Friday 27 December 2013

2013 autism research review on Questioning Answers

So, we're here again.

The end of another year and time to look back on some of the highlights of the blogging year that was 2013 on Questioning Answers. The question is: are we any further forward when it comes to the autism spectrum, it's aetiology, nature and improving quality of life?
Penshaw monument @ Paul Whiteley 

I'm going to be optimistic this year and say yes in some respects we are. But there is still much further to go...

Month by month here's a few posts on research that I thought were pretty important.

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January
Well it all started with a bang. Deborah Fein and colleagues published their optimal outcomes paper detailing how in a well-defined group of children with a previous diagnosis of autism, their autistic symptoms had abated. As you can imagine, the notion that at least some autism might not be as immutable as was first thought caused quite a stir (see here) but the evidence is starting to pile up for at least one developmental trajectory fitting this optimal outcome grouping. Further evidence for a correlation between air pollution and autism was also published. And I was also involved in publishing a review paper on the use of gluten- and casein-free (GFCF) diets for autism (see here) which is a topic I'll be coming back to later in this post.

February
Functional gastrointestinal (GI) problems do seem to be over-represented in cases of autism according to the study by Susie Chandler and colleagues. I know that this is not necessarily new news but from a UK perspective, the source of the message was an important part of this paper, which also applies to later research talked about in December. This month also saw the start of a whole slew of papers in 2013 suggestive of an increased risk of offspring autism where certain antiepileptics were used during the nine months that made us (see here). Maternal autoantibodies to foetal brain tissue also registered on the research radar which again, I'll be coming back to. Personally, I was saddened to hear about the death of Prof. Ann-Mari Knivsberg who was there from the start when it came to the whole GFCF diet and autism research. Rest in peace Ann-Mari.

March
Common ground was a key message from the consortium looking at the genetic overlap between conditions like autism, ADHD, schizophrenia and the like. In many respects that conclusion set the tone for many debates on clinical nosology vs. real-life presentation which were aired during 2013. Parent-reported autism prevalence figures in the United States suggested that 1 in 50 children presented with an autism spectrum disorder (ASD) in 2011-2012. Transgenerational effects were put forward as another variable influencing autism risk as per the paper by Emma Frans (see here). And that most contentious of topics, bowel disorders and autism, received some welcome attention from Stephen Walker (see here).

April
Autism or the autisms? was a questioned posed by Andrew Whitehouse continuing the theme of real-life autism and all that heterogeneity that accompanies presentation. Many authors have seemingly begun to realise that whilst common symptoms unite under the diagnostic label of autism, the cause and path of those symptoms may very well be numerous. The paper by Chloe Wong and colleagues looking at the methylome and autism continued the rise and rise of epigenetic research in relation to those autisms. The question of a connection between Lyme disease and autism also came under the research spotlight, as did the folding placenta (see here) and some interesting speculations on gut bacteria (see here) though not necessarily portrayed accurately in the accompanying media.

May
IMFAR 2013 was held in the beautiful Basque Country. One talk in particular seemed to capture those changing perspectives about autism (sorry, the autisms) as the world was introduced to ESSENCE (see here) by Prof Gillberg. May also saw one of the most significant changes to autism for many years as the latest update to DSM - the DSM-V - came into being, and with it a reshape of how we come to define the condition. Alongside, we were introduced to RDoC (see here) and the diagnostic vs. research battle commenced. Whilst slightly outside of core autism, but nevertheless potentially relevant as comorbidity, Mary Rogers and colleagues talked about depression and its correlation with C.diff infection.

June
Flaming June certainly lived up to its name this year here in the UK. The prevalence of autism in Canada took up two posts in June (see here and here). I was particularly interested to read the paper by Lau and colleagues on immune reactivity to gluten in cases of autism (see here). The implication from their results of a non-coeliac gluten sensitivity as potentially being present in cases set the tone for further interesting work in this area in the following months. Indeed continuing that dietary strand, the study by David Ruskin and colleagues describing the results of a ketogenic diet on a mouse model of autism also provided some rather informative reading.

July
The gold-standard trial by Cheryl Claiman and colleagues looking at the use of tetrahydrobiopterin (sapropterin or BH4) for cases of autism reported some rather interesting results in terms of a positive impact on presented autism traits. I'm becoming quite interested in what BH4 might be able to do for some cases of autism building on its potential for the archetypal 'diet can affect behaviour' condition that is Phenylketonuria (PKU). Gut bacteria also emerged again as a target for autism research based on the work by Kang and colleagues (see here) suggestive that gut bacterial diversity differences might be linked to the presentation of autism outside of just any GI comorbidity. Similar research on those trillions of passengers we all carry was also detailed with regards to Myalgic encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS). And there was the introduction of maternal autoantibody-related autism or MAR autism for short (see here). More on that shortly.

August
August was definitely a 'leaky gut' month. I posted a sort of overview of where autism research is currently up to when it comes to intestinal hyperpermeability and lo and behold, Laura de Magistris and colleagues go and add to the literature (see here). Still there was more to come. In other research news, there was an interesting update to the body of work looking at recurrence risk of autism in siblings (see here) and a nice case study on the potential value of NAC (N-acetylcysteine) for at least some autism (see here). Just outside of autism, the association between schizophrenia and everyone's favourite marker of inflammation, C-reactive protein also received some attention (see here). August also saw an important step forward for autism practice here in the UK with the publication of the last strand of guidance from NICE on managing children and young adults with autism (see here).

