2016 autism research review on Questioning Answers

Time flies! Once again, I'm posting my annual 'state of the science' autism research review, this time covering the particularly unusual year of 2016.

With around 300 blog entries to choose from, I'm changing the format this year to list a 'top 5' of areas where I think some scientific progress has been made. The caveat as ever being that there are still mountains to climb in terms of delineating aetiology, nature and importantly, how one can actually improve quality of life for those on the spectrum. At the foot of this post I've also detailed a few 'areas to watch' in the coming months/years too.

So, in no particular order, here goes:

1. Vitamin D and autism. As per my 'one to watch' prediction from the 2015 end-of-year review, there has been a veritable science feast focused on the sunshine vitamin/hormone in connection to autism (see here). The research discussions in 2016 started with some initial talk about 'clinical improvements' following supplementation with vitamin D (see here). This was accompanied by chatter about the possible use of pregnancy vitamin D affecting risk of offspring autism (see here and see here). Screening for vitamin D levels as and when a diagnosis of autism is received was also discussed (see here). Then, towards the end of the year, things got really interesting as one of the first controlled trials of vitamin D supplementation in autism was published (see here) with the promise of more to come (see here). The findings (double-blind, placebo-controlled) suggested that for some at least, vitamin D over placebo might have the ability to affect the presentation of some aspects of autism. The caveats? Well, larger controlled trials are required and one has to be careful about doses of vitamin D in light of some cautionary tales (see here). What else needs to be done on the topic of vitamin D and autism? Given the number of conditions the sunshine vitamin has been linked to - some labels potentially crossing over with autism - a wider view of any 'effects' outside of those just on core autism symptoms might be useful. This will probably also provide some more potentially information about the possible hows-and-whys of vitamin D action.

2. Autism as a plural condition. 'The autisms' is a phrase not unfamiliar to this blog (see here) but this year, a couple of papers really started putting some scientific flesh on to the bones of the argument for why we need to rethink autism. Discussions on the paper by Lynn Waterhouse and colleagues [1] (see here) set the tone for such a debate and how the label of autism serves a purpose in defining / describing symptoms but seemingly does little else when it comes to a research perspective looking at the hows-and-whys of autism. That autism seemingly appears alongside a long list of other conditions including quite a few of the various inborn errors of metabolism (see here and see here) substantiates the idea that a singular labels says very little about the 'essence' of autism. And speaking of ESSENCE (see here), there was yet more on this important topic. Another part of this 'pluralisation' debate is the fact that the 'autism is a lifelong condition' mantra rolled out again and again and again might not necessarily ring true for everyone who was once diagnosed on the autism spectrum (see here and see here). And to say that these children/adults were 'never autistic in the first place' does a real disservice to them, their parents and loved ones and the professionals who diagnosed them...

3. Meta-analysing autism. Mirroring what seems to be apparent in the research literature in general, a whole slew of meta-analyses and systematic reviews on the topic of autism emerged this year. We had reviews on long-term outcome and quality of life (see here), behavioural outcomes following exercise (see here), medication (see here and see here), joint intervention strategies (see here), pregnancy infection and offspring autism risk (see here) and allergic asthma and autism (see here) to name but a few. One of the particularly notable reviews of the collected data was that by Nevill and colleagues [2] on the topic of parent-mediated interventions for young children with autism. Covering a topic with more than a pinch of media hype this year (see here), the science behind the hype in this area actually turns out to be not that strong at the moment...

4. Real-world autism. Although I'm partial to reading quite a bit on the science about autism, one thing I hope I never forget is how that science translates into 'action' when it comes to autism, either in terms of 'hows-and-whys' or impacting on the day-to-day positives and negatives of living with the label. This year I've talked about more research on the topic of 'real world autism' covering various angles including: wandering and autism (see here), parents lived experience of offspring autism diagnosis and beyond (see here and see here), early mortality and autism (see here and see here), the so-called challenging behaviours (see here) and the employment stats (see here). Quite a few of these areas make for uncomfortable reading insofar as the widening gaps present between autism and not-autism. But just before anyone suggests that I'm somehow casting autism in shadow, many if not all of the issues raised in those posts are solvable. So for example, on challenging the idea that 'people with autism die younger' and in particular, tackling the heightened suicide risk seemingly present alongside autism, there are practical things that can be done (see here); not least appropriate screening for important comorbidities (see here) and managing accordingly. Yes, there are mountains to climb, but with a pair of sturdy 'research and clinical practice' walking boots, change is possible...

5. Immune function and autism. I've added this into my top 5 of scientific progress because the knowledge base around how the immune system may be linked to at least some 'types' of autism is increasing year on year. It's a huge topic in terms of both aspects covered and potential 'links' being made but a few choice areas include: 'autism genes' being linked to immune function (see here), immune-related conditions being over-represented in autism (see here) and some big names coming around to the idea of neuroinflammation and [some] autism (see here). In this section I'm also going to draw your attention to further evidence talking about infection 'correlating' with the onset of some autism (see here) and how important gut issues (that often have immune-related biochemistry linked in) associated with some autism have received some further welcome research attention (see here). On the basis of this and the wealth of other peer-reviewed research on this topic, it would be a brave person to say that the immune system has no link to at least some types of autism. Such research also opens up the possibility of alternative avenues for intervention too (see here and see here) (with no medical advice given or intended)...

So as you can see, it's been a busy research year again when it comes to the label of autism. Alongside some of the science covered I'd also draw your attention to some emerging ideas including the suggestion that autism genes are not just genes for autism (see here), the stats on the estimated numbers of people diagnosed with autism being still high (see here) and possibly still rising in some areas (see here) and the suggestion of a 'frank' presentation of autism (see here) as being put out there and what effects this might have on autism screening and diagnosis.

