Monday, 31 August 2015

Mesenchymal stem cell transplantation and a mouse model of autism

I once again tread carefully in this brief post talking about stem cells and autism on the back of what seems to be some growing research interest in this area (see here).

The paper by Hadar Segal-Gavish and colleagues [1] adds to this increasing interest with their efforts detailing what happened to a mouse model of autism (the BTBR mouse) following "intracerebroventricular MSC [mesenchymal stem cells] transplantation."

Looking at what happened when MSC transplantation was used, the authors highlight various behavioural and biological effects including: "a reduction of stereotypical behaviors, a decrease in cognitive rigidity and an improvement in social behavior." BDNF (brain-derived neurotrophic factor) was also reported to show changes following transplantation: "elevated BDNF protein levels in the hippocampus accompanied by increased hippocampal neurogenesis in the MSC-transplanted mice compared with sham treated mice."

The authors conclude: "Our study suggests a novel therapeutic approach which may be translatable to ASD [autism spectrum disorder] patients in the future."

Acknowledging that stem cells and autism is still a little bit of a hot potato in terms of the limited available research and more ethical questions about its use, these are interesting results. A recent opinion paper from Simberlund and colleagues [2] on the topic of MSC and autism highlighted the 'pitfalls and potential promises' of this line of investigation, and how despite almost universal scientific approval in terms of 'success' of this type of intervention so far, "substantial methodological and theoretical challenges and pitfalls remain before this can be considered a viable therapeutic option."

I'm gonna leave it at that for now.

Music: Aerosmith - Walk This Way.


[1] Segal-Gavish H. et al. Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice. Autism Res. 2015 Aug 10.

[2] Simberlund J. et al. Mesenchymal stem cells in autism spectrum and neurodevelopmental disorders: pitfalls and potential promises. World J Biol Psychiatry. 2015 Jul 31:1-8.

---------- Segal-Gavish H, Karvat G, Barak N, Barzilay R, Ganz J, Edry L, Aharony I, Offen D, & Kimchi T (2015). Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice. Autism research : official journal of the International Society for Autism Research PMID: 26257137

Saturday, 29 August 2015

Maternal obesity and offspring autism meta-analysed

So: "The meta-analysis results support an increased risk of autism spectrum disorder in children of women who were obese during pregnancy. However, further study is warranted to confirm these results."

That was the conclusion reached by Ya-Min Li and colleagues [1] looking at the collected peer-reviewed data currently available on how maternal weight might impact on offspring neurodevelopmental outcomes. Without wishing to blame or stigmatise (this is a blog based on the examination of cold, objective, peer-reviewed science) such results are not altogether unexpected based on instances where maternal weight might impact on offspring autism risk have been discussed (see here).

There are caveats to ideas of such an association. Not least that observational studies for example, often provide little information on 'cause and effect'. That not every child born to a mum who is overweight and/or obese develops autism should also be kept firmly in mind, as should the idea that overweight and/or obesity can sometimes sit with other comorbidity as part of the 'metabolic syndrome' so potentially introducing other variables into any association (see here). I might add that an array of other factors cross obesity and autism risk areas, not least mothers' nutritional status before and during pregnancy for example (see here).

That all being said, there is more science to do in this area. Thinking back to other discussions on data about how father's weight might also influence offspring autism risk (see here) and the idea of foetal programming [2] based to a large extent on the writings of the late David Barker, one gets some ideas of where science might want to start heading in continuing this line of inquiry.

Music: Keane - Everybody's Changing.


[1] Li YM. et al. Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis. J Autism Dev Disord. 2015 Aug 9.

[2] Lau C. & Rogers JM. Embryonic and fetal programming of physiological disorders in adulthood. Birth Defects Res C Embryo Today. 2004 Dec;72(4):300-12.

---------- Li YM, Ou JJ, Liu L, Zhang D, Zhao JP, & Tang SY (2015). Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis. Journal of autism and developmental disorders PMID: 26254893

Friday, 28 August 2015

Autoantibodies not implicated in cases of autism?

Contrary results are a common feature of the autism peer-reviewed research landscape. No sooner does one group publish the next 'big thing' when it comes to the singular term 'autism' than seemingly opposite results follow suit.

