Thursday, 30 November 2017

"psychiatric comorbidity may be the earliest manifestation of the onset of IMID in some individuals"

IMID shown in the title of this post refers to immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA) and formed quite an important part of the findings reported by Ruth Ann Marrie and colleagues [1] (open-access available here). This work adds to an area of increasing importance on how the physical and psychological/psychiatric might very well be linked by the immunological (see here for discussions on other recent work from this authorship group).

Similar to their last publication [2] Marrie et al relied on data out of the "the Canadian province of Manitoba" and included some 12,000 diagnosed cases of IMID. The aim of their study this time around was "to estimate the incidence of several psychiatric disorders, including depression, anxiety, bipolar disorder and schizophrenia, in the 5-year periods pre- and post-IMID diagnosis." Further: "We hypothesised that the incidence of psychiatric comorbidity would be higher in the incident IMID than in the matched general population cohorts pre- and post-IMID diagnosis."

Results: "the incidence of psychiatric comorbidity was increased in the IMID cohorts in the 5–10 years before IMID diagnosis." Minus too many sweeping generalisations, there is something potentially rather 'stunning' about such findings and the idea that for some at least, psychiatric findings might be a prelude to something rather more somatic a few years down the line. Authors also noted that post-IMID diagnosis, there was also a possible *connection* to receipt of a psychiatric label too.

Explanations? Well, with the requirement for quite a bit more independent analysis in this area of science, there are a few possibilities to consider. Authors talk about a possible "prodromal period for the IMID in which inflammation has developed sufficiently to increase the risk of psychiatric disorders but not to precipitate typical clinical manifestations of IMID." You'll note the use of the word 'inflammation' in that last sentence pertinent to the idea that inflammation as a component of immune function might well be doing lots and lots of different things (see here).

They also mention the possibility that "psychiatric disorders and IMID may share common aetiologic factors." So, drawing on a little autism research here, and how autism genes might not necessarily be just genes for autism (see here) and how such genetic overlap may include some of the genetics of immune function (see here), the feeling is that such sentiments could be pertinent to other labels too. Of course it's also important to note that outside of just structural genetics, there may be other non-genetic factors that could exert a possible effect such as the availability of certain nutrients for example (see here).

And there is another important point raised by Marrie and colleagues: "the occurrence of psychiatric disorders pre-diagnosis of IMID could potentially be conceptualised as early symptoms of IMID rather than as distinct comorbid conditions." This is something rather appealing to me following my reading of the research literature in this area down the years. Yet again drawing on research in autism, I've often thought that at least of the 'comorbidity' that is over-represented alongside a diagnosis of autism might actually be a lot more 'central' to some presentations. Take for example all the chatter about gastrointestinal (GI) issues being present alongside [some] autism (see here). Minus all the fluffy psychological explanations for the presence of various bowel issues alongside a diagnosis of autism, there is evidence that the bowel might be quite a bit more central to quite a few cases of autism under specific circumstances (see here). Further extending such work I note that bowel issues also might carry relevance to other behavioural/psychiatric diagnoses too (see here). If also proven in the context of 'psychiatric IMID' (if I can call it that), such a move away from notions of comorbidity towards more core issues has implications not just for screening and assessment but also management and treatment too...

Reiterating that quite a bit more work needs to be done on the whole 'immune system doing more than just traditional immune system things', I continue to find this area of research absolutely fascinating.


[1] Marrie RA. et al. Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease. Epidemiol Psychiatr Sci. 2017 Nov 3:1-10.

[2] Marrie RA. et al. Increased incidence of psychiatric disorders in immune-mediated inflammatory disease. J Psychosom Res. 2017 Oct;101:17-23.


Wednesday, 29 November 2017

Aluminium in brain tissue in autism: a first?

"These are some of the highest values for aluminium in human brain tissue yet recorded and one has to question why, for example, the aluminium content of the occipital lobe of a 15 year old boy would be 8.74 (11.59) μg/g dry wt.?"

That was one of the statements/questions posed in the paper by Matthew Mold and colleagues [1] covering yet another potential 'hot potato' topic in the area of autism research and science (see here). Indeed, the idea mentioned by Mold et al that: "Animal models of ASD [autism spectrum disorder] continue to support a connection with aluminium and to aluminium adjuvants used in human vaccinations in particular" is likely to met with furrowed brows in quite a few quarters given the recent goings-on with regards to some of the 'mouse' work in this area (see here).

But as far as I can see, the Mold data is a stand-alone piece of work that sought to cover a 'missing piece' in relation to how "no previous reports of aluminium in brain tissue from donors who died with a diagnosis of ASD" have been published in the peer-reviewed domain. In that respect, I'm covering it on this blog, hypothesis-free in terms of the possible wheres-and-hows...

Relying on one of the most personal and precious resources in autism research - brain tissue - "from the Oxford Brain Bank ", researchers examined brain tissue samples from various parts of the brain donated by families of "5 individuals with ADI-R confirmed (Autism Diagnostic Interview-Revised) ASD." As far as I can make out, we aren't told an awful lot about the 5 people studied aside from their diagnosis, sex/gender and age range. We don't for example, know about any comorbidities (autism rarely appears in some sort of diagnostic vacuum) or indeed, the reason(s) why they died.

Brain tissues were prepared and treated ready for analysis of aluminium content via "transversely heated graphite furnace atomic absorption spectrometry (TH GFAAS) using matrix-matched standards and an established analytical programme alongside previously validated quality assurance data." From what I gather, this is an accepted (albeit quite old) method for analysis of various trace metals in biological fluids including aluminium [2]. It's also worthwhile bearing in mind the publication record of some of the authors in the area of aluminium (see here) including research pertinent [3] to the Camelford 'incident'. Some people here in Blighty might remember Camelford, where the accidental addition of some 20 tonnes of aluminium sulphate into the local drinking water led to it being described as "Britain's worst mass poisoning event".

Alongside assaying for aluminium content in brain samples, researchers also examined brain sections to see where aluminium congregated in samples via the use of fluorescence microscopy. This involved the selective staining of cells for aluminium content and onward looking at where and what type of cell showed such staining.

Results: "The brains of all 5 individuals had at least one tissue with a pathologically-significant content of aluminium." Further: "The brains of 4 individuals had at least one tissue with an aluminium content ≥5.00 μg/g dry wt. while 3 of these had at least one tissue with an aluminium content 10.00 μg/g dry wt." I don't know enough about aluminium and what should or shouldn't be there, but I believe the authors hark back to some of their previous work to try and define "loose categories of brain aluminium content." In terms of the aluminium cell staining work, some interesting findings are reported pertinent to how "aluminium somehow had crossed the blood-brain barrier and was taken up by a native cell namely the microglial cell." Other authors had previously speculated on this scenario [4].