What next for autism research in 2017? Well I dunno. But I might speculate on a few things including: (a) the rise and rise of investigations into gut bacteria and autism (see here for one possible example) including research looking at potentially 'altering' gut bacterial profiles (see here), (b) more research looking at the DSM-5 catch-all category called SCD (see here) and what it means for autism as a whole, (c) CRISPR-Cas9 and autism research (carefully) continued (see here) (if patents and the like don't get in the way), (d) the development of the ICF core sets for autism continuing (see here) and (e) further investigations into conditions such as the connective tissue disorders in relation to autism (see here) bearing in mind how motor skills in relation to autism seems to be coming back into research fashion. On that last point also, and bearing in mind my other blogging interest in relation to the labels called chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME), I'm also wondering if it is time for someone, somewhere to think about looking at the prevalence of CFS/ME in autism or vice-versa? Provided that is, they can select the correct description of CFS/ME and can avoid any psychosomatic entanglements (see here)...

Anyhow, I wish you all (again) health and happiness for the New Year.

And finally for my brood of black belt karateka (not forgetting a brown belt too), a song about a tiger and never giving up. And thank you also for motivating me to get further into the sport even if you do think I'm better suited to kihon and kata over and above kumite... the cheek of it.

Later dudes.

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[1] Waterhouse L. et al. ASD validity. Review Journal of Autism and Developmental Disorders. 2016. Aug 10.

[2] Nevill RE. et al. Meta-analysis of parent-mediated interventions for young children with autism spectrum disorder. Autism. 2016. Nov 14.

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Waterhouse, L., London, E., & Gillberg, C. (2016). ASD Validity Review Journal of Autism and Developmental Disorders, 3 (4), 302-329 DOI: 10.1007/s40489-016-0085-x





Nevill, R., Lecavalier, L., & Stratis, E. (2016). Meta-analysis of parent-mediated interventions for young children with autism spectrum disorder Autism DOI: 10.1177/1362361316677838

ADHD symptoms and chronic fatigue syndrome?

With the pinnacle of the season of 'jolly' almost upon us, I'd like to make some brief discussion on the findings reported by Denise Rogers and colleagues [1] and specifically the observation that: "ADHD [attention-deficit hyperactivity disorder] symptoms were significantly greater in the CFS [chronic fatigue syndrome] group than in HC [healthy controls]."

With the aim of examining both the prevalence of fatigue in cases of ADHD and the prevalence of ADHD symptoms in adults with CFS (a term 'linked to' the condition called myalgic encephalomyelitis), researchers set about investigating several measures including self-reported (that's 'self-reported') fatigue "across groups of adults with ADHD (N = 243), CFS (N = 86), and healthy controls (HC) (N = 211)." The results were interesting insofar as that previous sentence on ADHD symptoms perhaps not being uncommon in cases of CFS vs. asymptomatic controls but also that: "Fatigue is a common clinical feature of attention deficit hyperactivity disorder (ADHD) in adulthood."

Accepting that there may be important implications from the notion that fatigue may be part and parcel of at least some ADHD (see here for example), the idea that ADHD signs and symptoms might be over-represented in cases of CFS is interesting, if not necessarily novel [2]. Minus any sweeping generalisations or psychobabble explanations of hows-and-whys (we've had quite enough of those in relation to CFS), I'd like to think that such an association could shed some light on the possible shared genetics, epigenetics and biochemistry of both conditions. Given also some initial data emerging on the potential usefulness of something like methylphenidate (indicated for cases of ADHD) for cases of CFS (see here) there are also avenues to explore in relation to shared drug targets across both conditions (see here for some discussion on oxidative stress for example). I'd like to see more study on this topic, bearing in mind how broad labels like CFS and ADHD can be. I'm also wondering whether researchers might also one day replace examination of ADHD traits with autistic traits so as to perhaps provide data on whether there may be other important associations to be had...

And with that I wish you all a very Merry Christmas and a happy and healthy New Year. I'm not done just yet with this years blogging adventures as my annual 'what was hot in autism research in 2016' post is scheduled sometime next week (if you're interested/bored of turkey/bored of watching Christmas films - delete as appropriate).

Music to close and as always at this time of year, it wouldn't be the same without Kirsty and Shane. And please, do try to stay out of the drunk tank this Christmas...

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[1] Rogers DC. et al. Fatigue in an adult attention deficit hyperactivity disorder population: A trans-diagnostic approach. Br J Clin Psychol. 2016 Dec 5.

[2] Sáez-Francàs N. et al. Attention-deficit hyperactivity disorder in chronic fatigue syndrome patients. Psychiatry Res. 2012 Dec 30;200(2-3):748-53.

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Rogers, D., Dittner, A., Rimes, K., & Chalder, T. (2016). Fatigue in an adult attention deficit hyperactivity disorder population: A trans-diagnostic approach British Journal of Clinical Psychology DOI: 10.1111/bjc.12119

Psychosis (sometimes) as an immune disorder?

"Some psychosis cases an 'immune disorder'" went the BBC headline with reference to the paper by Belinda Lennox and colleagues [1] talking about the detection of antibodies against the N-methyl-D-aspartate receptor (NMDAR) in cases of first-episode psychosis (FEP).

Although by no means a universal phenomenon, researchers reported that 3% of their 228 participants diagnosed with FEP who provided a blood sample showed the presence of NMDAR antibodies compared with none of the healthy controls (n=105) included for study. As part of the condition known as anti-NMDAR encephalitis, the presence of NMDAR antibodies can indeed include/induce psychotic features [2].