So it is with the paper under discussion today by Simran Kalra and colleagues [1] (open-access) who concluded that: "The idea that autoantibodies represent an underlying cause or are biomarkers for autism pathophysiology is not supported by this report."

Autoantibodies by the way, are part of the process whereby the body's immune system fails to recognise self as 'self' and mounts a response against the body's own tissue. It's a topic that has been discussed quite extensively with the autism spectrum in mind (see here for example) as part of a wider scientific debate about a role for immune function in at least some autism (see here).

The Kalra paper is open-access but a few details might be useful:

  • "Serological analysis was performed on typically developing children (n = 55), developmentally delayed children without autism (n = 24) and children diagnosed with autism (n = 104)." I believe this cohort of children were part of a larger study titled: 'Clinical and Immunological Investigations of Subtypes of Autism'.
  • Based on an interesting analytical method - Luciferase Immunoprecipitation Systems (LIPS) - used as an alternative to the more traditional ELISA methods, researchers initially set about looking for the presence of "autoantibodies against GAD65." GAD65 by the way, is part and parcel of the mechanism for synthesising GABA (see a previous post on this topic). They then extended the study focus to look for antibodies "against several other autoimmune-associated autoantigens, candidate neurological autoantigens, and viral proteins."
  • Results: well, when comparing study samples against samples from three people with diagnosed type 1 diabetes where GAD65 autoantibodies were to be expected to be present (and indeed were): "testing of serum from the typically developed children..., developmentally delayed children... and children with ASD... demonstrated no seropositive autoantibodies to GAD65.
  • Likewise when comparing autism samples with samples from "three positive control samples from subjects with systemic lupus erythematosus" for Ro52 - one of the anti-Ro antibodies found in cases of SLE - there was again nothing of note to see. Collectively the authors conclude that: "These findings rule out the possibility that GAD65 and Ro52 autoantibodies are biomarkers in ASD [autism spectrum disorder]."
  • Among the other results reported is an interesting remark when it comes to a retrovirus called XMRV. For those in chronic fatigue syndrome / myalgic encephalomyelitis circles, XMRV will probably be remembered for all the wrong reasons (see here) albeit with not all questions completely answered (see here). Kalra et al found nothing in terms of seropositivity when it came to autism and XMRV (and another target, mouse mammary tumor virus (MMTV)). They do however caution that "additional studies are needed to determine if other infectious agents, or the body's response to such infections agents, might play a role" in some autism.

These results are interesting. As per my opening comment on contrary results being part and parcel of autism research, the lack of GAD65 antibodies detailed is in direct contrast to previous findings such as those produced by Rout and colleagues [2] for example. Whilst there may be various reasons for the difference in findings including a role for the analytical method used, I was drawn to one comment made by Rout et al suggesting that there may be a subgroup of children with autism and/or ADHD (attention-deficit hyperactivity disorder) where further characterisation may be needed. That also reduced levels of GAD65 mRNA levels have been reported [3] in relation to autism (with appropriate caveats regarding tissue used for study) does not mean that GAD65 is off the research menu just yet.

The lack of XMRV antibody findings reported by Kalra et al in relation to their autism group is not necessarily new news. Previous studies such as the one from Satterfield and colleagues [4] basically said as much.

There are of course quite a few other types of autoantibodies and/or antibodies to infective agents that perhaps require more study using the technique utilised by Kalra and colleagues with autism in mind. The various contributions in this research area from the Saudi-Egyptian research tag-team that crop up on this blog every now and again (see here and see here) might be a next port of call. Anti-brain antibodies detailed by other teams might also receive the same treatment (see here). Who knows, researchers might also consider putting a little more flesh on the bones of all that folate receptor autoantibody research that is crying out for independent replication (see here) or even antimitochondrial antibodies (see here). Quite a few areas to consider.

As for the infection side of things and realising the important contribution that at least one of the authors on the Kalra paper has made to another area of research (Swedo and PANDAS/PANS) I can think of quite a few research studies to be done. My growing interest in enterovirus and autism (see here) or even enterovirus and ADHD (see here) is again requiring some further investigation. Perhaps a little more 'out there' are the ways and means that the methods detailed by Kalra might also be transferable to more ancient retroviruses such as the HERVs that have been discussed before on this blog (see here) with autism and various other conditions in mind (see here).

