabolic profiling in autism spectrum disorders Talanta, 114, 95-102 DOI: 10.1016/j.talanta.2013.03.064

Big data for autism and the promise of newborn bloodspots

An episode of the BBC program Horizon on 'Big Data' recently caught my attention. The content was a fascinating insight into how we are living in a data-rich age and how trawling/mining/dredging such data has the ability to advance medicine, predict crime and even make someone a few quid/dollars/euros on the stock market.

Gone (data) fishing @ Wikipedia  

I'm a big believer in big data. In particular how, with the right sources, technology, techniques and people, big data might be able to open up some real insights into many important areas including mental health research* and very possibly autism research with a specific focus on the science of biomarkers to aid things like early diagnosis. Indeed, I'm not the only one talking about this (see here).

I've spoken before on this blog about biomarkers for autism and other conditions - the promises, the problems, the future - and how alongside the various autism research banks (genes, brains, etc.) and systems biology chatter, we are just starting to understand the value of those big data resources such as the archived bloodspot samples which so many neonates provide these days.

Indeed with the greatest appreciation for pioneers like Robert Guthrie, I offer a post on an interesting paper by Gerald Mizejewski and colleagues** discussing results suggestive of potential candidate biomarkers for autism based on archived bloodspot samples. I should point out that this is not the first time that Dr Mizejewski has talked about the feasability of biomarkers for autism as per this article*** (open-access) as part of quite a distinguished research career it has to be said (see here) with a specific focus on an interesting molecule called alpha-fetoprotein****.

The most recent paper is unfortunately not at the time of writing open-access, so I'll just go through a few summary points about the work:

• This was a retrospective study based on that tantalising resource of archived bloodspot cards which sit in many a hospital basement. Out of a total case group of 200 families with a child with autism, 40 families with children aged between 3-5 years old were initially contacted for participation. This was eventually whittled down to 16 participants (all diagnosed with autism by the same clinician with the same diagnostic manual) for whom archived neonatal bloodspot cards were available. 
• Two age-matched control specimens located immediately before and after the dried bloodspot card in question in the filing system were also chosen.
• A small 3mm punch of the Guthrie cards was analysed by immunoassay which in this case, probed for 90 potential biomarkers covering everything from neurotrophins to cytokines, immunoglobulins to more direct inflammatory markers (including C-reactive protein).
• Some fancy statistical modelling was applied to the obtained results - including Bayesian information criterion (BIC) - which eventually resulted in three models of best-fit based on findings from the bloodspots of those who went to be diagnosed with an autism spectrum disorder (ASD). 
• The 'best model' of five compounds included some familiar names to this blog: glutathione-S-transferase (GST), IL-7, IL-5, TNF-beta and something called Lp(a) (lipoprotein a). Most were increased in quantity in the autism samples aside from GST which was decreased.
• There is a very nice illustration in the paper (Figure 3) showing how the potential connections between the biomarkers identified and some of the more biomedical themes of autism research might fit. So we have methionine metabolism mentioned (see here and here), oxidative stress (see here), gastrointestinal comorbidity (see here) and immune activation (see here) to name a few. It's all very systems biology.
• The authors caution that their results are preliminary and that although said biomarkers were modelled as being related to autism they "have not been confirmed to be causative with autism".

Before I get too carried away with this research, there are a few issues worth mentioning. Yes, the sample size was small in this preliminary communication and indeed very little information is provided about participants outside of just them fulfilling the DSM-IV criteria for autism in terms of things like comorbidity. Also why out of 200 families such a small number of participants were eventually included for study.

Indeed there is also an assumption from this study that a biomarker for autism is present in the neonatal phase which for example, might not take into account the issue of behavioural regression that seems to cover quite a percentage of cases.

Whilst the identified best-fit biomarkers are of potentially real interest to autism research as per other similar studies (see here), it is the method and resources used in this paper which is the real 'big data' story allied to all those lovely -omics which reign supreme these days. Parents in many countries will be acquainted with that bloodspot taken during the earliest days of infancy to test for various inborn errors of metabolism such as phenylketonuria (PKU). Many people don't however give a second thought to what happens to those bloodspot cards, and how valuable a resource they might constitute. Although not usually in the business of crystal-ball gazing, I would hazard a guess that we are one day going to hear big news about the big data from those archived bloodspot cards; if not with autism in mind, then something else.