This is interesting work. For anyone that has come across the book 'Brain on Fire' by Susannah Cahalan, there is a growing interest in how the presentation of psychiatric features can, on occasion, include a significant role for the immune system and particularly, the concept of autoimmunity (where the body's own immune system fails to differentiate between 'self' and 'other'). Some of the authors included on the Lennox paper have previously summarised and discussed the idea that NMDAR antibodies might show a connection to some cases of psychosis and conditions manifesting psychosis such as schizophrenia [3]. The current data tally with their previous conclusion that: "A minority of patients with psychosis are anti-NMDA receptor antibody positive" and onwards the idea that there may be many different 'roads' to psychosis in these days of plural conditions (see here).

Where next for this research area I hear you ask? Well, set against the idea that various autoimmune diseases might be over-represented alongside a diagnosis like schizophrenia (see here), one needs to tease out some of the hows-and-whys details. Does, for example, a history of autoimmune disease 'set someone up' for psychosis and/or schizophrenia? Or is the autoimmune element of it something that follows a diagnosis of psychosis and/or schizophrenia? I have some opinions on this based on other findings on how autoimmunity may come about for some (see here for some discussion on HERVs) taking into account other peer-reviewed ideas and data [4]. I don't profess to be right or offer any universal answer but it is interesting that endogenous virus expression does seem to be heightened in a condition like schizophrenia and said elements might be considered important in processes such as molecular mimicry as one mechanism of autoimmunity [5]. There is a research plan to carry out and specifically on the topic of how NMDAR antibodies come about.

The other important 'where next' for this area of investigation is the tantalising prospect that 'treating' said autoimmune reaction might have some important effects on the presentation of something like FEP. There are hints out there in the peer-reviewed literature of possible treatment options being available. I might for example, draw your attention to some overlapping work looking at anti-NMDAR encephalitis ('encephalitis' that is) and cases of autism (see here and see here) where intervention options are discussed. With no medical advice given or intended, methylprednisolone seems to have found therapeutic favour for some. Other, more aggressive treatment options have also been reported but further investigations are required.

I note the words 'immuno-psychiatry' are mentioned in the media reporting of the Lennox findings and I'm happy to see the profile of this area of research being elevated through such work. The idea that immune function(s) might be doing so much more than just identifying and eradicating foreign bodies to maintain our physical health continues to gather pace...

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[1] Lennox BR. et al. Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study. Lancet Psychiatry. 2016. Dec 7.

[2] Dalmau J. et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurology. 2011;10(1):63-74.

[3] Pollak TA. et al. Prevalence of anti-N-methyl-D-aspartate (NMDA) receptor [corrected] antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychol Med. 2014 Sep;44(12):2475-87.

[4] Slokar G. & Hasler G. Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia. Frontiers in Psychiatry. 2015;6:183.

[5] Trela M. et al. The role of molecular mimicry and other factors in the association of Human Endogenous Retroviruses and autoimmunity. APMIS. 2016 Jan-Feb;124(1-2):88-104.

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Lennox, B., Palmer-Cooper, E., Pollak, T., Hainsworth, J., Marks, J., Jacobson, L., Lang, B., Fox, H., Ferry, B., Scoriels, L., Crowley, H., Jones, P., Harrison, P., & Vincent, A. (2016). Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study The Lancet Psychiatry DOI: 10.1016/S2215-0366(16)30375-3

"New form of autism found"

"New form of autism found" went one of the headlines reporting on the paper by Dora C. Tărlungeanu and colleagues [1] and findings that "elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA [branched-chain amino acids] in human brain function." This work continues a rather important research story talking about how one 'type' of autism might have some important roots in relation to the branched-chain amino acids and their metabolism (see here and see here for more information).

So, mice were the focus on the paper by Tărlungeanu et al (including one Gaia Novarino on the authorship list) and an extension of the idea that the BCAAs may play an important role in some autism in these days of the plural 'autisms' (see here). SLC7A5 represents a gene that codes for a protein involved in the transport of BCAAs into the brain among other things. Researchers studied mice who were genetically 'edited' to present with a "deletion of Slc7a5 from the endothelial cells of the BBB [blood-brain barrier]." In effect, the area of the body where SLC7A5 serves those important transport duties, a hold-my-hand partner was missing resulting in lower brain levels of the BCAAS.

Researchers noted a few important things in those SLC7A5-missing mice; not least in relation to their mouse behaviour(s) and how bearing in mind mice are mice not people, they seemed to present with behavioural issues not a million miles away from that noted in relation to autism. 'Social interaction' was as I understand it, something potentially affected in those SLC7A5-missing mice. Further: "we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene" suggesting that their results might stretch to people too.

And then something else that might eventually be important: "we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice." Intracerebroventricular administration basically means an injection straight into the brain. After a few weeks of such injections, researchers noted that mouse behaviours began to change coincidental to the direct administration of those BCAAs.

This is interesting research. I know that not everyone on the autism spectrum presents with issues with the BCAAs (as far as we know). But in these days of increasing plurality when it comes to autism coupled to the rise and rise of study on the various inborn errors of metabolism in relation to autism (see here), this could be pertinent to at least one type of autism. I also appreciate that 'brain injections' of something like BCAAs are not exactly a desirable option for anyone so there is still some work to do in terms of how to correct any central BCAA deficiency if and when identified. Talk about a possible relationship between the BBB and autism in the Tărlungeanu paper also continues a theme (see here) where this important barrier separating the brain from the other contents of the body (and indeed, the outside world) might represent something potentially quite important to autism (see here) and indeed, with 'transporters' also in mind (see here).

Much more research is implied.

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[1] Tărlungeanu DC. et al. Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder. Cell. 2016. Dec 1.

