Thursday, 28 August 2014

Minocycline for schizophrenia?

"Minocycline may improve the psychopathology of schizophrenia, especially the negative symptoms, and seems to be well tolerated".
A Bachelors Drawer (apparently) @ Wikipedia 

That was the finding from the systematic review and meta-analysis undertaken by Oya and colleagues [1] looking at the collected literature on the use of "minocycline augmentation therapy in patients with schizophrenia receiving antipsychotic agents". Augmentation therapy by the way, refers to the addition of minocycline to existing pharmacotherapy for schizophrenia.

I wasn't all that surprised to read the Oya paper given that for some time now, there have been scientific rumblings about how antibiotics might do quite a bit more than just 'killing bacteria' [2]. "Scientists shocked" was how one media report has previously talked about this area of research; which conjures up all-manner of visions of stunned science-types walking around with lab coats on and mouths and eyes wide open in amazement.

The reports that minocycline might act on the negative symptoms of schizophrenia (see here) is also quite an important detail, because these are often the symptoms which affect daily living skills, potentially manifesting as "losing interest and motivation in life and activities, including relationships and sex... [and a] lack of concentration, not wanting to leave the house and changes in sleeping patterns". These are also the symptoms which tend to respond less well to traditional management strategies like medication.

The final question(s) are how and why does minocycline affect cases of schizophrenia? The paper from Zhang and Zhao [3] (open-access) provides quite a good overview of the various hypotheses put forward. Unsurprisingly, some effect on inflammation figures quite strongly in the suggestions put forward. I could go on and on and on about the various research in this area (see here for example) but won't on this occasion. Instead, I'll direct you to a previous post I wrote on minocycline and Fragile X syndrome (see here) which mentions some effect from minocycline on matrix metalloproteinase-9 (MMP-9). I'd like to think that this is a potentially important point because of the tie-in with something like homocysteine (see here), the big H, which has also been mentioned with schizophrenia in mind (see here). Just speculatin' of course.

Music to close. Frank Sinatra and something about a lot of coffee in Brazil?

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[1] Oya K. et al. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol. 2014 Aug 4.

[2] Levkovitz Y. et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010 Feb;71(2):138-49.

[3] Zhang L. & Zhao J. Profile of minocycline and its potential in the treatment of schizophrenia. Neuropsychiatr Dis Treat. 2014 Jun 17;10:1103-11.

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ResearchBlogging.org Oya K, Kishi T, & Iwata N (2014). Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Human psychopharmacology PMID: 25087702

Wednesday, 27 August 2014

Prenatal SSRI exposure and autistic traits

A quote to start today's post: "Our results suggest an association between prenatal SSRI exposure and autistic traits in children". That was a primary finding reported by Hanan El Marroun and colleagues [1] who looked at whether maternal depressive symptoms or a class of quite commonly used pharmaceutics - the selective serotonin reuptake inhibitors (SSRIs) - used to manage depressive symptoms, during pregnancy might impact on offspring development.
"Everything the light touches is our kingdom" 

Before progressing through some of the details around this area, I'm going to also direct your attention to a couple of important accompanying commentaries on the Marroun findings from Jones & McDonald [2] and Petersen and colleagues [3] (open-access). Both caution about reading too much too soon into the reported association between SSRIs and offspring outcomes, and the very real outcomes that can come about if psychiatric issues such as depression are not properly managed. Something I think most people might have heard about recently.

A few details about the Marroun paper might be useful:

  • Following some previous discussions correlating maternal SSRI use during pregnancy and offspring outcome with autism in mind (see here) including the quite recent papers by Harrington and colleagues [4] and Rai and colleagues [5], the authors looked to "prospectively determine whether intra-uterine SSRI exposure is associated with childhood autistic symptoms in a population-based study". 
  • "A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included" for study. The commentary from Petersen et al notes how small a group were actually exposed to SSRIs and how "these numbers rapidly dwindled when it came to the measurement of the outcome".
  • The Child Behavior Checklist and Social Responsiveness Scale (SRS) were used to assess "pervasive developmental and affective problems" and "autistic traits" respectively. 
  • Results: aside from an association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and autistic traits in children, researchers also reported that: "Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07-1.93) and affective problems (OR = 1.44, 95% CI 1.15-1.81)". The suggested link between maternal depressive symptoms and autistic traits was to some degree weaker than the SSRI exposure correlation.
  • The authors conclude that: "Long-term drug safety trials are needed before evidence-based recommendations are possible" as once again I'll direct you to the Jones and Petersen commentaries.