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* Ayers JW. et al. Seasonality in seeking mental health information on Google. Am JPrev Med. April  2013.

** Mizejewski GJ. et al. Newborn screening for autism: in search of candidate biomarkers. Biomark Med. 2013; 7: 247-260.

*** Mizejewski GJ. Biomarker testing for suspected autism spectrum disorder in early childhood: is such testing now feasible? Biomark Med. 2012; 6: 503-506.

**** Mizejewski GJ. Biological roles of alpha-fetoprotein during pregnancy and perinatal development. Exp Biol Med (Maywood). 2004; 229: 439-463.

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Mizejewski GJ, Lindau-Shepard B, & Pass KA (2013). Newborn screening for autism: in search of candidate biomarkers. Biomarkers in medicine, 7 (2), 247-60 PMID: 23547820

Autism, plasma cytokines and siblings

I'm gonna try and be fairly brief in this post on the paper by Valerio Napolioni and colleagues* (open-access) looking at plasma cytokine profiles in cases of autism and their asymptomatic siblings. Brief because (a) the paper is open-access and (b) the participant groups (autism: n=25; sibling controls n=25) were relatively small so one has to be quite careful in extrapolating the findings with any large degree of confidence.

Siblings by Paul Klee @ WikiPaintings  

Just in case you are new to cytokines, we are talking biological signalling and communication, and in particular, the language of inflammation both pro- and anti-inflammatory (see this post).

With the autism spectrum conditions in mind, research into cytokines has filled quite a few peer-reviewed papers** from lots of different perspectives (see here and here for example). The main message so far is that it is complicated as per everything about autism and immune function.

Despite the quite small participant group, the Napolioni paper does seem to be an important paper for a few reasons:

• They report no overall difference in cytokine profiles - measuring 40 cytokines - between cases of autism and their asymptomatic siblings. This despite the fact that autism symptoms and total IQ measures were different. That was the paper's headline.
• But.... "the cytokine/chemokine levels in our subjects did correlate with the quantitative clinical traits"  or in other words, certain analysed parameters seemed to match with level of severity of autistic traits as measured by schedules such as VABS and SRS. "IL-1β appears to be the cytokine most involved in the quantitative traits".
• When looking at the children with autism according to various clinical subgroups - non-verbal, functional gastrointestinal (GI) issues, history of regression, history of allergies - a few correlations were noted. So, children who were non-verbal seemed to show higher levels of cytokines such as IL-10, one of the more anti-inflammatory cytokines. Children with accompanying GI issues seemed to show higher levels of more pro-inflammatory cytokines like IL-1β and IL-6 compared with those without GI problems. Reported regression as part and parcel of symptom onset also seemed to show some correlation with specific cytokines too.

As the authors point out correlation does not imply causation. Such that just because they reported connections between cytokines and functioning and other factors does not necessarily mean that these observations are causative of autism (or anything else). That being said, as I hinted before, this is not the first time that cytokines and their connection to immune function have been discussed in the autism research literature (see yet another example of this here***); many correlations in similar directions makes for some interesting discussions at least.

That headline that children with autism and their siblings did not significantly differ in their cytokine profile carries a few possibilities for interpretation. The authors suggest that this could be evidence of "an ‘autism endophenotype’ that expands immune dysfunction to family members who are seemingly unaffected by the core symptoms of autism". One might also say the same thing about the Gondalia paper**** on gut bacteria in cases of autism and siblings (see here).

Assuming that the broader autism phenotype (BAP) does not come into play here, one might speculate that (a) cytokine profiles are not related to the presence of autism, or (b) that the manifestation of autism, some autism, is representative of cytokine involvement but in addition to other factors in terms of the affected sibling - "when an environmental stress (for example, prenatal exposure to environmental toxins, viral and bacterial infections, parental microchimerism, etc.) occurs during development". This last point takes me back to that 1971 John Money study on the appearance of familial autoimmune related conditions 'round about' the presence of autism and a similar correlation. Part of a predisposition to autism?

I note from Figure 4 of the paper, that when it came to summarising the various associations across the groups (and sub-groups), quite a few of the very significant differences seemed to be due to differences in IQ, which was tested using the Stanford-Binet Intelligence Scales (fifth edition). Aside from previous messages of caution on the use of this measure in autism research*****, one has to wonder whether this might be a more pertinent variable when it comes to cytokines and autism. I don't know enough about cytokine profiles in intellectual disability in children for example, to make any novel claims about this, but certainly intellectual development has been mentioned in the research literature with certain cytokines in mind******.