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Tărlungeanu, D., Deliu, E., Dotter, C., Kara, M., Janiesch, P., Scalise, M., Galluccio, M., Tesulov, M., Morelli, E., Sonmez, F., Bilguvar, K., Ohgaki, R., Kanai, Y., Johansen, A., Esharif, S., Ben-Omran, T., Topcu, M., Schlessinger, A., Indiveri, C., Duncan, K., Caglayan, A., Gunel, M., Gleeson, J., & Novarino, G. (2016). Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder Cell, 167 (6), 1481-2147483647 DOI: 10.1016/j.cell.2016.11.013

Generation R does gestational vitamin D levels and autistic traits

"Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny."

So said the findings reported by Vinkhuyzen and colleagues [1] (open-access) reporting on data derived from "the Generation R Study, a population-based prospective cohort from fetal life onward, based in Rotterdam, The Netherlands." I've talked about this study initiative before on this blog (see here) but this time around its scientific eyes turned towards the possibility that vitamin D - the sunshine vitamin/hormone - might have some important connections to the presentation of some of the facets of autism or at least autistic traits. Yes, yet again, vitamin D and autism comes into view (see here)...

The Vinkhuyzen paper is open-access for all to see (and has already received some media exposure) but here are a few choice details:

• Hypothesis: explore "the association between gestational 25OHD concentrations and a widely used parent-report continuous measure of autism-related traits—the Social Responsive Scale (SRS)." Said levels of 25-hydroxyvitamin D (25OHD) (the functional unit of vitamin D assessment) were obtained from "maternal mid-gestation sera and from neonatal sera (collected from cord blood)." SRS scores relevant to offspring were provided by parents "when the children were ~6 years of age."
• Results: well, this certainly wasn't an under-powered study as data for "4229 children and their mothers were available with measures of vitamin D concentrations drawn from maternal blood at mid-gestation and/or drawn from cord blood at time of birth as well as data on the SRS, 2489 children and their mothers were available with measures of vitamin D concentrations at both time points." Approximately 16% of mothers were classed as deficient based on that mid-gestation serum sample rising to 36% when looking at cord blood samples. As I've mentioned before, issues with vitamin D generally fall into a few bandings associated with insufficiency and deficiency at the lower end of typical.
• "In all analyses, 25OHD deficiency or lower 25OHD concentrations were associated with higher (more impaired) SRS scores." This was based on the use of an "18-item abridged version of the questionnaire" that specifically looked at "behavioural features related to social cognition, social communication and autistic mannerisms." Remember, this was a study looking at autistic traits not autism diagnoses. Interestingly too, authors were also able to restrict their analysis to "offspring with European ethnicity" and reported similar results associating lower vitamin D levels and higher SRS scores. This subgroup analysis perhaps ties into other research where ethnicity has been suggested to be a factor in relation to vitamin D levels and diagnosed autism (see here).

So, there you have it. Yet more evidence linking vitamin D and autism and/or autistic traits; this on the back of my previous entry not-so-long-ago (see here) talking about supplementation as a potential means to affect presentation of at least some autism, with appropriate caveats (see here). It's getting increasingly difficult to say that there is 'no connection' between the two factors.

Strengths of the Vinkhuyzen study? Well, as I said, it was big in terms of participant numbers. I note also the authors proudly announce: "We used a gold standard assessment of 25OHD concentrations" in light of the application of "isotope dilution liquid chromatography-tandem mass spectrometry." A gold star for the authors indeed in light of some 'chaos' when it comes to the hows and whys of measuring vitamin D status. Limitations: well, as per every study that looks at the association between a small number of variables, there are potentially a million and one other factors that might also account for the results. Another gold star is due for the authors' mention of the fact that vitamin D seems to be 'associated' with various diagnostic labels outside of rickets these days (see here for example) and hence one cannot rule out that traits or diagnoses not specifically covered by the study could have exerted some effect. More so when one considers how much autistic traits might not be just autism-specific traits (see here). I might also add that subsequent work could/should also be looking at the genetics of vitamin D metabolism not just functional levels of the stuff (see here).

A final quote from the authors to close: "Just as prenatal folate supplementation has reduced the incidence of spina bifida, we speculate that prenatal vitamin D supplementation may reduce the incidence of ASD." I know such sentiments might not be welcomed by everyone, and the assumption that autistic traits are 'always a negative thing' needs some continued careful consideration. The ideas however that: (a) nutrition might impact on both psychology and physiology and (b) that where appropriate and/or where wanted, use of vitamin D supplement might impact on risk of autism or the presentation of autism, are ideas that are deserving of a lot more investigation.

And again, minus any charges of clinical or medical advice being given on this blog (they're not), here is what the UK Government (or parts of the UK) are currently saying about vitamin D and the population as a whole...

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[1] Vinkhuyzen AA. et al. Gestational vitamin D deficiency and autism-related traits: the Generation R Study. Mol Psychiatry. 2016 Nov 29.

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Vinkhuyzen AA, Eyles DW, Burne TH, Blanken LM, Kruithof CJ, Verhulst F, Jaddoe VW, Tiemeier H, & McGrath JJ (2016). Gestational vitamin D deficiency and autism-related traits: the Generation R Study. Molecular psychiatry PMID: 27895322

Gut barrier integrity meets blood-brain barrier integrity with autism in mind

"In the ASD [autism spectrum disorder] brain, there is an altered expression of genes associated with BBB [blood-brain barrier] integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity."

Although pretty enthused to see research linking names like Anna Sapone, Tim Buie and Alessio Fasano in the recent paper published by Maria Fiorentino and colleagues [1] (open-access), I was slightly less impressed with the use of the term 'the ASD brain' in their paper potentially joining two concepts that I've been quite interested in down my research years: gut barrier and blood-brain barrier function in the context of autism. Yes, I accept that those most precious of resources, donated brains from the deceased, represented some of the 'material' under scientific scrutiny, but if science has learned anything about autism down the years, it is that sweeping generalisations such as terms like 'the autism brain' don't reflect what the existing research tells us about the heterogeneity under the label. I might just as well use the term 'blogger brain' to denote some of my activities, but such a label tells you nothing about me aside from my pastime.

