Tuesday, 30 August 2016

A prenatal 'unhealthy' diet and offspring ADHD?

'Scientists study link between unhealthy pregnancy diet and ADHD' went one media headline covering the paper by Jolien Rijlaarsdam and colleagues [1].

The name of the research game was again to draw on data derived from ALSPAC (Avon Longitudinal Study of Parents and Children) (yes, again) to look-see "the degree to which prenatal high-fat and -sugar diet might relate to ADHD [attention-deficit hyperactivity disorder] symptoms via IGF2 DNA methylation for early-onset persistent (EOP) versus low CP [conduct problems] youth." In other words: "Experts examine how a diet high in fat and sugar could alter baby’s DNA in a way that might cause behavioural problems."

To do this meant looking at around 80 youth presenting with early-onset conduct problems compared with around 80 youths who didn't have the same magnitude of issues. Data on maternal nutrition captured for the two groups (ALSPAC did a lot of data collecting!) was cross-referenced with group status and also epigenetic - methylation - status of the insulin-like growth factor 2 gene (IGF2). IGF2 is a gene that seems to be pretty active during the nine months that made us but less so as we enter the big, wide world. As the name suggests it seems to have a 'growth' role which is probably why issues with this gene have also been associated with the development of a number of cancers.

Results: "Prenatal ‘unhealthy diet’ was positively associated with IGF2 methylation at birth for both the EOP and low CP youth." Minus any 'blame', such results suggest that maternal diet might be important for the developing child. I know this is it not exactly a shock, but in these days of more and more research and clinical focus on the special time called pregnancy, the idea that particular epigenetic changes might come from a chosen diet is a potentially important one.

Further: "For EOP only: (a) higher IGF2 methylation predicted ADHD symptoms; and (b) prenatal ‘unhealthy diet’ was associated with higher ADHD symptoms indirectly via higher IGF2 methylation." The higher IGF2 methylation - higher ADHD symptoms is an interesting association. Methylation - the addition of a methyl group - is normally taken to mean gene silencing suggesting that a malfunction of the the IGF2 gene and/or lower levels of its protein product might have some important implications. At this point I might add that whilst there is a bit of a research gap when it comes to IGF2 and behaviour specifically linked to ADHD, there is some interesting animal research looking at mice engineered to show low levels of the protein product in terms of behaviours such as anxiety [2] alongside "a role for the placenta in long-term programming of emotional behaviour." Cutting edge stuff to be sure.

"At present, this is not a study that would change my clinical practice, but if intervention studies resulting from this work show nutritional support in pregnancy can have an effect then we should take any opportunity we can to help." That was one comment from a physician discussing the results of the Rijlaarsdam study that I would agree with. The fact that the study focuses on just one gene in amongst the thousands potentially linked to conduct problems and ADHD is something to bear in mind.

Set however within the context that food can seemingly also affect behaviour and psychiatry as well as physiology (see here for example) I'd like to think that more studies on nutrition during pregnancy would be forthcoming and quickly on this important topic.

To close, thanks to Gene for the laughter...


[1] Rijlaarsdam J. et al. Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems. J Child Psychol Psychiatry. 2016 Aug 18.

[2] Mikaelsson MA. et al. Placental programming of anxiety in adulthood revealed by Igf2-null models. Nat Commun. 2013;4:2311.


ResearchBlogging.org Rijlaarsdam J, Cecil CA, Walton E, Mesirow MS, Relton CL, Gaunt TR, McArdle W, & Barker ED (2016). Prenatal unhealthy diet, insulin-like growth factor 2 gene (IGF2) methylation, and attention deficit hyperactivity disorder symptoms in youth with early-onset conduct problems. Journal of child psychology and psychiatry, and allied disciplines PMID: 27535767

Monday, 29 August 2016

The ketogenic diet and the BTBRT+Tf/J mouse model of autism

I was rather interested to read the findings reported by Richelle Mychasiuk & Jong Rho [1] suggesting that the expression of certain genes might be affected by adoption of a ketogenic diet in one of the more familiar mouse models of autism (the BTBRT+Tf/J 'dangermouse').

The ketogenic diet (KD), consisting of "a high-fat low-carbohydrate anti-seizure and neuroprotective diet" has been of some interest to autism research over the years (see here). Its potential usefulness has also been explored in mouse models of autism including the BTBR mouse model (see here) and this latest research should be viewed in that context.

The name of the research game this time around was to investigate "changes in mRNA [messenger RNA] and gene expression in the BTBR mouse model of ASD [autism spectrum disorder] that may contribute to the behavioral phenotype" including what happened to said gene expression following the use of a KD. Looking in mouse brains, researchers found a few genes that seemed to be differentially expressed in the BTBR mice compared to controls. Perhaps more important to this post however was the observation that following the use of a KD, there were some potentially important changes: "brain regions demonstrated improvements in ASD deficits associated with myelin formation and white matter development."

