Wednesday, 29 February 2012

Gluten and casein-free diets for autism

A very quick post to bring to your attention a recently published paper which has just started to make an impact on various social media. The paper is by Pennesi and Cousino Klein* and reports on a survey of parent  responses on the efficacy of using a gluten- and casein-free diet with their children with autism. The press release accompanying the paper is here.

At the moment I don't have the full-text so can't really add more than what information is currently available and so will probably end up posting again about this paper. Yes, it is data based on an on-line survey; yes, it exclusively relies on parent - primary caregiver report and so yes it is not by any means gold-standard when it comes to methodological quality. I will perhaps apologise for the 'parent - primary caregiver' bit and the implication that somehow theirs is not an important voice. It is, and potential bias aside, certainly when you look at the history of GFCF diets and autism, it was parents who made the first observations about a possible effect, so I feel a bit of respect is due.

Perhaps carrying a degree of bias myself about such work (here), I'd like to think that there are things that can be learned from this study as there are in all studies; if only where to start channelling a little more research time and effort to further inform the science in this area.

* Pennesi CM. & Cousino  Klein L. Effectiveness of the gluten-free, casein-free diet for children diagnosed with autism spectrum disorder: Based on parental report. Nutritional Neuroscience. February 2012.
DOI: 10.1179/1476830512Y.0000000003

Tuesday, 28 February 2012

Pesticides and cognition: once bitten?

A recent interesting tweet from Prof. Keith Laws led me into this post. He posted a link to this study by Gunnell and colleagues* which conservatively suggested that approximately a third of suicides world-wide in 2002 were via pesticide ingestion. That's just over a quarter of million deaths in 1 year from pesticide self-poisoning. A very sobering statistic indeed.

An article by Starks and colleagues** looking at pesticide exposure and cognition has similarly caught my eye. I did make an initial attempt to talk about pesticides in relation to autism a while back on this blog and had promised to do some follow-up posts as a result. The post of rural vs. urban settings in relation with autism was a sort of reintroduction of the topic. This post is slightly different in that autism is not really part of the current study but rather looking at the effects of one or more high pesticide exposure events (HPEE) on cognitive abilities amongst pesticide applicators.

The basics:

  • Neurobehavioural testing was carried out on 693 private pesticide applicators (all male) not previously reporting a physician-diagnosed pesticide poisoning event.
  • Study recruits were assessed via various measures using NES3 to ascertain various CNS functions. This included tests such as: the Digit-Symbol test for visual scanning and information-processing ability, Sequences A, a test of motor speed and tracking and seven other tests.
  • Participants were also asked about whether they had ever been involved in a HPEE via a questionnaire (prior to their enrollment in the study as part of the AHS). 
  • The results indicated that about a quarter of participants reported at least one HPEE which included exposure to various -cides (herbicides, insecticides, fungicides, etc). Bearing in mind that participant numbers whilst in the 100s were not particularly large, a HPEE seemed to adversely affect scores on the Digit-Symbol and Sequence A tests. The authors were keen to point out that the overlap in what these tests looked at might suggest that these results were not just a chance finding.

Several things from this study stuck out for me. Aside from pesticide applicator perhaps being one of the less desirable jobs that I personally would like to do, the results suggested that even after one HPEE not counting as an acute poisoning event, there may very well be some lasting CNS effects. I know that this might seem unsurprising given what pesticides do and their various ways/routes of performing their job, but in a world of fallibility I wonder if this paper would make it to a potential applicators 'welcome to the job pack'?

* Gunnell D. et al. The global distribution of fatal pesticide self-poisoning: Systematic review. BMC Public Health. 2007; 7: 357.

** Starks SE. et al. High pesticide exposure events and central nervous system function among pesticide applicators in the Agricultural Health Study. International Archives of Occupational and Environmental Health. September 2011.

Sunday, 26 February 2012

N-Acetylcysteine (NAC) and autism

The recent publication of a study by Hardan and colleagues* detailing the results of a randomised, controlled trial of N-Acetylcysteine (NAC) for autism in children has caught my eye. From what I am led to believe, there were a few glimpses at what this study might have shown before its official peer-reviewed publication. I might add that I am by no means the first blogger to pick this study up (see here).

NAC is an interesting compound which has a variety of potential uses ranging from dealing with acetaminophen (paracetamol) overdose to applications based on its mucolytic action. A post last year over at Evolutionary Psychiatry had quite a nice summary of its various effects and links to potentially autism-relevant things like glutamate and also glutathione. My mind also wanders back to the sulphation issues in cases of autism which seem to have been forgotten in recent times.

I am sorry that I can't post a link to the full-text of the paper in this post, but please take my word that here is a summary of the paper in its entirety:

  • This was a double-blind, randomised, placebo-controlled trial looking at 12 weeks supplementation with NAC with children (aged 3-10 years) diagnosed with autism. Doses were tied into 4 week blocks, starting at 900mg once daily for the first 4 weeks, then twice daily up to 8 weeks and three times daily for the last 4 week block. This schedule was based on published studies of NAC in other areas of health regarding tolerance.
  • Data was acquired for 29 children (14 children on NAC and 15 on placebo) based on presented behaviour as measured using the Aberrant Behaviour Checklist (ABC), the Clinical Global Impression (CGI) scales, the Repetitive Behaviour Scale-Revised (RBS-R), and the Social Responsiveness Scale (SRS).
  • Significant effects following NAC supplementation were noted on the primary outcome measure - the ABC - and in particular, the irritability subscale. That is NAC supplemented participants showed a group improvement on this measure, particularly at 4 weeks compared with baseline, although also continuing to improve up to the week 12 endpoint.
  • Stereotypic/repetitive behaviours also saw some group improvement in the NAC supplemented arm of the trial, on both the ABC and RBS-R scales. Global clinical improvement based on the CGI for the NAC group was: n=5 much improved, n=6 minimally improved, n=2 no change and 1 child was judged much worse.
  • Only few adverse effects were noted across the groups, mostly gastrointestinal (NAC = 11/14 with GI adverse effects vs. placebo = 7/15).

The first comments to make about this study is that (a) it was a pilot trial, (b) a short-term pilot trial and (c) completing participant numbers were low. That and the fact that behavioural outcomes were the sole purpose of this paper means that outside of what was overtly noted, no other conclusions based on biochemistry can be appropriately drawn from the results. I would however temper that last statement based on the trial registration entry for this research (here) which indicates some further investigation on levels of glutathione (GSH) and related metabolites in blood might be forthcoming.

All being said and done, every research area needs to start somewhere and as far as PubMed is concerned, this seems to be the first time that NAC has put in an appearance as an intervention option for autism spectrum conditions. The authors do speculate on two main modes of action for NAC based on glutamatergic modulation and/or antioxidation. I don't really think that I can offer too much more in the way of which hypothesis might be more relevant given that there is quite 'strong' evidence for both mechanisms potentially pertaining to cases of autism. Some evidence at least.