September
MAR autism y'say? Well, storm clouds appeared at the suggestion that such research might be translated into something like a commercial test (see here). Indeed, with that notion of maternal immune activation and offspring signs and symptoms in mind, observations from monkeys (not just rodents) suggested similar issues to be present (see here). The presentation of autistic-like symptoms in cases of eating disorders was reported. As was yet more discussion on the use of certain antiepileptics during pregnancy potentially impacting on offspring behaviour (see here). October however had two main highlights for me though: (i) the publication of our first follow-up paper to the ScanBrit study of a GFCF diet (see here) on potential best-responder characteristics, and (ii) the study from Jonas Ludvigsson and colleagues on issues with gluten in autism probably not being coeliac (celiac) disease but potentially something just as interesting (see here). The rise of non-coeliac gluten sensitivity? Indeed, the Ludvigsson paper prompted one Alessio Fasano to say something pretty monumental on his analysis of the study which I'll quote again: "In the past, we have had the believers and nonbelievers when it came to the role of gluten in autism ... Hopefully this paper can clarify, once and for all, that a subset of those with autism has gluten sensitivity, a condition triggered by gluten but distinct from celiac disease." [source is here].

October
Continuing the theme of dietary intervention and autism (I'm not obsessed honest!), the paper by Graf-Myles and colleagues caught my attention and their notion that, assuming correct nutritional support, the horror that is the GFCF diet might not be as rotten a diet as first thought. I was also interested in the review by Xu and colleagues who upon meta-analysing all the relevant data concluded that maternal diabetes did seem to show a connection with a heightened risk of offspring autism (see here). Parental stress and the various ways and means that autism research has suggested it could be tackled was also covered in October (see here); as was the news that the autism numbers game here in the UK might be showing a plateau in prevalence and incidence rates (see here). Scientific replication also played it's part in autism research as per the 'failure to replicate' paper from Robinson and colleagues when looking at SNPs predicting autism (see here). Oh and MAR autism also showed an autoimmunity side...

November
I was very interested to read the paper by Lynne Wang and colleagues replicating some earlier findings on a possible role for Sutterella in cases of autism (see here). That and the suggestion of a particularly high prevalence of autism associated with cases of Neurofibromatosis 1 (NF-1) from Garg et al. A possible role for iodine and autism was also the topic of some preliminary research chatter (see here) as was paracetamol exposure, albeit not exactly with autism in mind (see here). And then there was the suggestion of overlap between a specific part of the autism spectrum and the issue of synaesthesia (a mixing of the senses) to consider.... bearing in mind a few gaps in the presented study.

December
Two pretty big papers started the month of December. Beginning with one of, possibly the, largest study so far looking at the presence of functional bowel issues in cases of autism we were again reminded that autism does seem to be over-represented when it comes to such problems. This was followed by the paper by Elaine Hsiao and Paul Patterson (see here) and others which brought their earlier conference proceedings on the presence of leaky gut in the maternal immune activated mouse model to the peer-review arena. Words like 'incredible' were used to describe the potential of altering the gut microbiota and impacting on both gut permeability and presented 'autistic-like' symptoms in their mice. I was enthused but remind readers that mice are mice not humans. Indeed that same sentiment distinguishing mice from humans was similarly applied to some interesting work suggestive of GI issues in the valproate mouse model of autism. That all being said, we also got some more confirmation that leaky gut can appear in real people with autism as per the Dalton findings. I'd hazard a guess that I'll be blogging about gut permeability and autism further in 2014 and beyond.

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And rest. Of course there was lots more research considered in 2013 but I assume you'll be too busy eating those turkey left-overs for me to overload you any further.

I think I am justified in repeating my optimistic appraisal that we know a little bit more about autism at the end of this year than we did at the beginning. The main themes as I see it are:

  • autism is probably better described as 'the autisms' with various different develomental trajectories present in different people,
  • there is so much more to autism than it just being related to 'the brain',
  • comorbidity is important; often very important, and
  • 'immutable and lifelong' are words which might not necessarily apply to every single case of autism bearing in mind we don't yet know for who and the precise reasons why. 

Finally, if you noticed the picture at the top of this post, it's one of my own taken back in September this year, of Penshaw monument (see here for more information) here in the bracing North-East of England. Oh and there's some legend to accompany this splendid structure... about a worm and no, not those kinds of worms, which I assume we'll be hearing more about in 2014 (see abstract T177).

And with that, here is to 2014 and no doubt, another interesting year for autism research ahead. Thanks for reading and a Happy New Year to you and yours.

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It's a difficult task but my autism research paper of the year (2013) goes to....

Fein D. et al. Optimal outcome in individuals with a history of autism. J Child Psychol Psychiatry. 2013 Feb;54(2):195-205. doi: 10.1111/jcpp.12037.

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ResearchBlogging.org Fein D, Barton M, Eigsti IM, Kelley E, Naigles L, Schultz RT, Stevens M, Helt M, Orinstein A, Rosenthal M, Troyb E, & Tyson K (2013). Optimal outcome in individuals with a history of autism. Journal of child psychology and psychiatry, and allied disciplines, 54 (2), 195-205 PMID: 23320807

Monday 23 December 2013

Heightened anxiety in children with autism

Given that a certain portly chap with a white beard (yes, one of those fat yet fit types) is heading the way of many a household over the coming hours, I'm going to be quite brief in this post about the paper by Victoria Hallett and colleagues* who concluded that their "findings support previous reports of heightened anxiety in children with ASDs [autism spectrum disorders]". The realisation that Christmas can itself be a significant source of anxiety to many people as per the BBC article (here) is perhaps also worth directing your attention to, given the potential for overlap when discussing autism.
By Emile not Santa [Claus] @ Wikipedia 

I've talked (and talked) about how various forms of anxiety do seem to be over-represented when it comes to autism (see here for the mega-post) and the various ways and means that science has so far offered when it comes to helping to manage or relieve such issues, acknowledging that we still have some distance to go on this topic.