OK I said I would try and be brief with this post and have failed miserably. The Napolioni paper has though been worth it though for the potential insights that it might provide into the complex world of cytokines and immune function in relation to the presentation of autism.

To close, and following yet more 'we'll win it next year' commentary with regards to the UK entry in the event that is the Eurovision Song Content, might I suggest a group for your serious consideration as a contender next year?

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* Napolioni V. et al. Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder. Journal of Neuroinflammation 2013; 10: 38.

** Goines PE. & Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment. Neurotoxicol Teratol. 2013; 36: 67-81.

*** Ricci S. et al. Altered cytokine and BDNF levels in autism spectrum disorder. Neurotox Res. April 2013.

**** Gondalia SV. et al. Molecular characterisation of gastrointestinal microbiota of children with autism (with and without gastrointestinal dysfunction) and their neurotypical siblings. Autism Research. 2012; 5: 419-427.

***** Coolican J. et al. Brief report: data on the Stanford-Binet Intelligence Scales (5th ed.) in children with autism spectrum disorder. J Autism Dev Disord. 2008; 38: 190-197.

****** von Ehrenstein OS. et al. Child intellectual development in relation to cytokine levels in umbilical cord blood. Am J Epidemiol. 2012; 175: 1191-1199. 

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Napolioni V, Ober-Reynolds B, Szelinger S, Corneveaux JJ, Pawlowski T, Ober-Reynolds S, Kirwan J, Persico AM, Melmed RD, Craig DW, Smith CJ, & Huentelman MJ (2013). Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder. Journal of neuroinflammation, 10 PMID: 23497090

Darth DSM-5 and autism

Blue Harvest @ Wikipedia @ Family Guy

I need to create a suitable atmosphere for this post, so try this music for size and think Blue Harvest...

Right. The wait is over. The discussions / arguments / objections / agreements are all confined to history. Drum roll, spotlight centre-stage... enter DSM-5 and into unknown territory we all go, particularly with autism, sorry.. autism spectrum disorders (ASDs) in mind.

As you can see from the link above to the new diagnostic guidelines from the American Psychiatric Association (APA) the diagnosis of autism has, as was widely anticipated, changed somewhat to encompass quite a few adaptations (see this previous post).

I'm not saying too much more on this at the present time, bearing in mind 'spectrum' is a word which seems to get more of a mention in this revision of the DSM; and not just with autism in mind (see here and here*).

Obviously things aren't going to just change overnight with DSM-5 as it is eventally rolled out. Clinicians will need to learn some new diagnostic brushstrokes. Remember too that DSM is only one part of the diagnostic manuals currently in use (although even ICD is subject to revision in coming years already mentioning something called Social Reciprocity Disorder?). That being said, the implications of DSM-5 on issues like the autism numbers game - same as what happened across previous versions - are probably going to be subject to some pretty intense scrutiny over the coming years.

Don't also be under any disillusion that the new changes are going to herald any giant leaps forward in autism research anytime soon. Interestingly, Dr Tom Insel, head of the US National Institute of Mental Health (NIMH) was recently quoted as saying that "NIMH will be re-orienting its research away from DSM categories", reported also by other authors** (open-access). In other words, even with the fresh smell of new DSM in the air, a new 'nosology' is already planned.

To close, Peter 'Han Solo' Griffin on TIE fighters... dan-dan-da-dan, da-da-dan-dan-dan...

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* Adam D. Mental health: on the spectrum. Nature. 2013; 496: 416-418.

** Lai M-C. et al. Subgrouping the autism “spectrum": reflections on DSM-5. PLoS Biol. 2013; 11: e1001544.

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Lai M-C, Lombardo MV, Chakrabarti B, & Baron-Cohen S (2013). Subgrouping the Autism “Spectrum": Reflections on DSM-5 PLoS Biology

Meta-analysing MTHFR and autism

I told you so.

I'm talking about the paper by Pu and colleagues* who meta-analysed the currently available literature looking at two SNPs in everyone's favourite Scrabble classic gene, MTHFR in relation to autism spectrum disorders (ASDs). Said gene controls production of methylenetetrahydrofolate reductase (MTHFR) which fits very snugly into the whole one carbon metabolism cycle (see here).