NAC has other medicinal uses also which one cannot at the moment rule out as being relevant to at least some cases of autism. I'm thinking about this fairly recent study on NAC inhibiting certain inflammatory cytokines under 'mild oxidative' conditions which could potentially be relevant given the links posited between autism and inflammation.

An interesting pilot trial opening up another area for further investigation.

* Hardan AY. et al. A randomized controlled pilot trial of oral N-Acetylcysteine in children with autism. Biological Psychiatry. February 2012.
DOI: 10.1016/j.biopsych.2012.01.014

Thursday, 23 February 2012

Autism and migration: new clues?

Autism in the Somali population, particularly the migrating Somali population, has been the topic of some debate down the years. I think back to the 2010 study by Barnevik-Olsson and colleagues* detailing an autism prevalence in Somalis living in Sweden of 0.98% compared with 0.21% in children of non-Somali origin alongside other factors related to vitamin D for example. OK, the vitamin D link is still speculative but the migratory aspect remains an interesting association. Enter a new study into the debate from Magnusson and colleagues** detailing some population based findings relating to parental migration status and risk of autism spectrum condition.

The summary:

  • Based on an analysis of various records for the total child population of Stockholm County, Sweden (N=589,114) between 2001 and 2007, children with autism defined as high- and low-functioning were identified. I know some people don't like the terms 'high' and 'low' functioning as descriptors of autism, but in this case the authors were referring to cases where intellectual disability was or was not present.
  • A total of 4952 cases of autism were identified; 2097 cases comorbid with learning disability (42%) and 2855 cases of autism without (58%). These splits are roughly in line with other data such as that reviewed by O'Brien and Pearson***.  
  • When looking at children of migrant parents, there was an increased risk of having a child with autism and learning disability (OR = 1.5) and this risk was particularly pronounced for those migrating from countries with a low human development index and for children whose mothers migrated just before or during pregnancy (OR = 2.3).
  • When it came to risk of having a child with autism without intellectual disability, there was actually a decreased risk for migrant mothers compared to children born to indigenous mothers. Whether this was a true reflection of risk or due to the fact that immigrant families might be less likely to seek child development services is unknown.
  • These results were not explained by socio-economic, age or obstetric factors.

There are quite a few potentially important implications from this work which require comment.

Over 40% of cases of autism identified in this study were diagnoses of autism and learning disability. One of the blogs I like to follow is Harold Doherty's blog. Some of his more recent discussions have surrounded what will happen to those cases of autism and learning disability in the proposed revisions to the DSM criteria for autism. With the current figures in mind, the question has to be asked whether this kind of relationship will be picked up in any future studies if and when the new guidance is enshrined in diagnostic law.

One also needs to comment on the environmental implications from this latest study. The fact that risk of offspring with autism was elevated just before or during pregnancy implies that genes alone cannot guide this association. I say cannot guide this association but possibly they could if one was to assume that some epigenetic relationship may be evident. I think again back to the prenatal vits and SNPs study on autism from last year. So, assuming that mum is migrating from a warm, sunny environment to a cold, not so sunny (at least not with as strong a sun) environment, where the food may be different, the external environment different (including the 'chemical' environment) and the associated 'stress' that comes with moving to a different part of the world. Mmm.. seems to me that there are plenty of factors ripe for further study there.

Ultimately this is another study of population association and one has to bear in mind the limitations in terms of what information that can bring. Having said that, on top of the other immigrant studies undertaken on autism, there is a growing argument that more focused investigation might yield some interesting clues as to risk and potentially aetiology at least in some cases of autism.

* Barnevik-Olsson M. et al. Prevalence of autism in children of Somali origin living in Stockholm: brief report of an at-risk population. Developmental Medicine & Child Neurology. 2010; 52: 1167-1168

** Magnusson C. et al. Migration and autism-spectrum disorder: population-based study. British Journal of Psychiatry. February 2012.
DOI: 10.1192/bjp.bp.111.095125

*** O'Brien G. & Pearson J. Autism and learning disability. Autism. 2004; 8: 125-140.
DOI: 10.1177/1362361304042718

Flame-proofed genetically-engineered mice and autism

If you clicked on to this post expecting to see the very latest in 'superhero' mice complete with special flame-resistant powers, I'm afraid that you are going to be disappointed. If however you are interested in how genes and environment wrapped up in 'the new kid on the block discipline' of epigenetics might provide some clues about autism-like behaviours, you might just be in luck.

Not quite Mickey @Paul Whiteley
The study in question is this one by Woods and colleagues* with some interesting observations on what happens to a genetically-engineered mouse exposed to polybrominated diphenyl ethers (PBDEs). PBDEs have been covered on this blog previously with regards to autism. The net result of the work so far suggested that just about everyone is carrying some level of these POPs in them but perhaps some responses to these chemicals might be slightly altered in cases of autism for whatever reason (see here).

The latest study from Woods et al went one stage further:

  • Mice were genetically-engineered to carry a defect in the methyl-CpG-binding protein 2 gene MECP2 (Mecp2-308) similar to that seen in Rett syndrome (RTT).
  • These female mice were exposed perinatally to BDE-47, mated with male wild-type mice and their offspring examined for various developmental, behavioural and epigenetic outcomes.
  • The main results: Mecp2-308 females exposed to BDE-47 were less fertile. Their female offspring also engaged in less social interaction with familiar mice alongside some issues with learning and memory coinciding with global hypomethylation of adult brain DNA (changes to DNA methyltransferase 3a, Dnmt3a). 
  • In short: epigenetic pathways were implicated in social and cognitive outcomes.

There are a few important points to note from this research. Primary among them is the issue of whether Rett syndrome, or more specifically the mutation associated with Rett syndrome, is the same as autism in a wider context. Looking at the current ICD and DSM listings, Rett syndrome (RTT) is a condition with a few ties to autism (at least for now).

First reported by Dr Andreas Rett, an Austrian physician, RTT is now known to be a genetic condition which almost exclusively affects girls (almost exclusive). Although still the source of some investigation, diagnosis of RTT is predominantly carried out on the basis of observed features and characteristics complemented by genetic testing for mutations on the X chromosome gene MECP2 and other less common mutations. The observed behaviours associated with RTT overlap with autism and also other conditions such as cerebral palsy. At least one of the authors on the Woods paper, Prof. Janine LaSalle, has a bit of an interest in the epigenetic links between RTT and autism.

Translating results from a mouse model to real-life autism has been covered on this blog in previous posts so I'm not going to get too deeply into that argument. Suffice to say that rodent models are still finding some favour as models of autism**. I suppose the fact that female offspring of dams with mutation & exposure were the ones where most of the interesting results were found at least provides some support for the whole nature-nurture relationship observed and the focus on the X-chromosome (females = XX, males = XY).