The Hallett paper in respect of finding 'parent-reported' anxiety to be present in children with autism is no new thing. That being said, their analysis based on data from TEDS (Twins Early Development Study) adds a new twist to the research in this area, as does their suggestion that "Unaffected co-twins of children with ASDs also showed increased anxiety, generating questions about the potential etiological overlap between ASDs and anxiety". Yes it certainly does generate questions, and in particular, whether the broader autism phenotype (BAP) might have another potential diagnostic string to add to its bow.

I note that at least some of this authorship group have previously talked about autism, twins and issues like anxiety (as part of the so-called internalising traits) as per papers like this one** and this one***. I was drawn to a particular quote in one of those papers: "these traits may serve to exacerbate each other over time" suggestive that intervention-wise at least, treating something like anxiety might have some interesting knock-on effects on the presentation of core autism traits and vice-versa. Another discussion for another time methinks, perhaps alongside the recent paper by Boulter and colleagues**** on intolerance of uncertainty in relation to anxiety present in cases of autism?

Anyhow, without further ado, I wish you all Happy Christmas or Seasons Greetings if you prefer. Stay tuned for the mega-roundup post of autism research that has appeared on this blog during 2013 coming up in the next few days. I leave you with some sound advice when it comes to cooking that over-sized turkey that you've probably bought to avoid any unfortunate incidents or undesirable trips to the smallest room in the house. Oh, and some research news that will hopefully raise a smile to any Hobbit fan...

And just before I go, yet again Shane and Kirsty perform for you the best Christmas song ever...

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* Hallett V. et al. Exploring anxiety symptoms in a large-scale twin study of children with autism spectrum disorders, their co-twins and controls. J Child Psychol Psychiatry. 2013 Nov;54(11):1176-85.

** Hallett V. et al. Association of autistic-like and internalizing traits during childhood: a longitudinal twin study. Am J Psychiatry. 2010 Jul;167(7):809-17. 

*** Hallett V. et al. Investigating the association between autistic-like and internalizing traits in a community-based twin sample. J Am Acad Child Adolesc Psychiatry. 2009 Jun;48(6):618-27.

**** Boulter C. et al. Intolerance of Uncertainty as a Framework for Understanding Anxiety in Children and Adolescents with Autism Spectrum Disorders. J Autism Dev Disord. 2013 Nov 24. 

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ResearchBlogging.org Hallett V, Ronald A, Colvert E, Ames C, Woodhouse E, Lietz S, Garnett T, Gillan N, Rijsdijk F, Scahill L, Bolton P, & Happé F. (2013). Exploring anxiety symptoms in a large-scale twin study of children with autism spectrum disorders, their co-twins and controls J Child Psychol Psychiatry, 54 (11), 1176-1185 DOI: 10.1111/jcpp.12068

Thursday 19 December 2013

Autism in the Somali population in Minneapolis

I see that the report from Amy Hewitt and colleagues* (open-access) providing results from The Minneapolis Somali Autism Spectrum Disorder Prevalence Project has been published and has started to generate some media interest (see here).
Gondereshe @ Warya @ Wikipedia 

The long-and-short if it was that based on some concerns that children of Somali origin seemed to be over-represented when it came to a diagnosis of an autism spectrum condition, otherwise known as 'otismo' among some in the Somali community, the research wheels were set in motion in the City of Minneapolis to see if there were indeed disparities in the numbers of children presenting with autism. The project was "expanded" above and beyond just asking about prevalence of autism in Somali children vs. non-Somali children to importantly include other questions; not least: "Were children with ASD and of Somali descent more likely to have intellectual disability than children with ASD who were not of Somali descent?" I was particularly interested in the intellectual disability (ID) issue in light of other research suggesting that there may indeed be an over-representation of ID alongside autism in migrant children from countries of the African continent or with a low 'human development index' (see here and more recently here).

Without trying to simply plagiarise the Hewitt report, there are a few key findings worthy of comment.

  • Bearing in mind how researchers collected information about autism - screening and reviewing health records - from a total population numbering above 12,000 7-9 year olds in 2010, the autism prevalence rate in Minneapolis was estimated to be 1 in 48 children. This figure covered all children irrespective of any ethnicity differences.
  • Specifically looking at children of Somali origin, 31 children out of a total of 1007 children were judged to be on the autism spectrum equating to a prevalence of 1 in 32 children. Nearly half of the Somali children identified as being on the autism spectrum were done so via inspection of a combination of school and health records (48%).
  • Within the range of other ethnic groupings examined, 120 out of a total of 4,336 white children were also judged to be on the autism spectrum, making a prevalence estimate of 1 in 36 children.
  • Just as important, all the Somali children with autism were reported to have some degree of ID (this being ascertained as an IQ level below 70).
  • The average age at diagnosis for Somali children was 5.3 years, exceeding all other ethnic groups and above the overall mean age at diagnosis of 4.9 years.

There's not too much more to add to those factoids aside from the need for quite a bit more research into this area given the data indicating that almost 1 child in every classroom aged between 7-9 years old will potentially present as being on the autism spectrum. The fact that Somali children, and indeed white children, presented with prevalence estimates of autism above that of other ethnic groups potentially offers some clues as to where research might next head in terms of genetics, epigenetics and even environmental differences tied into such categorisations. I've speculated before about the possibility of something like a vitamin D link** given the differences in sun exposure between Somalia and the City of Minneapolis, but I dare say the whole thing is going to be a lot more complicated than just this one potential precipitating factor.