Bearing in mind mice are mice not people, this is interesting work. It does not imply that use of a ketogenic diet is going to be for everyone with autism in terms of 'altering' gene expression and onwards positively affecting the presentation of the condition. What it does imply is further exploration is required into how use of something like a KD might have quite a few effects that could explain why for some people it is a life-changer (see here). The idea that we don't all walk around with our genes in the 'on' position is also reiterated and potentially provides a roadmap for looking at gene expression when it comes to lots more different intervention options used with autism in mind...


[1] Mychasiuk R. & Rho JM. Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder. Autism Res. 2016 Aug 16. 


ResearchBlogging.org Mychasiuk R, & Rho JM (2016). Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder. Autism research : official journal of the International Society for Autism Research PMID: 27529337

Saturday, 27 August 2016

On autism spectrum disorder [research] validity

Today I'm directing your reading attention to a really, really interesting paper by Lynn Waterhouse and colleagues [1] (open-access) whose review findings suggest that: "the ASD [autism spectrum disorder] diagnosis lacks biological and construct validity."

The paper is a bit of a long read but most definitely worth it as the quite complicated subject of exactly what goal the label of autism actually serves is discussed. The results of various questions posed by the authors suggest: "No unitary ASD brain impairment or replicated unitary model of ASD brain impairment exists. ASD core diagnostic symptoms are not uniquely linked and are only very rarely expressed without nondiagnostic symptoms. ASD has no reliable early predictor, no unitary developmental course, no unitary life outcome, no unitary recurrence risk, no unitary pattern of BAP [broader autism phenotype] features, and no standard homogeneous subgroups." They conclude that from a research perspective at least, disbanding the label of autism as it currently stands is the next logical step. Said disbanding "is likely to be reductive and uncomfortable" particularly when it comes to all those grand [sweeping] theories of autism put forward down the years. Feathers would not doubt be ruffled.

The authors do make reference to two important concepts when it comes how we might want to rethink autism: the Research Domain Criteria framework (RDoC) and Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations (ESSENCE). One is an attempt to move away from simple psychiatric labels as somehow denoting homogeneity, the other is the recognition that labels rarely appear in some sort of diagnostic vacuum. Both are in some way the future of autism research and indeed, the future is already now.

I'm impressed with the paper from Waterhouse et al. The authors have done a good job of basically saying that as things stand, one single label covering such a diverse and heterogeneous group is not fit for purpose. To see real progress in autism research, science needs to think more about those 'autisms' (see here) and stop using the label of autism as the starting point for research (see here). I struggle to disagree with both those sentiments and other authors appear to have reached similar conclusions [2]. Exactly what that means for the autism in the future - from both a research and clinical perspective - is still a little up in the air but the label has weathered change before and no doubt will continue to do so.

And if that isn't enough reading material for you, how about the latest instalment from the British Psychological Society here in Blighty when it comes to autism? Perhaps this will need a revision or two as the Waterhouse suggestions start to percolate through the research community?


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

[2] Geier DA. et al. Examining genotypic variation in autism spectrum disorder and its relationship to parental age and phenotype. Appl Clin Genet. 2016 Jul 28;9:121-9.


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

Friday, 26 August 2016

What does the Autism Spectrum Quotient (AQ) actually measure?

"Higher AQ [Autism Spectrum Quotient] scores were associated with higher scores of loneliness, social anxiety, depression, and anxiety, as well as with lower scores of quality of life (QoL)."

Those were some of the key findings reported by Phil Reed and colleagues [1] who used the very popular 'are you autistic?' AQ screening tool to look at the presence of autistic traits "along with depression, anxiety, loneliness, quality of life, and social anxiety" in a University student cohort (N=413).

Finding that among their research population some 8% scored above the cut-offs used by the AQ, researchers also reported those important 'associations' all tied into QofL.

Accepting that I'm probably a little biased when it comes to the 'problematic' use of the AQ as a screening tool for autism (see here and see here), my interpretation of the Reed results plays into the idea that the AQ is certainly picking up something, but exactly what is still the source of some debate (see here). I might for example, point you in the direction of the findings by Kitazoe and colleagues [2] who, based on similar student cohort, talked about "qualitatively different groups" over and above "a single homogeneous group" when it came to high scorers on the AQ.

It is also pretty well accepted that issues such as social anxiety and depression are over-represented when it comes to a diagnosis of autism (see here and see here respectively) and one has to wonder whether the AQ might be tuned into to the features of those labels over and above core autism. Indeed, going back a few years, the findings reported by Kunihira and colleagues [3] kinda signalled as much where personality traits "toward an obsessional personality" were seemingly connected to AQ scores in a non-autistic population as well as "higher depression and anxiety." Such findings might also be 'useful' when it comes to looking at the AQ in the context of eating disorders too [4].

