2014 autism research review on Questioning Answers

I like warm hugs...

Time flies doesn't it? And here we are yet again at the end of another research year and a time to reflect on the blogging highlights of 2014 on Questioning Answers. Once again the question is: are we any further forward when it comes to the autism spectrum, it's aetiology, nature and improving quality of life for those on the spectrum?

Once again, I'm going to be optimistic and say 'yes' in some respects we are, as autism research continues at a pace. The caveat being that there is still much more to do, particularly in translating research findings into practical strategies for improving quality of life for those on the autism spectrum and their loved ones who both want and require it.

As per previous years' reviews (see 2011, see 2012, see 2013), month by month I'm gonna give you an indication of some of things I thought were important enough to discuss on this blog, bearing in mind how blogging might just fill a gap between science and the translation of science.

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January
Treatable inborn errors of metabolism in cases of autism was the first entry for 2014, beginning an important theme that the diagnosis of autism or autism spectrum disorder (ASD) should be a starting point for further investigations not an end-point process. The summary paper by Cao and colleagues talking about the gut microbiome and autism (so far) offers a new frontier for part of that research agenda combined with the growing emphasis of comorbidity clusters talked about in a few papers. And yes that includes gastrointestinal (GI) comorbidity, which I'll be coming back to shortly. The introduction of the DSM-5 diagnostic criteria covering autism also received a mention in January with a specific focus on how its use might affect the autism numbers game. The new label of social communication disorder (SCD) also got a mention.

February
Optimal outcome continued to receive research attention and further moves towards the idea that the autisms (plural) might include a number of different developmental trajectories. Anti-brain antibodies and autism was another theme in receipt of further study too, but with a few caveats still remaining. The fantastic resource that is the Taiwan National Health Insurance Research Database (NHIRD) continued to give in research terms as per the curious suggestion that a diagnosis of asthma might be a risk factor for autism. A few other areas previously discussed in the autism research literature also got further attention as per findings on bumetanide and autism and issues with the BCKDK gene in relation to at least some types of autism.

March
1 in 68. That was the revised autism prevalence estimate from the US CDC with lots of discussions around the hows and whys. Obesity and autism also continued to receive some well-deserved research attention reflective of another important focus in 2014 looking at the physical health and activity levels of those on the autism spectrum. A specific female phenotype of autism was also a discussion point this month. More generally, inflammation in relation to psychiatry was also covered.

April
I fulfilled a lifelong ambition in April 2014 when my book was published. One of the prominent themes of the book was how the use of a gluten- and/or casein-free diet might be indicated for 'some' autism, something which may very well tie into some interesting work done on the opioid antagonist naltrexone with autism in mind. Those GI issues that some people have been talking about for many, many years with autism in mind also continued to receive supporting research evidence on their over-representation in the autism spectrum. The paper from Suzanne Goh and colleagues talking about mitochondrial dysfunction being part of a neurobiological subtype of autism also represents an important addition to the research in that area.

May
'Environment as important as genes in autism' was one of the sentiments expressed by the findings from Sven Sandin and colleagues looking at heritability and relative recurrence risk with autism in mind. Continuing that theme was an interesting case report about autism following enterovirus encephalitis and even further congential CMV infection as potentially being related to some offspring autism. The paper from Luke Taylor and colleagues concluding that vaccines were not associated with autism (via meta-analysis) created some column inches, albeit including one paper which itself became the topic of quite a bit of discussion. Again with some self-indulgence in mind, my small contribution to a paper on formulating low dose naltrexone into a cream also hit the peer-reviewed shelves. Not exactly autism-relevant for now but...

June
What should autism research focus on? That was the question asked (and answered) by the paper from Pellicano and colleagues. The answer varied according to who was asked but it appears translational research impacting on day-to-day life is what is required more often than not. Sorry to keep going on about optimal outcome and autism but yet another paper was published on this topic and for the first time, the suggestion that certain intervention strategies might make a difference was presented. Vitamin D and autism is a topic in the research ascendancy in 2014 particularly following the results presented by Eva Kočovská and colleagues. I also covered the sunshine vitamin/hormone from another point of view in June: depression and vitamin D which might be relevant to comorbidity with autism in mind. Kata training might be a good way to keep in shape and help with a few other issues associated with autism was the conclusion reached in a post on the use of martial arts. And finally, cytokine involvement in autism got a meta-analysis concluding that there is potentially much more to see in this research area. I for one wouldn't disagree with that last sentence.

July
The document on medical comorbidities occurring alongside a diagnosis of autism from the parent group Treating Autism here in the UK was published. Free to download and pretty comprehensive is the recommendation that I would give, highlighting again that a diagnosis of autism is a starting point not an end-point for further clinical scrutiny. Mercury exposure and autism or ADHD (attention deficit hyperactivity disorder) got it's own meta-analysis suggesting that there may be more to see when it comes to certain sources of the heavy metal mercury. Staying on the topic of heavy metals and childhood development, lead (Pb) exposure also got a further research battering when it comes to neurodevelopmental outcome. There is seemingly very little good to say when it comes to lead exposure particularly during childhood. Gait issues and joint hypermobility in relation to the autism spectrum was discussed, again with the requirement for further work in this potentially important area. And the research net is seemingly closing in on how prenatal valproate exposure might affect developing brains.