In the same way that the emerging data on prenatal valproate exposure *might* link into offspring outcome including the presence of autism (see here), so the Marroun paper potentially adds another medicine to the list. I would perhaps temper that last sentence by adding that the valproate story is perhaps a little further along in terms of rodent models of prenatal valproate exposure mimicking some features of autism (see here) and the data providing something like mechanisms to be looked at with further investigations in mind [6]. Still, the CDC Treating for Two initiative might be once again relevant.

The added complication with the SSRI-autism correlation is the discussion about maternal depressive symptoms also potentially mediating any link with offspring autism or autistic traits. The paper by Sørensen and colleagues [7] (open-access here) kinda hinted that this and other important confounding factors might impact on any studies of association, including details like: "paternal antidepressant use during the time of pregnancy was not associated with an increased risk of autism spectrum disorders, except for a 30% increase when the fathers took SSRI". Even more recently Clements and colleagues [8] talked about how maternal "major depression" confounded any medication relationship with offspring presentation. They also talked about a link with ADHD which brings me back to yesterday's post on comorbidity (see here)...

One would do well not to discount such confounding factors at this stage. Indeed, if one assumes that depression might have a physiological link to something like inflammation for example [9] we then start to arrive at the increasingly important research looking at maternal inflammation as being a risk factor for offspring autism (see here). And before you ask, yes, C-reactive protein (CRP) has been linked to depressive symptoms as per the meta-analysis by Valkanova and colleagues [10].

The Marroun results are interesting and add something to an increasing bank of peer-reviewed literature [11] suggestive of a possible link between SSRI use during pregnancy and offspring outcomes. On the basis of the current existing literature and with my blogging caveat of no medical advice given or intended, I would be minded to conclude that there is quite a bit more experimental investigation to be done on this category of medicines. But I don't yet think there is enough clear evidence to conclusively put an elevated risk of offspring autism on the list of potential side-effects of these medicines.

Music then. Scissor Sisters and Laura.

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[1] Marroun HE. et al. Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children. The British Journal of Psychiatry. 2014; 205: 95-102.

[2] Jones I. & McDonald L. Living with uncertainty: antidepressants and pregnancy. The British Journal of Psychiatry. 2014; 205: 103-104.

[3] Petersen I. et al. Prenatal exposure to selective serotonin reuptake inhibitors and autistic symptoms in young children: another red herring? The British Journal of Psychiatry. 2014; 205: 105-106.

[4] Harrington RA. et al. Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay. Pediatrics. 2014 Apr 14.

[5] Rai D. et al. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ. 2013 Apr 19;346:f2059.

[6] Bambini-Junior V. et al. Prenatal Exposure to Valproate in Animals and Autism. Comprehensive Guide to Autism. 2014: 1779-1793.

[7] Sørensen MJ. et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol. 2013 Nov 15;5:449-59.

[8] Clements CC. et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Molecular Psychiatry. 2014. August 26.

[9] Berk M. et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 Sep 12;11:200.

[10] Valkanova V. et al. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013 Sep 25;150(3):736-44.

[11] Rais TB. & Rais A. Association Between Antidepressants Use During Pregnancy and Autistic Spectrum Disorders: A Meta-analysis. Innov Clin Neurosci. 2014 May;11(5-6):18-22.

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ResearchBlogging.org Marroun, H., White, T., van der Knaap, N., Homberg, J., Fernandez, G., Schoemaker, N., Jaddoe, V., Hofman, A., Verhulst, F., Hudziak, J., Stricker, B., & Tiemeier, H. (2014). Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children The British Journal of Psychiatry, 205 (2), 95-102 DOI: 10.1192/bjp.bp.113.127746

Tuesday, 26 August 2014

76% of youths with autism meet ADHD diagnostic criteria?