It's worthwhile mentioning/reiterating some of the limitations of this work before any grand sweeping judgements or generalisations are made. Not only was this a very, very small study with no specific control samples available during this particular investigation, but the amount of tissue available to researchers was limited. One cannot also rule out issues such as sample degradation being a factor (see here) given the lack of specific details on the samples being investigated. As I said, brain samples are one of the most precious resources available to autism research.

There is however a need for much more research in this area, particularly when going back to the opening statement/question of this post in terms of amount of aluminium detected and where it seemed to congregate in the brain samples analysed. Indeed, with all the chatter about microglia and inflammation in relation to [some] autism down the years (see here for example), it's looking increasingly *interesting* that aluminium might play some kind of role, for some at least. Added to independent findings suggesting that the blood-brain barrier should also be target for further study for some (see here) and observations that upwards of about 15% of individuals with an ASD might present with elevated levels of aluminium in other tissue types (see here) and future work is indicated on a larger scale minus hype and/or generalisations. I might also suggest that further research be directed on the basis of other organs potentially affected by aluminium concentrations such as the kidneys..

I'm also minded to point out that following other work on other metals in the context of autism (see here), I'm still siding with the idea that various genetic and biological mechanisms involved in the *removal* of metals may be 'atypical' in relation to at least some autism. If that is the case, there could be several different ways to potentially intervene [5]...


[1] Mold M. et al. Aluminium in brain tissue in autism. Journal of Trace Elements in Medicine and Biology. 2017. Nov 26.

[2] Bradley C. & Leung FY. Aluminum determined in plasma and urine by atomic absorption spectroscopy with a transversely heated graphite atomizer furnace. Clin Chem. 1994 Mar;40(3):431-4.

[3] King A. et al. Unusual neuropathological features and increased brain aluminium in a resident of Camelford, UK. Neuropathol Appl Neurobiol. 2017 Oct;43(6):537-541.

[4] Morris G. et al. The putative role of environmental aluminium in the development of chronic neuropathology in adults and children. How strong is the evidence and what could be the mechanisms involved? Metab Brain Dis. 2017 Oct;32(5):1335-1355.

[5] Yu L. et al. Lactobacillus plantarum CCFM639 can prevent aluminium-induced neural injuries and abnormal behaviour in mice. Journal of Functional Foods. 2017; 30: 142-150.


Tuesday, 28 November 2017

"findings suggest a protective effect of CRP" on schizophrenia risk?

Science is often a puzzling endeavour. Sometimes, just when you think that you've got something nailed down, scientific results appear that 'trash' long held, cherished beliefs. So it was with the publication of the results by Fernando Pires Hartwig and colleagues [1] who presented findings looking at "the effect of inflammatory markers on schizophrenia risk" based on the use of "a mendelian randomization (MR) design."

MR, by the way, is a interesting technique based on the principle that "genetic variants that either alter the level of, or mirror the biological effects of, a modifiable environmental exposure that itself alters disease risk should be related to disease risk to the extent predicted by their influence on exposure to the environmental risk factor." It's a technique that has already been applied to inflammatory markers in the context of schizophrenia on more than one occasion (see here and see here). Those inflammatory markers studied have included ones which were covered by the Hartwig paper. Specifically: "Genetically elevated circulating levels of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R)." I should also point out that Hartwig and colleagues have some research form in the area of applying MR to various aspects of medical science (see here).

As per an accompanying editorial on the Hartwig paper [2], the long-and-short of it was that researchers "used 2-sample MR to test for a potentially causal relationship between inflammation and schizophrenia and to improve inference for the association between genes, inflammatory biomarkers, and risk of developing schizophrenia." I can't claim any specific expertise in the use of MR (see here for a good overview [3]) but it appears that data on single-nucleotide polymorphisms (SNPs) in relation to those inflammatory markers was used to test whether said markers might be linked 'causally' to risk of schizophrenia. Their results were interesting: "we did not find strong evidence that lifelong exposure to increased action of these proinflammatory cytokines increases schizophrenia risk, as previously hypothesized" and indeed that: "blockade of IL-6 effects and low CRP levels might instead increase schizophrenia risk." This is contrary to quite a lot of other research in this area (see here for example).

There are a few words of caution to attach to the Hartwig results that need mentioning not least the primary tenet on which analyses are based: genetic variants (SNPs) affecting something like CRP are of primary importance to schizophrenia. I don't for example, see anything in the data looking at gene function/expression being affected as a result of non-structural changes to the genome via something like epigenetic 'alterations' for example (and there is such a thing as epigenetic Mendelian randomization y'know). I say this on the basis that other genes involved potentially involved in processes linked to DNA methylation have also been *associated* with cases of schizophrenia (see here). The authors also caution that their analyses are based on "lifelong exposure to elevated cytokine and CRP levels" and that exposure during 'critical windows' might be the important issue when it comes to any change in schizophrenia risk. Similarly they note that "it is possible that IL-6 and CRP effects on schizophrenia risk are related to a maternal effect (eg, maternal susceptibility to infections during pregnancy), so that our findings are explained by the correlation between maternal and offspring genotypes." This final point is based on the idea that maternal infection during pregnancy (or the biological consequences of) seems to be quite a big risk factor for at least some presentations of schizophrenia (see here) as well as [cautiously] other labels (see here). Here, the importance of a reprogrammed immune system during pregnancy might also come into play alongside any maternal 'susceptibility'.

Personally I'm not yet ready to totally trash the idea that the immune system, and specifically elevations in inflammatory markers such as CRP and other pentraxins, might not be important to some schizophrenia risk in a more detrimental way. I appreciate that one has to be careful when talking about immune system markers and their inflammatory direction (see here for some chatter on IL-6 and its pro- and anti-inflammatory natures) but the existing data is too evident to just discard on the basis of one new study, despite it's scientific prowess. I don't however doubt that there may be several confounding variables linked to increases in CRP in schizophrenia; not least the impact of something like increased body mass index (BMI) that seems to follow some cases of schizophrenia [4]. These variables need to be further explored, particularly in the context of what side-effects pharmacological management of schizophrenia might have (see here). And I also hat-tip the paper by Manu and colleagues [5] applying the Bradford Hill's guidelines on 'causation' to this area and concluding that (upto 2014) "there is insufficient evidence that the replicated, strong association between schizophrenia and elevated inflammatory markers has etiopathological relevance"...

For now however, the Hartwig findings reiterate that science is an ever-changing, ever-evolving process...


[1] Hartwig FP. et al. Inflammatory Biomarkers and Risk of Schizophrenia: A 2-Sample Mendelian Randomization Study. JAMA Psychiatry. 2017. Nov 1.

[2] Byrne E. et al. Inference in Psychiatry via 2-Sample Mendelian Randomization—From Association to Causal Pathway? JAMA Psychiatry. 2017. Nov 1.

[3] Sheehan N. et al. Mendelian Randomisation and Causal Inference in Observational Epidemiology. PLoS Med. 2008; 5(8): e177.

[4] Fernandes BS. et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Mol Psychiatry. 2016 Apr;21(4):554-64.