After that little rant, the paper from Fiorentino is an interesting one in that the goal was to "investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD." To do this, tissue from both brain and gastrointestinal (GI) tract donated by a small number of deceased and non-deceased participants who were diagnosed with autism, schizophrenia or nothing related (not-autism controls) were analysed "for gene and protein expression profiles." This work was undertaken on the basis of "the interconnectivity of the gut–brain axis, [that] suggests that inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of antigens or activated immune complexes through a permissive blood–brain barrier (BBB), can be part of the chain of events leading to neuroinflammation and thereby subsequent disease." I might add that the use of the word 'disease' in that sentence is, I think, aiming to describe the physiological effects of 'leaky barriers' not the diagnosis of autism. It is unfortunate however that 'disease' still continues to be banded around in the context of autism [2].

I think it's important to stress that the Fiorentino study was in effect two studies: one that looked at brain samples from one participant group who had died, and one that looked at GI samples from those who were still living (at the time of sample collection) and who presented with "GI symptoms undergoing esophagogastroduodenoscopy (EGD) for clinically indicated reasons." This was not a study where biological samples - brain and gut - came from the same person but rather a mash-up. Keep that in mind for now. The sorts of genes that were focused in on were those "associated with the formation, integrity, and function of the BBB and neuroinflammation" and included the claudins and something called MMP-9 and MMP-2 that have been discussed previously on this blog (see here) with leaky barriers in mind. The key words are 'barrier integrity' when it comes to the list of compounds that were under inspection.

Results: well it was good to see the authors list details of each of the participants from which tissue were used in their study. Brain tissue from the deceased with autism for example, is subject to quite a few factors that can influence the outcome of any results obtained; not least whether specific comorbidity accompanied their autism diagnosis and the nature of their death. Indeed, looking through the various case report numbers, I'm struck by how young many participants, particularly those diagnosed with autism, were at the time of their death. This ties into other discussions and debates (see here).

"Our molecular analysis of the BBB integrity and function shows an altered BBB in the ASD subjects evaluated." This was evidenced by elevations in the gene expression of MMP-9 and its proposed connection to disturbances of BBB integrity. Further: "Of the four claudins (i.e., CLDN-1, -3, -5 and -12) that to date are thought to be incorporated in the BBB... we found that two were significantly more expressed in the ASD brain as compared in HC [healthy controls]." Once again I might suggest the term 'healthy controls' is not an inappropriate one when it comes to determining not-autism or not-schizophrenia.

Then to analysis of those [independent] gut biopsy samples: "results, showing increased expression levels of pore-forming (66% of the ASD samples) and decreased levels of barrier-forming (75% of the ASD samples) TJ [tight junction] components in the duodenal samples, suggest an impaired gut barrier and serve as a proof of concept to support the hypothesis of a gut–brain axis dysfunction in a subgroup of ASD patients." So, those compounds linked to making the gut barrier more 'leaky' were seemingly increased in expression, and those linked to making the gut barrier less 'leaky' were reduced in quite a few of the samples from those diagnosed with autism. Mmm...

There is quite a bit more science included in the Fiorentino study but I think I've gone on long enough in this post. Suffice to say that the whole gut-brain axis thing with autism in mind gets a boost but more work is indicated, not least with larger sample groups and perhaps combining tissues from gut and brain from the same person. I would also like to see a little more done on this topic with some 'interventions' in mind, based on the other autism research that potentially links the authors (see here). Drawing for example, on a paper written by Prof Fasano titled: 'Zonulin, regulation of tight junctions, and autoimmune diseases' [3] suggesting that "gliadin, a storage protein present in wheat and that triggers celiac disease in genetically susceptible individuals, also affect the intestinal barrier function by releasing zonulin" one might see how far from being a set-in-stone state of affairs, dietary changes for some on the autism spectrum, might actually set in motion a host of biological changes pertinent to this area of work. And such changes might not be just confined to accepted gluten-related conditions either...

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[1] Fiorentino M. et al. Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Molecular Autism. 2016; 7:49.

[2] Simms MD. When Autistic Behavior Suggests a Disease Other than Classic Autism. Pediatr Clin North Am. 2017 Feb;64(1):127-138.

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

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Fiorentino, M., Sapone, A., Senger, S., Camhi, S., Kadzielski, S., Buie, T., Kelly, D., Cascella, N., & Fasano, A. (2016). Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders Molecular Autism, 7 (1) DOI: 10.1186/s13229-016-0110-z

Pregnancy influenza infection not linked to offspring autism

"There was no association between maternal influenza [flu] infection anytime during pregnancy and increased ASD [autism spectrum disorder] risk."

So said the findings reported by Ousseny Zerbo and colleagues [1] continuing a research theme from this author (see here for example) looking at how various infections 'encountered' during critical periods of pregnancy may / may not impact on offspring autism risk. This time around the focus was on viral infections and in particular "maternal influenza infection and vaccination from conception date to delivery date" as derived from either diagnosis using ICD-9 criteria or "a positive laboratory result for influenza based on the Prodesse ProFlu+ Assay (Hologic), a multiplex real-time polymerase chain reaction in vitro diagnostic test." Said participants numbering nearly 200,000 children were all born "at Kaiser Permanente Northern California from January 1, 2000 to December 31, 2010, at a gestational age of at least 24 weeks." The press release accompanying the publication can be seen here.