This is an important study and certainly sets a precedent for looking at the effects of environmental factors on other genetic findings related to autism via the engineered mouse model approach. Having said that I am trying not to get too excited about such findings given the lack of consistent genetic markers for autism, the wide heterogeneity and numerous comorbidities present and the number of potential environmental factors potentially at work.

To finish, a song from Sheffield's rock-tastic royalty called animal.

* Woods R. et al. Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation. Human Molecular Genetics. February 2012.
DOI: 10.1093/hmg/dds046

** Buxbaum J. et al. Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features. Molecular Autism. Feburary 2012.
DOI: 10.1186/2040-2392-3-1

Tuesday, 21 February 2012

Allergic disease and neurodevelopment

We have contact @ Paul Whiteley
The publication of the recent 'game-changer' by Sapone and colleagues* (full-text) defining a spectrum of gluten-related disorders outside of just coeliac disease got me thinking again about allergy, its definition and relationship to lots of different things.

Allergy has been discussed previously on this blog and in particular, how the tangled mess that is allergy and intolerance might link into some cases of autism spectrum conditions. The net result of that post was to say that based on the cumulative evidence so far, classical allergy, as defined by the presence of type 1 immediate IgE hypersensitivity, is probably not going to be one of the more important mechanism in relation to autism in general. I say this acknowledging that IgE-mediated allergy is nevertheless present in cases of autism; as per the ethos on this blog, autism is seemingly not protective of other comorbidity.

Another interesting paper hit my radar recently by Meldrum and colleagues**. Interesting because it suggests that allergic disease in early infancy might correlate with certain findings in relation to neurodevelopment. I was fortunate to receive a full-text copy of the paper and there are a quite a few interesting findings to note.

The summary:

  • Four hundred and twenty term infants from mothers with confirmed allergic disease made up the initial study population as part of a larger randomised trial looking at the effects of high dose DHA-enriched fish oil supplements compared with a placebo oil.
  • A 12-month immunology assessment was undertaken consisting of skin prick testing to a range of different allergens alongside parental questionnaires and clinical assessment by a paediatric immunologist. Various operational criteria were used to determine atopic diseases such as eczema, asthma and allergic rhinoconjunctivitis.
  • An 18-month neurodevelopmental assessment was undertaken consisting of 3 schedules: (i) the Bayley Scales of Infant Toddler Development (BSID-III), (ii) the Achenbach Child Behaviour Checklist (CBCL) and (iii) the Macarthur-Bates Communicative Development Inventory (MCDI). The CBCL in particular looks for signs of various developmental conditions including ADHD and pervasive developmental issues.
  • Taking into account various confounding variables including whether fish oil supplementation might have had any bearing on results, various mixed data were available based on the tests and testing occasions. So out of 323 infants, around 40% (129/323) presented with confirmed eczema and 13% with an IgE-mediated food allergy (44/323). These rates are high because mum's allergic history deemed offspring allergy risk to be elevated.
  • When comparing those with any allergic disease vs. no allergic disease on the various neurodevelopmental measures undertaken at 18 months, composite scores of motor behaviour on the the BSID-III were negatively associated with allergic disease present at 12 months (p=0.003) remaining significant even after adjustment for confounders (p=0.016). More specifically, those with eczema showed significantly lower gross motor skill scores compared with no eczema to be present (adjusted, p=0.001). There were other interesting trends but nothing that really reached statistical significance. When it came to correlation between allergy status and the DSM-orientated scores on the CBCL, nothing turned up as significantly different although there was some link suggested between non IgE-mediated food allergies and internalising/externalising behaviours.

As per the author discussions, the key point to this work was the suggested link between allergic disease and composite motor skill scores and the possibility of a neuro-immune interaction. I know to some this might seem like a coincidental relationship given the multitude of other factors which might also show association. To others however this might make perfect sense; that the immune system and various neurological systems might actually 'talk' to, or 'modify', each other through biological mechanisms such as inflammation and even more psychological aspects such as stress. I think about the report of fever affecting the presentation of some cases of autism and the proposed association between inflammation and alexithymia (definition here) as possible examples of this complicated relationship in an area which is crying out for more study.

I finish this post with an ode to the Irish Rover and it's crew including Barney McGee, Johnny McGirr and the skipper Mick McCann (RIP poor old dog). Farewell also to Niall Quinn and the great service he has done to the city of Sunderland particularly to local children's hospital services - "Go raibh maith agat".

* Sapone A. et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Medicine. February 2012.
DOI: 10.1186/1741-7015-10-13

** Meldrum SJ. et al. Allergic disease in the first year of life is associated with differences in subsequent neurodevelopment and behaviour. Early Human Development. 2012
DOI: 10.1016/j.earlhumdev.2011.12.032

Sunday, 19 February 2012

Schizophrenia, coeliac disease and cerebral blood flow

Weather @ Paul Whiteley
Day: Sunday 19th February 2012. Weather: cold, bright. Mood: upbeat. Dear Diary, exactly a year since I began my blogging odyssey and I'm still enjoying the experience.

Speaking of the past, let's set the way-back machine a little further back to 1997. The UK swayed to the tune of 'Things can only get better' alongside a rare win at Eurovision. Bill Clinton also started his second term in office. An interesting paper also appeared by De Santis and colleagues* detailing some surprising findings in a case of comorbid schizophrenia and coeliac (celiac) disease. In some quarters, this single person study has taken on almost cult status. My opinion: it is interesting and I'll attempt to try and explain why.

I discuss this paper because despite being a case study, there are potentially some important facts which have never really been followed up with more rigorous study. I apologise that I can't link to a full-text of the paper so you will have to take my word for it or visit your nearest academic library to get a full-text copy.

The person at the centre of this report was a 33 year old woman admitted to hospital with weight loss and severe diarrhoea. She had a previous history of schizophrenia (diagnosed by DSM-III-R) progressively becoming more severe with accompanying "autistic disorder, social/occupational dysfunction, affective flattening and inferential thinking".

Upon admission, schizophrenia was again confirmed (by DSM-IV) alongside various other laboratory findings including low iron levels without anaemia. Coeliac disease (CD) was diagnosed on the basis of anti-endomysial antibodies and villous atrophy following jejunal biopsy. A brain SPECT scan -  (99mTc)HMPAO SPECT - was performed following some irregular activity in the fronto-temporal left hemisphere picked up on EEG. The scan showed an area of hypoperfusion in the left frontal cortex.

What this all basically means was that verifiable diagnostic accounts of schizophrenia and CD were picked up in this patient alongside some noticeable restriction in blood flow to a part of the brain thought to be involved in integrating various perceptual information and other executive functions.

Implementation of a gluten-free diet is reported to have quickly improved both physical and psychiatric symptoms "within a few days". Alongside expected gains in body weight, a repeat SPECT scan was undertaken after 6 months using as similar procedures as possible to the first scan to allow a reliable slice by slice analysis. The results were surprising in that there was a "complete normalization of the brain perfusion". The woman remained symptom-free and medication-free for at least a year at follow-up obviously maintaining her gluten-free diet.