It's also interesting to note that the Hewitt report includes some mention of 'interventions' for autism, and quite prominently, the use of 'dietary and nutritional interventions'. Although the authors are right to be wary and sceptical of the effectiveness of any 'universal' intervention for autism (sorry the autisms), it got me wondering whether this was given such prominence specifically because of the chatter about such an intervention including the horror that is a GFCF diet, or whether there may be some differences in the effectiveness of such interventions with an ethnic slant? I might add I'm not talking about 'eating right for your blood type' or anything like that but there is always the example of ethnicity and lactose intolerance and its potential link to cases of autism for example. Food for thought anyway.

Whatever your interpretation of the Hewitt report, there are important practical lessons to be learned in terms of screening, diagnosis and the provision of services for those children diagnosed with autism whether of Somali origin or any other ethnic group. And once again, parents of children with autism were a primary driving force behind getting this research done and bringing it into the public arena...

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* Hewitt A, Gulaid A, Hamre K, Esler A, Punyko J, Reichle J. & Reiff M. (2013). Minneapolis Somali autism spectrum disorder prevalence project: Community report 2013. Minneapolis, MN: University of Minnesota,  Institute on Community Integration, Research and Training Center on Community Living

** Fernell E. et al. Serum levels of 25-hydroxyvitamin D in mothers of Swedish and of Somali origin who have children with and without autism. Acta Paediatr. 2010 May;99(5):743-7. 

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ResearchBlogging.org Fernell E, Barnevik-Olsson M, Bågenholm G, Gillberg C, Gustafsson S, & Sääf M (2010). Serum levels of 25-hydroxyvitamin D in mothers of Swedish and of Somali origin who have children with and without autism. Acta paediatrica (Oslo, Norway : 1992), 99 (5), 743-7 PMID: 20219032

Tuesday 17 December 2013

Gut permeability in teens with autism and SEN

Naturally I was going to be interested in the findings of Neil Dalton and colleagues* comparing a measure of gut permeability in teenagers (well, those aged 10-14 years old) diagnosed with an autism spectrum disorder (ASD) (n=103) and those with special educational needs (SEN) (n=30).

Regular readers are probably well used to some of my discussions on the possibility of a triad of issues - gut permeability, gut bacteria and immune function - being related to cases of autism. Indeed not so long ago I posted a sort of 'where is research up to' with gut permeability in relation to autism (see here). Already in light of the recent Patterson lab findings on leaky mice guts and immune activation (see here) this megapost is out of date. And now with the Dalton findings it's even more out of date, such is the rapidity of scientific research (and the responsiveness of blogging).

Anyhow, back to the Dalton findings. Well, I've got to really start with a quote from their study: "no statistically significant group difference in small intestine permeability in a population cohort-derived group of children with ASD compared with a control group with SEN". This was based on quite a nice participant number of teens (yes, I'll mention that again) where gut permeability was "assessed by measuring the urine lactulose/mannitol (L/M) recovery ratio by electrospray mass spectrometry-mass spectrometry". That mass spectrometry (MS) mention adds some significant credibility to the detection methods used to assay for those markers of intestinal permeability.

That being said, the devil is in the detail when it comes to the study findings outside the group comparisons between autism and SEN participants. So: "Eleven children (9/103 = 8.7% ASD and 2/30 = 6.7% SEN) had L/M recovery ratio > 0.03". L/M recovery ratios refers to the amount of lactulose and mannitol sugars recovered in urine generally suggested to be below 0.03 to be a 'normal' result (see here). In effect, 8.7% of the children with autism in the Dalton cohort presented with leaky gut.

I have to say that I am a little bit surprised by the Dalton results and how much they contrast with the other work in this area particularly the de Magistris findings** in terms of the percentage of children showing abnormal gut permeability (36% vs. 8%). One might assume that there are potential population differences (UK vs. Italy) or that even age at gut permeability analysis might be an issues. Realising that use of a gluten- and casein-free (GFCF) diet also seems to impact on gut permeability issues (as was perhaps the cases when considering the Robertson paper***) is another potential place to look for reasons for the disparity across the results. If I also had to ask one further thing about the Dalton paper, it would be to have included a typically-developing group alongside their autism and SEN cohorts so we could frame the results with previous data.

In terms of the publication team and very possibly the cohort used for this study, I'm not altogether sure but I think we might have already heard something about these participants insofar as that 'functional bowel problems do seem to be present in autism' work published by Chandler and colleagues earlier this year (see here). I base that on the single result of a participant with autism showing a result representative of "more definitely pathological" gut hyperpermeability (leaky gut) and being subsequently presenting with "undiagnosed asymptomatic celiac disease". Indeed, 1 out of 103 teens with autism presenting with autism is not a dissimilar figure from other work****; bearing in mind the Ludvigsson paper on 'not quite coeliac disease' but something else being potentially related to autism (see here).

So, yet again, more data suggesting that when it comes to gut permeability, autism (at least some cases of autism) is much more deserving of further inquiry. That also 6.7% of the small participant group with SEN also showed potential issues with a leaky gut might also be an important area of future investigation.

Now about zonulin - any takers for a study on that molecule and autism?

[Update: January 2014. Thanks to the wonder that is PubMed Commons, I've transmitted some of my thoughts on this paper to the PubMed entry: http://www.ncbi.nlm.nih.gov/pubmed/24339339].

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* Dalton N. et al. Gut Permeability in Autism Spectrum Disorders. Autism Research. 2013. Dec 12. 10.1002/aur.1350

** de Magistris L. et al. Alterations of the Intestinal Barrier in Patients With Autism Spectrum Disorders and in Their First-degree Relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

*** Robertson MA. et al. Intestinal permeability and glucagon-like peptide-2 in children with autism: a controlled pilot study. J Autism Dev Disord. 2008 Jul;38(6):1066-71.

**** Batista IC. et al. Autism spectrum disorder and celiac disease: no evidence for a link. Arq Neuropsiquiatr. 2012 Jan;70(1):28-33.