Music: John Newman - Come And Get It.


[1] Kalra S. et al. No evidence of antibodies against GAD65 and other specific antigens in children with autism. BBA Clinical. 2015. August 8.

[2] Rout UK. et al. Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. Eur Child Adolesc Psychiatry. 2012 Mar;21(3):141-7.

[3] Yip J. et al. Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res. 2009 Feb;2(1):50-9.

[4] Satterfield BC. et al. PCR and serology find no association between xenotropic murine leukemia virus-related virus (XMRV) and autism. Mol Autism. 2010 Oct 14;1(1):14.

---------- Kalra, S., Burbelo, P., Bayat, A., Ching, K., Thurm, A., Iadarola, M., & Swedo, S. (2015). No evidence of antibodies against GAD65 and other specific antigens in children with autism BBA Clinical DOI: 10.1016/j.bbacli.2015.08.001

Thursday, 27 August 2015

Fish oils preventing psychosis: long-term effects?

"This is the first study to show, to the best of our knowledge, that a 12-week intervention with omega-3 PUFAs [polyunsaturated fatty acids] prevented transition to full-threshold psychotic disorder and led to sustained symptomatic and functional improvements in young people with an at-risk mental state for 7 years (median)."

So said the quite remarkable findings reported by Paul Amminger and colleagues [1] (open-access available here) who followed up their previous research study [2] looking at the effects of a 12-week supplementation program consisting of either 1.2 grams per day of fish oil or placebo. On that previous occasion, said omega-3 PUFA supplement ("700 mg of eicosapentaenoic acid (20:5n3), 480 mg of docosahexaenoic acid (22:6n3), and 7.6 mg of mixed tocopherol (vitamin E)") reduced the risk of progression to psychotic disorder in individuals at ultra-high risk of psychosis for up to a year post-intervention baseline.

The latest results represent quite an impressive post-intervention follow-up to the original Amminger study. Looking at some of the original cohort of participants and drawing on several types of information including screening / questionnaire data and "rate of prescription of antipsychotic medication", the authors were able to quite confidently conclude that "omega-3 PUFAs may offer a viable longer-term prevention strategy with minimal associated risk in young people at ultrahigh risk of psychosis."

Insofar as the precise hows and whys of omega-3 PUFAs potentially affecting psychosis risk, well, we are left in quite a typical position of speculating. "Omega-3 PUFAs provide a range of neurochemical activities via modulation of neurotransmitter (noradrenaline, dopamine and serotonin) reuptake, degradation, synthesis and receptor binding, as well as anti-inflammatory and anti-apoptotic effects, and the enhancement of cell membrane fluidity and neurogenesis." Take yer pick, bearing in mind there may also be additive and interacting effects within this menu of potential modes of action.

If one assumes however that the possible connection between omega-3 PUFAs and various behavioural and psychiatric labels might have some commonalities (see here and see here for example), one might see a few additional ways and means that 'mode of action' might become a little clearer in the future. One factor, cognitive decline linked to cases of psychosis onset, might not however be the prime factor extrapolating from other recent results [3]...

Music: Felix Jaehn - Ain’t Nobody (Loves Me Better).


[1] Amminger GP. et al. Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nat Commun. 2015 Aug 11;6:7934.

[2] Amminger GP. et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010 Feb;67(2):146-54.

[3] Chew EY. et al. Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function. JAMA. 2015; 314: 791-801.

---------- Amminger GP, Schäfer MR, Schlögelhofer M, Klier CM, & McGorry PD (2015). Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nature communications, 6 PMID: 26263244

Wednesday, 26 August 2015

Atopic dermatitis and autism: systematically reviewed

I briefly want to bring the paper from Lucia Billeci and colleagues [1] to your attention today and the suggestion that following their systematic review of the current peer-reviewed literature, there seemed to be something of "an association between ASD [autism spectrum disorder] and AD [atopic dermatitis]."

Atopic, by the way, refers to sensitivity to allergens, and in the case of AD, how such sensitivity manifests on the skin causing itchiness, redness and the skin to become sore potentially also making it more prone to other infections.