Love at first sight? @ Wikipedia  

Regular readers might know that I have a bit of a thing for MTHFR with autism in mind. And how MTHFR serves an important purpose in reducing the compound 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and onward its links to homocysteine (see here) and methionine (see here) and all that methylation palava.

For a good summary (well, at least I think so) you might also want to have a look at this older post detailing the process, complete with hand-drawn diagram by yours truly.

In essence, Pu et al reiterated the important role than the MTHFR C677T SNP might have to some cases of autism; in particular how "the C677T polymorphism was found to be associated with ASD only in children from countries without [folic acid] food fortification" denoting the potentially important link with the vitamin of the hour, folate (folic acid, vitamin B9) (see here).

There's little more for me to add to this post that hasn't already been said. MTHFR is probably not going to be an issue for everyone with autism, and indeed might also be potentially important to other conditions outside of the autism spectrum (see here for a discussion of that recent schizophrenia paper). Mmm... perhaps another part of that common ground and potential RDoC variable?

The nutrition link is perhaps something which adds to the view that environment might be a modifier of risk of some ASDs bearing also in mind the overlap with things like vitamin B12 (see here). That being said I'm also going to draw your attention back to all that folate receptor autoantibody stuff too just to bear in mind.

I told you so.

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* Pu D. et al. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism Res. May 2013.

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Pu D, Shen Y, & Wu J (2013). Association between MTHFR Gene Polymorphisms and the Risk of Autism Spectrum Disorders: A Meta-Analysis. Autism research : official journal of the International Society for Autism Research PMID: 23653228

RDoC and the cross-roads of psychiatry

The Irish poet Brendan Behan is, I think, credited with the phrase: "There's no bad publicity except an obituary". One wonders how appropriate this phrase might be to the 'diagnostic Bible' (except that it isn't) which is DSM-V which is poised to make its entrance into the World in the coming days.

The real Homer @ Wikipedia 

Indeed, the story of DSM-V even before it hits the diagnostic shelves of all good psychiatric bookshops, has the makings of an epic piece of poetry or literature, or at least a Storify tale. Drama, intrigue and divisions reminiscent of Good and Evil (I'll let you decide who has taken which role) are all included.

The various debates on the details of the psychiatric diagnoses contained in DSM-5 have seemingly unearthed smouldering questions about the way mental health is classified, and whether such classifications are helpful for those at the receiving end of such diagnoses, the social-medical world and indeed the wider research universe.

Two papers recently published under the heading of 'Current controversies in psychiatry' (understatement of the year) by the BioMedCentral journal series add fuel to the diagnostic debate fire. Ian Hickie and colleagues* (open-access) provide an interesting commentary on clinical classifications in mental health, and how reverse translation "that is, working back from the clinic to the laboratory" might be a direction to think about. Bruce Cuthbert and Tom Insel** (open-access) bring forward the concept album that is RDoC (Research Domain Criteria) and its potential "to transform the approach to the nosology of mental disorders". Their notion of the seven pillars of RDoC harks back to the writings of one T.E. Lawrence.

Both opinion papers acknowledge that the psychiatric labelling systems we have at the moment are not perfect and reflect the feeling of common ground across various diagnostic labels.

I've followed a fair bit of the DSM-V development discussions with autism, sorry the autisms, in mind and how it has morphed into the larger question of how useful labels and tick-box criteria are to the real world. Speaking within the confines of the proposed categorisation of autism spectrum disorder (ASD) it strikes me that much of the debate boils down to the lack of progress made in isolating the biological factors which define conditions like autism. Yes, heterogeneity and maturation have played their part in cloaking autism from biological definition, but despite the seemingly very close relationship between one or two of the gold-standard autism assessment instruments and the new revisions proposed to DSM, one doesn't get the sense that autism will be revealing its definitive biological footprint anytime soon.

Although not a novel idea, I have often wondered whether some simple changes to the way that research is carried out in autism circles might yet yield some knowledge gains. So for example, moving away from autism as a diagnosis as being the primary variable; instead focusing on those all important endophenotypes and their discriminating factors. I've talked about work from the MIND Institute as one example of this direction, but there are others too (yep, branched chain amino acids). Intervention, or rather response to intervention is another possible discriminating factor. Y'know best responders vs. non-responders vs. worst responders to the myriad of interventions out there for conditions like autism. Obviously the question then is: how do you categorise responder status?