Autism is not normally a stand-alone diagnosis. I've mentioned that point a few times on this blog, stressing how a clinical diagnosis of autism appears to increase the risk of various other behavioural, psychiatric and somatic diagnoses also [variably] being present over a lifetime. Part of that comorbidity has been talked about in discussions about ESSENCE (see here) and the excellent document produced by Treating Autism on medical comorbidities occurring alongside autism (see here) for example. Prof. Gillberg's recent scientific publication called 'Autism Plus Versus Autism Pure' [1] kinda adds to this notion and his very strongly worded sentiments: "It is high time that the comorbidities, sometimes even more important than the autism, came back on the diagnostic agenda".
Cheeky... @ Wikipedia 

Outside of the more traditional comorbidities mentioned in the same breath as some autism, such as learning disability (intellectual disability) and epilepsy or seizure-type disorders, quite a lot of attention is being focused on the overlap between autism and attention-deficit hyperactivity disorder (ADHD). Indeed, the paper by Gagan Joshi and colleagues [2] very much thrusts ADHD into the autism diagnostic arena with their assertion of: "A high rate of comorbidity with ADHD was observed in psychiatrically referred youth with ASD [autism spectrum disorder], with a clinical presentation typical of the disorder".

The Joshi paper sought to "compare the clinical presentation of ADHD between youth with autism spectrum disorder (ASD) and ADHD and a sample of youth with ADHD only". What they found is something remarkably similar to the typical presentation of ADHD (without autism) insofar as age of onset and "distribution of diagnostic subtypes, the qualitative and quantitative symptom profile, and symptom severity". I might add that their participant group was classified as "High-Functioning" (their words not mine) so one needs to be mindful that only one part of the autism spectrum was surveyed.

What is perhaps slightly worrying from the Joshi results was the finding that: "a significant majority of ASD youth with ADHD failed to receive appropriate ADHD treatment". ADHD treatment, as I've mentioned in previous posts, normally implies pharmacotherapy but can also include other intervention options as per discussions on things like dietary changes potentially being useful for some (see here). Indeed, I've talked about the some of the results from things like the use of a gluten- and casein-free (GFCF) diet when applied to autism and how ADHD-type symptoms might be the more important targets for intervention (see here). The idea also that outside of just affecting ADHD symptom profiles, intervention might also have knock-on effects for other areas as per the review by Daley and colleagues [3] is similarly important.

I don't want to linger further on this issue aside from reiterating that the presentation of autism is, more often than not, part of a complex tapestry of presentation which can cover various other diagnostic categories. ADHD or sub-threshold ADHD-type symptoms are being realised as fairly frequent companions to a diagnosis of autism. The changes to the diagnostic criteria for ADHD (see here) will no doubt further expand the link between autism and ADHD, placing yet more emphasis on how autism is not normally a stand-alone diagnosis.

Music to close. Ray Charles and You Don't Know Me.

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[1] Gillberg C. & Fernell E. Autism Plus Versus Autism Pure. J Autism Dev Disord. 2014 Jun 24.

[2] Joshi G. et al. Symptom Profile of ADHD in Youth With High-Functioning Autism Spectrum Disorder: A Comparative Study in Psychiatrically Referred Populations. J Atten Disord. 2014 Aug 1. pii: 1087054714543368.

[3] Daley D. et al. Behavioral Interventions in Attention-Deficit/Hyperactivity Disorder: A Meta-Analysis of Randomized Controlled Trials Across Multiple Outcome Domains. J Am Acad Child Adolesc Psychiatry. 2014 Aug;53(8):835-847.e5.

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ResearchBlogging.org Joshi G, Faraone SV, Wozniak J, Tarko L, Fried R, Galdo M, Furtak SL, & Biederman J (2014). Symptom Profile of ADHD in Youth With High-Functioning Autism Spectrum Disorder: A Comparative Study in Psychiatrically Referred Populations. Journal of attention disorders PMID: 25085653

Monday, 25 August 2014

mTOR-regulated autophagy and autism mouse models

I was intrigued to read the paper by Guomei Tang and colleagues [1] (open-access) and their assertion that: "mTOR [mammalian target of rapamycin]-regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD [autism spectrum disorder] models with hyperactivated mTOR".
"Re-verify our range to target... one ping only".

If that opening paragraph sounds like scientific gibberish, I'll refer you to one of the many media write-ups of the study (see here) describing how, among other things, researchers looked at brain tissue from the deceased with autism compared with those asymptomatic for autism and counted 'spines' (dendritic spines) - protrusions from a neuron. They reported "increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe". This is interpreted as "an oversupply of synapses" in certain parts of the brain and lead to headlines such as: "Scientists discover people with autism have too many brain 'connections'". All of this ties into the debates about brain connectivity in autism [2].