"Maternal influenza infection during pregnancy was not associated with increased ASD risk in this study, and the association did not vary by the timing of influenza infection." Importantly, authors also looked at whether maternal influenza vaccination during pregnancy was also related to offspring ASD risk based on the data contained in their patient databases. The results pertinent to pregnancy flu vaccination and offspring risk were not exactly cut-and-dried as "in an initial analysis unadjusted for multiple comparisons" the authors reported seeing a 'slightly increased' risk for offspring autism associated with maternal vaccination during the first few months of pregnancy. This was set against data indicating no significant association between maternal influenza vaccination covering 'anytime' during pregnancy. Indeed, after "adjusting for the multiplicity of hypotheses tested" they concluded that the first trimester vaccination - offspring autism risk was potentially a 'chance finding'. Minus any scaremongering and to be on the safe side the authors suggested that "additional studies are warranted to further evaluate any potential associations between first-trimester maternal influenza vaccination and autism."

Aside from a few potential 'weakness' attached to the Zerbo results including the fact that "subclinical infections or illnesses for which women did not seek medical attention" were not counted in the data, these are interesting results. Quite a few times on this blog I've covered the so-called maternal immune activation (MIA) hypothesis - where mum's reprogrammed pregnancy immune system is 'challenged' and potentially has implications for offspring development - and this work kinda falls into that category of autism science. Indeed, I've talked about the possibility quite recently (see here). Drawing also on data looking at season of conception/birth as potentially being important to pregnancy viral/bacterial exposure and onward offspring outcomes (see here) there has been a steady stream of peer-reviewed publications hinting at a potentially important 'association' between infection exposure in-utero and developmental outcomes for the child. The current Zerbo data however put a bit of a research spanner in the works when it comes specifically to any pregnancy flu and offspring autism risk suggestion albeit with the continued requirement for further investigations in this area covering other infections.

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[1] Zerbo O. et al. Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder. JAMA Pediatr. 2016 Nov 28.

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Zerbo O, Qian Y, Yoshida C, Fireman BH, Klein NP, & Croen LA (2016). Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder. JAMA pediatrics PMID: 27893896

Non-febrile seizures in children with autism vs unaffected siblings

"Children with idiopathic ASD [autism spectrum disorder] are significantly more likely to have non-febrile seizures than their unaffected siblings, suggesting that non-febrile seizures may be ASD-specific."

So said the findings from Lena McCue and colleagues [1] (open-access) continuing a research theme looking at one of the important 'comorbidities' that seems to be over-represented when it comes to a diagnosis of autism (see here). Idiopathic autism or ASD refers to autism as the primary diagnosis and not something tied to an existing condition where autism can also present. Non-febrile seizures are seizures without fever (where fever can very much result in seizures).

McCue et al "conducted a secondary analysis of data from a registry-based retrospective cohort study of 731 children with ASD and their 192 children unaffected siblings from the AGRE project for whom phenotypic data were collected." Data from around 320 families with at least one child diagnosed with an ASD (n=610) were compared with sibling data (n=160) in relation to the presence of non-febrile seizures. Siblings (not autism) were chosen as the control group because "siblings share, on average, fifty percent of genes as well as the same environment" so perhaps providing an alternative to just general population control groups.

Results: "The prevalence of non-febrile seizures in the ASD group was 8.2% (50/610) and 2.5% in the unaffected siblings (4/160)." What this tells us, aside from the increased frequency of non-febrile seizures in those children diagnosed with autism, is that so-called 'unaffected' siblings are not completely immune to seizures or seizure-linked conditions minus fever. Further: "the odds of having non-febrile seizures increased with age..., presence of GI [gastrointestinal] dysfunction..., and those with a history of febrile seizures had five times the odds of reporting non-febrile seizures."

I was particularly interested in the observations that: (a) gastrointestinal (GI) dysfunction, denoting functional bowel issues such as constipation or diarrhoea, were pretty well over-represented among the children with autism in this cohort, similar to other research (see here) and (b) said GI issues might itself/themselves 'up' the risk of non-febrile seizures in relation to autism. In these days of the 'gut-brain axis' where the grey/pinkish matter floating in the skull might not be totally separate and independent from the more mucus-y matter situated in the torso (see here for example), it strikes me as important that further investigations be carried out on how epilepsy might not just be a 'brain-thing'. We have for example, evidence pertinent to an autoimmune connection to some epilepsy (see here) that has implications for other autoimmune conditions affecting the gut too as per the notion that 'birds of an autoimmune feather may flock together'. That also one of the primary 'treatments' for epilepsy not responsive to the usual anti-epileptic medicines is the ketogenic diet (see here) is something else to consider when talking about gut and brain potentially being quite close neighbours.

"Our study found a five-fold higher lifetime prevalence of non-febrile seizures in children with idiopathic ASD from largely multiplex families compared to their unaffected siblings. These findings suggest that the reported non-febrile seizures may be ASD-specific and cannot be explained by genetic predisposition alone." With that conclusion from the study authors, one might similarly also suggest that the presence of autism in affected children vs. siblings also cannot be explained by genetic predisposition alone...

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[1] McCue LM. et al. Prevalence of non-febrile seizures in children with idiopathic autism spectrum disorder and their unaffected siblings: a retrospective cohort study. BMC Neurology. 2016; 16:245.

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McCue, L., Flick, L., Twyman, K., Xian, H., & Conturo, T. (2016). Prevalence of non-febrile seizures in children with idiopathic autism spectrum disorder and their unaffected siblings: a retrospective cohort study BMC Neurology, 16 (1) DOI: 10.1186/s12883-016-0764-3

ADHD, not autism, might count when it comes to 'comorbid psychiatric symptomatology'

A quote to begin this fairly brief post: "Our study concluded that higher levels of ADHD [attention-deficit hyperactivity disorder] severity-not ASD [autism spectrum disorder] severity-were associated with a higher prevalence of comorbid psychiatric symptomatology in school-age children with ASD. These findings may encourage clinicians to thoroughly assess ADHD symptomatology in ASD children to better inform treatment planning."