August
Bipolar disorder might be frequent in adult Asperger syndrome was the conclusion reached by Vannucchi and colleagues. But it might not be straight-forward to diagnose. The more classical relationship between some autism and learning disability (intellectual disability) was also considered from a prevalence point of view. Continuing the comorbidity theme was the suggestion that three-quarters of youth with an ASD might meet the criteria for ADHD and that psychosis might be more likely to follow a childhood neurodevelopmental diagnosis. Real ESSENCE or autism plus in action. Oh, and beware the hype around oxytocin and [all] autism...

September
Another diagnosis got pluralised... the schizophrenias (apparently). Sally Rogers and colleagues talked treating autism very early with again, the requirement for a lot more work in this area. The difference between DSM-5 and DSM-IV autism diagnoses were also highlighted. Zinc and copper got discussed with autism in mind, and more evidence of a complicated relationship between anxiety, sensory issues and gut problems was put forward by Micah Mazurek and colleagues. Gut issues were also proposed to be a factor potentially impacting on the absorption and bioavailability of medications used for some people with autism. Slightly outside of autism research, epigenetics got a first look at Chronic Fatigue Syndrome (CFS).

October
[Most] children with autism do not lack the capacity to engage in physical activity but for some reasons, activity levels are down compared with those not on the autism spectrum. Pregnancy infection might elevate the risk of offspring autism was the conclusion from Lee and colleagues. There was more to see when it came to vitamin D supplementation, both with autism in mind and perhaps with other conditions in mind too, although I hasten to add that I'm not giving medical or clinical advice on this or any topic. How stable is a diagnosis of Asperger syndrome was the question asked by Helles and colleagues, and when it comes to anxiety and the autism spectrum, are we talking about an intolerance of uncertainty as a primary factor? Oh, and remember SCD? Well, it might just be the catch-all label for the broader autism phenotype, and of course, broccoli and autism, the mechanism for which might also tie into the growing suggestion that air pollution might affect autism risk.

November
More from Pellicano and colleagues was published on the topic of autism research, and where autism research producers and consumers agree and disagree. The growing suggestion of autism or autistic traits appearing in some cases of Down's syndrome also gathered pace with the suggestion of a new clinical entity: Down Syndrome Disintegrative Disorder. Metabolomics and autism was another research topic with a growing fan base as per the [monster] paper by Paul West and colleagues. The pendulum swung again on the question of what factors might be linked to the increasing numbers of cases of autism being diagnosed (at least up to the late 1990s). And then there was leaky gut... and where that concept might be heading with quite a few conditions in mind. There was also a new player introduced to autism research from the cascade of compounds derived from everyone's favourite aromatic amino acid tryptophan: N-acetylserotonin - watch this space?

December
'Rather than using just one parameter when looking at potential biomarkers for autism, why not use several' was the very logical thinking by Yang and colleagues looking at cytokines and cortisol as a potential diagnostic tag-team. I can't disagree with their strategy if perhaps worrying a little about the term 'biomarker' when applied to all autism, heterogeneity, comorbidity and all. The diagnosis of autism is seemingly protective of nothing when it comes to other medical comorbidity as per the findings from Chiang and colleagues looking at the small but present increased risk of cancer. I tried not to sensationalise that paper but at the same time didn't want to shy away from such evidence-based findings. Telomeres, the shoelace tips of chromosomes got a mention as did an overview of the (non)link between smoking during pregnancy and offspring autism risk (with caveats). The blogging year ended as is started with a look at another inborn error of metabolism with autism in mind. 'Screening' seems to be the important word when it comes to such issues...

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So there you have it. Another year in the life of Questioning Answers and another year of autism research. With all the optimism and enthusiasm I have for such studies and investigations, there is still an awfully long way to go before anyone can start celebrating about how lives have been 'transformed' and inequalities reduced as a result. The Pellicano studies in particular, provide a stark reminder of how little we still know about autism and how far we need to go to make research truly translational including that of murine and related research.

At this point, I would normally pick one paper which really set a new standard in autism research in 2014. Given however the amount of research blogged about this year and some real moves towards 'big data' (be that based on that Taiwanese Insurance Database or other datasets) I'm struggling to select just one piece of research. So instead, three papers which I thought made an impact:

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Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. (Masi and colleagues).

Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. (Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators)

Mitochondrial Dysfunction as a Neurobiological Subtype of Autism Spectrum Disorder. (Goh and colleagues).

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And just before I go, a few tributes celebrating the lives of some of those who brought their considerable experience and expertise to bear on autism research: Lorna Wing, Elizabeth Newson and Paul Patterson. May you rest in peace.

Thanks for looking in, seasons greetings and a Happy New Year to all. Back in 2015 with lots more.

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Masi A, Quintana DS, Glozier N, Lloyd AR, Hickie IB, & Guastella AJ (2014). Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Molecular psychiatry PMID: 24934179





Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators, & Centers for Disease Control and Prevention (CDC) (2014). Prevalence of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002), 63 (2), 1-21 PMID: 24670961





Goh S, Dong Z, Zhang Y, DiMauro S, & Peterson BS (2014). Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: evidence from brain imaging. JAMA psychiatry, 71 (6), 665-71 PMID: 24718932

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency and autism?