[5] Manu P. et al. Markers of inflammation in schizophrenia: association vs. causation. World Psychiatry. 2014 Jun; 13(2): 189–192.


Monday, 27 November 2017

MoBa does... prenatal exposure to acetaminophen and offspring ADHD risk

MoBa mentioned in the title of this post refers to the Norwegian Mother and Child Cohort Study, an initiative that has figured quite a few times on this blog (see here and see here and see here for examples).

This time around [1] scientific attention turned to a question of growing research importance: does acetaminophen - paracetamol to us here in Blighty - use during pregnancy affect the risk of offspring being diagnosed with attention-deficit hyperactivity disorder (ADHD)? The data thus far on the issue of this pain-relieving, antipyretic medicine and offspring health has been discussion-provoking to say the least (see here and see here)...

The findings reported by Eivind Ystrøm and colleagues [1] are based on observations for over 100,000 offspring "including 2246 with ADHD." Both "maternal use of acetaminophen during pregnancy and... paternal use before pregnancy" were included in the statistical mix designed to estimate "hazard ratios (HRs) for an ADHD diagnosis."

The results were not exactly unexpected given what has gone on before in this area of investigation. Acetaminophen use was pretty widespread across all pregnancies; approximately 50% of mums had used it at some point. Short-term use during pregnancy - less than 8 days - actually correlated with a decreased risk of offspring ADHD according to the Ystrøm findings. More chronic use of the medicine however - "more than 29 days of maternal acetaminophen use" - showed an opposite relationship, yielding something like a 200% increase in offspring ADHD "even after adjusting for indications of use, familial risk of ADHD, and other potential confounders."

Alongside the suggestion that short-term paracetamol use was associated with a decreased risk for offspring ADHD was another 'make you think' finding: "Paternal and maternal use of acetaminophen were similarly associated with ADHD." Here, a father's use of paracetamol a month or so before conception seemed also to affect the risk for offspring ADHD too. In some media interest on this paper, the authors speculate "that "it could be that fathers who use a lot of acetaminophen have a higher genetic risk for ADHD" or that long-term use of the medicine might lead to changes in sperm." I might add that given the focus on paracetamol as a pain-relieving medicine, the topic of pain and ADHD is already something present in the peer-reviewed science domain (see here). Further research is called for in an accompanying editorial on the Ystrøm paper by Mark Wolraich [2] noting the benefits of using 'big data' from initiatives such as MoBA.

Accepting that the Ystrøm results suggest correlation and not necessarily causation, not everyone has been overwhelmed by the findings. I note in that lay media piece about the research, a few critical voices have suggested that "children diagnosed with ADHD by codes in their medical records" is no substitute for the real 'diagnostic' thing. Personally, I don't see this argument as being particularly valid as anyone that reads anything about MoBA would probably realise. Scandinavian countries and their population databases have some of the best collected and kept databases in the world in terms of reliability and applicability of population health data and statistics. A quick check on PubMed regarding the amount of peer-reviewed data that has been generated from MoBA for example, illustrates that point well.

Perhaps a more pertinent issue is the question of whether longer-term use of paracetamol during pregnancy could denote a more serious underlying maternal illness/injury which might have a more powerful effect on the risk of offspring ADHD than medicine use itself. This is a similar sort of argument to that put forward in relation to pregnancy antidepressant use and various offspring outcomes detailed in the research literature (see here) and similarly, is not something that can be answered by study designs such as those used by Ystrøm.

But then other the questions arise: 'Is paracetamol use during pregnancy safe?' 'How much is safe?' and 'What are the alternatives?' At this point I'm going to stand back and say little more given my blogging caveats of no medical and/or clinical advice given or intended. I will refer you to some current opinion on this topic provided in the peer-reviewed domain [3] alongside suggesting that more large and smaller-scale investigations are required, including that on 'adjacent' diagnoses in relation to pregnancy paracetamol use too (see here)...


[1] Ystrøm et al. Prenatal Exposure to Acetaminophen and Risk of ADHD. Pediatrics. 2017. Oct 30.

[2] Wolraich ML. An Association Between Prenatal Acetaminophen Use and ADHD: The Benefits of Large Data Sets. Pediatrics. 2017. Oct 30.

[3] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.


Saturday, 25 November 2017

Sexual orientation as a function of autistic traits? Not so fast...

I was in two minds as to whether or not I should blog about the findings reported by Christiane Rudolph and colleagues [1] describing results observing that: "Autistic traits are associated with minority sexual orientation, and perhaps with uncertain self-identification and/or a defiance of traditional ways of categorizing sexual identity."

Two minds because (a) I'm not a great fan of sweeping generalisations in the context of autism or 'autistic traits' or anything related, and (b) although autism and sexual attraction preference(s) is a growing area of research interest (see here for example), I did wonder what the aim of the Rudolph study was, being as it was, based on 'autistic traits in the general population'. Was it trying to make a case for autistic traits as somehow being related to a person's sexual preference or just adding to the existing autism literature based on non-clinical population findings? As per this entry that you're reading, I did decide to take on the Rudolph findings because peer-reviewed science is peer-reviewed science. Also, how one has to exercise some degree of caution with the current results as they stand for various reasons...

So, the aim of the research game was to examine "autistic traits and sexual orientation" and whether one might be *associated* with the other. Over 47,000 adults were initially invited to participate; the cohort self-completed the Autism Spectrum Quotient (AQ) (the AQ-10) to measure 'autistic traits' and were also asked about their sexual orientation (hetero-, homo-, bisexual, none of the above). You'll immediately note that researchers were looking at two primary variables, albeit in quite a large sample group.

Results: "Participants with autistic traits were more likely to identify as bisexual (OR 1.73; 95% CI 1.01–2.9) and to feel that their sexual orientation could neither be described as hetero-, homo- nor bisexual (OR 3.05; 95% CI 2.56–3.63), compared to individuals without autistic traits." I say all that accepting that if one looks closely at the confidence intervals (CIs) particularly for the association with bisexuality - "95% CI 1.01–2.9" - you'll see that it comes ever so close to crossing 1 (1.01) which typically translates as no statistical difference between the groups.

The findings do kinda accord with what has been noted in other 'diagnosed autism' research literature. 'Uncertainty in attraction' and bisexuality, for examples, have been mentioned before (see here) as being potentially over-represented when examined in the context of the autism spectrum and continue to do so [2]. One might also opine that the presence of certain autistic traits (AQ measured of course) might also mean that 'honesty' in relation to some very personal questioning on sexual identity/preference(s) might be more likely among this group when extrapolating from other findings [3]. Indeed, greater honesty and also greater tolerance [4] it seems...