Anyhow, I can't see anything happening too quickly despite all this talk about rethinking nosology given that DSM-IV was with us for 19 years. That's not however to say that changes might not already be afoot...

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* Hickie IB. et al. Clinical classification in mental health at the cross-roads: which direction next? BMC Medicine 2013; 11: 125.

** Cuthbert BN. & Insel T. Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Medicine 2013; 11: 126.

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Ian B Hickie1, Jan Scott, Daniel F Hermens, Elizabeth M Scott, Sharon L Naismith, Adam J Guastella, Nick Glozier, & Patrick D McGorry (2013). Clinical classification in mental health at the cross-roads: which direction next? BMC Medicine, 11

An interesting case report on autism and diet

Nodding syndrome.

Ever heard of it? Well, up until a few days ago I hadn't. That is before coming across articles on the topic by Richard Idro and colleagues* (open-access) and Angelina Kakooza-Mwesige and colleagues** (open-access). Whilst not specifically my line of expertise or interest, I was intrigued to read about how nodding and other symptoms of the epileptic variety, at least in some cases, seemed to be precipitated by food and showed a potential nutritional angle.

Curving spacetime @ Wikipedia  

Granted, the hows and whys of nodding syndrome are still a mystery, but the first thought that went through my mind was whether any specific types of food(s) might be implicated. Y'know in a similar vein to Marios Hadjivassiliou and the notion of gluten ataxia*** for example? Just speculating...

With all that talk of food and behaviour in mind there are a few things that piqued my attention towards the paper by Herbert & Buckley**** seemingly part of a string of articles looking at the topic of dietary intervention published in the Journal of Child Neurology. The first thing was the title of the paper: "Autism and Dietary Therapy" simply because I have some research interest in this area. Perhaps I might have mentioned it before...

Next was the authorship list, focused on at least one of the authors, Dr Martha Herbert (no disrespect intended to Dr Buckley). Alongside an already distinguished career in autism research, Dr Herbert is also making some waves with her new book: 'The Autism Revolution' co-authored with Karen Weintraub who wrote that very interesting Nature article on autism prevalence a few years back.

Finally, a sentence from the paper abstract: "Over the course of several years following her initial diagnosis, the child’s Childhood Autism Rating Scale score decreased from 49 to 17, representing a change from severe autism to nonautistic, and her intelligence quotient increased 70 points".

Such a dramatic description of change in presentation might once have been received with a very, very sceptical eye. Indeed I assume that still might be the case in some quarters. The publication of the Deborah Fein study (see here and here) on optimal outcome in relation to autism in conjunction with the rising tide of research looking at the potential benefits of early intervention for cases of autism, have perhaps made such observations slightly more 'acceptable', at least to some elements of the autism research community. Indeed I was also very taken by the recent BBC interview of Kristine and Jacob Barnet which discussed similar changes to symptom presentation in a young man now tipped for some absolutely amazing things. The fact that said changes detailed in the Herbert & Buckley paper seemed to occur at the same time that a "gluten-free casein-free ketogenic diet" was being followed is... interesting.

Now round about this time, some people might be thinking what does this study actually show? A case study of a girl / young woman with autism where comorbid epilepsy was controlled both by anti-seizure medication and a ketogenic diet (yes, such a diet has been linked to the control of cases of epilepsy). Said dietary intervention originating in the gluten- and casein-free (GFCF) dietary domain. As time went on, seizures dissipated and over time her clinical scores on the CARS reduced indicative of quite a change in her autism presentation.

One of course might say, a single case study, it means very little in the grand methodological scheme of things. That is unless you think back to the mantra 'if you've met one person with autism, you've met one person with autism' highlighting the power of the N=1 where autism is concerned (see here). That and the interesting viewpoint expressed by people like Gary Mesibov on the issue of evidence-based medicine when applied to a extremely heterogeneous condition like autism, sorry the autisms.

I am interested in the coincidental factors reported in this paper. I have questions: did the (almost) resolution of the epileptic symptoms carry any influence on the presentation of autism? In particular, I'm thinking back to that very interesting piece of research which suggested one particular type of autism (and epilepsy) might be related to a metabolic issue with the branched-chain amino acids (see here). Is this a potential model for that epilepsy-autism relationship for some people on the spectrum? What about the "resolution of morbid obesity" also reported; could this similarly have had any effect on symptom presentation?