That was the research bottom line reported by Rosleen Mansour and colleagues [1] following their examination of how a pretty common comorbidity accompanying a diagnosis of autism (see here) might well play an important role in terms of other 'comorbid psychiatric symptomatology' among those with autism.

I'm interested in these findings for several reasons. A diagnosis of autism does seem to elevate the risk of receipt of various other psychiatric diagnoses (see here for example). As I've just said, ADHD is a pretty common comorbidity when it comes to autism (see here). A diagnosis of ADHD (and not the medication commonly used to manage such symptoms) seems to elevate the risk of receipt of various other psychiatric diagnoses too (see here). It's not too difficult to suggest that autism per se might not be 'the most important variable' when it comes to at least some people's risk of other psychiatric diagnoses being received. Indeed, there is another potentially important strand of evidence to include in this proposal, in terms of the continued experiences of some of those who 'move off the autism spectrum ' (see here).

More research is implied with one important question to answer about the nature of the synergy between autism and ADHD when it comes to any enhanced risk of psychiatric comorbidity...

So, Rogue One finally sees the cinematic light of day...

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[1] Mansour R. et al. ADHD severity as it relates to comorbid psychiatric symptomatology in children with Autism Spectrum Disorders (ASD). Res Dev Disabil. 2016 Nov 24;60:52-64.

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Mansour R, Dovi AT, Lane DM, Loveland KA, & Pearson DA (2016). ADHD severity as it relates to comorbid psychiatric symptomatology in children with Autism Spectrum Disorders (ASD). Research in developmental disabilities, 60, 52-64 PMID: 27889487

Urinary metabolomics in autism turns up tryptophan (again)

"The tryptophan metabolic pathway collectively displays the largest perturbations in ASD [autism spectrum disorder]."

So said the findings reported by Federica Gevi and colleagues [1] (open-access) who provide yet more 'metabolomic' data when it comes to autism to add to the already quite voluminous peer-reviewed matter on this topic (see here for example).

Just in case you aren't analytical chemistry-saavy, metabolomics is basically the study of the various chemical fingerprints that the multitude of cellular processes going on in the body leave behind. It's the technology available these days that makes metabolomics the discipline that it is, as words such as mass spectrometry and nuclear magnetic resonance (spectroscopy) fill the metabolomic airwaves coupled with some rather smart statistics and software to translate all that captured data into something meaningful.

Gevi et al report results based on the analysis of urine samples from a small-ish group of children diagnosed with an ASD ("idiopathic ASD") compared with samples from a similar number of not autism controls. The aim was to focus on "autistic and unrelated typically developing children 2–8 years old, tightly matched by age, sex, Italian ancestry, and city of origin within the country" and look-see whether a particular HPLC-mass spec technique "hydrophilic interaction chromatography (HILIC)-LC-electrospray ionization (ESI)-MS" might provide some important data on autism vs. not autism.

Results: well, it's always nice to get a research mention in such studies as per the line: "Data were normalized by urinary specific gravity, because creatinine excretion may be abnormally reduced in ASD children" with reference to some work published a few years back [2]. Indeed, this is not the first time creatinine has cropped up in autism metabolomic studies (see here) and is perhaps worthy of quite a bit more study itself (see here).

The authors report that urine samples from those with autism vs. those with not-autism are "largely distinguishable" based on some nifty analysis of the compounds examined from those groups. They even provide a 'top 25 discriminating metabolites' summary to illustrate this fact. Before venturing further into this list, I would perhaps advise some caution however. Caution based on the fact that urine contains many hundreds/thousands of small molecules or chemical entities as a function of being a waste product and carrying waste products from a multitude of different biological processes. It's not outside the realms of possibility that with such a huge number of metabolites, any two groups could be separated out, not just those based on the appearance of autism or not...

Anyhow: "The “metabolome overview” obtained through metabolic pathway analysis (MetPA) shows tryptophan metabolism, purine metabolism, vitamin B6 metabolism, and phenylalanine-tyrosine-tryptophan biosynthesis as the four most perturbed metabolic pathways in ASD." The reference to the aromatic amino acid called tryptophan (the stuff that eventually ends up as serotonin and melatonin) used in the title of this post kinda points to where the money might be when it came to these particular results. I've been interested in tryptophan metabolism and autism for quite a while now (see here for example) and how, outside of the whole serotonin/melatonin bit, there is quite a lot more to see besides. Mention of something called the kynurenine pathway by Gevi is interesting; not least because this pathway overlaps with other conditions/labels too (see here). This pathway might also have some important implications when it comes to epilepsy (see here) as a comorbidity to autism too.

It's also interesting (to me at least!) to note that the authors found something related to the indoles in their analyses too. So: "we also detect a significant increase in indole derivatives of bacterial tryptophan including indolyl 3-acetic acid, indoxyl sulfate, and most prominently, indolyl lactate." Indoxyl sulfate, a uremic toxin - something that is not great for the kidneys - crops up yet again [3] and importantly, highlights how bacteria can also 'go to work' on tryptophan in the gut. Indole -3-acetic acid also brings back research memories in relation to an indole compound close to my research heart, indolyl-3-acrylolyglycine (IAG) [4] that has received a bit of a research bruising quite recently [5] (the authors of that study and another one [6] however, really need to rethink their paper titles insofar as them not actually testing whether dietary intervention actually 'affects' levels of IAG or related metabolites but nonetheless implying so).