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ResearchBlogging.org Neil Dalton, Susie Chandler, Charles Turner, Tony Charman, Andrew Pickles, Tom Loucas, Emily Simonoff, Peter Sullivan, & Gillian Baird (2013). Gut Permeability in Autism Spectrum Disorders Autism Research DOI: 10.1002/aur.1350

Saturday 14 December 2013

Sensitizing to gluten?

Actually the title to this post should really read 'sensitising' rather than 'sensitizing' as a function of my Limey status. No mind, today I'd like to introduce you to two pretty unusual papers which I stumbled across in recent times which have the common denominators of (a) both being about gluten and the possible induction of problems with gluten, and (b) both carrying Marios Hadjivassiliou as part of the authorship team. They're both open-access too.

The first paper is by Currie and colleagues* who concluded that: "Alcohol related cerebellar degeneration may, in genetically susceptible individuals, induce sensitization to gluten". The second paper by Ludvigsson & Hadjivassiliou** in a similar vein suggested that there was a: "very small excess risk for future CD [coeliac disease] in individuals with an earlier head trauma".

Why am I talking about these papers you might ask? Well, outside of any autism-gluten research obsession I might have, I was interested to read about how an issue with gluten might come about as a function of an environmental insult; in these cases, alcohol abuse and head injury. Just however before I stray away from the autism-gluten science, the keen reader might have already spotted the name Ludvigsson, Jonas Ludvigsson, as being one and the same lead author on that 'not coeliac disease but something gluten related' paper in relation to cases of autism (see here for some discussion).

I'm not going too heavily into these papers but it strikes me that there are a few possible connections to be made from the cumulative data. Autoimmunity is the source of some speculation in both papers. The Currie paper speculates that: "autoimmunity may have a role to play in the development of ataxia in patients that drink excessively". Ataxia by the way, refers to a group of conditions which affect motor skills. Similarly, L & H (because they both have particularly long surnames) talk about "an autoimmune response against transglutaminases triggered by the brain injury". The transglutaminases (plural) or at least one of them (tTG) have already been talked about on this blog with reference to the process of coeliac (celiac) disease (see here).

That 'development of autoimmunity' suggestion also leads into another potential commonality across these papers: the cerebellum. Part of the brain long thought to be involved in motor control (as well as other cognitive functions), the suggestion is that "antigliadin antibodies may arise after a cerebellar insult rather than being the cause of it per se" in the alcohol study. The head injury paper provides an equally interesting commentary, if a little less 'proven' by results: "head trauma resulting in cerebral and cerebellar insults may trigger autoimmunity against TG6 which in turn may lead in some genetically susceptible individuals, to the development of CD".

If I've got all my factoids correct, there is a rather interesting hypothesis to test from these collected results. Take an immune system which genetically looks a little like that seen in coeliac disease with regards to those HLA-DQ2 and DQ8 heterodimers. Add an environmental insult which in particular, targets the cerebellum or indeed some other part of the brain. For whatever reason, the exposure to that insult starts to do odd things to "normally shielded" self epitopes such as TG6 which "may result in the immune system reacting to self-antigens in the central nervous system ultimately leading to autoimmunity". Gluten just happens to be one of the external agents to which antibodies also start being produced against as self and other start to become mixed up, and hey presto, you're gluten sensitive.

OK, I know there is still much to do in this area of research and by no means should anyone take such a hypothesis as fact at this point in time. Marios Hadjivassiliou has done a lot of work in the area of extra-intestinal presentation of gluten issues (see here for example***) but we're not yet in a position to start definitively linking all the pieces together just yet. That and the differences between the two papers discussed in this post in terms of what was looked at (antigliadin antibodies vs. patient register details for head injury and/or small intestinal biopsy reports) and how participants were examined, means I am to a large extent comparing apples and oranges.

Still, I do find this line of inquiry to be quite fascinating. I'm also thinking back to the paper by Emily Severance and colleagues**** on how infection with the gondii (that's Toxoplasma gondii) in a mouse model might also be able to invoke an immune reaction to gluten (see here for my take of the study). There's more to come on this blog from Dr Severance, but again, speculations on immune activation through the slightly different environmental process of infection translating into a immunological effect against gluten.

But still the possibility of an acquired sensitivity to dietary gluten...

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* Currie S. et al. Alcohol induces sensitization to gluten in genetically susceptible individuals: a case control study. PLoS One. 2013 Oct 15;8(10):e77638.

** Ludvigsson JF. & Hadjivassiliou M. Can head trauma trigger celiac disease? Nation-wide case-control study. BMC Neurol. 2013 Aug 9;13:105.

*** Hadjivassiliou M. et al. Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry 2002;72:560-563.

**** Severance EG. et al. Anti-gluten immune response following Toxoplasma gondii infection in mice. PLoS One. 2012;7(11):e50991.

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ResearchBlogging.org Currie S, Hoggard N, Clark MJ, Sanders DS, Wilkinson ID, Griffiths PD, & Hadjivassiliou M (2013). Alcohol induces sensitization to gluten in genetically susceptible individuals: a case control study. PloS one, 8 (10) PMID: 24204900




ResearchBlogging.org Ludvigsson JF, & Hadjivassiliou M (2013). Can head trauma trigger celiac disease? Nation-wide case-control study. BMC neurology, 13 PMID: 23927742

Wednesday 11 December 2013

Intestinal inflammation in the valproate mouse model of autism

Gut inflammation and autism.

Laughing or smirking? Wikipedia 
Words which still have the ability to furrow brows and precipitate eye rolling. Whatever your views on this topic, whether based on science or politics or both, there is no getting away from the evidence suggestive that in SOME cases of autism, issues with that deepest, darkest realm - the gut - do seem to be present.