The authors were obviously quite taken aback by these findings although I suspect not totally surprised by them. Inevitably discussions are filled with excerpts from the late Kurt Dohan and his ideas on schizophrenia and wheat intake as well as one of the modern day champions of research into the neurological effects of untreated CD, Dr Marios Hadjivassiliou. One phrase in particular stands out from the paper: ".. that schizophrenic symptoms may be the expression of organic disease, such as coeliac disease, rather than primary psychiatric illness".

I said that there were quite a few aspects of this study which have never really been followed up. Not being a neurologist or anything related, I don't know enough about SPECT scans as to be able to offer an informed opinion on their accuracy or not. Certainly with the advances that have been made in the intervening 15 years, I would imagine that technologies like fMRI might be slightly more descriptive in terms of the results produced. Scanning on just two occasions might also be subject to some bias.

Accepting that use of a gluten-free diet for schizophrenia, autism, ADHD or any other behaviourally-defined condition that you might care to mention is not exactly mainstream, I would be inclined to suggest that there is a study or two waiting to happen here. So, monitoring things like cerebral blood flow and related brain-based markers before and after use of a gluten-free diet alongside various behavioural indices. SPECT scans still mark the autism research landscape as per articles like this one. Indeed I am quite surprised that many more intervention studies in psychiatry don't look at things like cerebral blood flow when it comes to outcome measures, even as per models such as that described in this study on primates. Monitoring such parameters where schizophrenia and CD are comorbid or how about where autism and CD are comorbid? Too much perhaps..?

I don't want to get too carried away with this single-case report because for all we know, this might be a one in seven billion event. Having said that, every theory has to start somewhere, and at the moment, no-one appears to be producing contrary evidence to the report from De Santis et al.

To finish, more memories of 1997 courtesy of Hanson.

* De Santis. et al. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. Journal of Internal Medicine. 1997; 242: 421-423.

Thursday, 16 February 2012

Mercury, creatinine, outliers and autism

There are certain areas of the autism research landscape which have created real divisions among some professionals, scientists and people with autism and their families. One of them surrounds the relative contribution (or not) of heavy metals such as mercury to the onset and presentation of autism in some people. The theory being that environmental exposure to mercury (in whatever form) may somehow interfere with things like neuronal development and contribute to some of the symptoms seen in autism at least in some people. Quite a good overview of the whole debate is presented by Garrecht & Austin* (full-text). The obvious background support to this theory are the very real effects that have been documented as being associated with environmental mercury exposure, particularly in children. The other side of the coin is the epidemiological evidence suggestive of no overall connection between certain mercury-related exposure factors and events and the rising numbers of cases of autism.

A recent study by Barry Wright and colleagues* (full-text) contributes some more to this area of research with their findings of no overall difference in urinary mercury excretion, but (and it is a big but) a small number of outlier results perhaps warranting further research attention.

So, their study summarised:

  • From an initial participant group (N=251) comprising 54 UK children with autism, 42 of their siblings and 155 children without autism (121 going to mainstream school and 34 children attending a special school), urinary mercury levels were attained in 230 children via ICP-MS. The analysing laboratory was blind to who was who.
  • Based on analysis of mercury concentration either correcting or not correcting for creatinine (an important urinary ratio marker), no significant group differences were noted across the participants. Even allowing for age, gender and the number of amalgam fillings, there were no significant differences and including analysis of various other metals such as lead, cadmium and copper, no significant group differences were noted.
  • That being said, there were a small number of 'outliers' whose results appeared to indicate elevated levels of mercury to be present. These results appear in the autism and special school group (assuming that this group included children with other learning or developmental issues).

Depending on your viewpoint, you could interpret these results a number of ways. You could say, no overall group differences so mercury is not going to be an issue in relation to autism and is certainly not driving the increase in cases. On the other hand you could say, OK no group effect but given that autism is a heterogeneous condition driven by the phrase 'if you've met one person with autism, you've met one person with autism' the results don't preclude a small subgroup whose presentation might be tied into a factor like mercury. It all depends on your point of view. Also as per the study discussion, levels of urinary mercury is one thing, levels of mercury in blood, plasma, brain, etc. is another.

I also note another interesting detail from the study. Let me run a sentence past you: "A lower creatinine in the ASD group (not statistically significant) raises the mercury to creatinine ratio in this subgroup, but not to statistically significant levels". I was interested to read this in view of my own research interest in creatinine in relation to autism (see here). The logic goes that a lower level of urinary creatinine might artificially inflate whatever other metabolite you are looking at as per this previous post. Granted in this study, they looked at both corrected and uncorrected concentrations and found no group difference on either occasion but still the question of why creatinine levels might have been lower is an interesting one.

* Garrecht M. & Austin DW. The plausibility of a role for mercury in the etiology of autism: a cellular perspective. Toxicological & Environmental Chemistry. 2011; 93: 1251-1273
DOI:  10.1080/02772248.2011.580588

** Wright B. et al. A Comparison of Urinary Mercury between Children with Autism Spectrum Disorders and Control Children. PLoS ONE. February 2012.
DOI: 10.1371/journal.pone.0029547

Wednesday, 15 February 2012

The glutamate:glutamine ratio and autism

There they go again.

An Athenian butterfly @ Paul Whiteley
That Saudi Arabian autism research group who figured so heavily on this blog in 2011 have yet another publication out in this one by Abu Shmais and colleagues* (full-text) examining nitrogen-related parameters and autism. I'll admit that I'm a fan of this group; not only for the quantity of research that they are producing but the fact that there is clear evidence of 'blue-sky' thinking in their research material. These chaps are quietly contributing to some really interesting avenues in some cases of autism spectrum conditions, albeit at the moment based on quite small participant numbers.

Their latest offering asks a few interesting questions but before summarising some of them, I just want to run a sentence by you from the paper's introduction: "A recent epidemiological study in Saudi Arabia established the autism prevalence at 6:1000 (Talat; unpublished data, personal communication)". Bearing in mind that there are some important differences between personal communications about unpublished data and the public communication of the peer-reviewed variety, lots and lots of questions immediately start to appear in my mind about how this figure was arrived at, what criteria for autism used and if accurate, why the slight discrepancy with the [less than] 1 in 100 figure usually cited for the UK, US, Canada, etc. (or 1 in 38 if you believe the SK study last year). Answers on a postcard please addressed to...