But... the AQ, the AQ... Regular readers of this blog probably already know what I think about the AQ as one of the premier 'are you autistic?' schedules (see here). It's most definitely measuring something, but I'm minded to suggest that that 'something' is not always exclusively autism or autism spectrum disorder (ASD) (see here and see here). In the context of using AQ with a supposed non-clinical population, I'll refer you to the findings reported by Phil Reed and colleagues [5] for example, who similarly noted that: "Higher AQ scores were associated with higher scores of loneliness, social anxiety, depression, and anxiety, as well as with lower scores of quality of life (QoL)." It's not outside the realms of possibility that the 'autistic traits' being measured by Rudolph et al may have also included facets of these states/conditions/labels, particularly if one assumes that issues like anxiety and depression are very much over-represented in the context of autism (see here) and given the large participant numbers included for study. At this point I'll also add in my view that when we talk about depression and anxiety as being 'comorbid' to autism, I don't think we're actually doing justice to how pervasive such issues can be for a person and whether they should instead be considered as something more than just comorbidity à la Mildred Creak and colleagues...

Insofar as other research *linking* elevated AQ scores in some 450,000 people to STEM (science, technology, engineering and mathematics) career choices (see here), or AQ scores being "significantly positively correlated with eating disorder psychopathology" [6] or even AQ scores potentially being associated with lower income [7] I'll leave you to debate/argue what the implications may or may not be in light of the Rudolph findings and why we should perhaps be rather cautious about any sweeping generalisations.

It's not that I don't 'accept' the Rudolph results for what they are, but I'm still however unsure about what the final aim of the study was...


[1] Rudolph CES. et al. Brief Report: Sexual Orientation in Individuals with Autistic Traits: Population Based Study of 47,000 Adults in Stockholm County. Journal of Autism & Developmental Disorders. 2017. Oct 30.

[2] George R. & Stokes MA. Sexual Orientation in Autism Spectrum Disorder. Autism Res. 2017. Nov 21.

[3] de Schipper E. et al. Functioning and disability in autism spectrum disorder: A worldwide survey of experts. Autism Res. 2016 Sep;9(9):959-69.

[4] Dewinter J. et al. Sexuality in adolescent boys with autism spectrum disorder: self-reported behaviours and attitudes. J Autism Dev Disord. 2015 Mar;45(3):731-41.

[5] Reed P. et al. Loneliness and Social Anxiety Mediate the Relationship between Autism Quotient and Quality of Life in University Students. Journal of Developmental and Physical Disabilities. 2016; 28: 723-733.

[6] Tchanturia K. et al. Characteristics of autism spectrum disorder in anorexia nervosa: A naturalistic study in an inpatient treatment programme. Autism. 2017 Nov 1:1362361317722431.

[7] Skylark WJ. & Baron-Cohen S. Initial evidence that non-clinical autistic traits are associated with lower income. Molecular Autism. 2017; 8: 61.


Friday, 24 November 2017

Is there a bidirectional relationship between autism core symptoms and anxiety?

"Our results do not support a bidirectional relationship between the ASD [autism spectrum disorder] core symptom domains and anxiety" said the findings reported by Jorieke Duvekot and colleagues [1].

Initially including 130 children diagnosed with an ASD who were then whittled down to 79 some 2 years later, researchers wanted to find out more about the "potential differential relationships of the two core symptom domains of ASD - social communication impairment and restricted, repetitive behavior - with anxiety over time." This based on the fact that anxiety disorders seem to be very much over-represented when it comes to autism (see here) and can be absolutely disabling for both the person concerned and for those significant others around them. I might add that this research group have some 'research form' when it comes to longitudinal autism research [2] coinciding with this latest publication.

The chosen method of analysis was the use of a crossed-lagged model which typically involves studying two or more variables over two or more occasions to ascertain any association(s) or not. After adding the variables under investigation into the statistical mix, authors observed that "anxiety symptoms predicted social communication impairment over time" but not the other way around. They also reported no bidirectional relationship between anxiety and restricted, repetitive behaviours, again over time.

I have to say that I was a little confused by these results. Confused because, as someone on Twitter pointed out (thanks Frank), the quite young (mean) age group of the cohort (6.7 years) might be an important variable when it comes to both the presentation and measurement of something like anxiety. I'm not saying that anxiety is not a feature of early childhood autism - indeed again this research group have some peer-reviewed experience in this area [3] - just that it would probably be a lot easier to spot and diagnose when clinical in older children/young adults assuming the correct instrument is used. To say therefore that there was no support for a bidirectional relationship between core autism symptoms and anxiety might not exactly be accurate across the autism spectrum age-groupings.

That's not the only thing that confused me: the lack of any type of relationship between anxiety and those restricted, repetitive behaviours (I'll call them RRBs for short) detailed by Duvekot et al is seemingly contrary to other research in this area [4] albeit research looking at core symptoms and anxiety over a similar time frame. Take for example the findings reported by Vicki Bitsika & Christopher Sharpley [5] (see here for my take) who observed among other things that "experiencing difficulty in changes in routine was associated with a 10-fold increase in risk of GAD [generalised anxiety disorder]." Yes, the focus was on the use of the "GAD subscale of the Child and Adolescent Symptom Inventory (CASI-4 GAD)" and one has to be careful with causality, but it does make some sense to suggest that the 'stress' of something impacting on RRBs might be enough to induce not just anxiety, but clinical anxiety even in the longer term. I'll also throw in the findings reported by Ashwood and colleagues [5] for good measure too, illustrating how one of the premier 'are you autistic?' screens (yes, the AQ) has some real problems when it comes to things like GAD mimicking ASD and potentially inflating AQ scores "leading to false positives." Such work implies that the core facets of autism might be very much interlinked with the core facets of anxiety (and vice-versa); something that I would also expect to see manifest over a longer time period. I await more research on this important topic.

To close, and related to today's content on core symptoms and comorbid conditions, I want to refer you to the article published by Ginny Russell and colleagues [6] and the importance of engaging with the community your are studying. To quote: "While treating autism per se. was seen as problematic by some, treating specific co-occurring problems was seen as helpful in some circumstances." My question: what happens if and when by treating co-occurring issues, one does start to impact on core symptoms or vice-versa? Indeed, if one assumes that some of the most debilitating and 'life-changing' aspects of autism may very well be tied into the presentation of core symptoms (see here and see here for examples), what then happens to such 'problematic' views? Difficult questions with no easy answers...


[1] Duvekot J. et al. Examining bidirectional effects between the autism spectrum disorder (ASD) core symptom domains and anxiety in children with ASD. J Child Psychol Psychiatry. 2017 Oct 27.

[2] Duvekot J. et al. Design and Cohort Characteristics of the Social Spectrum Study: A Multicenter Study of the Autism Spectrum Among Clinically Referred Children. J Autism Dev Disord. 2017 Jan;47(1):33-48.

[3] Duvekot J. et al. Symptoms of autism spectrum disorder and anxiety: shared familial transmission and cross-assortative mating. J Child Psychol Psychiatry. 2016 Jun;57(6):759-69.

[4] Rodgers J. et al. The relationship between anxiety and repetitive behaviours in autism spectrum disorder. J Autism Dev Disord. 2012 Nov;42(11):2404-9.