The next part of the Tang findings revolve around one of the possible 'whys' for their surplus of synapses findings talking about possible issues with the process of autophagy [3] - a sort of cellular housekeeping. The idea being that there are processes at work which clear out cells which we don't need or that are damaged including synaptic pruning. Here, the authors focused on something called mTOR (which has been previously discussed on this blog) specifically with it's link to autophagy [4]. Based on a mouse model of tuberous sclerosis (see here), a condition associated with autistic-like behaviour [5], researchers reported issues with mTOR activity which seemed to overlap with the findings of synaptic oversupply noted in brain samples from those with autism. Further "the medication rapamycin both restores normal synaptic pruning and reduces autism-like behaviors in a mouse model of autism" according to another commentary on the Tang study.

The NHS Choices website has already given the Tang study the once-over (see here) and noted: "this research is in its very early stages. It mainly helps our understanding of the brain changes that may be involved in this condition. It is too soon to say whether it could lead to any treatment for autism spectrum disorders, and even if it does it is likely to be a long way off". I'd echo those sentiments as well as adding a few of my own.

First, although no expert on the analysis of neural tissue, I note some more knowledgeable commentators have talked about how careful one has to be when drawing too many conclusions based on postmortem studies (see here). This also means taking into account the effect of any comorbidity that appeared alongside the diagnosis of autism and what role that might play in any results obtained. Second, is the reliance on a mouse model of autism (emphasis on 'mouse model') which, although overlapping with some autistic behaviours and with possibly related findings [6], is not necessarily representative of quite a lot of autism. Tuberous sclerosis for example, does seem to show some kind of relationship with autism [7] but as with other proposed less idiopathic types of autism (see here) one has to be a little bit careful in over-extrapolating any connection. Same goes for when one talks about increased spine density being found in all autism [8]. Finally, rapamycin is not exactly what one might call a desirable medication as a consequence of it's primary use and possible side-effects. I'm not saying that it doesn't have it's uses, just that when applied to real people with autism (not mouse models), the peer-reviewed literature is currently very, very sparse when it comes to efficacy and importantly safety. That being said, there may be other ways to inhibit mTOR [9] bearing in mind my caveat about not giving medical or clinical advice on this blog...

Music then. Rather Be...

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[1] Tang G. et al. Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits. Neuron. 2014. August 21.

[2] Uddin LQ. et al. Reconceptualizing functional brain connectivity in autism from a developmental perspective. Front Hum Neurosci. 2013 Aug 7;7:458.

[3] Glick D. et al. Autophagy: cellular and molecular mechanisms. J Pathol. 2010 May;221(1):3-12.

[4] Jung CH. et al. mTOR regulation of autophagy. FEBS Lett. 2010 Apr 2;584(7):1287-95.

[5] Reith RM. et al. Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol Dis. 2013 Mar;51:93-103.

[6] Isshiki M. et al. Enhanced synapse remodelling as a common phenotype in mouse models of autism. Nat Commun. 2014 Aug 21;5:4742.

[7] Smalley SL. Autism and tuberous sclerosis. J Autism Dev Disord. 1998 Oct;28(5):407-14.

[8] Wei H. et al. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome. PLoS One. 2012;7(5):e36981.

[9] Theoharides TC. et al. Focal brain inflammation and autism. J Neuroinflammation. 2013 Apr 9;10:46.

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ResearchBlogging.org Tang, G., Gudsnuk, K., Kuo, S., Cotrina, M., Rosoklija, G., Sosunov, A., Sonders, M., Kanter, E., Castagna, C., Yamamoto, A., Yue, Z., Arancio, O., Peterson, B., Champagne, F., Dwork, A., Goldman, J., & Sulzer, D. (2014). Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits Neuron DOI: 10.1016/j.neuron.2014.07.040

Saturday, 23 August 2014

You heard me right... autism prevalence and meat consumption

"The paper presents some exploratory analyses demonstrating the correlation between particular aspects of meat consumption and autism prevalence". The paper by Wojciech & Ewa Pisula [1] (open-access) does indeed suggest that there may "a correlation between increasing meat consumption and autism prevalence".
"Goonies never say die!"

Readers are invited to draw their own conclusions on such a correlation. Personally, I'm not yet convinced that meat consumption is the primary driving force behind the increase in cases of autism being diagnosed worldwide outside of any mention of the word 'correlation'.