There are a range of other findings reported by Gevi and colleagues but I don't want to bore you with all the details. Suffice to say that metabolomics continues its research rise with autism in mind, and provides some rather interesting results. Of course there is more to do in this area; not least the focus on subgroups in these days of 'the autisms' and perhaps a little more metabolomic inquiry when it comes to the myriad of intervention options put forward 'for autism'. Who for example, wouldn't like to see metabolomic profiles pre- and post-folinic acid for example alongside the myriad of other interventions detailed in the peer-reviewed literature? Indeed, I might also advocate a little more investigation on whether specific patterns of urinary compounds might also be related to specific behavioural facets of autism. Given the move towards gut bacteria as potentially showing involvement in some of the results obtained by Gevi et al, it would also be interesting to see if 'altering' certain types of gut bacteria (see here for example) might also have some interesting knock-on effects when it comes to the metabolites detected too? There is quite a bit more to do.

Music and more bad lip reading.... sick of blue milk?

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[1] Gevi F. et al. Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism. Molecular Autism. 2016l 7: 47.

[2] Whiteley P. et al. Spot urinary creatinine excretion in pervasive developmental disorders. Pediatr Int. 2006 Jun;48(3):292-7.

[3] Diémé B. et al. Metabolomics Study of Urine in Autism Spectrum Disorders Using a Multiplatform Analytical Methodology. J Proteome Res. 2015 Dec 4;14(12):5273-82.

[4] Bull G. et al. Indolyl-3-acryloylglycine (IAG) is a putative diagnostic urinary marker for autism spectrum disorders. Med Sci Monit. 2003 Oct;9(10):CR422-5.

[5] Wilson J. et al. Can urinary indolylacroylglycine (IAG) levels be used to determine whether children with autism will benefit from dietary intervention? Pediatr Res. 2016 Nov 23.

[6] Dalton NR. et al. Measurement of urine indolylacroylglycine is not useful in the diagnosis or dietary management of autism. Autism Res. 2016 Aug 29.

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Gevi, F., Zolla, L., Gabriele, S., & Persico, A. (2016). Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism Molecular Autism, 7 (1) DOI: 10.1186/s13229-016-0109-5

'My child is not talking'. Online concerns and internet-based screening for autism?

"Online communities are used as platforms by parents to verify developmental and health concerns related to their child."

That was the starting point for the study results reported by Ben-Sasson & Yom-Tov [1] (open-access available here) who approached an increasingly important issue related to how the Internet and social media in particular, is fast becoming one of the 'go-to' options when it comes to parental concerns about their child's development and the question: could it be autism?

So: "we analyzed online queries posed by parents who were concerned that their child might have ASD and categorized the warning signs they mentioned according to ASD [autism spectrum disorder]-specific and non-ASD-specific domains." The online queries included for study came from "the Yahoo Answers platform" between June 2006 and December 2013. There's a lesson there to reiterate that the Internet is an open platform and what you post is typically in the public domain and hence fodder for many different purposes...

Authors turned up quite a few thousand queries, determining that over 1000 were "posted by parents who suspected their child might have autism". They randomly selected 195 to be used as the basis for this study. I personally don't know why 195 were selected and not rounded up to say 200, but ho-hum. Content analysis - analysing the content of the post! - was undertaken first "to rate a child's risk of ASD as either low, medium, or high". High risk was defined "as concerns related to at least two types of ASD-specific sign, 1 from the RRBI domain and another from the Social and Communication domains" among other things. Then content analysis was used to "identify the types of warning signs noted by parents." From these analyses: "each query received an ASD global risk score and was coded for either presence or absence of each sign domain and its subdomains."

Results: from the 195 queries selected, the vast majority were posted in relation to a boy and most concerned a boy who was aged under 3 years. Contrary to the title of this blog post - 'My child is not talking' - the majority of queries were actually in relation to repetitive and restricted behaviors and interests (RRBI) although concerns related to language were not too far behind in frequency. In relation to those categorisations of low, medium and high risk groups, over half of the queries were labelled as high risk. Interestingly, there were fewer language concerns noted in those allocated to the low risk group than the medium or high risk groups, so perhaps I wasn't so far off with using those 'my child is not talking' words in the title.

But things didn't just stop there for the authors, as the words "test the efficacy of machine learning tools in classifying the child's risk of ASD based on the parent's narrative" are also noted in their paper. Machine learning as in, 'giving computers the ability to learn without being explicitly programmed' according to one definition, is something that has cropped up on the blog before with autism in mind (see here for example). This led to the production of a decision tree - yes or no - "for distinguishing low-risk queries from medium- and high-risk queries." This is interesting but I'd perhaps like to see it tested independently before I say too much more.

In these days of continued austerity and seemingly evermore limited resources when it comes to things like autism assessment and screening for various reasons, this kind of work has an important place. Certainly I don't think posting symptoms on-line with ever replace autism screening, and one has to bear in mind that at least here in the UK, we might have (knowingly or unknowingly) already initiated population autism screening in children (see here) as a consequence of changes to the Healthy Child Program. But with the technological advances being made where machine learning and the connected artificial intelligence are starting to make strides in relation to science and medicine, I don't doubt that one day parents will be typing in their child's symptoms on-line and somehow and somewhere Dr Google or some related system(s) might be talking back...

Music and more bad lip reading applied to Star Wars: No, it's not the future (and watch Chewie holler).

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[1] Ben-Sasson A. & Yom-Tov E. Online Concerns of Parents Suspecting Autism Spectrum Disorder in Their Child: Content Analysis of Signs and Automated Prediction of Risk. J Med Internet Res. 2016 Nov 22;18(11):e300.

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Ben-Sasson A, & Yom-Tov E (2016). Online Concerns of Parents Suspecting Autism Spectrum Disorder in Their Child: Content Analysis of Signs and Automated Prediction of Risk. Journal of medical Internet research, 18 (11) PMID: 27876688