Whether based on the presence of functional bowel issues (see here and here) or something rather more fundamental (see here), research continues to discover that the so-called second brain might have quite an important role to play in SOME cases of autism. This is not new news by the way (see here); the idea for which predates a certain [retracted] paper in 1998.

The recent paper from the laboratory of Paul Patterson (see here) suggesting that there may be issues with gut permeability (the so-called leaky gut) in offspring of a mouse model of maternal immune activation (MIA) during pregnancy was surprising to say the least. Whilst quite a lot of the media on this study went for the gut bacteria angle and bacteria potentially influencing behaviour (again, not necessarily new news), the forgotten angle of that paper was how immune activation in mother mice might be quite importantly linked to gut physiology of offspring.

As I see it, there's an important triad emerging in this area consisting of gut bacteria, gut barrier function and immune function potentially pertinent to lots of different issues and conditions. But what do I know?

It is again with mouse models and autism in mind, that I'm posting about the study from Caroline de Theije and colleagues* and their suggestion that offspring of the valproic acid (VPA) mouse model of autism might similar show 'gastrointestinal issues'. In particular: "VPA in utero- exposed male offspring showed epithelial cell loss and neutrophil infiltration in the intestinal tract".

The possible connection between foetal exposure to valproate and subsequent developmental outcomes has witnessed an explosion of interest this year (2013). Of course, the very fact that science has a VPA murine model of autism is testament to the fact that for quite a few years, there have been rumblings of a potentially important connection between the two factors. The recent data however, have led to some speculation which goes well beyond just correlation as per the paper by Harden**.

Back to the de Theije paper, and as follows a well-trodden research routine, it was a case of exposing pregnant mice (not, I hasten to add the usual BTBR dangermouse of autism) to either saline or more actively, valproic acid. Offspring mice were then studied both behaviourally and physiologically, upon which, intestinal issues of the inflammatory kind were detected in the VPA exposed mice. The authors conclude that: "gender-specific inflammatory conditions are present in the small intestines of VPA in utero- exposed mice and are accompanied by a disturbed serotonergic system in the brain as well as in the intestinal tract". Ergo, brain and gut seem to be implicated in the VPA murine model of autism, and boy mice seem to be the more fragile ones which some might seem as fitting in with the current data on the sex ratio of autism.

Similar to the MIA work, the VPA model with the gut in mind is at present solely focused on mouse models. Mouse models, in cold, hard scientific terms, tend to be good models to work with because well, they rely on mice not humans. Therein however, lies an issue: can a condition as complex and heterogeneous as autism really be recreated in mice? I'll leave the philosophers out there to ponder that question.

Bearing such a methodological issue in mind, the identification of something potentially going on gut-wise in the VPA model might actually turn out to be a useful finding. Assuming that someone is able to replicate these findings, one might begin to question what happens when said intestinal inflammation is treated in the VPA exposed offspring, and whether there may be any implications for intervention in humans for example, with autism in mind but also with conditions headed under the banner of foetal valproate syndrome***. I note in another paper from de Theije and colleagues**** there does seem to be some interest in the "gut-to-brain connection" with autism in mind so perhaps this is something already under consideration by the authors.

Perhaps even more speculatively, and with the recent Hsaio paper***** in mind, I should also ask the question of whether gut bacteria might be the next research target for the VPA mouse model of autism? Oh sorry, the authors have already thought of that******(what clever people).

Some music to close. I'm actually quite taken by the updated version of 'Dream a little dream' by Mr Williams & Ms Allen if the truth be known. Not that I'm implying that anyone outside of my brood should be dreaming about me...

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* de Theije CGM. et al. Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav Immun. 2013 Dec 6. pii: S0889-1591(13)00589-8.

** Harden CL. In Utero Valproate Exposure and Autism: Long Suspected, Finally Proven. Epilepsy Currents. 2013; 13: 282-284.

*** Kini U. Fetal valproate syndrome: a review. Paediatr Perinatal Drug Therapy. 2006; 7: 123-130.

**** de Theije CGM. et al. Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol. 2011 Sep;668 Suppl 1:S70-80.

***** Hsiao EY. et al. Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders. Cell. 2013 Dec 3. pii: S0092-8674(13)01473-6.

****** de Theije CGM. et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun. 2013 Dec 11.

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ResearchBlogging.org de Theije CG, Koelink PJ, Korte-Bouws GA, Silva SL, Mechiel Korte S, Olivier B, Garssen J, & Kraneveld AD (2013). Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav Immun. DOI: 10.1016/j.bbi.2013.12.004

Even more air pollution and autism risk findings

Air pollution.

I'm pretty sure most people are aware of all the talk about air pollution these days and how the human body is not particularly fond of air pollution in terms of potential adverse health outcomes (assuming that is, you leave things like selenium out of the equation). If you happen to live in China, I'm sure your mind was put at ease when reading about 'The Five Surprising Gains from the Smog'... or maybe not.

Most people generally find it easier to accept that air pollution might show a possible connection with something like respiratory diseases for example, given that the airways are generally a first point of entry for said pollution getting access to the body (although not the only route). Mention that something like autism risk for example, might also be linked to air pollution exposure and I'm sure that a significant degree of eye-rolling begins, alongside mutterings of the old 'correlation is not the same as causation' argument.
The Alchemist @ Wikipedia 

Personally I'm quite intrigued by the results emerging looking at something like childhood or maternal exposure to air pollution and proximity to sources of air pollution being linked to child or offspring autism risk. In these times of the autisms and various external forces implicated in autism risk (think valproate for example and the recent special reminder from the MHRA on this matter; even someone mentioning the word 'proven' [1] as if such a thing exists) I don't think we can rule most things out yet.