I started this blogging year (2014) with a post talking about the need for further research consideration for a possible role of inborn errors of metabolism in relation to the presentation of at least some autism (see here). It is therefore timely that I (almost) end this year's blogging odyssey with reference to the paper by Amy Brown and colleagues [1] and their suggestion that although: "VLCAD deficiency does not have a significant impact on cognitive or motor skills" there may still be merit in looking further at very long chain acyl-CoA dehydrogenase (VLCAD) deficiency where: "Some children may be vulnerable to speech, social and behavioural issues."

Rule 42: All persons more than a mile high
must leave the court immediately

Although based on quite a small participant number (N=7), probably reflective of the fact that VLCAD deficiency is quite a rare disorder ("estimated at 1:30,000 in the US"), Brown and colleagues reported various findings based on the use of "a comprehensive neuropsychological assessment battery that assessed IQ, language, attention, memory, executive functioning, motor skills, behaviour, and social skills". Parents were also asked about their child's abilities in terms of things like social skills and behaviour.

Quite a few of the parameters investigated suggested that kids with VLCAD deficiency were average or above on their performance and presentation of skills. That being said: "Parents' questionnaires identified one child as having social skills deficits, and two as having behavioural problems such as hyperactivity. One child rated high on an autism spectrum subscale; another was formally diagnosed with autism spectrum disorder-both children were symptomatic at birth." I can't specifically provide you with answers as to how and why VLCAD deficiency might link to autism/autistic traits, but will provide you with a link to a previous paper [2] talking about long chain acyl-CoA dehydrogenase (LCAD) deficiency with a case report of autism in mind. LCAD and VLCAD have some interesting history. In that case, acyl-carnitines were discussed as potentially being relevant, which may very well tie into some other work in this area (see here). The fact also that carnitine is used as part of the treatment regime for some VLCAD deficiency might also overlap with other autism research (see here).

The two children talked about with autism in mind, one diagnosed with an autism spectrum disorder (ASD) and the other with some indication of autistic-like traits, hint at how some of the inborn errors of metabolism may yet provide some interesting insight into at least some autism. The paper by Burrage and colleagues [3] for example, updating on the field of branched-chain amino acid (BCAA) metabolism, offers further discussion on the possibility of a more generalised association as per the rise and rise of 'BCKDK autism'.

Bearing in mind our growing realisation of the plurality of autism - 'the autisms' - denoting not just the heterogeneity covered under the umbrella clinical description but also that more than one road might lead to the presentation of autistic traits, examining the inborn errors of metabolism with autism in mind is an area of great scientific potential. It benefits from some testable genetic/biological starting points with the detection of those inborn errors of metabolism which may provide some important insights into how [some] autism might come about. Given that some of those errors of metabolism can also be 'corrected' in various ways, it might also provide some pretty interesting data on how behavioural presentation might also be affected. Remember PKU? I'd like to see a lot more in this area.

A quick heads-up... tomorrow (30th December 2014) I'm gonna publish my annual round-up of some of the blogging highlights here on Questioning Answers in 2014. You're all invited to drop in and take a gander...

And then to some music: Elvis and Suspicious Mind.

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[1] Brown A. et al. Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening. Mol Genet Metab. 2014 Oct 12. pii: S1096-7192(14)00314-X.

[2] Clark-Taylor T. & Clark-Taylor BE. Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial beta-oxidation by long chain acyl-CoA dehydrogenase. Med Hypotheses. 2004;62(6):970-5.

[3] Burrage LC. et al. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum Mol Genet. 2014 Sep 15;23(R1):R1-8.

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Brown A, Crowe L, Andresen BS, Anderson V, & Boneh A (2014). Neurodevelopmental profiles of children with very long chain acyl-CoA dehydrogenase deficiency diagnosed by newborn screening. Molecular genetics and metabolism PMID: 25456746

Pre-eclampsia exposure and autism

A few weeks back, the paper from Cheryl Walker and colleagues [1] reporting that: "Children with ASD [autism spectrum disorder] were twice as likely to have been exposed in utero to preeclampsia as controls with TD [typical development]" provided some column inches in certain media quarters.

How dare you insult Hero's Duty, you little guttersnipe!

Although not the first time that pre-eclampsia - a hypertensive state characterised by proteinuria occurring during pregnancy and potentially affected by/affecting the placenta - has been mentioned in the autism research literature [2] (open-access), the value-added bit to the Walker paper was the use of participants/data included in the CHARGE study. As an aside, CHARGE has been mentioned a few times on this blog (see here for example).

The Walker study looked at maternal self-reports and details "abstracted from medical records" of "Preeclampsia and placental insufficiency" in their cohort comprising some 500 children diagnosed with an ASD and nearly 200 diagnosed with developmental delay (DD) compared against 350 asymptomatic controls. Compared against those TD children, those with autism were more frequently reported to have been exposed to pre-eclampsia during gestation. Further, some relationship between pre-eclampsia severity and autism risk was also observed. The authors also noted: "Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia."