Back to the paper:

  • The analysis of nitrogen containing compounds and their metabolism makes up the main reason for this paper so inevitably compounds such as ammonia (NH3) get a mention. More specifically how the the body harvests nitrogen from lots of different sources (including those funny amino acids which I seem to been talking a lot about recently) and consequently disposes of it. 
  • In terms of nitrogen metabolism, and concepts like the nitrogen balance, some familiar names crop up noted previously in autism research including glutamate and glutamine and how these compounds are involved in the removal of ammonia from the brain in the absence of important urea cycle enzymes.
  • Fasting blood samples were collected from 20 participants with autism and compared with 20 controls. There is a bit of typo in the methods section which states that controls were all male and in the next breath, 16 males and 4 females(!) 
  • Based on analyses looking at enzyme activity (5'-nucleotidase, adenosine deaminase and glutamate dehydrogenase), ammonia, urea, creatine, nitric oxide (NO), GABA, glutamate and glutamine - catch my breath - there were a few interesting results.
  • Mean plasma levels of creatine, glutamate and GABA were elevated in autism compared to control means. By contrast plasma glutamine levels were lower. Looking at the values and standard deviations, these differences seemed pretty pronounced particularly across the glutamate:glutamine ratio. The results coincided with significant increases in 5'-nucleotidase and a marginal mean decrease in adenosine deaminase activity (p=0.048).
  • A little bit of statistical wizardry (ROC) applied to the results suggested that the glutamate:glutamine ratio was the best measure of determining autism samples from controls based on a ratio cut-off value of 0.906. 

So what does all this tell us? Well, lots of things; some perhaps more important than others bearing in mind the small participant numbers. I'm going to focus specifically on the glutamate - glutamine findings as per the title of the post because the results are cumulatively most significant, as once again amino acid chemistry red flags are raised. I should also point out that plasma levels of glutamate and glutamine might not necessarily be the same as 'brain levels' as per the blood-brain barrier (BBB) and its amino acids transporters [note: I have a post scheduled soon on P-glycoprotein and BBB transport].

Not for the first time have elevated levels of glutamate and lower levels of glutamine been reported in autism research. The paper by Shimmura and colleagues** (open-access) found similar results in their analysis and once again pointed to the potential discriminatory power of this finding in cases of autism independent of learning disability from asymptomatic controls. Even Jim Adams and colleagues have reported similar trends (at least with regards to glutamate) on top of other group findings. As for searching the brain, well there is some evidence of issues there too at least in certain areas of the brain.

Fine, the result is pretty consistent but what does it mean?

Most commentary on glutamate reverts back to it being an excitatory neurotransmitter with reference to the hyperglutaminergic hypothesis of autism. I don't really want to go to heavily into the details of the hypothesis in this post but alongside elevated levels of glutamate, there is a corresponding decrease in activity of enzymes linked to glutamate metabolism (GAD65 & 67) and increased gliosis. Only a few days ago, a new paper*** was discussing the presence of autoantibodies to GAD65 in a subgroup of children with autism (and ADHD) which is probably not good news either.

The glutamine findings are also quite interesting. Abu Shmais and colleagues talk about how glutamine is an essential part of the process removing ammonia from the brain via processes such as glutamine synthetase. Low levels of glutamine may potentially reflect issues with this process. Outside of this however, other potential roles for glutamine need to be highlighted seemingly independent of the brain, in the liver and gut for example. The evidence for a connection between glutamine and glutathione (GSH) is also at the back of my mind bearing in mind the evidence so far on GSH in relation to autism.

A post on a sister blog discussed the issue of glutamine and its relationship to some gastrointestinal findings with its simplified role as the 'food of the gut' in terms of things like its effect on gut barrier function. It is therefore conceivable that low plasma levels of glutamine are probably not going to be particularly good for maintaining a healthy gut barrier; even outside of other confounding issues such as sulphation, etc. It might seem like a peripheral finding but more and more there is a realisation that physiology and psychology are linked as per the recent constipation - language impairment findings in autism.

So, another finding which requires large scale replication and another possible 'marker' for autism research is discussed. As time goes on, I am really starting to appreciate just how important amino acid chemistry is to lots of different functions and states outside of the classsic phenylalanine and PKU direction.

To finish something a little bit different as I ask the question: are you a man or a muppet (or perhaps neither)?


* Abu Shmais GA. et al. Mechanism of nitrogen metabolism-related parameters and enzyme activities in the pathophysiology of autism. Journal of Neurodevelopmental disorders. February 2012.
DOI: 10.1186/1866-1955-4-4

** Shimmura C. et al. Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS ONE. October 2011.
DOI: 10.1371/journal.pone.0025340

*** Rout UK. et al. Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. European Child & Adolescent Psychiatry. February 2012

---------- Abu Shmais GA, Al-Ayadhi LY, Al-Dbass AM, & El-Ansary AK (2012). Mechanism of nitrogen metabolism-related parameters and enzyme activities in the pathophysiology of autism. Journal of neurodevelopmental disorders, 4 (1) PMID: 22958401

Monday, 13 February 2012

High lactate levels reported in about 1 in 5 children with ASD

I'm quite conscious of the fact that my last post on aromatic amino acids and bacteria was quite technical and jargon-filled. I apologise to readers for this. I perhaps got a little bit carried away with an area close to my research heart. This post also deals with some complex issues; the difference being that this time I admit to being no expert on mitochondrialactate or any related metabolite in relation to autism or anything else. I will try and describe some of the research leading to the post announcement but please don't take my word as gospel.

The sentence making up the title of this post was contained as part of this paper published by Dhillon and colleagues* (full-text). The manuscript is of the review-type looking at the various research on a possible relationship between mitochondrial DNA (mtDNA) and autism spectrum conditions and the 1 in 5 figure comes from this paper by Oliveira and colleagues**.

I guess it might be useful to introduce some basic information about lactate. First, don't confuse lactate with lactose or lactase mentioned in a previous posts on issues with milk. Neither be put off by all the jargon coming up - 'keep calm and carry on' as they say. It all starts with an energy source; in this case glucose, and how energy is released/metabolised via a process called glycosis; that is the conversion of glucose to pyruvate. I use the word pyruvate (and lactate) to generally mean pyruvic acid (or lactic acid) bearing in mind the chemistry of acids and bases in physiological terms.

Pyruvate forms an essential part of the Krebs cycle which onward ties into the electron transport chain and adenosine-5'-triphosphate (ATP), the energy transporter. There is quite a good graphical description of this process here. Pyruvate is also the important compound when it comes to lactate as a result of the enzyme lactate dehydrogenase making the change between the compounds under conditions without oxygen.  There is also some involvement with the coenzyme NAD+ (and NADH) but I don't want to complicate things any further. Pyruvate also cropped up in a previous post as one of five potential serum biomarkers for schizophrenia. Suffice to say that alterations in the levels of lactate might potentially indicate some pretty important things going on.

It was perhaps this paper by Coleman and Blass*** which really started the ball rolling with regards to lactate in which they reported an overlap between a diagnosis of autism and lactic acidosis. Lactic acidosis (high lactate levels and low pH levels) can result as a consequence of many different reasons including exercise and even that most final of processes rigor mortis; much to do with an absence of oxygen. Mitochondrial dysfunction has been suggested to be one source of this lack of oxygen (or at least issues with the Kreb's cycle functioning) as per the oft-cited review article by Rossignol and Frye.