I am however open to further study on aspects of food or food production potentially being linked to autism in some roundabout way as per areas talking about dioxin exposure through food consumption (see here) or even animal antibiotic use being linked into changing gut microbiota [2] (open-access) (see here too) bearing in mind my not over-selling the whole gut bacteria bit (see here).

I might also draw your attention to some "fundamental limitations" that the authors include about their hypothesis:

"1. None of the authors is an epidemiologist. Our experience is in different fields, namely comparative psychology (first author) and clinical child psychology (second author).

2. The data presented here do not cover sufficient ground to facilitate the proposal of a precise hypotheses.

3. We did not have enough data to run confirmatory analyses, therefore we have limited ourselves to purely correlational statistics, while providing raw numbers retrieved from the cited sources.

4. It is very likely that the real variable that may definitively explain the observed correlations remains invisible, and what we see is just a surface aspect of the phenomenon."

'Nuff said.

And speaking of meat, I'll also draw your attention to the recent BBC Horizon programme looking at meat and health by Dr Michael Mosley (see here). Although not the best of Dr Mosley's TV efforts (particularly the 'making sense of the statistics' section and the N=1 experiment) the message seems to be that meat - real meat not the processed stuff - in moderation is probably not going to be particularly harmful to health for those that choose an omnivorous diet. Oh, and fat isn't necessarily the bad guy but those trillions of beasties which inhabit our gut might need some further inspection [3]. If however you want an alternative form of animal protein which has a more environmentally friendly footprint, how about mussels a few times a week?

Some music then and having finally taken the plunge into the wonder that is Spotify, I discovered a bit of a blast from the past: A.M. 180 from Grandaddy. Be prepared for more nuggets in future posts...

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[1] Pisula W. & Pisula E. Autism prevalence and meat consumption - a hypothesis that needs to be tested. Medical Hypotheses. 2014. August 14.

[2] Forslund K. et al. Country-specific antibiotic use practices impact the human gut resistome. Genome Res. 2013. 23: 1163-1169

[3] Koeth RA. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. 2013; 19: 576–585.

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ResearchBlogging.org Wojciech Pisula, & Ewa Pisula (2014). Autism prevalence and meat consumption - a hypothesis that needs to be tested Medical Hypotheses : 10.1016/j.mehy.2014.08.007

Friday, 22 August 2014

Serum microRNA profiles and autism

I cannot pretend to be an expert on microRNA (miRNA). Indeed, it was only after reading the paper by Mahesh Mundalil Vasu and colleagues [1] (open-access) talking about serum microRNA profiles in children diagnosed with an autism spectrum disorder (ASD), that I started my learning journey about these small non-coding RNAs. So please, go easy with me on this one...

Hamlet @ Wikipedia 
Quite a good [short] introduction to microRNAs can be found here. If you want something a little more comprehensive then I might direct you to the paper by Bartel which can be found here [2] (open-access). Basically, miRNAs are a type of post-transcriptional regulator. "Once made, miRNAs can suppress gene expression by inhibiting translation or promoting mRNA degradation". There you have some hints as to why miRNAs might be quite important; as Vasu and colleagues put it: "MicroRNAs (miRNAs) have recently emerged as prominent epigenetic regulators of a variety of cellular processes, including differentiation, apoptosis and metabolism".

A few details from the Vasu paper might be useful, bearing in mind the paper is open-access and snippets of the findings were reported at IMFAR 2014:

  • "Total RNA, including miRNA, was extracted from the serum samples of 55 individuals with ASD and 55 age- and sex-matched control subjects, and the mature miRNAs were selectively converted into cDNA". The average of participants in both groups was around 11 years old.
  • Screening was undertaken looking at the expression and quantification of miRNAs to determine whether there were any differences between autism and control groups. Further analysis was completed "to predict the target genes and altered pathways of differentially expressed miRNAs".
  • Results: "In the preliminary array screening, we observed an altered expression of 14 miRNAs in the ASD samples compared to those of controls". Some miRNAs were up-regulated; others down-regulated. Some 'fine-tuning' of this list of miRNAs differentially expressed in the autism group ended up with 13 miRNAs. Analysis of the genetic targets of these MiRNAs came up with several possible relations - "600 predicted genes and 18 neurological pathways" - but the top 10 neurological pathways covered "axon guidance, TGF-beta signaling, MAPK signaling, adherens junction, regulation of actin cytoskeleton, oxidative phosphorylation, hedgehog signaling, focal adhesion, mTOR signaling and Wnt signaling". Some of these processes have been talked about previously with autism in mind, for example, as per the article by Wang & Doering [3] on mTOR and autism (see also a previous post on this blog). mTOR is also enjoying some even more recent coverage too [4].
  • Based on scores for the autism group derived from the ADI-R (Autism Diagnostic Interview - Revised), researchers did not find any significant correlations between miRNA expressions and the core behavioural domains. 
  • The authors did [tentatively] suggest that: "Five miRNAs showed good predictive power for distinguishing individuals with ASD". We'll see how this pans out in future work...