Whilst appreciating that not nearly a week goes by without scientific research linking something or other to a higher risk of autism and the subsequent possibility of 'correlation burnout', these are interesting results. Pregnancy hypertension - high blood pressure - as part of pre-eclampsia is an important factor driving various adverse effects/events which can impact on both developing foetus and mother (e.g. placental abruption). Maternal hypertension as part of the condition called metabolic syndrome has previously been linked to an increased risk of offspring autism [3] (see here for my take on the study) as well as being a potential stand-alone factor [4].

The link between pre-eclampsia and placental insufficiency (where the placenta does not deliver the optimal amount of oxygen or nutrients to the baby) is also a potentially intriguing point with autism in mind. Regular readers might remember some of my previous discussions on the Barker (foetal programming) hypothesis proposed by the late David Barker, and the idea that nutrition in-utero might have some pretty profound consequences for offspring later life health. Although hesitant to say that issues mediated by placental function are directly linked to autism, there is a growing appreciation that the placenta may be a further point of inquiry when it comes to offspring neurodevelopmental functions. Take for example other work by Walker and colleagues related to trophoblast inclusions in relation to autism [5] (see here for my previous discussion on this research) as one example. Perhaps more speculatively is the suggestion that a short interpregnancy interval (IPI) might also increase the risk of offspring autism [6] and what this could also mean from a 'depletion of micronutrients' point of view potentially similar to a placental insufficiency scenario.

What is becoming clearer from this and other research on the 'nine months that made us' in relation to autism or other neurodevelopmental diagnoses, is that further efforts are required to tease apart various factors. So:

(a) What are the process by which adverse pregnancy conditions impact on offspring outcomes? Do we already have research precedents as per the paper by van Gelder and colleagues [7] talking about "physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the aetiology of major birth defects, including congenital heart defects and hypospadias". Both congential heart defects and hypospadias have been previously mentioned in the autism research literature (see here and see here respectively).

 and

(b) Linked to the previous question(s), who is more likely to be at risk of such issues, and what intervention(s) might mean for offspring and mother alike?

Music: Dolly sings Jolene at Glastonbury 2014.

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[1] Walker CK. et al. Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay. JAMA Pediatrics. 2014. 8 December.

[2] Gardener H. et al. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009 Jul;195(1):7-14.

[3] Krakowiak P. et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012 May;129(5):e1121-8.

[4] Polo-Kantola P. et al. Obstetric risk factors and autism spectrum disorders in Finland. J Pediatr. 2014 Feb;164(2):358-65.

[5] Walker CK. et al. Trophoblast Inclusions Are Significantly Increased in the Placentas of Children in Families at Risk for Autism. Biological Psychiatry. 2013; 74: 204-211.

[6] Gunnes N. et al. Interpregnancy interval and risk of autistic disorder. Epidemiology. 2013 Nov;24(6):906-12.

[7] van Gelder M. et al. Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case-control study. BJOG. 2014 Nov 14. doi: 10.1111/1471-0528.13138.

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Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, & Hertz-Picciotto I (2014). Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay. JAMA pediatrics PMID: 25485869

Late/moderately preterm kids at risk for a positive autism screen

If you're sick of the sight of tinsel and/or turkey (delete as appropriate), I promise no more mention of them in this post. Just a brief introduction to the the paper by Alexa Guy and colleagues [1] (open-access) who concluded that: "LMPT [late and moderately preterm] infants are at significantly increased risk for positive autistic screen."

Megamind, incredibly handsome criminal
genius and master of all villainy!

Based on the [final] analysis of data from some 600 LMPT infant and 760 term-born infants taking part in a study initiative here in the UK, researchers looked at M-CHAT (Modified Checklist for Autism in Toddlers) scores derived from parental questioning when the child was 2 years old. They found: "LMPT infants were at significantly increased risk for a positive M-CHAT questionnaire screen compared with term-born infants, and this remained significant after application of the follow-up interview and exclusion of infants with neurosensory impairments." Further that their findings: "provide empirical evidence that screening for ASD is especially confounded in preterm populations" as a function of the the high false-positive rate found compared against the term-born controls.

M-CHAT has cropped up a few times on this blog (see here for example). In recent times, the schedule has undergone a bit of (further) revision, evolving into the M-CHAT-R/F [2] (see here for further details) to further improve on its sensitivity statistics when it comes to assessing risk of an autism spectrum disorder (ASD). Indeed, as per the Guy quote: "An M-CHAT follow-up interview is essential as screening for autism spectrum disorders is especially confounded in preterm populations" one can perhaps see where M-CHAT R/F might be particularly handy for further study of this important group.

These results add to an already sizeable volume of peer-reviewed research literature hinting that the timing of our very earliest introduction into the world might influence risk of neurodevelopmental issues such as autism and/or a positive screen for potential autism. That being said, the various factors linked to time in-utero such as birth weight as potentially impacting on development illustrate how complex an issue this might be. How we screen for autism in among the various complexities of preterm births (and lower birth weight) remains a question on many people's minds, including the possibility of using more than one instrument [3].

Music to close: Norwegian Wood.

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[1] Guy A. et al. Infants Born Late/Moderately Preterm Are at Increased Risk for a Positive
Autism Screen at 2 Years of Age. J Pediatrics. 2014. 5 December.