[5] Ashwood KL. et al. Predicting the diagnosis of autism in adults using the Autism-Spectrum Quotient (AQ) questionnaire. Psychological Medicine. 2016;46(12):2595-2604.

[6] Russell G. et al. Selective patient and public involvement: The promise and perils of pharmaceutical intervention for autism. Health Expect. 2017 Oct 31.


Thursday, 23 November 2017

Yet more "lost their diagnosis" and autism research. Not for all but...

The question posed in the title of the paper by Solomon and colleagues [1] - "What will my child's future hold?" - examining the "phenotypes of autism spectrum disorder (ASD) based on trajectories of intellectual development from early (ages 2-3 ½) to middle (ages 5-8) childhood" - is an interesting one and a question that many parents/caregivers will probably ask or have asked at one point or another.

It's also an important question because throughout all the sweeping statements that have been made about the autism spectrum past and present, the generalisation that ALL autism is 'lifelong' is one of the more popular ones despite [peer-reviewed scientific] evidence pointing to the contrary (see here for example).

By saying all that I'm not trying to minimise the effect(s) that autism has on the lives of many, many people day-in and day-out throughout their lives and the varying requirements for suitable support. Just that, as per the notion 'if you've met one autistic person, you've met one person with autism' (or words to that effect), the experience(s) of continually hitting the diagnostic thresholds across the lifespan is likely to be different for different people as a function of many, many different factors. I say this acknowledging for example, the rise of 'compensation' in the context of autism recently (see here).

Solomon et al drew on data derived from the Autism Phenome Project including over 100 children "initially diagnosed with ASD." Researchers were particularly interested in cognitive trajectories as measured by IQ between 2 and 8 years of age and whether autistic and other related symptoms/traits were also affected by any changes to intellectual functioning. As it happens, they might be...

"A four class model best represented the data" meaning that participants typically fell into one of four 'patterns' with regards to their intellectual functions/trajectories. This included: "High Challenges (25.5%), Stable Low (17.6%), Changers (35.3%), and Lesser Challenges (21.6%) groups." As per the title of this post, I'm particularly interested in those described as 'Changers' or 'Lesser Challenges' who "demonstrated the most significant IQ change that was accompanied by adaptive communication improvement and declining externalizing symptoms" and "showed a significant reduction in ASD symptom severity" respectively. Indeed, within the Lesser Challenges group we are told that "by age 8, 14% of them no longer met ADOS-2 criteria for ASD." In other words, they did not reach cutoffs for the diagnostic criteria for an autism spectrum disorder (ASD) using a gold-standard assessment instrument and so could be considered not autistic by diagnostic standards.

Also important to the Solomon findings was the observation that: "Intervention history was not associated with group status." I'm not going to say too much more about this at the present time, but if replicated, the implications are pretty huge particularly where the current drive towards early intervention in autism is leading us (see here).

Although not always welcomed by everyone, the idea that a diagnosis of autism is permanent and immutable for all does not stand up well to scientific scrutiny. The best guess estimates currently suggest that somewhere between 9 and 12% of children/adults will 'lose their diagnosis' (see here and see here); also potentially affecting the presence of some important over-represented comorbidity too (see here). The old 'they weren't autistic in the first place' argument is a typical response from some nay-sayers on this topic; something which unfortunately contributes to the denigration of some important parts of the autism spectrum. Certainly a part of the autism spectrum that we can learn a lot from as the Solomon results are starting to show.

Indeed, given the other 'biological' focuses of the Autism Phenone Project [2] I'm hoping that we'll eventually see further results from this initiative providing important information on possible biological correlates linked to those who "no longer met ADOS-2 criteria for ASD". If ever there was a research study needed on autism, it is one including a little more biological and genetic information about those who move from autism to not-autism and what it could mean for the wider autism spectrum and particularly the concept of 'the plural autisms'...

To close, 'I want a deep fried turkey'....


[1] Solomon M. et al. What will my child's future hold? phenotypes of intellectual development in 2-8-year-olds with autism spectrum disorder. Autism Res. 2017 Oct 27.

[2] Onore CE. et al. Levels of soluble platelet endothelial cell adhesion molecule-1 and P-selectin are decreased in children with autism spectrum disorder. Biol Psychiatry. 2012 Dec 15;72(12):1020-5.


Wednesday, 22 November 2017

Antibodies against gluten in autism don't correlate with leaky gut markers

The paper by Jan Józefczuk and colleagues [1] provided some intriguing observations pertinent to quite a few topics previously discussed on this blog. Not only was there mention of anti-gliadin antibodies (AGA) and more specifically the finding that increased IgG-AGA was found in a quarter of their 77 participants with autism included for study, but also the important point: "An increased production of antibodies related to gliadin and neural TG6 [neural transglutaminase 6in ASD [autism spectrum disorder] children is not related to serological markers of an impaired intestinal barrier."

It's worthwhile breaking down some of the details of the Józefczuk findings and what they might mean. I'll warn you that this is likely to be a bit of a long-read blog post so please, get comfy and read on...

So, AGA and more specifically, IgG-AGA represent the immune system 'recognising' gliadin, an important part of the protein gluten. IgG-AGA are typically found in many people diagnosed with the archetypal gluten-related autoimmune condition called coeliac (celiac) disease (although this measure is not considered diagnostic) but also alongside other more 'non-coeliac' gluten sensitivity conditions too (see here). The finding of elevated IgG AGA in cases of autism is by no means a new one (see here) (yes, this data came from the AGRE program [2] so no quibbling about the diagnosis of autism or anything like that). Other data has indicated that the presence of such antibodies seems to be a good reason to attempt a gluten-free diet (see here) which is music to my autism research ears (see here) and a good evidence-based reason to quiet down those who might 'challenge' such dietary intervention in the context of [some] autism. Then also is the idea that the presence of IgG AGA in conditions not totally unrelated to autism (see here) *might* play an important role in something like 'peripheral' inflammation [3] and whether the same could be true for [some] autism...

Next: "antibodies against neural transglutaminase 6 (TG6)" described by the authors as present in about 5% of their cohort is also an important finding. Turning up in a variety of different conditions [4] (although not yet considered 'mainstream' in certain quarters), some of the most interesting, and potentially relevant, labels where TG6 might be present include something called gluten ataxia [5], a neurological 'sign' characterised by a 'lack of voluntary coordination of muscle movements that includes gait abnormality.' Again, the data is compelling insofar as the use of a gluten-free diet as an intervention option [6] where gluten ataxia is diagnosed. With specific regards to autism and TG6 antibodies, I think the Józefczuk paper provides the first research outing for the two together (at least in a PubMed search). Other transglutaminase antibodies however, have been reported in the context of autism (see here for example) with the need for lots more investigations including with reference to the overlap between autism and coeliac disease (see here). At this point, I'll also note that gluten ataxia has not yet been linked to autism despite ataxia potentially showing some connection to some cases [7].