You have for example, the data from Heather Volk and colleagues [2] which was talked about in this post compounded by the data from Tracy Ann Becerra and colleagues [3] (see this post) both quite recently pinpointing something of a statistical association at least. That and other studies looking at a possible association.

Enter then another study by Volk and colleagues [4] which adds another layer of intrigue and complexity to the air pollution link by suggesting that a certain kind of genotype combined with air pollution exposure might elevate the risk of autism. There has been some media coverage of this paper (see here).

I suppose the first thing to take from the latest Volk paper is it's concentration on gene x environment interactions potentially modifying the risk of something like autism. I'm sure readers are used to hearing about [variable] gene-environment interactions quite loudly proclaimed these days as accounting for the presence of autism, but to see a study looking experimentally at the issue is very refreshing.

The next thing to note about the Volk paper is the specific focus on the MET receptor tyrosine kinase (MET) gene and a particular version of this gene potentially interacting with something like air pollution. In the post titled: 'I'm glad I MET you' (no prizes for the headline there) I talked about some other rather interesting findings when it came to MET and autism. Alongside all the chatter about things like synaptic development which MET has been tied to [5] was the suggestion that "the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37+73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P=0.003)" as per the paper from Heuer and colleagues [6]. Maternal autoantibodies, as regular readers might know, are an upcoming area with autism risk in mind (see here).

It is then perhaps no surprise that the MET rs1858830 genotype, same as that one looked at with maternal autoantibodies in mind, was also the focus on the recent Volk paper and in particular the 'CC' genotype (see here for some information on zygosity). This genotype seems to be one which is more commonly noted in relation to cases of autism [7]. Indeed, based on an analysis of participants involved with the CHARGE initiative (beincharge!) the authors suggested: "Subjects with both MET rs1858830 CC genotype and high air pollutant exposures were at increased risk of autism spectrum disorder compared with subjects who had both the CG/GG genotypes and lower air pollutant exposures". Big words, I'm sure you'll agree.

These results are obviously crying out for replication for starters. The focus of this study was (a) on one gene, one specific variant of one gene, in our entire genome (b) looking at structural issues with said gene not necessarily gene function as per that rising star which is epigenetics for example might have on gene expression, and (c) based on air pollution exposure estimates from "local traffic-related sources and regional sources (particulate matter, nitrogen dioxide, and ozone)". With those factors in mind, caution still needs to be applied to these results before anyone goes and tries to for example, market any sort of genetic test for air pollution related autism or anything similar... Oh and 'steering clear of cities' is probably not a realistic option for most people either. Indeed, even residing in the countryside has been linked to autism risk (see here).

But still I'm interested in these results and indeed, the next question of biological processes from genes to environment to development and behaviour.

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[1] Harden CL. In Utero Valproate Exposure and Autism: Long Suspected, Finally Proven. Epilepsy Currents 2013; November/December 2013: 13; 282-284.

[2] Volk HE. et al. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry. 2013 Jan;70(1):71-7.

[3] Becerra TA. et al. Ambient air pollution and autism in Los Angeles county, California. Environ Health Perspect. 2013 Mar;121(3):380-6.

[4] Volk HE. et al. Autism Spectrum Disorder: Interaction of Air Pollution with the MET Receptor Tyrosine Kinase Gene. Epidemiology. 2013 Nov 14.

[5] Judson MC. et al. A new synaptic player leading to autism risk: Met receptor tyrosine kinase. J Neurodev Disord. 2011 Sep;3(3):282-92.

[6] Heuer L. et al. Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression. Transl Psychiatry. 2011 Oct 18;1:e48. doi: 10.1038/tp.2011.48.

[7] Jackson PB. et al. Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder. Autism Res. 2009 Aug;2(4):232-6. doi: 10.1002/aur.87.

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ResearchBlogging.org Volk HE, Kerin T, Lurmann F, Hertz-Picciotto I, McConnell R, & Campbell DB (2013). Autism Spectrum Disorder: Interaction of Air Pollution with the MET Receptor Tyrosine Kinase Gene. Epidemiology (Cambridge, Mass.) PMID: 24240654

Monday 9 December 2013

Autism and the [changing] preschool developmental profile

I'd like to begin with a quote from the paper by Hedvall and colleagues* who reported findings based on a study of developmental trajectory for 208 preschoolers diagnosed with an autism spectrum condition: "Changes in developmental profiles during preschool years are common in children with ASD".
Seasons: Autumn @ Wikipedia 

Their naturalistic study suggested that the very early years of autism, at least some autism, and its presentation are characterised by "considerable change over time" and the requirement for "follow-up assessments" in order to more accurately measure where the sands of autism have settled prior to the start of school.

Their reporting that intellectual disability (ID) also might have a maturational aspect to its appearance alongside cases of autism (i.e. not common in early diagnosis but present in about 50% of cases at follow-up) also provides some food for thought in terms of whether this reflects a specific comorbidity or indeed, something more central to specific types of autism (yes, the autisms), though carrying a different timescale of presentation.

I'm not altogether sure but I think we might have seen the Hedvall cohort used in another study by Fernell and colleagues** during their study looking at early intervention and autism. In that paper, the same number of preschoolers with autism (N=208) were followed "in a naturalistic fashion" and their various experiences of an ABA (applied behaviour analysis) program recorded. If it is one and same cohort, it's likely then that we are probably not talking about developmental changes occurring just spontaneously in some sort of intervention vacuum. Sort of what happens in real-life.