I look forward to seeing more research done on this important topic (something ripe for more University student research projects perhaps).


[1] Reed P. et al. Loneliness and Social Anxiety Mediate the Relationship between Autism Quotient and Quality of Life in University Students. J Dev Phys Disabil. 2016. Aug 12.

[2] Kitazoe N. et al. Whether the Autism Spectrum Quotient consists of two different subgroups? Cluster analysis of the Autism Spectrum Quotient in general population. Autism. 2016 Apr 30. pii: 1362361316638787.

[3] Kunihira Y. et al. 'Autistic' traits in non-autistic Japanese populations: relationships with personality traits and cognitive ability. J Autism Dev Disord. 2006 May;36(4):553-66.

[4] Mansour S. et al. Emotions mediate the relationship between autistic traits and disordered eating: A new autistic-emotional model for eating pathology. Psychiatry Res. 2016 Aug 8;245:119-126.


ResearchBlogging.org Reed, P., Giles, A., Gavin, M., Carter, N., & Osborne, L. (2016). Loneliness and Social Anxiety Mediate the Relationship between Autism Quotient and Quality of Life in University Students Journal of Developmental and Physical Disabilities DOI: 10.1007/s10882-016-9504-2

Thursday, 25 August 2016

Hospitalisation for infection and risk of death by suicide

"An increased risk of death by suicide was found among individuals hospitalized with infection in prospective and dose-response relationships. These findings indicate that infections may have a relevant role in the pathophysiological mechanisms of suicidal behavior."

Some intriguing data has been recently reported by Helene Lund-Sørensen and colleagues [1] (open-access) examining the possibility that certain types of infection (or perhaps the biological response to infection) might increase the risk of suicidal behaviour. Some good media coverage about the study can be read here.

If your sticking with my interpretation of the results, Denmark was the the source of the data, as yet again one of those quite amazing Scandinavian population registries provides a starting cohort of around 7 million people "observed for a total of 149 061 786 person-years" from which subsequent results are derived.

Sadly, some 32,000 suicides (completed) were recorded during the study period; around a quarter of such reports were among people who had "previously been diagnosed as having an infection during a hospitalization." Such data was reported in terms of incidence rate ratios (IRRs) and equated to those hospitalised for infection being 42% more likely to die by suicide than those not hospitalised for infection. The 'dose-response' relationship eluded to in that opening sentence refers to the finding that the more serious the infection and/or the longer the hospital stay (treatment), the more likely the risk of death by suicide. Such an association also held when adjustment was made for potential confounding variables such as sex, age and socio-economic status.

Accepting that suicide - whether contemplated, attempted or completed - is a very complicated and often very individual process these are interesting results. Of course one has to be slightly careful in drawing too many conclusions from such data given both the large number of 'infections' included as part of the analyses and the possible "psychological effect of being hospitalized with a severe infection." The Lund-Sørensen data is still data built on association not necessarily 'cause and effect'.

Still, adding to the increasingly popular idea that infections or the biological response to infection at critical periods of development and life can seemingly affect behaviour (see here and see here for a few more potential examples) as well as physiology, the current study makes an important case for further study in this area. Not least because even if only playing a role in a small proportion of suicides, there may be important screening and possible intervention avenues to explore. I'm also wondering what such a possible association might mean with regards to the 'transmission' of certain infections and potential suicide risk? Y'know added to the speculation that some types of depression could perhaps be relabelled as an infectious disease [2] and in light of the strong connection between depression and suicidal behaviours...


[1] Lund-Sørensen H. et al. A Nationwide Cohort Study of the Association Between Hospitalization With Infection and Risk of Death by Suicide. JAMA Psychiatry. 2016. Aug 10.

[2] Canli T. Reconceptualizing major depressive disorder as an infectious disease. Biology of Mood & Anxiety Disorders. 2014; 4:10


ResearchBlogging.org Lund-Sørensen H, Benros ME, Madsen T, Sørensen HJ, Eaton WW, Postolache TT, Nordentoft M, & Erlangsen A (2016). A Nationwide Cohort Study of the Association Between Hospitalization With Infection and Risk of Death by Suicide. JAMA psychiatry PMID: 27532502

Wednesday, 24 August 2016

ALSPAC says maybe to link between prenatal paracetamol exposure and childhood behavioural difficulties

ALSPAC - the Avon Longitudinal Study of Parents and Children - continues to give in research terms as today I approach the findings reported by Evie Stergiakouli and colleagues [1]. They observed that: "Children exposed to acetaminophen [paracetamol] prenatally are at increased risk of multiple behavioral difficulties, and the associations do not appear to be explained by unmeasured behavioral or social factors linked to acetaminophen use insofar as they are not observed for postnatal or partner’s acetaminophen use." Some media attention for the study can be found here.