I have questions about the role of the diet adopted in this case. A ketogenic diet, as well as finding some value in cases of epilepsy or seizure disorders, has also been looked at with autistic behaviours in mind. Yep, at least one trial***** albeit preliminary, suggested that this might be an option for some people on the spectrum bearing in mind I'm not making any recommendations. Down the years I've also heard anecdotal reports about how the GFCF diet might have aided in the reduction/amelioration of certain signs and symptoms linked to autism. The paper by Stephen Genuis (see this post) is one example. Just before you say something along the lines of 'there is no methodologically sound experimental evidence for dietary effect'; well, yes and no (see here) accepting the need for much more rigorous experimental study and that the evidence is not all one-way (see here).

If anyone has alternative explanations for the change in symptoms outside of just healthier eating, any placebo effect or just the research attention paid to the participant in question, please feel free to post them in the comments section. That being said, no mumbo-jumbo please like I've being reading today which has been roundly answered by psychiatry. Going back to the Fein study and the promise of more details to come, I'll be interested to see whether they report any of their optimal outcomers were following such a dietary intervention alongside other interventions.

And finally... one of the main points I take from the Herbert & Buckley paper is how it underscores the need for (a) a greater, more controlled look at the potential efficacy of dietary intervention - in whatever form - in relation to cases of autism, including the important categorisation of 'best' and 'non' responders, and (b) mechanisms... how on earth could removal of specific foodstuffs affect the presentation of autism? Leaky gut? Changes to the various populations of our bacterial masters? Allergy or intolerance similar to that noticed in cases of schizophrenia for example? I've talked about some of these potential options in a previous paper (see here******) if you're at all interested. (Sorry about the blatant self-promotion).

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* Idro R. et al. Nodding syndrome in Ugandan children—clinical features, brain imaging and complications: a case series. BMJ Open 2013; 3: e002540.

** Kakooza-Mwesige A. et al. Nodding Syndrome in Ugandan Children and Adolescents: Menage A Trios of Epilepsy, Autism, and Pediatric Catatonia. Autism 2012; 2: e112.

*** Hadjivassiliou M. & Grünewald R. The neurology of gluten sensitivity: science vs. conviction. Practical Neurology. 2004; 4: 124–126.

**** Herbert MR. & Buckley JA. Autism and dietary therapy. J Child Neurol. May 2013.

***** Evangeliou A. et al. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol. 2003; 18: 113-118.

****** Whiteley P. et al. How could a gluten- and casein-free diet ameliorate symptoms associated with autism spectrum conditions? Autism Insights 2010; 2: 39-53.

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Herbert, M., & Buckley, J. (2013). Autism and Dietary Therapy: Case Report and Review of the Literature Journal of Child Neurology DOI: 10.1177/0883073813488668

Depression or antidepressant use linked to C.diff infection?

"There's no mystical energy field that controls my destiny". So said a very sceptical Han Solo.

Regular readers might know that I'm a bit of fan of the whole gut-brain axis; indeed other kinds of axes too. I know that to some it might sound a bit daft that what goes on in our deepest, darkest bowels might actually have some important effects on the operations of the grey-pinkish matter floating around in skull central - and vice-versa -  but nonetheless it interests me. The gastrointestinal (GI) tract is not quite the mystical energy field that Captain Solo was referring to, but make no mistake, we are still very much in the infancy of looking at the connection between the two systems*.

Black dog @ Wikipedia  

I've tended to discuss/speculate on the gut-brain relationship with regards to cases of autism spectrum disorder (ASD) on this blog. In this post I'm branching out to look at the paper by Mary Rogers and colleagues** (open-access) on a potentially new dimension to the gut-brain conversation with depression and Clostridium difficile infection in mind.

The Rogers paper is open-access and has also attracted some media attention as a result (see here and here for the press release). The long-and-short of it was that based on two studies - a sort of scientific BOGOF - looking at the rates of C.diff infection (CDI) in participants with and without depression and the potential effects of antidepressant medication use and hospital-acquired CDI, some interesting correlations were noted. Note that word 'correlations'...