Moving on and we have the finding that: "Mean levels of zonulin and I-FABP [intestinal fatty acid binding proteins] in ASD [autism spectrum disorder] patients were similar to those found in healthy controls." Further: "Serum concentrations of zonulin and I-FABP showed no statistically significant association with antibody positivity." OK, zonulin is another topic of interest to this blog particularly in light of other recent findings with autism in mind (see here). Still the topic of considerable debate, zonulin has been described as "a biomarker of impaired gut barrier function for several autoimmune, neurodegenerative, and tumoral diseases" [8]. The data so far seems to indicate that gliadin - that component of gluten - 'induces' zonulin release [9] hinting that diet may be an important variable when it comes to 'impaired gut barrier function' otherwise known as intestinal hyperpermeability (or more imprecisely, leaky gut). I-FABP is something I'm a little less sure about in any context. It has been mentioned in the peer-reviewed research arena with autism in mind [10] but I can claim not expertise on this specific marker.

The Józefczuk findings report that zonulin levels in their cohort with autism were similar to "to those found in healthy controls" which is contrary to those previous findings in autism published by Erman Esnafoglu and colleagues [11]. They (Esnafoglu et al) concluded that: "Serum zonulin levels were significantly higher in the patients with ASD (122.3 ± 98.46 ng/mL) compared with the healthy controls (41.89 ± 45.83 ng/mL). " Forgetting (but not excusing) the incorrect use of 'healthy controls' in that paper, there is something of a difference between the Esnafoglu and Józefczuk results. One could argue that this is simply reflective of 'conflicting' autism research more generally (see here) but one might also question things like the analytical ways-and-means of assaying for something like zonulin too (see here).

The observation that zonulin (and I-FABP) levels showed 'no statistically significant association with antibody positivity' whilst informative is something I've been thinking about quite a bit. I don't have any easy answers as to why they found what they found aside from assuming that such data is evidence for how "increased immune reactivity against gluten" might not be specifically related to "the effect of intestinal barrier abnormalities" in relation to autism. This relationship assumes that abnormal gut permeability is the route through which gluten fragments (peptides) gain access to the wider central nervous system (CNS) which then elicits that immune response. It is a little surprising that no relationship was found given that one of the ways that zonulin is released is ingestion of gliadin and the assumption that gluten needs to be present in the diet for antibodies to be formed against it. But there you go. I suppose one might entertain the possibility that zonulin as a biomarker of impaired gut barrier function might not be the optimal way of measuring gut barrier function and including other more direct measures [12] could be the way forward to resolving this issue further.

Either way, research on immunological responses to gluten and notions of atypical gut permeability in the context of 'some autism' are seemingly not going away any time soon. Indeed, even medical professionals are seemingly not adverse to prescribing a gluten-free diet in the context of [some] autism [13]...


[1] Józefczuk J. et al. The Occurrence of Antibodies Against Gluten in Children with Autism Spectrum Disorders Does Not Correlate with Serological Markers of Impaired Intestinal Permeability. J Med Food. 2017 Oct 26.

[2] Lau NM. et al. Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS One. 2013 Jun 18;8(6):e66155.

[3] Kelly DL. et al. Anti Gliadin Antibodies (AGA IgG) Related to Peripheral Inflammation in Schizophrenia. Brain Behav Immun. 2017 Oct 23. pii: S0889-1591(17)30476-2.

[4] Gadoth A. et al. Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2015 Jun;72(6):676-81.

[5] Hadjivassiliou M. et al. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol. 2008 Sep;64(3):332-43.

[6] Hadjivassiliou M. et al. Dietary treatment of gluten ataxia. Journal of Neurology, Neurosurgery, and Psychiatry. 2003;74(9):1221-1224.

[7] Ahsgren I. et al. Ataxia, autism, and the cerebellum: a clinical study of 32 individuals with congenital ataxia. Dev Med Child Neurol. 2005 Mar;47(3):193-8.

[8] Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012;1258(1):25-33.

[9] Clemente MG. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003 Feb;52(2):218-23.

[10] Pusponegoro HD. et al. Maladaptive Behavior and Gastrointestinal Disorders in Children with Autism Spectrum Disorder. Pediatr Gastroenterol Hepatol Nutr. 2015 Dec;18(4):230-7.

[11] Esnafoglu E. et al. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects. Journal of Pediatrics. 2017; 188: 240-244.

[12] Bischoff SC. et al. Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterology. 2014;14:189.

[13] Rubenstein E. et al. The prevalence of gluten free diet use among preschool children with autism spectrum disorder. Autism Res. 2017 Nov 20.


Tuesday, 21 November 2017

"Spending constraints" a.k.a austerity and a mortality gap?

I try not to be too political on this blog given the focus on peer-reviewed science and my notable lack of political interest or motivation. It is however difficult to completely separate science and politics from each other given the world that we live in. A world that still commonly uses the term 'austerity' quite a few years after 'the crisis', alongside a realisation that behind headlines on the continued drive(s) towards 'fiscal security' and 'balancing the books' there are inevitably going to be winners and losers.

The paper by Jonathan Watkins and colleagues [1] highlights some of the extreme 'not winners' potentially stemming from the "relative constraints in public expenditure on healthcare (PEH) and social care (PES)" here in Blighty over recent years. They concluded that: "Spending constraints between 2010 and 2014 were associated with an estimated 45 368 (95% CI 34 530 to 56 206) higher than expected number of deaths compared with pre-2010 trends." Further, that if current trends continue in relation to funding "approximately 150 000 additional deaths may arise between 2015 and 2020." Cue the sharp intake of breath as words such as 'economic murder' have been banded around in the popular press discussing this research (see here).

I'm not going to go into all the details of the Watkins findings on this occasion. The data for the study was derived from various public databases in relation to population mortality, spending on health and social care and related variables. I don't doubt that as per other debates on the 'weekend effect' for example, different people with different mindsets might arrive at different conclusions based on such data. 'Lies, damn lies and statistics' is a phrase that springs to mind. With my very rudimentary reading and understanding of the Watkins data, I can't however see any obvious flaws in their methods or logic behind their results; aside that is from remembering that correlation does not always equal causation. Others have voiced similar sentiments (see here).

"By setting, deaths at care homes and at home contributed most to the observed ‘mortality gap’, while hospital mortality was lower than expected." The authors specifically attribute such data to the gap between spending on social care vs. spending on health care; also noting that "the recent drive to move patients with poor prognoses and who have reached their ceiling of care away from the hospital environment to care homes or their own homes may have contributed to this." One interpretation of this is that those who are elderly and/or vulnerable placed outside of the hospital environment are perhaps disproportionately being burdened with the effects of austerity.  And one possible solution? Well: "Our study suggests that the number of NHS-qualified nurses is the strongest tested mediator of the relationships between spending, and care home and home mortality." One solution but not the only solution.