Mary Coleman was again in many respects ahead of the game with her lactic acidosis findings in relation to cases of autism. Nearly 20 years after, Pauline Filipek and colleagues looked again at the whole pyruvate-lactate relationship in their study looking at carnitine deficiency and mitochondrial dysfunction in relation to autism. To quote: "Results for pyruvate, lactate, ammonia and alanine... collectively present a consistent picture of mild mitochondrial dysfunction". Don't even get me started on related findings on the amino acid alanine.

Other studies have suggested similar elevations in lactate although not universally so. Al-Mosalem and colleagues reported an approximate 40% increase in levels of lactate in children diagnosed with autism compared to controls. A finding similarly reported by some of the author group under separate cover. Indeed with these and various other reports I might be inclined to suggest that chronic elevations in lactate levels together with some of its relations might very well be important to the biology of at least some people with autism. As to how lactate levels may or may not directly impinge on the presented behaviours of autism is still a point of speculation.

To finish, the Cardigans in celebration of Valentines Day with Lovefool. Please don't forget that special someone (noting that flowers bought from the nearest petrol station are not generally that romantic).


* Dhillon S. et al. Genetics and mitochondrial abnormalities in autism spectrum disorders: a review. Current Genomics. 2011; 12: 322-332.

** Oliveira G. et al. Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Developmental Medicine & Child Neurology. 2005; 47: 185-189

** Coleman M. & Blass JP. Autism and lactic acidosis. JADD. 1985;15: 1-8

---------- Oliveira, G., Diogo, L., Grazina, M., Garcia, P., Psych, A., Marques, C., Miguel, T., Borges, L., Vicente, A., & Oliveira, C. (2007). Mitochondrial dysfunction in autism spectrum disorders: a population-based study Developmental Medicine & Child Neurology, 47 (3), 185-189 DOI: 10.1111/j.1469-8749.2005.tb01113.x

Friday, 10 February 2012

Autism, aromatic amino acids and gut bacteria: a hypothesis

Mass-ive @ Paul Whiteley
The publication of an interesting article by T. Andrew Clayton* in FEBS Letters (full-text) with a speculative hypothesis regarding the amino acid phenylalanine, gut bacteria and autism has my full attention. A quick search for the author suggests quite an accomplished research career with a scientific publication track-record to boot particularly in the area of metabolomics and with some very distinguished company. That and mention of one Prof. Glenn Gibson in the acknowledgements leads me to believe that this chap knows what he is talking about.

This paper was always going to attract my attention because it made reference to the compound trans-indolylacryloylglycine or IAG and autism. What on earth is IAG I hear you ask? Well it's a compound, a peculiar metabolite of the amino acid tryptophan, that has surrounded the research I have been involved in for many years both from a detection and possible biological marker point of view. As it happens, the initial speculation on IAG potentially being a more general biomarker for autism has subsided as per this article and this article but that's not to say that it may not be relevant to some groups on the autism spectrum, particularly those who also present with comorbid gastrointestinal issues. Indeed there still remains the possibility that there may be some 'relationship' between IAG, gluten and the so-called leaky gut (more on this later).

The crux of the current paper is that another amino acid, phenylalanine, which shares more than a passing relationship with other aromatic amino acids particularly tryptophan and tyrosine in terms of the 'give-and-take' ability of the respective hydroxylase enzymes and the shared use of cofactors such as BH4, is influenced by certain types of gastrointestinal bacteria. This in turn might also explain some of the origins of IAG, derived from tryptophan.

I will hopefully not get too technical here but there are some important points raised in the paper which are perfectly testable in an autism research and other context.


  • The proposed model is based on two different rat urinary phenotypes distinguished by a favourite metabolomics method, NMR spectroscopy - one of the gold standards. One rat phenotype - the 'HIP' phenotype - produces rather a lot of urinary hippurate, whilst the other phenotype - the chlorogenic acid phenotype - is characterised by low levels of urinary hippurate and elevated levels of 3-(3-hydroxyphenyl)propionic acid (3-HPPA). The differences between the biochemistry of the two phenotypes is gut bacterial composition not readily attributed to factors like different diets.
  • Proposals for the bacterial agents and biochemical pathways pertinent to these rat phenotypes is given with specific focus on the origin of the benzoic acid that consequently forms the hippurate levels seen in the HIP phenotype. Words like cinnamic acid and PAL are also included.
  • Transposing the various biological reactions noted in phenylalanine and tyrosine on to tryptophan, Clayton moves through the production of IAG from tryptophan via a most interesting intermediary compound called indole-3-acrylic acid (IAA). IAA is thought to be quite a reactive molecule which subsequently conjugates with glycine to form IAG, also able to potentially do various things because of its flat planar chemical geometry. There is for example, some prior speculation that IAA may have some 'membrane-busting' potential in relation to autism as a result of its dose-dependent effect on prostaglandin (E) production, but this observation still remains preliminary. 

Acknowledging that this is a hypothesis paper and so still subject to some degree of testing, I am very curious about some of the concepts detailed. Elevated levels of 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA) have been reported in cases of autism, a compound which fits rather nicely into the whole phenylalanine-bacteria connection with particular focus on an old bacterial friend, Clostridia. This accompanied by various other related findings in cases of autism such as elevated levels of urinary 4-hydroxyhippuric acid detailed in this paper adds to the curiosity.

Speculation on some role for IAG and precursors in relation to autism and particularly some reported [non-significant] differences to levels according to use of a gluten-free diet, has again been something of interest to me for a while. Allowing for interfering variables based on urine sample concentration noted in some cases of autism, the question of why a gluten-free diet in particular, might affect urinary IAG levels has always been a puzzle. Does a gluten-free diet affect gut bacterial composition? Likely, according to this paper. Does the gluten-free diet affect gut permeability? Yes it probably does to some extent and the de Magistris results seem to back that up in cases of autism. Could gut bacteria contribute to gut permeability either directly or peripherally through the formation of IAG or related mechanisms? Mmm... I dunno.

There is a lot to take in with this recent paper and even after a few reads I still find myself not fully understanding all of the chemistry. Nevertheless an important connection has been posited between our gut bacterial masters and their potential effect on important aspects of our biochemistry. I would like to think that I will post further about some of the implications of this hypothesis as more research starts to move into this area.

To end, an oldie but goodie which was the soundtrack to a favourite film of mine. Cue Richard Dreyfuss.. "I never had friends later on like the ones I had when I was 12...".

* Clayton TA. Metabolic differences underlying two distinct rat urinary phenotypes, a putative role for gut microbial metabolism of phenylalanine and a possible connection to autism. FEBS Letters. February 2012.
DOI: 10.1016/j.febslet.2012.01.04

Thursday, 9 February 2012


There is always a degree of trepidation when submitting a research article or letter to a journal or professional periodical. You spend weeks, sometimes months, getting your article just right (or so you think), formulating a persuasive cover letter to the Editor and checking and re-checking that all your text and  figures are complete, labelled and set in the right font and type. Then off it goes and the waiting begins. 