Primary among the findings was the suggestion that the chances of CDI were higher in those presenting with depression: "After adjusting for demographic characteristics, comorbidities and frequency of medical visits, there was a 36% increase in the odds of developing CDI for individuals with major depression compared with those without major depression" (CI: 1-06-1.74, p=0.016). Indeed when it came to the label of "emotional, nervous or psychiatric problems", the CDI risk was found to be even higher (OR: 1.47). Certainly some interesting data, made all the more credible by the fact that the total sample size numbered in the thousands.

When it came to medication use, there were some equally interesting associations (not) made. So for example, laboratory confirmed CDI (via stool testing) seemed not to correlate with the majority of medicines participants were also taking at the time of testing. The exceptions were mirtazapine (OR: 2.14) and fluoxetine (OR: 1.92) which were individually associated with an approximate doubling of CDI risk and also carrying some dose-related associations.

Authors also reported that polypharmacy - if I can use that word with less than 5 meds being taken - might also impact on CDI risk, as per the "significant interaction between mirtazapine and trazodone" where "the odds of a positive C. difficile test were 5.72 times greater" bearing in mind the small participant numbers who were prescribed these two drugs combined. As per the press on this paper: "People who have been prescribed these types of anti-depressants need to keep taking them unless otherwise advised by their physician"; a viewpoint that I can only echo at this stage.

You can perhaps see why I might be interested in this line of research. There is of course the chicken-and-egg question about which came first: microbial changes which place a person at greater risk of CDI and perhaps depression, or depression leading to changes to the gut microbiota and onwards elevated CDI risk. I'm not going to speculate too much on what came first because I dare say the clinical picture is going to be much more complicated than such a simple question. I've talked before about the possibility of a bi-directional relationship between gut bacteria and behaviour (at least in mice) and my viewpoint has changed very little in the intervening years. Bear also in mind that the hows and whys of depression (in all its forms) are likely to be numerous; perhaps even related to our earliest years****

It's interesting that the authors discuss quite a few important overlapping pieces of research in their summary of their findings related to things like the presence of bowel disease in cases of depression*** and that magical word 'inflammation'*****. To quote: "It is possible that there is a lifelong liaison between the gut microbiota and neurologic response to external stimuli" which certainly does seem to link in with at least some of the current research literature.

Alongside the tentative associations made by Rogers et al on the issue of depression and CDI, I find my mind wandering back to the question of whether such an association might be something which could be translated into therapeutic options. Y'know whether treating the CDI actually had any quantifiable impact on the presentation of depression or vice-versa. Indeed whether one of the more unusual methods suggested to help combat CDI - yep, the fecal transplant - might also impact on depression via changes to the gut microbiota as per the very preliminary reports from other conditions such as chronic fatigue syndrome (CFS)? That and possibility that gut bacteria might, just might, be in cahoots with other more barrier-related issues******, makes for some interesting suggestions for further scientific inquiry*******.

To end, y'know I prefer Constantiople over Istanbul....

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* Collins SM. & Bercik P. Gut microbiota: intestinal bacteria influence brain activity in healthy humans. Nature Reviews Gastroenterology and Hepatology. May 2013.

**  Rogers MAM. et al. Depression, antidepressant medications, and risk of Clostridium difficile
infection. BMC Medicine 2013; 11: 121.

*** Graff LA. et al. Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management. Inflamm Bowel Dis. 2009; 15: 1105-1118.

**** Parboosing R. et al. Gestational influenza and bipolar disorder in adult offspring. JAMA Psychiatry. May 2013.

***** Vogelzangs N. et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry. 2012; 2: e79.

****** Maes M. et al. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord. 2012; 141: 55-62.

******* Hughes PA. et al. Immune activation in irritable bowel syndrome: can neuroimmune interactions explain symptoms? Am J Gastroenterol. May 2013

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Rogers, M., Greene, M., Young, V., Saint, S., Langa, K., Kao, J., & Aronoff, D. (2013). Depression, antidepressant medications, and risk of Clostridium difficile infection BMC Medicine, 11 (1) DOI: 10.1186/1741-7015-11-121

Does melatonin affect leaky gut? Relevance to autism

Shocker alert: medicines might have more effects than those listed on the patient information leaflet.

I like being surprised. I particularly like being surprised about medicines and health, and how many of the medicines which even reside in the typical household medicines cabinet* might carry the potential to do so much more than that listed on the package insert.