I've talked before on this blog about diagnostic stability and instability when it comes to autism (see here). Whilst accepting that 'universals' when it comes to autism are generally few and far between outside of the almighty diagnostic criteria, the conclusion reached on that post was that stability with regards to a diagnosis of autism is surprisingly, quite an unstable thing. When particularly applied to the early years and their growing importance when it comes to autism (see here) one might speculate that such instability presents its own issues particularly in these times when chatter about really early autism diagnosis is becoming more frequent and louder and louder. Discussion about the important issue of regression which might also interfere with any notion of a universal prenatal or early autism diagnostic test is also worth noting. That also different children on the autism spectrum might present with different developmental trajectories is an important point to emphasise, particularly in these times of optimal outcomers for example (see here).

Whilst the Hedvall data provides a cautionary tale that we should be mindful of how dynamic autism might be in the early years (and perhaps even beyond), I'd like to think that it won't be used as an excuse for delaying assessment and diagnosis too much and the subsequent impact that can have....

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* Hedvall A. et al. Autism and developmental profiles in preschoolers: stability and change over time. Acta Paediatr. 2013 Oct 8. doi: 10.1111/apa.12455.

** Fernell E. et al. Early intervention in 208 Swedish preschoolers with autism spectrum disorder. A prospective naturalistic study. Res Dev Disabil. 2011 Nov-Dec;32(6):2092-101.

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ResearchBlogging.org Hedvall A, Westerlund J, Fernell E, Holm A, Gillberg C, & Billstedt E (2013). Autism and developmental profiles in preschoolers: stability and change over time. Acta paediatrica (Oslo, Norway : 1992) PMID: 24237479

Thursday 5 December 2013

Leaky mice guts, bacteria and autism (part 2)

So, leaky gut, the gut microbiota and the immune system in relation to autism then? Maybe not so 'on the fringe' as you might have thought.

Readers are asked to consider this entry an extension of the post I published last year (see here) talking about some very interesting research coming out of the laboratory of Prof. Paul Patterson at CalTech. If you need any sort of background, Prof. Patterson and his team have for quite a while been investigating the concept of maternal immune activation (MIA) in relation to autism and schizophrenia risk and the notion that maternal infection during pregnancy might have the ability to impact on offspring outcomes*. At least in mice.

The mice will play @ Wikipedia 
In my previous post, the interest was in a report on a report on a report given at the Society for Neuroscience (2012) meeting which appeared to detail the presence of gut hyperpermeability (yep, the so-called leaky gut) in offspring of the maternal immune activated (MIA) mouse model.

Indeed, the various members of the Patterson lab also suggested that said issues with increased gut permeability might also be 'modified' by the introduction of Bacteroides fragilis via a proposed effect on the the levels of a uremic compound called 4-ethylphenylsulfate.

With the publication by Elaine Hsiao and colleagues** this initial report has now seen the peer-reviewed light of day as was hinted at in a recent piece on gut bacteria potentially guiding "the workings of our minds" and on Prof. Patterson's blog.

As perhaps would be expected, there are few other details to discuss about the paper outside of what has already been seen. We know that the work included pregnant mice who were immune challenged by a mock virus. We know a little more about the types of mouse behaviours that were observed as a result of being a MIA offspring and which seemed to be affected by the introduction of B. fragilis. And we know some more details about the effect of feeding B. fragilis on 4-ethylphenylsulfate levels. Actually, there are two pretty good interpretations of the study on the SFARI site (here) and the Autism Speaks site (here).

We still also know that this was a study of mice and not humans and that questions remain about how and why gut bacteria seemed to affect gut permeability and the relationship to presented behaviours. These points certainly merit me repeating my oft-cited caveat on this blog about not giving medical or clinical advice.

Still, this work (if and when replicated) potentially represents another turning point when it comes to our understanding about the autisms. It further suggests autism, some types of autism, might not just soley be a 'brain-based' condition*** but rather a more multi-organ condition. Indeed, if we're talking about that 'gut-brain axis' which has been banded about for a good few years now with autism in mind, the mouse findings imply that altering parameters in the gut may very well have an impact on presented behaviour as per the interest in dietary intervention and autism for example (see here).

Indeed with my own professional interest in food and autism in mind, I'm also wondering whether some of the behavioural effects noted from a dietary change in cases of autism might actually reflect dietary changes impacting on the types of bacteria predominating in the gut as per other findings and the recent revelations from Martinez-Medina and colleagues****. I might add that this does not exclude a more direct effect on barrier integrity also and indeed, my still waiting for someone to publish on levels of [General] zonulin when it comes to autism.

The Hsiao study also provides a potentially important tie-up between the triad which is gut bacteria, gut permeability and immune function in relation to cases of autism. Yes, there are still big gaps in our knowledge about how these systems fit together, but what we are starting to realise is that there is an intricate relationship between them which might be even more profound than we've ever realised.

A game-changer paper?

[Update: January 2014. The PhD thesis of Elaine Hsiao is now available to view open-access with all data pertaining to this and other studies].

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* Garay PA. et al. Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav Immun. 2013 Jul;31:54-68.

** Hsiao EY. et al. Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders. Cell. 2013. 5 December.

*** Coury DL. et al. Gastrointestinal Conditions in Children With Autism Spectrum Disorder: Developing a Research Agenda. Pediatrics. 2012; 130: S160-S168.

**** Martinez-Medina M. et al. Western diet induces dysbiosis with increased E coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut 2014; 63: 116-124.

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ResearchBlogging.org Elaine Y. Hsiao, Sara W. McBride, Sophia Hsien, Gil Sharon, Embriette R. Hyde, Tyler McCue, Julian A. Codelli, Janet Chow, Sarah E. Reisman, Joseph F. Petrosino, Paul H. Pattersons, & Sarkis K. Mazmania (2013). Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders Cell DOI: 10.1016/j.cell.2013.11.024