[2] Robins DL. et al. Validation of the modified checklist for Autism in toddlers, revised with follow-up (M-CHAT-R/F). Pediatrics. 2014 Jan;133(1):37-45.

[3] Dudova I. et al. Comparison of three screening tests for autism in preterm children with birth weights less than 1,500 grams. Neuropsychiatr Dis Treat. 2014 Nov 17;10:2201-2208.

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Guy, A., Seaton, S., Boyle, E., Draper, E., Field, D., Manktelow, B., Marlow, N., Smith, L., & Johnson, S. (2014). Infants Born Late/Moderately Preterm Are at Increased Risk for a Positive Autism Screen at 2 Years of Age The Journal of Pediatrics DOI: 10.1016/j.jpeds.2014.10.053

Gluten-free diet affecting EEG findings?

Acknowledging that a certain 'jolly' person with a beard wearing a red suit will be visiting a few homes across the globe quite soon (the only time of the year that most people would let a stranger enter their home via a chimney) I want to briefly direct your attention to the paper by Parisi and colleagues [1] talking about how in "the presence of unexplained EEG abnormalities and/or other neurological disorders/SDB [sleep disordered breathing] an atypical or silent CD [coeliac disease] should also be taken into account."

Merry Christmas.

One sentence in particular took my attention: "After 6 months of GFD [gluten-free diet] headache disappeared in 72% of children and EEG abnormalities in 78%" based on examination of a small participant group (N=19) "with a new biopsy-proven celiac disease (CD) diagnosis."

Coeliac disease (CD), gluten and EEG abnormalities is something I'm actually quite interested in. As per my previous musings, I'm not expert on the dark art that is EEG (see here) but I am interested in how EEG findings might relate to CD and in particular, the suggestion that CD might also have a neurological effect for some (see here). The idea that embarking on a gluten-free diet (the primary intervention for CD) might 'correct' unusual EEG patterns and/or their clinical signs is by no means a new one as per studies such as the one from Diaconu and colleagues [2] talking about the use of the diet and a 'favourable course' when it came to migraine and epilepsy.

Hopefully without too much speculation or controversy, the possibility that a gluten-free diet might impact on EEG issues and/or epilepsy outside of CD has also cropped up in my own research. My dabbling in the science of gluten-free diets for cases of autism (stress on 'cases' [3]) has led me to hear some individual instances where the diet seemed to accompany positive changes to the presentation of seizures in cases of autism [4]. I've talked about individual cases documented in the research literature where a gluten-free diet might have been part and parcel of seizure control in relation to autism (see here), also as a segment of the regime known as a ketogenic diet (see here). One of the studies which I think is missing from the body of research looking at dietary intervention in autism (some autism, perhaps some autism falling into that non-coeliac gluten sensitivity category) is whether impacting on 'unusual' EEG patterns might be something to look at when it comes to gluten removal...

Merry Christmas! And the usual 'best seasonal song ever' link... The Pogues and Kirsty MacColl.

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[1] Parisi P. et al. Role of the gluten-free diet on neurological-EEG findings and sleep disordered breathing in children with celiac disease. Seizure. 2014 Oct 6. pii: S1059-1311(14)00267-2.

[2] Diaconu G. et al. Celiac disease with neurologic manifestations in children. Rev Med Chir Soc Med Nat Iasi. 2013 Jan-Mar;117(1):88-94.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2014 Oct 14:1-6.

[4] Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2013 Jan 4;6:344.

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Parisi P, Pietropaoli N, Ferretti A, Nenna R, Mastrogiorgio G, Del Pozzo M, Principessa L, Bonamico M, & Villa MP (2014). Role of the gluten-free diet on neurological-EEG findings and sleep disordered breathing in children with celiac disease. Seizure PMID: 25457448

The bipolar - schizoaffective - schizophrenia spectrum?

"This pattern of results is consistent with the conceptualisation of a spectrum of disorders, ranging from BDP [bipolar disorder] at one end, to SAD [schizoaffective disorder] in the middle, and SCZ [schizophrenia] at the other end." So concluded the paper by Serafino Mancuso and colleagues [1] examining clinical data derived from the Australian Survey of High Impact Psychosis (SHIP).

The thing about perfection is that it's unknowable.

I'm not going to dwell too long on this paper aside from suggesting that such results add to a growing trend in psychiatry asking whether our current compartmentalising way of diagnosing mental health issues is actually fit for purpose à la RDoC (Research Domain Criteria). A few weeks back Virginia Hughes talked about 'Category Fail' based to a large extent on the paper by London [2] who suggested that: "The use of autism as a diagnostic category guiding translational research is fraught with so many problems that the validity of research conclusions is suspect." Sentiments which have been rumbling on for quite a few years now.

The Mancuso results are complemented by quite a few other findings suggestive of fuzzy boundaries when it comes to giving psychiatric labels and their associated qualities. Plucking randomly from the peer-reviewed literature, the paper from Silver & Bilker [3] for example, talking about people with schizophrenia showing "impairments in [the] recognition of identity and emotional facial clues" as part of social cognition carries hints of what has been described in cases of autism for example. The findings reported by Langdon and colleagues [4] talking about a specific Theory of Mind (ToM) impairment in their cohort with early psychosis provides further evidence for the non-exclusivity of this concept when similarly talked about with autism in mind (see here). I might add that I'm not a great fan of the link between ToM and autism anyway.