I don't mind admitting that I have probably had more negative replies than positive ones over my research career with regards to paper submissions. I am probably setting myself up for a fall in saying that as the shouts of 'your research is c**p' begin to resonate. The usual reply to such rejection is to stop feeling sorry for yourself (which normally lasts about a day), follow-up the peer reviewer comments as best you can, and look for another home for the manuscript and start the whole process again.

So it was recently with a short piece I submitted to The Psychologist, the monthly publication of the British Psychological Society (BPS). The manuscript in question was a short review titled 'The psychology of the gut'. It was an attempt to summarise a few areas which seem to crop up quite a lot of this blog with regards to how our gastrointestinal tract (gut) might not necessarily just have a 'digesting food' role and bring it to a wider psychology-related audience. With articles like this recent one from a Psychologist on autism, I do wonder if we perhaps need to update a few people.

To be fair, the psychology/gut submission was always a bit of a long shot for consideration for publication; something discussed with the Editor who was very nice about the whole thing (and no, I'm not just saying that to score Brownie points). There was an option to shorten the piece to a letter for further submission, but I don't think that is for me when there is so much to discuss. So instead I'm going to do something else, and reproduce the article as a link for this post. I know, I know, (i) 'where is the peer-review', and (ii) 'this is a blog not a professional publication'. My answer: so what.

By writing this piece, I am not turning my back on peer-review and scientific publication; not by any means. But in this day and age when the Internet is power and social media gives everyone a voice, why can't my voice be heard also?

Tuesday, 7 February 2012

Bone health, casein-free diet and autism

The Handy Man can @ Paul Whiteley
Bones, aside from being the nickname of the good Doctor McCoy (whose name has been mentioned in a Lancet article very recently), have already featured on this blog and here we are again with a rather long entry it has to be said.

Of all the studies so far done which have included some element of autism and the gluten- and casein-free diet, one has stuck in my mind in particular. The study in question was by Hediger and colleagues* and looked at bone cortical thickness in boys with an autism spectrum condition. They reported that bone thickness seemed to be reduced in cases of autism compared to reference values and this reduction was particularly marked for those on a casein-free diet.

Casein-free diet = removal of mammalian dairy produce from the diet = important source of calcium.

As someone who has put quite a bit of time into looking at the potential efficacy (and safety) of restriction diets for some cases of autism, these were quite worrying results given the potential long-term implications of following a casein-free diet and balancing potential gains in behavioural outcomes with potential losses to long-term physical health.

At the time I remember talking to quite a few people in the know about autism, calcium and bone health and where this could all eventually lead. Some said that the study whilst interesting needed a lot more follow-up in terms of participant numbers, suitable control groups (rather than reliance on population reference ranges), looking at bone mineral density not just thickness and the various other factors the authors themselves listed as potential confounders such as the presence of gastrointestinal (GI) disorders, vitamin D levels and limited physical activity. Others said that outside of a known food allergy, this study was evidence that dietary changes should not be made for people with autism and to close the book.

A few subsequent papers have attracted my attention since. This paper by Mouridsen and colleagues** reports on the numbers of fractures reported in autism compared with not-autism. I apologise that I am only able to provide the paper abstract (having myself taken advantage of the Springer open-access window last year to get the full-text). The authors specifically set out to look at fractures on the basis of the Hediger findings, looking at adults diagnosed with autism as children (n=118) compared to matched controls (n=336) to see if the risk of fractures was higher in autism potentially as a result of the low bone thickness described. The results were interesting in that the autism group actually presented with a lower level of fracture than the comparison group (11.9% vs. 24.7%). There were some differences in the positioning of fractures between the groups where participants with autism were at greater likelihood of fracturing their forearm than controls (5.9% vs. 3.2%) but less likely to fracture their hand or wrist (2.5% vs. 8.0% p=0.05). This last result on the hand and wrist was particularly relevant to the Hediger findings given that they relied on measurements from the "second metacarpal on the hand-wrist radiographs" (one of the bones linking your finger to your hand).

Whilst it was slightly comforting to read these results, Mouridsen et al make some interesting comments about other factors potentially affecting their results including the more protective environment that participants with autism were likely to live in, less alcohol abuse, lower rates of sporting activities and tool use, etc. They also point out that recording hospital visits because of fracture might not necessarily mean fewer fractures; other less severe fractures might have occurred but not been known about or recorded. My mind also wanders back to issues like pain perception and autism which in some people has been suggested to be slightly different.

A second paper by Mary Hediger and colleagues (open-access)*** also caught my eye. Interestingly Hediger et al were following up one of their confounding variables, a role for vitamin D, to potentially account for some of their earlier results. The results were mixed. On the one hand , no significant group differences were noted in circulating vitamin D levels as reported through plasma levels of 25(OH)D between children with autism (on and off a casein-free diet) and a comparison group. On the other hand, 54/89 (61%) of the total children involved in the study were vitamin D deficient (below the AAP 20ng/ml threshold). Whether or not the fact that control participants were having tonsillectomies at the time of sampling affected the results, I don't know but there does seem to be some suggestion that recurrent tonsillitis might be linked to lower vitamin D levels anyway.

Whilst not wishing to belittle the original findings from Hediger and colleagues on bone thickness and a potential effect from a casein-free diet, I do wonder if more authoritative work is required in this area before too many conclusions are drawn. To some extent this paper by Goodarzi and Hemayattalab**** has tried to cover the calcium / physical activity aspects but there still remains much to do. Not so long ago I discussed vitamin D and gut barrier integrity and the various inferences that "could" be made from this research. Intestinal conditions such as coeliac (celiac) disease have long been linked to bone health including some interesting data on bone thickness. More recently studies have suggested bone health can be [positively] affected by use of a gluten-free diet in cases of coeliac disease.  I'm not necessarily saying that these same conditions are relevant to autism but certainly one does wonder about those cases where bowel issues and hyperpermeability of the gut have been reported as comorbid.

Now.. if I said the word Chumbawumba would you perhaps partake in a bit of tub-thumping with me?

* Hediger M. et al. Reduced bone cortical thickness in boys with autism or autism spectrum disorder. JADD. 38: 2008

** Mouridsen SE. et al. Fractures in individuals with and without a history of infantile autism. A Danish register study based on hospital discharge diagnoses. JADD. 2011

*** Molloy C. et al. Plasma 25(OH)D concentration in children with autism spectrum disorder. Dev Med Child Neurol. 52: 2010

**** Goodarzi M. & Hemayattalab R. Bone mineral density accrual in students with autismspectrum disorders: Effects of calcium intake and physical training. Res Autism Spectrum Disorders. November 2011.