Looking at 18 studies covering the topic of AD and other atopic diseases in relation to autism using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, authors concluded that "the frequencies of AD in ASD compared with a control group ranged from 7 to 64.2 %." Accepting such variability, they concluded that there may be quite a bit more to see in terms of an 'association' between the diagnostic entities.

I've covered the idea of a connection between autism and atopy quite a few times on this blog (see here and see here). Although to some extent confused by a possible relationship with other comorbidity that quite regularly feature alongside autism (attention-deficit hyperactivity disorder, ADHD), the idea of a sort of skin-brain axis with autism in mind (see here) does seem to be gaining some scientific traction on the basis of such data. That and the idea that immune function (a driver of conditions such as atopy) might be closely linked to at least some autism (see here for example) and one gets further peer-reviewed evidence that research efforts might need to be increased.

Oh, and that atopy and psychiatry might also extend further than just autism and/or ADHD is potentially important [2]...

Music: Foxes - Body Talk.


[1] Billeci L. et al. Association Between Atopic Dermatitis and Autism Spectrum Disorders: A Systematic Review. Am J Clin Dermatol. 2015 Aug 8.

[2] Catal F. et al. Psychiatric disorders and symptoms severity in preschool children with atopic eczema. Allergol Immunopathol (Madr). 2015 Aug 3. pii: S0301-0546(15)00092-0.

---------- Billeci L, Tonacci A, Tartarisco G, Ruta L, Pioggia G, & Gangemi S (2015). Association Between Atopic Dermatitis and Autism Spectrum Disorders: A Systematic Review. American journal of clinical dermatology PMID: 26254000

Tuesday, 25 August 2015

MOCOS: a new candidate for autism research

I'll freely admit that until reading the paper by François Féron and colleagues [1] (open-access available here) I had never heard of MOCOS (MOlybdenum COfactor Sulfurase) before.

Described as "an enzyme of the purine metabolism that sulfurates the molybdenum cofactor, thus allowing the two downstream enzymes—xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX1)—to be active", researchers reported that in nasal stem cells provided by a small group of adults diagnosed with an autism spectrum disorder (ASD), MOCOS was down-regulated compared with analyses of similar cells from asymptomatic controls. They concluded that differences related to MOCOS might be important: "likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders."

I'm intrigued.

The Féron paper is open-access but a few details might be useful:

  • Eleven participants diagnosed with autism (autism spectrum disorder, ASD) were included for study. Interestingly, DSM-5 diagnostic criteria were used to confirm the presence of ASD. Age and gender matched asymptomatic (for autism) controls were also used. As per the supplementary information included with the main article (see here), the authors characterised their participant group pretty well from various different angles.
  • A nasal biopsy was performed on participants in order to extract "nasal olfactory stem cells" based on a previously published technique [2]. Again, it's new news to me that you can get stem cells from the nose but apparently the "olfactory epithelium is also a nervous tissue that produces new neurons every day to replace those that are damaged by pollution, bacterial of viral infections. This permanent neurogenesis is sustained by progenitors but also stem cells residing within both compartments of the mucosa, namely the neuroepithelium and the underlying lamina propria."
  • Based on a "non-hypothesis-driven approach" Féron et al set about looking for "transcriptome anomalies" between the groups. Alongside other potentially important differences they stumbled across MOCOS in relation to their autism cohort and decided to look-see whether this might have some impact on cerebral functions using a classical worm model - Caenorhabditis elegans (C. elegans). A "genetic ablation of mocs-1 (the MOCOS ortholog)" engineered into the worm induced "an alteration of the response to oxidative stress and is responsible for abnormal neurotransmission phenotypes." Human cell studies confirmed this data.

Despite the small participant group, the MOCOS findings might carry some weight in view of some of the other 'dysregulated' genes that turned up with the ASD group in mind. So: "9 out of these 156 genes—ADAM23, CADM1, FOS, FOSB, JAG1, MEST, OXTR, SFRP1 and XIST—have been previously associated with ASD." You might note the mention of OXTR in that list, denoting the oxytocin receptor gene bearing in mind the cautious history in that area. That also pathway analysis of the genes differentially regulated in the autism group "identified developmental disorders and gastrointestinal diseases as two of the most represented categories associated with these genes" adds to the interest, bearing in mind the term 'over-represented' when it comes to bowel issues and autism (see here).