 Leaking? @ Wikipedia  

Take for example the recent paper I bumped into by Sommansson and colleagues** continuing their scientific journey through the potential gastrointestinal effects of melatonin***. Melatonin - as many people with a connection to the autism spectrum disorders (ASD) or more generally neurodevelopmental disorders**** might know - is almost becoming the treatment of choice for issues with sleep disturbance*****. That's not to say it's for everyone, and also not necessarily the only potential option bearing in mind my caveat about not giving medical or any other advice.

I've talked about melatonin with autism in mind quite a few times on this blog (see here for example). Not only because the source material for melatonin (in the body) is tryptophan, one of those truly remarkable aromatic amino acids, but also because outside of the traditional sleep-wake link, melatonin might be quite the molecular 'handyman'****** (or handywoman). Indeed it is with the ethos of that last study by Boga and colleagues in mind that I head into the two Sommansson reports.

The first thing to note about the the Sommansson reports is that they are both studies on rats. I know that in recent times, there has been some chatter about using rodents to model conditions like autism (see here) focused in particular on the dangermouse that is the BTBR mouse model. In the current studies, the variable of rodent behaviour is not relevant given that the authors were looking at the physiological data pertaining to intestinal permeability (leaky gut) with melatonin as the primary variable.

Ah yes, intestinal permeability aka leaky gut. The same leaky gut that a recent NHS Choices entry described as being expounded by "largely nutritionists and practitioners of complementary and alternative medicine". Just for the record I am neither of those two occupational options but I am a believer in the concept in relation to quite a few conditions. And you can perhaps understand why I'm so interested in the Sommansson reports whereby leaky gut - or gut hyperpermeability - seems to be positively affected (i.e. reduced) by the introduction of melatonin, at least in rats. Indeed how this might fall into line with other observations of leaky gut being defined in cases of ASD (see here) and very possibly in a mouse model of autism (see here). A part of the effect of melatonin administration in cases of autism?

I'm not by the way falling hook, line and sinker for the author's observations that "melatonin reduces ethanol- and wine-induced increases in duodenal paracellular permeability partly via enteric neural pathways involving nicotinic receptors" being the same conditions as that found in cases of autism or any other condition. As far as I am aware children with autism are not knocking back copious amounts of alcohol, so one has to be careful about extrapolating such specific conclusions to the population with such tentative data. That and the fact that we currently know so little about gut barrier issues in cases of autism; assuming that people like this chap (yes, you Alessio Fasano with your zonulin et al) might shed some light on it in the near future. Oh and should I also mention the suggested link******* between melatonin being a modifier of toll-like receptor signalling too?

But... if anything the Sommansson papers might lead us to ask some pertinent questions about responses to melatonin both in general and also with autism in mind. A simple-ish experiment: two groups, randomised to melatonin or placebo, looking at the traditional responses to melatonin in terms of sleep and quality of sleep, at the same time some before and after measures of the lactulose:mannitol ratio and whether there is any correlation between supplementation, response and gut permeability. All fairly noninvasive by all accounts but if you really wanted to go to town you might also want to look at other measures like glutathione for example******** which has also found a spot in autism research.

But don't listen to my ramblings... listen instead to the these guys who are still going strong.

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* Berk M. et al. Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Medicine 2013; 11: 74.

** Sommansson A. et al. Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo. Am J Physiol Gastrointest Liver Physiol. May 2013.

*** Sommansson A. et al. Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivo. J Pineal Res. 2013; 54: 282-291.

**** Gringras P. et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. BMJ. 2012; 345: e6664.

***** Malow BA. et al. A practice pathway for the identification, evaluation, and management of insomnia in children and adolescents with autism spectrum disorders. Pediatrics. 2012; 130: S106-S124.

****** Boga JA. et al. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Rev Med Virol. 2012; 22: 323-338.

******* Kang JW. et al. Melatonin protects liver against ischemia and reperfusion injury through inhibition of toll-like receptor signaling pathway. J Pineal Res. 2011; 50: 403-411.

******** Swiderska-Kołacz G. et al. The effect of melatonin on glutathione and glutathione transferase and glutathione peroxidase activities in the mouse liver and kidney in vivo. Neuro Endocrinol Lett. 2006 ; 27: 365-368.

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Sommansson A, Wan Saudi WS, Nylander O, & Sjöblom M (2013). Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo. American journal of physiology. Gastrointestinal and liver physiology PMID: 23639810