Of course, one might also see the concept of a spectrum of psychiatric conditions to be itself rather too simplified when it comes to describing and categorising behaviours and actions. The growing pluralisation of autism - 'the autisms' - and schizophrenia - 'the schizophrenias' - perhaps implies that 'tapestry' might be a better way to define presented symptoms, bearing in mind the potential number of permutations of displayed symptoms and underlying genetic/biological issues that may be evident. It might also cover the evidence talking about overlapping spectrums also.

It's all getting rather complicated...

Music: Chase & Status - Lost & Not Found.

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[1] Mancuso SG. et al. A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: Results from the Second Australian national psychosis survey. J Affect Disord. 2014 Sep 30;172C:30-37.

[2] London EB. Categorical diagnosis: a fatal flaw for autism research? Trends Neurosci. 2014 Nov 14;37(12):683-686.

[3] Silver H. & Bilker WB. Social cognition in schizophrenia and healthy aging: Differences and similarities. Schizophr Res. 2014 Nov 15;160(1-3):157-162.

[4] Langdon R. et al. Theory of mind and neurocognition in early psychosis: a quasi-experimental study. BMC Psychiatry 2014, 14:316

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Mancuso SG, Morgan VA, Mitchell PB, Berk M, Young A, & Castle DJ (2014). A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: Results from the Second Australian national psychosis survey. Journal of affective disorders, 172C, 30-37 PMID: 25451392

Cytokines activating the kynurenine pathway in schizophrenia?

I'm a bit of a fan of tryptophan biochemistry on this blog. This quite remarkable aromatic amino acid and it's off-shoot metabolites, which appear to have no end of biological uses, have taken quite a bit of my blogging time down the years. Most recently was the suggestion that a metabolite slotting in between serotonin (5-HT) and melatonin might require quite a bit more investigation when it comes to at least some cases of autism (see here).

See ya later, President Fartfeathers.

The findings reported by Lilly Schwieler and colleagues [1] (open-access here) add to the scientific interest and their assertion that: "IL-6 [interleukin-6] induces the KYN [kynurenine] pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA [kynurenic acid] in patients with schizophrenia." IL-6 by the way, is a cytokine (chemical messenger of the immune system) which is normally taken to be a pro-inflammatory cytokine (see here). Kynurenine and it's metabolic relations, are yet another set of compounds derived from tryptophan. The kynurenic hypothesis of schizophrenia (see here) hints at some of the research history this compound (and metabolites) has with the condition.

The Schwieler paper is open-access but a few pointers might be in order:

• Looking at a "well-characterized cohort of olanzapine-treated patients with chronic schizophrenia" researchers set about looking at cerebrospinal fluid (CSF) levels of various cytokines compared to a small participant group of asymptomatic controls "free from current signs of psychiatric morbidity or difficulties in social adjustment at the time of sampling".
• Previously measured levels of "tryptophan metabolites of the KYN pathway" were also included in the study bundle. Researchers also looked at a possible 'interplay' between IL-6 and kynurenic acid in human astrocyte cultures. This involved stimulation of said cultures with IL-6 and measuring KYNA using triple quadrupole mass spectrometry.
• Results: "The CSF IL-6 concentration was elevated in patients with chronic schizophrenia compared with controls." No real surprises there considering what has been reported previously in this area of schizophrenia research [2] and the growing idea of inflammation and psychiatry being linked. 
• CSF levels of kynurenine and kynurenic acid were also elevated in the schizophrenia group compared to controls, but no significant differences were noted in the starting material (tryptophan) between the groups. Authors also confirmed that IL-6 did indeed significantly raise levels of kynurenic acid (KYNA) in astrocyte cultures.
• They conclude that "The increased production of KYNA in fetal human astrocytes following exposure of IL-6 shows that this cytokine is able to induce the activity of the KYN pathway." This process may also pertain to schizophrenia.

Aside from the limitations already pointed out by the authors in terms of some analytical issues and the spot sampling methodology employed, I might also point out that whilst participants with schizophrenia were all taking olanzapine (and other meds in some cases), the asymptomatic controls were "free from medication for at least 1 month". Granted olanzapine is not generally thought to directly impact on levels of IL-6 for example [3] but one can't discount that other, more indirect effects might come into play. Indeed, I'm going to be talking about olanzapine, gut bacteria and weight gain (see here) early in the New Year.

I'd like to introduce the paper by Johansson and colleagues [4] at this point, and their observations related to kynurenic acid and related metabolites in "cultured skin fibroblasts obtained from patients with bipolar disorder, schizophrenia or from healthy control individuals." Looking at cells specifically from participants (with all their biological heterogeneity), they similarly concluded that there was an "increase in ratio between neurotoxic 3-HK [3-hydroxykynurenine] and neuroinhibitory/neuroprotective KYNA following exposure to cytokines" in the bipolar and schizophrenia groups compared to controls. The 3-HK finding might be of even greater interest to schizophrenia given the suggestion of a link with redox modulation [5] and the idea that oxidative stress might be a factor to the condition [6].