The suggestion that "MOCOS misexpression increases sensitivity to oxidative stress" is also an important part of the Féron findings. Oxidative stress and autism has quite a bit of peer-reviewed research history (see here for example) particularly in areas such as glutathione metabolism (see here) albeit not universally [3]. It's not beyond the realms of possibility that MOCOS may indeed be a contributory factor to such issues being present in some cases.

Further work is required in this area to corroborate the Féron data using larger participant numbers for example. With that in mind, I'll be keeping my eye open for more work on MOCOS and autism and whether it lives up to its 'new player' status...

Music: Weezer and Undone.


[1] Féron F. et al. Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Mol Psychiatry. 2015 Aug 4.

[2] Girard SD. et al. Isolating nasal olfactory stem cells from rodents or humans. J Vis Exp. 2011 Aug 22;(54). pii: 2762.

[3] Durieux AM. et al. Cortical and subcortical glutathione levels in adults with autism spectrum disorder. Autism Res. 2015 Aug 20.

---------- Féron F, Gepner B, Lacassagne E, Stephan D, Mesnage B, Blanchard MP, Boulanger N, Tardif C, Devèze A, Rousseau S, Suzuki K, Izpisua Belmonte JC, Khrestchatisky M, Nivet E, & Erard-Garcia M (2015). Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Molecular psychiatry PMID: 26239292

Monday, 24 August 2015

Social Anxiety Disorder and autism (again)

So: "A large subset (50 %) of the adults with ASD [autism spectrum disorder] met diagnostic criteria for SAD [social anxiety disorder]."

That was the conclusion reached in the paper by Brenna Maddox & Susan White [1] looking at the overlap between autism and SAD in a small-ish participant group. Social anxiety disorder by the way, refers to 'a persistent and overwhelming fear of social situations'. Alongside a growing body of peer-reviewed research talking about the often disabling aspects of anxiety when comorbid to autism (see here), the specific focus on social anxiety disorder is something emerging from the evidence base so far. I've talked about it previously on this blog (see here) although the frequency reported by Maddox & White is quite a bit greater than that noted by Bejerot and colleagues [2].

Management is very much implied from such findings given the significant distress and impediment that SAD can cause to an individual. Hopefully not too 'out there' I might also suggest that there may be more than one way that science could help overcome/manage such difficulties (see here) outside of medication and the various manifestations of talking therapy. Insofar as the connection between autism and SAD, further research is of course indicated; including whether, as has been suggested with children with autism, social anxiety might have something of a pivotal role in the success or not of intervention outcome(s) (see here).


[1] Maddox BB. & White SW. Comorbid Social Anxiety Disorder in Adults with Autism Spectrum Disorder. J Autism Dev Disord. 2015 Aug 5.

[2] Bejerot S. et al. Social anxiety in adult autism spectrum disorder. Psychiatry Res. 2014 Dec 15;220(1-2):705-7.

---------- Maddox BB, & White SW (2015). Comorbid Social Anxiety Disorder in Adults with Autism Spectrum Disorder. Journal of autism and developmental disorders PMID: 26243138

Saturday, 22 August 2015

Maternal folate status and offspring autism risk: where are we up to?

I'd like to briefly draw your attention to the review published by Elizabeth DeVilbiss and colleagues [1] today, covering "what is known about the role of folate in the aetiology of neurodevelopmental disorders."

Folate, is a topic that has graced this blog a few times with autism in mind (see here for example) based on various ideas that folate status during pregnancy might have the ability to modify offspring risk of autism [2] alongside the idea that autoimmune processes might act on folate receptors in some cases of autism (see here) and what this might subsequently mean for pathology / management. The specific idea that folate levels and folate supplementation during pregnancy might influence autism risk has garnered the most research attention, seemingly also crossing geographies too [3].