Continuing the research journey on a topic not unfamiliar to this blog (see here and see here for example) that exposure to paracetamol during the nine months that made us might not be a totally benign affair, Stergiakouli et al analysed data for some 7,700 mothers included in the initiative between 1991 and 1992. Questions about paracetamol use at 18 and 32 weeks of pregnancy were asked of mothers and maternal reports of child behaviour problems at 7 years using the Strengths and Difficulties Questionnaire (SDQ) were thrown into the research mix.

Results: those behavioural difficulties potentially associated with maternal paracetamol use at both 18 and 32 weeks of pregnancy included both conduct problems and hyperactivity symptoms. Researchers were also able to record no (significant) connection between post-natal paracetamol use nor partner paracetamol use and childhood behavioural problems. They concluded that "the timing of acetaminophen use might be important" and that "the association between prenatal acetaminophen exposure and childhood behavioral problems is not explained by unmeasured familial factors linked to both acetaminophen use and childhood behavioral problems and that the findings are consistent with an intrauterine effect."

Combined with the various other studies suggesting an association between prenatal exposure to paracetamol and offspring behavioural 'issues' the case for a possible link is growing. ALSPAC has a number of methodological strengths to its design, not least "the availability of prospective information on acetaminophen use during the second and third trimesters of pregnancy and postnatally by the mother and by her partner." The fact that numerous potentially confounding variables were also controlled for is another bonus for the study results: "maternal age at birth, parity, socioeconomic status, smoking and alcohol consumption during pregnancy, prepregnancy body mass index (BMI), maternal self-reported psychiatric illness, and possible indications for acetaminophen use." This is pretty strong data (or at least as strong as the other data published on this topic).

Mechanism(s) of effect? Still something that needs a little more work I'm afraid, before any precise information is revealed. The authors go with some ideas based on the "endocrine-disrupting properties of acetaminophen" for example, but let's wait and see before anyone makes too many sweeping generalisations. I might however suggest that the possibility of a link between paracetamol exposure and asthma (see here) could be important in light of what asthma might mean for the risk of presentation of ADHD (attention-deficit hyperactivity disorder) for example (see here). Just a thought and bearing in mind the evidence linking paracetamol use and asthma is not always all on-way.

Further studies are required on this increasingly important topic. Please also bear in mind no medical or clinical advice is given or intended on this blog. Speak to your physician if you need more information about pain relief during pregnancy.


[1] Stergiakouli E. et al. Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood. JAMA Pediatrics. 2016. Aug 15.


ResearchBlogging.org Stergiakouli, E., Thapar, A., & Davey Smith, G. (2016). Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood JAMA Pediatrics DOI: 10.1001/jamapediatrics.2016.1775

Tuesday, 23 August 2016

Autism and/or ADHD in Down's syndrome

"High rates of ASD [autism spectrum disorder] and ADHD [attention-deficit hyperactivity disorder] were found: 17 (42%) and 14 (34%) of the 41 children met DSM criteria for ASD and ADHD respectively."

That was the conclusion reached in the study by Ulrika Oxelgren and colleagues [1] looking at the "prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD) in a population-based group of children and adolescents with Down syndrome." The population in this case comprised 60 children and young adults diagnosed with Down's syndrome (Down syndrome if you prefer) and the gold-standards that are the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) were the instruments of choice when arriving at decisions of whether autism might be present or not.

New news? No it's not new news that autism (whether in diagnosis or in traits) may be over-represented when it comes to Down's syndrome (see here and see here for other research-based examples). There has even been a suggestion that regression - a key part of at least some autism - may be part and parcel of some cases of Down's syndrome (see here) too.

Oxelgren et al suggest that the combination of Down's syndrome and the "intellectual disability and medical disorders" that can accompany Down's syndrome added to a possible higher rate of autism potentially make for "a severely disabled group" worthy of far greater attention when it comes to screening and intervention. I don't think anyone would disagree with such sentiments and in particular, how preferential autism screening should once again be added to a growing list of diagnoses and labels. Indeed, such data in particular directs further attention to the link between intellectual (learning) disability and autism (see here and see here).


[1] Oxelgren UW. et al. Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study. Dev Med Child Neurol. 2016 Aug 9.


ResearchBlogging.org Oxelgren UW, Myrelid Å, Annerén G, Ekstam B, Göransson C, Holmbom A, Isaksson A, Åberg M, Gustafsson J, & Fernell E (2016). Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study. Developmental medicine and child neurology PMID: 27503703