MicroRNAs have been talked about with autism in mind previously in the peer-reviewed literature. The paper by Vaishnavi and colleagues [5] (open-access) for example, talked about SNPs (single nucleotide polymorphisms) "perturbing miRNA-mediated gene regulation [that] might lead to aberrant expression of autism-implicated genes". Indeed, they identified "9 MRE [miRNA recognition elements-modulating SNPs and another 12 MRE-creating SNPs in the 3'UTR of autism-implicated genes". Certainly this work might put those 'common genetic variants' into something of a new light.

Ziats & Rennert [6] in their discussions about "differentially expressed microRNAs across the developing human brain" talked about miRNAs potentially being linked to a variety of neurodevelopmental conditions. Schizophrenia and autism were the conditions talked about by Mellios & Sur [7], with the lion's share of work currently going to schizophrenia [8] over autism. That being said, I'd wager that there will be more to see from research looking at miRNAs and autism in the coming years especially when Vasu et al reported: "The differentially expressed miRNAs in this study... were previously reported to have altered expression in schizophrenia... supporting the contention that ASD and schizophrenia share common neurobiological features". Common ground indeed.

I'm still getting my head around miRNAs and autism, and by no means should this entry be viewed as anything other than an amateur attempt to explain them and their potential importance to autism and various other conditions [9]. The Vasu results, whilst preliminary, offer a good roadmap to further investigation being undertaken bearing in mind the various other areas being examined beyond just traditional genomics and the very important focus on gene expression. Now, about miRNAs and comorbidity like ADHD [10]...

Music then, and how about a spot of Johnny Cash and I Walk the Line.

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[1] Vasu MM. et al. Serum microRNA profiles in children with autism. Molecular Autism. 2014; 5: 40

[2] Bartel DP. MicroRNAs: Genomics, Biogenesis, Mechanism, and Function. Cell. 2004; 116: 281-297.

[3] Wang H. & Doering LC. Reversing autism by targeting downstream mTOR signaling. Front Cell Neurosci. 2013 Mar 26;7:28.

[4] Tang G. et al. Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits. Neuron. 2014. August 21.

[5] Vaishnavi V. et al. Mining the 3'UTR of autism-implicated genes for SNPs perturbing microRNA regulation. Genomics Proteomics Bioinformatics. 2014 Apr;12(2):92-104.

[6] Ziats MN. & Rennert OM. Identification of differentially expressed microRNAs across the developing human brain. Mol Psychiatry. 2014 Jul;19(7):848-52.

[7] Mellios N. & Sur M. The Emerging Role of microRNAs in Schizophrenia and Autism Spectrum Disorders. Front Psychiatry. 2012 Apr 25;3:39.

[8] Sun E. & Shi Y. MicroRNAs: small molecules with big roles in neurodevelopment and diseases. Experimental Neurology. 2014. August 13.

[9] Ru Y. et al. The multiMiR R package and database: integration of microRNA-target interactions along with their disease and drug associations. Nucleic Acids Res. 2014 Jul 24. pii: gku631.

[10] Kandemir H. et al. Evaluation of miR18a-5p, miR22-3p, miR24-3p, miR106b-5p, miR107, miR125b-5p, and miR155a-5p levels in children and adolescents with attention deficit hyperactivity disorder. Neuroscience Letters. 2014. August 12.