What's more to say on this topic? Well, not much more aside from the fact that there may be a complicated relationship between immune function - immune signalling - and amino acid biochemistry which may very well impinge on presented behaviour. Such links also offer some interesting prospects for potential intervention too...

And to some music: Lower Than Atlantis - Here We Go.

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[1] Schwieler L. et al. Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. J Psychiatry Neurosci. 2014 Dec 2;39(6):140126.

[2] Kunz M. et al. Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr. 2011 Sep;33(3):268-74.

[3] Hori H. et al. Effects of olanzapine on plasma levels of catecholamine metabolites, cytokines, and brain-derived neurotrophic factor in schizophrenic patients. Int Clin Psychopharmacol. 2007 Jan;22(1):21-7.

[4] Johansson AS. et al. Activation of kynurenine pathway in ex vivo fibroblasts from patients with bipolar disorder or schizophrenia: cytokine challenge increases production of 3-hydroxykynurenine. J Psychiatr Res. 2013 Nov;47(11):1815-23.

[5] Colín-González AL. et al. The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum. Brain Res. 2014 Nov 17;1589:1-14.

[6] Flatow J. et al. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013 Sep 15;74(6):400-9.

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Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, Finn A, Bhat M, Samuelsson M, Lundberg K, Dahl ML, Sellgren C, Schuppe-Koistinen I, Svensson C, Erhardt S, & Engberg G (2014). Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway. Journal of psychiatry & neuroscience : JPN, 39 (6) PMID: 25455350

Vitamin D for autism... a double-take?

Yes, I know. Another post on the 'day of rest' but I promise you that this will not become a habit. The reason: the paper by Feiyong Jia and colleagues [1] published in the premier journal Pediatrics. The authors describe a case report of a young child with autism who is observed to have shown improvement in some of the core symptoms of autism following supplementation with the [sunshine] vitamin/hormone of the hour: vitamin D. Further reporting on the paper can be seen here.

Although the paper is interesting - "stressing the importance of clinical assessment of vitamin D3 deficiency and the need for vitamin D3 supplementation in case of deficiency" - and fits in well with my borderline obsession with vitamin D, my interest was piqued because we have actually seen something similar from this research group before [2]. On this and that occasion, 'possibly' reporting on the same "32-month-old boy with ASD [autism spectrum disorder] and vitamin D3 deficiency". I've also discussed the previous Jia paper on this blog before (see here).

I'm gonna say little more on this topic aside from reiterating my reiteration(?) on that previous post about Jia et al talking about their description of a single case report and how one has to be very careful about generalising to the very wide and very heterogeneous autism (or autisms). Yes, there may indeed be issues with vitamin D levels / availability when it comes to some people on the autism spectrum [3] (see here for example) but science is still feeling it's way around this topic and where such a finding might link into the grand scheme of things with a diagnosis of autism spectrum disorder in mind.

I'm also minded to bring to your attention two other papers also appearing in the same journal and reporting with vitamin D in mind: Hart and colleagues [4] detailing more results from the Raine study on what maternal vitamin D levels might mean for offspring outcomes, and McNally and colleagues [5] (who has some research history with vitamin D in mind) talking about how to correct any deficiency. That all being said bearing in mind my prime [blogging] directive: no medical or clinical advice given or intended.

Now, about that Sunday lunch...

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[1] Jia F. et al. Core Symptoms of Autism Improved After Vitamin D Supplementation. Pediatrics. 2014. December 15.

[2] Jia F. et al. Vitamin D Supplementation Improves Autistic Symptoms in a Child with Autism
Spectrum Disorder. Asian Case Reports in Pediatrics. 2014; 2: 21-24.

[3] Pioggia G. et al. Autism and lack of D3 vitamin: A systematic review. Research in Autism Spectrum Disorders. 2014; 8: 1685-1698.

[4] Hart PH. et al. Vitamin D in Fetal Development: Findings From a Birth Cohort Study. Pediatrics. 2014. December 15.

[5] McNally JD. et al. Rapid Normalization of Vitamin D Levels: A Meta-Analysis. Pediatrics. 2014. December 15.

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Feiyong Jia, Bing Wang, Ling Shan, Zhida Xu, Wouter G. Staal, & Lin Du (2014). Core Symptoms of Autism Improved After Vitamin D Supplementation Pediatrics : doi: 10.1542/peds.2014-2121

Joint hypermobility and links to psychiatry

"The relationship between JH/HDCT [joint hypermobility / heritable disorders of connective tissue] and mental disorders merits further attention in order to improve current knowledge and clarify a possible common etiology."

There is nothing in the desert and no man needs nothing.

That was the conclusion reached in the paper by Carolina Baeza-Velasco and colleagues [1] looking at the possibility of some interesting connections, outside of just physical presentation, when it comes to the range of conditions headed under the label 'disorders of connective tissue'. The list of diagnoses potentially 'associated' with JH/HDCT by Baeza-Velasco et al is pretty long: "anxiety disorders, depression, schizophrenia, neurodevelopmental disorders (autism, attention deficit/hyperactivity disorder [2], and developmental coordination disorder), eating disorders, personality disorders and substance use/misuse."