Sunday, 5 February 2012

Plasma neurokinin A and autism

Peptides, those short-ish chains of amino acids, have featured quite a bit down the years in autism research circles. Notwithstanding speculations on the opioid-excess hypothesis as to why a gluten- and casein-free diet seems to have some effect on the symptoms of some people with autism, peptides also hold/held some interest in other areas of the autism research landscape. I talk about peptides such as the ever-so cuddly oxytocin and secretin for example.

Enter another peptide, neurokinin A, into the field and an interesting report published in December 2011 by Mostafa and AL-Ayadhi* (full-text). Before getting into the nitty-gritty of the content and possible meaning, it is interesting to note that this is the same team who quite extensively published on autism last year (2011) and in particular, those quite peculiar findings in relation to low levels of progranulin.

Aside from being a peptide, a neuropeptide, neurokinin A has an interesting role in the mechanism of inflammation, as part of their family trade (the tachykinins). It is with this in mind, that the authors set out to study this peptide and turned up some interesting results:

  • Serum levels of neurokinin A and anti-ribosomal P protein antibodies were measured for 70 children diagnosed with an autism spectrum condition and 48 age- and sex-matched asymptomatic controls. I can't really offer a very intellectually satisfying account of what anti-ribosomal P protein antibodies are, aside from the fact that they have been noted in autoimmune conditions such as systemic lupus erythematosus (SLE) and elevated titers (levels of antibodies) have been noted during lupus psychosis
  • As a group, participants with autism showed significantly higher levels of serum neurokinin A than controls. Based on CARS criteria, specifying autism presentation as mild/moderate or severe, participants with a more severe autistic presentation presented with much greater group levels of neurokinin A than those judged mild/moderate. 
  • Anti-ribosomal P protein antibodies were present in around 40% of participants with autism although I can't find anything in the paper which provides comparative data on control participants. The authors also suggest that there was a significant correlation between levels of neurokinin A and anti-ribosomal P protein antibodies (r=0.34, p=0.004). Not being one to quibble, the data does look rather messy from my angle (see figure 2) and r=0.34 is not, it has to be said, that good a value of correlation given that CARS and neurokinin A levels correlated by r=0.62 [r=1 = perfect correlation].

On the basis of their presented data, I would tend to suggest that the neurokinin A findings are probably the more exciting results included in this paper and certainly provide some interesting fodder for further study. Non-neuronal cell production of the tachykinins seems to be a focus of the paper and an interesting suggestion that exposure events to various environmental factors (food, pollutants, etc) might trigger the production of neurokinin A from immune-related cells.

Another interesting perspective to all this is the role of neurokinin A (and other tachykinins such as substance P) on airway disease such as asthma. No data is provided in the current paper on the rates of respiratory symptoms in their patient group (breathlessness, wheeze, coughing) aside from exclusion of participants with 'allergic, inflammatory or autoimmune disorders' or those 'receiving any medications' so we can only speculate on any connection. Certainly my previous posts on asthma and autism and airways and autism perhaps direct some attention to a possible connection between elevated neurokinin A and cases where respiratory comorbidity might be present, the other side of which may need to look at whether neurokinin A levels correlates with autism severity correlates with airway symptoms?

To end, a little classic Smiths.. what a charming man.

* Mostafa GA. & AL-Ayadhi LY. The possible link between the elevated serum levels of neurokinin A and anti-ribosomal P protein antibodies in children with autism. Journal of Neuroinflammation. December 2011.
DOI:  10.1186/1742-2094-8-180

Thursday, 2 February 2012

The geography of autism: urban or rural?

A short sentence in the abstract to a paper by Kiani and colleagues* caught my attention recently. The paper reported on the distribution of autism spectrum and other conditions in the UK according to defined designations of geographical location. In other words, whether there were any differences in reported rates according to whether people were living in a rural or an urban area. The authors suggested that among their sample (N=2713), autism spectrum disorders in particular, were more common in people living in rural areas.

I was interested in this work for several reasons. Quite a few years ago an undergraduate psychology student - 'Big bad BB' (you know who you are) - came and did some work with us involving pin-mapping where people with autism and related conditions resided on a large map of the UK. I need to track down the results which were published as conference proceedings to check but I faintly remember some interesting 'trends' emerging from this data not entirely dissimilar from the current paper.

Of course there could be lots of reasons to account for the reported results. Socio-economic status, where people work, or just a wish for a bit of quiet and tranquillity are a few factors. Those of you who regularly read this and my other blog might also pick up a bit of interest in the 'chemical world' around us, and in particular the various descriptions of exposure patterns and relative risk of lots of things. Suffice to say that when I think about rural areas and countryside, apart from rolling hills and cows and sheep chewing the cud, I unfortunately also tend to think 'pesticides'.

I'm not on this occasion going to get too alarmist based on the findings of the current paper. Trawling back through the research archives, the data is fairly mixed when it comes to asking the question 'where do you live' with regards to autism. This paper based on Taiwanese data suggested that residing in rural parts was actually less likely to get you an autism diagnosis than being an urban dweller but there again, rural Taiwan might not be the same as rural England or rural elsewhere. Data from Western nations do point to 'urbanisation' as being a potential contributory factor in the increasing numbers being diagnosed with autism. Remember freeways (motorways in England) and autism? Bear also in mind that (a) where you currently live is not necessarily the same as where were you born or where your parents lived before you were born and (b) very few people tend to live in city centres, at least here in the UK; more often than not you get a doughnut effect in terms of residence being outside of a hollow built-up city centre.

That all being said I'm not ready to discount the current results as an artifact or fluke just yet. The study by Roberts and colleagues** published a few years back which suggested that pregnant women living close to sprayed fields had a six-fold increase in later offspring diagnosis of autism comes to mind. Having done a little bit of reading on the persistence and potential effects of things like pesticides, it is perhaps unwise to rule out any 'environmental' factor in relation to autism, at least some cases of autism, just yet. Certainly here in the UK, the potential health implications of pesticide exposure seems to still be on the research menu as per this study description by Galea and colleagues***. We await their findings.

[Update 15/02/12: Found the pin-mapping data we undertook. A poster presentation 'UK Autism Demographics' Budd, B. 2000: Autism: perspectives on progress. University of Durham. pp.207-214. Yes, proportionally more people with autism living in rural areas based on analysis of 784 people with autism in the UK (1996-2000)].

* Kiani R. et al. Urban–rural differences in the nature and prevalence of mental ill-health in adults with intellectual disabilities. Journal of Intellectual Disability Research. February 2012.
DOI: 10.1111/j.1365-2788.2011.01523.x

** Robert E. et al. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environmental Health Perspectives. 2007; 115: 1482-1489.
DOI: 10.1289/ehp.10168

*** Galea KS. et al. Biological monitoring of pesticide exposures in residents living near agricultural land. BMC Public Health. November 2011.
DOI: 10.1186/1471-2458-11-856