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ResearchBlogging.org Mundalil Vasu, M., Anitha, A., Thanseem, I., Suzuki, K., Yamada, K., Takahashi, T., Wakuda, T., Iwata, K., Tsujii, M., Sugiyama, T., & Mori, N. (2014). Serum microRNA profiles in children with autism Molecular Autism, 5 (1) DOI: 10.1186/2040-2392-5-40

Thursday, 21 August 2014

Autism, ADHD and allergy: Taiwan and big data (again)

"Children with ADHD [attention-deficit hyperactivity disorder] or ASD [autism spectrum disorder] had an increased risk of allergic comorbidities, and those with both ADHD and ASD had the highest".
"You built a time machine.. out of a DeLorean"

That was the conclusion arrived at in the paper by Ting-Yang Lin and colleagues [1]. For regular readers of this blog, this was yet another example of how Taiwan leads the way when it comes to the concept of 'big data' specifically employed with neurodevelopmental conditions in mind. That Taiwan National Health Insurance Research Database is proving to be a very valuable resource indeed.

A few details from the latest study:

  • "5386 children aged less than 18 years with ADHD alone, 578 with ASD alone, 458 with ADHD + ASD, and 25,688 non-ADHD/ASD age- and sex-matched (1:4) controls were enrolled in our study". I don't think anyone can say that this was an underpowered study.
  • The presence of various allergic diseases including asthma and atopic dermatitis were looked at among participant groups and compared.
  • Results: Odds ratios (ORs) suggested that the autism, ADHD and combined autism + ADHD groups were all more likely to present with comorbid allergic conditions compared to asymptomatic controls. This, taking into account "age, sex, and level of urbanization". The combined group seemed to be a greater risk of allergic disease than the autism or ADHD alone groups (OR: 2.2 95% CI: 1.83–2.79).
  • "ASD children with more allergic comorbidities were associated with a greater likelihood of ADHD". 

Quite a bit of this data taps into previous findings based on the examination of the Taiwanese insurance database insofar as the link between asthma (see here and see here) and neurodevelopmental diagnoses, so no real surprises there. The intriguing prospect that an increasing allergic burden in cases of autism seemed to elevate the risk of comorbid ADHD being present is the value-added part to the Lin study. What autism research is starting to understand is that comorbidity is quite a big issue (see here) and, outside of learning disability (see here) and epilepsy (see here), ADHD seems to figure quite prominently (see here). 

Bearing in mind that correlation is not the same as causation, I'd like to see quite a bit more investigation into that autism - allergy - ADHD relationship talked about by Lin et al. Genetics might be a good starting point as per the growing realisation about 'common ground' when it comes to various behaviourally-defined conditions (see here). The recent paper looking at the possible genetics of schizophrenia [2] linking into immune functions (see here) might set the tone for further inquiry in this area. Given the growing body of research looking at immune function and autism (see here and see here for examples) one might see how allergic diseases may show more than a passing connection to at least some cases.

I'd also be minded to suggest that environment might also be something to look at with this possible relationship in mind. Food is something of a potential common denominator when it comes to at least some autism and some ADHD (see here) so perhaps further investigation might be required there. The paper by de Theije and colleagues [3] talked quite a bit about food allergy and autism and ADHD for example. I don't know enough about how food might tie into something like asthma or atopic eczema as to present any knowledgeable information about links. I'd hazard a guess that looking at something like the gastrointestinal (GI) tract and things like the gut microbiota [4] might also be worthwhile.

Music to close, and something uplifting from The Smiths...

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[1] Lin T-Y. et al. Autistic spectrum disorder, attention deficit hyperactivity disorder, and allergy: Is there a link? A nationwide study. Research in Autism Spectrum Disorders. 2014; 8: 1333-1338.

[2] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511: 421-427.

[3] de Theije CG. et al. Food allergy and food-based therapies in neurodevelopmental disorders. Pediatr Allergy Immunol. 2014 May;25(3):218-26.

[4] Molloy J. et al. The potential link between gut microbiota and IgE-mediated food allergy in early life. Int J Environ Res Public Health. 2013 Dec 16;10(12):7235-56.

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ResearchBlogging.org Lin, T., Lin, P., Su, T., Chen, Y., Hsu, J., Huang, K., Chang, W., Chen, T., Pan, T., Chen, M., & Bai, Y. (2014). Autistic spectrum disorder, attention deficit hyperactivity disorder, and allergy: Is there a link? A nationwide study Research in Autism Spectrum Disorders, 8 (10), 1333-1338 DOI: 10.1016/j.rasd.2014.07.009