With a UK budget announcement set for later this week, I wonder if the Watkins findings might figure in relation to the suggestion that "a cumulative spending increase of approximately £25.3 billion would be required to close this gap across health and social care by 2020/2021, equating to around £6.3 billion annually." Yes, those are some quite staggering sums of money, but at the end of day what is to be valued more: balancing the books or plugging quite a significant mortality gap? (and even some of our elected officials seem to be interested in this debate).


[1] Watkins J. et al. Effects of health and social care spending constraints on mortality in England: a time trend analysis. BMJ Open 2017;7:e017722.


Monday, 20 November 2017

"the importance of considering how autism acceptance could contribute to mental health in autism"

The quote heading this post comes from the findings reported by Eilidh Cage and colleagues [1] (open-access) who sought to examine how "experiences and perceptions of autism acceptance could impact on the mental health of autistic adults."

Using an on-line survey "to test the relationship between perceived autism acceptance and mental health (specifically, depression, anxiety and stress)" findings are reported based on responses from over 110 people diagnosed as on the autism spectrum. I say 'diagnosed as on the autism spectrum' but as with any internet survey, there is always a degree of 'trust' that autism diagnoses are being reported faithfully just as it is with other labels that were under study: "a high proportion of participants reported additional diagnoses." Indeed, I also note that "11 participants reported that they did not currently have a formal diagnosis of autism" and were still included in some of the analyses...

No mind, the authors sought to 'quantify' autism acceptance given no measure currently exists by asking various questions including "whether they felt that society (specified as the general public, made up of people who did not personally know them) generally accepted them, with “yes”, “no”, “sometimes” and “prefer not to say” as response options." Responses were also sought to statements such as "over the past week, I have felt accepted by society as an autistic person/person with autism" and onward "perceptions of autism acceptance from different sources." This was complemented by responses to the Depression, Anxiety and Stress Scale (DASS-21).

Results: "depression was predicted by autism acceptance from external sources (society, family and friends) and personal acceptance" but anxiety was not seemingly *linked* to autism acceptance. Drilling down further into their results, researchers observed that "greater personal autism acceptance predicted lower depressive symptoms" indicating that variables such as self-esteem might mediate any risk of presenting with depressive signs and symptoms [2] (see here for my take). This is something that perhaps tallies with other research talking about autistic traits and wellbeing [3].

The author has also written a piece for The Conversation on her research study (see here).

I'm not quite sure why the ever-fluffy psychological concept of 'Theory of Mind' (ToM) needed to be introduced into the Cage paper given that no measure of ToM was actually included in the study. A quick search of other published research from these authors reveals that ToM is a feature there too [4]. The authors talk about how "Theory of Mind ability may impact on perceptions of autism acceptance" but I'm not so sure that this is particularly important. It's kinda like suggesting that society is completely autism aware and accepting/accommodating but those on the spectrum 'don't seem to understand it' as a result of any ToM issues, which is of course, a nonsense. ToM also still requires a bit more investigation into what it actually means and covers (see here) including the idea that issues with ToM might themselves be 'impaired' as a result of something like depression (see here). I'd also point out that quite a few other over-represented diagnoses potentially appearing alongside autism also seem to present with ToM issues [5] too...

"There is still a long way to go in understanding and tackling the high prevalence of mental health difficulties in autism, but we believe that the social model approach is a useful and positive lens through which mental health outcomes could be improved." That was the conclusion reached by authors on the basis of their findings. I would agree that there is still a long way to go on the topic of mental health and autism and the social model approach - "disability is caused by the way society is organised, rather than by a person’s impairment or difference" - is an option for further research of this kind. But I would also caution that one needs to balance such a perspective with others too (see here), and accept that the organisation of society is not always the most disabling aspect of a person's disability, particularly when it comes to something like depressive symptoms. Indeed, to say that depressive symptoms accompanying autism might merely be a facet of a 'lack of acceptance' or a lack of understanding from society or the individual themselves, risks plunging autism back into some pretty dark times (see here) and is likely to conflict with various other views. From a clinical point of view, it ignores some very serious research on the wide spectrum that is depression potentially present for all-manner of different reasons, being relevant to the equally wide spectrum that is autism (see here for a discussion on how depression might actually be something rather more fundamental to some autism over just being 'comorbidity'). At worst, it may even delay or put people off from seeking timely recognised treatments when depression becomes 'clinical', which could be a rather dangerous path to start down (see here).

Having said all that, I don't however think too many people would argue with the idea that personal perception(s) whether positive or negative are likely to impact on a person's mental (and physical?) health and wellbeing. If one is constantly feeling like an 'outsider' or excluded or feels that ones needs are not being met, added to a possible history of being bullied or loneliness or indeed, with other clinical labels also potentially being present for example, one is likely to build up a mindset appropriate to such a situation which probably includes some advanced risk for depressive signs and symptoms. From that point of view, much more needs to be done to look at the ways and means of impacting those personal perceptions; possibly taking into account other relevant research which has some [evidence-based] suggestions on things like societal inclusion and increasing access to it (see here) for those who want this option, alongside other complementary strategies where some [peer-reviewed] evidence is present (see here) and continues to be produced (Google the 'HUNT Cohort Study' to see what I mean). I say all this reiterating that something like chronic loneliness can very much be a major contributor to issues like depression.

I also understand the calls to make society more autism-accepting which I think most people would support as being pertinent across the ENTIRE autism spectrum (see here). I'm however, a little unsure of the real-life plan and details of the plan attempting to achieve this goal; particularly in the current climate when even getting a timely diagnosis seems to be an uphill struggle and when also many on the autism spectrum are seemingly left to fend for themselves post-diagnosis. Society it seems, is getting much more autism aware (for good or bad based on current media portrayals for example) but not necessarily getting more autism accommodating nor necessarily putting important words into actions. Indeed, one could argue that other societal factors like unemployment and financial hardship readily experience by those with autism are probably as, if not more, important to their experiences of something like depression yet little appears to be done to improve such issues for the vast majority...

As for the "experiences of “camouflaging” [that] could relate to higher rates of depression" also mentioned in the Cage article, I have quite a lot of time for this area of autism research (see here). Particularly the idea that camouflaging is not necessarily an all-female pursuit in the context of autism (see here) and how truly energy-sapping it can be for many, many people on the spectrum...


[1] Cage E. et al. Experiences of Autism Acceptance and Mental Health in Autistic Adults. J Autism Dev Disord. 2017. Oct 25.

[2] McCauley JB. et al. Self-Esteem, Internalizing Symptoms, and Theory of Mind in Youth With Autism Spectrum Disorder. J Clin Child Adolesc Psychol. 2017 Oct 19:1-12.

[3] Rodgers JD. et al. Brief Report: Personality Mediates the Relationship between Autism Quotient and Well-Being: A Conceptual Replication using Self-Report. J Autism Dev Disord. 2017 Sep 16.

[4] Cage E. et al. Reputation management: evidence for ability but reduced propensity in autism. Autism Res. 2013 Oct;6(5):433-42.