From the point-of-view of this blog, mention of the word 'autism' is perhaps the most important suggested link, harking back to some previous discussion of joint hypermobility and gait with the autism spectrum in mind (see here). I'm still pretty interested in seeing this issue followed up in the autism research arena bearing in mind the possible influence of comorbidity as per findings related to the presence of anxiety and joint hypermobility [3] and the question of which comes first: autism or hypermobility?

Music: Glow by Ella Henderson.

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[1] Baeza-Velasco C. et al. Joint hypermobility and the heritable disorders of connective tissue: clinical and empirical evidence of links with psychiatry. Gen Hosp Psychiatry. 2014 Oct 16. pii: S0163-8343(14)00264-3.

[2] Baeza-Velasco C. et al. Connective tissue problems and attention deficit and hyperactivity. ADHD Attention Deficit and Hyperactivity Disorders. 2014. 1866-6647

[3] Sanches SB. et al. Anxiety and joint hypermobility association: a systematic review. Rev Bras Psiquiatr. 2012 Jun;34 Suppl 1:S53-60.

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Baeza-Velasco C, Pailhez G, Bulbena A, & Baghdadli A (2014). Joint hypermobility and the heritable disorders of connective tissue: clinical and empirical evidence of links with psychiatry. General hospital psychiatry PMID: 25459977

Uric acid and bipolar disorder

Bipolar disorder appearing again on this blog this week? It's just the way that the papers fall...

With a title like: 'Increased uric acid levels in bipolar disorder subjects during different phases of illness' I was hardly likely to pass up the opportunity to discuss the paper by Umberto Albert and colleagues [1] and their suggestion that there may be a lot more to see when it comes to "a purinergic dysfunction associated with BD [bipolar disorder]".

I lost the defuser gun when I misplaced the invisible car.

Based on the analysis of serum uric acid (UA) levels in 150 participants formally diagnosed with BD compared with "150 age- and gender-matched subjects with MDD [major depressive disorder], OCD [obsessive compulsive disorder], or Schizophrenia", researchers reported that: "Mean serum UA levels (5.06±1.45 vs. 4.17±1.05mg/dL) and rates of hyperuricaemia (30.7% vs. 6.7%) were significantly higher in the bipolar than in the control group." The authors pointed out the limitations of their study: "Our study suffers from the lack of a healthy comparison group; moreover, longitudinal data are missing" so no need for me to say anything further in that respect.

Uric acid, more commonly associated with a condition like gout, has been getting quite a bit of research attention when it comes to behaviour and psychiatry down the years. I've talked previously on this blog about the intriguing work suggestive of a possible connection between levels of uric acid and impulsivity (see here) highlighting a possible biology - trait connection. As per the Albert findings - "No differences were detected between bipolars in different phases of illness, with all three groups (manic, depressive and euthymic bipolars) showing significantly higher UA levels as compared to controls" - other research has hinted that the relationship between uric acid and BD is quite a bit more than just one related to trait [2]. I'm open to accepting that this might however change as more research is done on this topic.

Mechanism of effect for uric acid in BD? A very good question. Unfortunately I don't have a good answer at the moment, aside from reiterating the Albert suggestion "of a purinergic dysfunction associated with BD". Going all the way back to the 1921 book by Emil Kraeplin where the connection between uric acid and "manic symptoms" was discussed, there is quite a long history attached to this area. Even further back, the paper by Sutherland (1892) [3] talked about uric acid diathesis in children exemplified by: "keen precocious minds, and small restless bodies; they are excitable, nervous, bright and amusing at one time, and greatly depressed at another". Lithium salts were the treatment of choice for the 'gouty diseases' [4] and perhaps might offer some further explanation for the mechanism of effect in BD.

Other than that I can say no more, aside from pointing out that if one considers uric acid to be an agent of inflammation [5] and associated with other inflammatory responses [6], one might entertain some possible association between elevated levels of the stuff and other potentially important work in the area of BD...

And to close: White Coats by Foxes.

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[1] Albert U. et al. Increased uric acid levels in bipolar disorder subjects during different phases of illness. J Affect Disord. 2014 Nov 15;173C:170-175.

[2] Kesebir S. et al. Increased uric acid levels in bipolar disorder: is it trait or state? J Biol Regul Homeost Agents. 2013 Oct-Dec;27(4):981-8.

[3] Sutherland GA. On some Symptoms Associated with the Uric Acid Diathesis in Children. Br Med J. 1892 Apr 23;1(1634):856-8.

[4] Amdisen A. & Hildebrandt J. Use of lithium in the medically ill. Psychother Psychosom. 1988;49(2):103-19.

[5] Shi Y. Caught red-handed: uric acid is an agent of inflammation. The Journal of Clinical Investigation 2010;120(6):1809-1811. doi:10.1172/JCI43132.

[6] Lyngdoh T. et al. Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study. PLoS One. 2011;6(5):e19901.

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Albert U, De Cori D, Aguglia A, Barbaro F, Bogetto F, & Maina G (2014). Increased uric acid levels in bipolar disorder subjects during different phases of illness. Journal of affective disorders, 173C, 170-175 PMID: 25462413