[5] Wang Y-Y. et al. Theory of mind impairment and its clinical correlates in patients with schizophrenia, major depressive disorder and bipolar disorder. Schizophrenia Res. 2017. Nov 7.


Saturday, 18 November 2017

Probiotics degrading gluten peptides - part 4

Here we go again. Probiotics degrading gluten peptides part 4 adds to previous posts on this topic (see part 1 here, part 2 here and part 3 here).

The difference this time around? People. People actually eating a a test meal containing gluten - "a porridge containing 0.5 g gluten" - and being given a potential gluten-degrading preparation - "Aspergillus niger-derived prolyl endoprotease (AN-PEP)" - or a placebo whilst their gastric and duodenal content was sampled for gluten concentrations over a 3-hour period after. So described the results published by Julia König and colleagues [1] continuing a research theme from this group [2].

AN-PEP was the product under the research spotlight following some previous scientific findings [3] suggesting that unlike various other digestive enzyme supplements, this stuff showed some pretty good actions/effects on immunogenic gluten peptides. Following a "randomized placebo-controlled crossover study" design, researchers followed 16 participants "with self-reported gluten sensitivity" (but not coeliac disease or wheat allergy) across 3 test days when on each day either a high dose of AN-PEP was given, or a low dose of AN-PEP was given or a placebo was given. Details of the high and low doses included: "The low dose tablets provided 83300 Protease Picomol International (PPI), and the high dose 166700 PPI of AN-PEP enzyme (1 PPI is the amount of enzyme that releases one picomole of p-nitroaniline per second under defined assay conditions)."

This was quite an invasive study as researchers had to gain access to parts of the gastrointestinal (GI) tract of participants and so: "Subjects attended each test day after an overnight fast, and a multi-lumen nasoduodenal catheter was placed with one lumen tip in the gastric antrum and one lumen tip 15 cm lower in the duodenum." It was then a case of drawing off stomach and duodenal samples and analysing for gluten content. Further: "success of AN-PEP in degrading gluten was defined as at least 50% gluten degradation compared to placebo, calculated as area under the curve (AUC) over 180 min."

Results: "It actually works" was a quote from one of the authors of the paper in previous media attention of this study before peer-reviewed publication. "In the stomach, gluten levels were reduced from 176.9 to 22.0 in the high dose and to 25.4 μg × min/ml in the low dose. In the duodenum, gluten levels were reduced from 14.1 in the placebo to 6.3 in the high dose and to 7.4 μg × min/ml in the low dose." AN-PEP appeared to be doing its designated job. Importantly too: "No severe adverse events were reported" over the course of the study period.

Scientific replication is the name of the game following the König results. Replication with larger sample numbers and also potentially looking at whether such a preparation might be useful for those diagnosed with something like coeliac disease or other accepted immune-related pathology linked to gluten consumption. I say that acknowledging that a gluten-free diet is the best that science and medicine currently has for the management of coeliac disease. The authors also note that they "did not perform a double-blinded placebo-controlled gluten challenge as sometimes suggested to confirm the diagnosis of gluten sensitivity" in their participants. This kinda intersects with the continuing discussions about what non-coeliac gluten/wheat sensitivity actually is (see here).

"In conclusion, our study showed that the AN-PEP enzyme is effective in degrading small amounts of gluten as part of a complex meal in the stomach. Even though the use of AN-PEP is not intended to replace a gluten-free diet in gluten-related disorders, it appears to be effective as a digestive aid protecting against the unintentional intake of gluten." I can't argue with that and look forward to seeing more on this topic in future.


[1] König J. et al. Randomized clinical trial: Effective gluten degradation by Aspergillus niger-derived enzyme in a complex meal setting. Sci Rep. 2017 Oct 12;7(1):13100.

[2] Salden BN. et al. Randomised clinical study: Aspergillus niger-derived enzyme digests gluten in the stomach of healthy volunteers. Aliment Pharmacol Ther. 2015 Aug;42(3):273-85.

[3] Janssen G. et al. Ineffective degradation of immunogenic gluten epitopes by currently available digestive enzyme supplements. PLoS One. 2015 Jun 1;10(6):e0128065.


Friday, 17 November 2017

On iron and vitamin D and autism

"This study suggests that deficiency of iron and Vitamin D as well as anemia were more common in autistic compared to control children."

'This study' refers to the findings reported by Abdulbari Bener and colleagues [1] (open-access available here) who set out to "investigate iron deficiency anemia and Vitamin D deficiency among autism children" in Qatar, a part of the world not renowned for its 'lack of sunshine' (a source material for the production of vitamin D).

Looking at some 300 children diagnosed with an autism spectrum disorder (ASD) and an equal number of controls, not-autism controls "who visited the primary health-care centers", researchers concluded that as a group, those with autism were more likely to present with low serum iron levels (and various related measures) and further that: "Vitamin D deficiency was considerably more common among autistic children." The authors provide some background details on what constitutes vitamin D deficiency and other 'levels': "Participants were classified into four categories: (1) severe Vitamin D deficiency, 25OHD <10 ng/ml; (2) moderate deficiency, 25OHD 10–19 ng/ml; (3) mild deficiency, 25OHD 20–29 ng/ml; and normal/optimal level is between 30 and 80 ng/ml."

When attempting to ascertain what factors might be important to the autism vs. not-autism participants, researchers reported that: "serum iron deficiency, serum calcium levels, serum Vitamin D levels; ferritin, reduced physical activity; child order, body mass index percentiles, and parental consanguinity can all be considered strong predictors and major factors associated with autism spectrum disorders." I might add that consanguinity defined as "unions between couples who share at least one common ancestor" is perhaps something more 'culturally-relevant' to autism in certain countries and societies [2] but not necessarily widely applicable...

What's more to say about the Bener findings? Well, given that issues with iron (see here) and issues with vitamin D (see here) are no strangers to the autism research landscape, there is little novelty in the conclusions reached even if being "the first report on an establishing level of iron deficiency in children with autism in Qatar and in Arabian Gulf Countries." The implication is again that preferential screening and treatment of such issues should be offered when a diagnosis of autism is received, save any further health inequalities arising. Whether or not treating something like iron deficiency and/or vitamin D issues will impact on behavioural presentation (see here) is perhaps an issue for another day. I say this bearing in mind the sentiments expressed in the recent paper by Philippe Autier and colleagues [3] examining the collected data on vitamin D supplementation "on non-skeletal disorders" and results seemingly "strengthening the hypothesis that low vitamin D status is a consequence of ill health, rather than its cause."


[1] Bener A. et al. Iron and vitamin D levels among autism spectrum disorders children. Ann Afr Med. 2017 Oct-Dec;16(4):186-191.

[2] Mahajnah M. et al. Clinical characteristics of autism spectrum disorder in Israel: impact of ethnic and social diversities. Biomed Res Int. 2015;2015:962093.

[3] Autier P. et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017 Oct 25. pii: S2213-8587(17)30357-1.