The DeVilbiss review is quite comprehensive in its scope and material covered, summarising "relevant biological, genetic and epigenetic mechanisms" and the various science that has been done so far on this topic. I would certainly agree with their sentiments that "existing evidence is inconclusive" (as previously indicated) in light of the numerous confounding variables also potentially linked to offspring autism risk. That being said, and acknowledging where folate metabolism sits in terms of areas such as MTHFR genetics (see here) and the whole vitamin B12 story (see here) and perhaps beyond (see here), I do think there is more to see in this area and perhaps outside of autism and related neurodevelopmental conditions (see here). Without jumping on the whole epigenetics bandwagon, the link between the folate cycle and DNA methylation in particular (see here) offers a whole slew of research ideas ripe for further investigation.

Music: Lost Frequencies - Are You With Me.


[1] DeVilbiss EA. et al. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. Br J Nutr. 2015 Aug 5:1-10.

[2] Schmidt RJ. et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012 Jul;96(1):80-9.

[3] Surén P. et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013 Feb 13;309(6):570-7.

---------- DeVilbiss EA, Gardner RM, Newschaffer CJ, & Lee BK (2015). Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. The British journal of nutrition, 1-10 PMID: 26243379

Friday, 21 August 2015

Digestive enzymes and autism

"The ASD [autism spectrum disorder] group receiving digestive enzyme therapy for 3 months had significant improvement in emotional response, general impression autistic score, general behavior and gastrointestinal symptoms. Our study demonstrated the usefulness of digestive enzyme in our population of ASD patients."

So said the results of a randomised, placebo-controlled clinical trial published by Khaled Saad and colleagues [1] (open-access available here) on the use of a specific digestive enzyme supplementation called Neo-Digestin. Looking at outcomes from about 100 children diagnosed with an ASD (by DSM-IV-TR), about half in receipt of Neo-Digestin (n=47) and half receiving a placebo of sucralose syrup, researchers reported something potentially to see based on CARS (Childhood Autism Rating Scale) scores and another measure called the Global Behavior Rating Scales (GBRS). The GBRS was incidentally used an an outcome measure during one of the trials of secretin with autism in mind [2] so has some history when it comes to pancreatic digestive enzyme functions.

Saad et al reported that compared to placebo, the Neo-Digestin group showed some significant positive changes in scores between baseline and intervention albeit restricted to the emotional response aspect of CARS and an overall reduction in autistic behaviours ("general autistic impression score"). Likewise on the GBRS, children in the enzyme supplement group "had significant improvement in two parameters including general behavior and gastrointestinal symptoms (quality of stools, abdominal pain, vomiting and food variety)." Importantly, whilst some side-effects were reported by the enzyme supplement group - "skin rashes, itching and abdominal pain" - we are told that these were mild and transient.

As always, these are interesting results. The particular formulation used by Saad and colleagues contained papain (1.6g) and pepsin (0.8g). Given three times a day (15ml/day in all) over the course of the trial, there is some obvious logic in what processes might have been affected by such an intervention with a focus on protein and peptide degradation in the gastrointestinal tract. Think of proteins as long pearl necklaces with each pearl the equivalent of an amino acid (hence the building blocks of proteins). Breaking that long pearl necklace down into smaller chains (peptides) and eventually the constituent amino acids is a prime function of digestive enzymes and has some autism research history (see here). A similar sort of thing has also been proposed by all that CM-AT work, but not necessarily with proteins/peptides in mind (see here). There could be lessons to learn from coeliac disease research in this area too (see here).

The Saad results are in direct contrast to the findings reported by Sujeeva Munasinghe and colleagues [3] who observed very little to see in their study of another digestive enzyme supplement with autism in mind. The devil however, could be in the detail in terms of differing formulations and possibly some overlap when it comes to digestive enzymes affecting specific issues such as "improvement in food variety" for example. The focus on gastrointestinal (GI) issues such as functional bowel problems being potentially 'improved' by such preparations is also important given the extensive coverage of such problems being 'over-represented' when it comes to a diagnosis of autism (see here) and the question of what can be done to relieve such symptoms as and when they occur.

What's more to say? Well, more studies are of course indicated. As Saad details: "Digestive enzymes are inexpensive, readily available, have an excellent safety profile, and have mildly beneficial effects in ASD patients." I'd perhaps also like to see a few more 'biological' parameters included in any future research on this topic; things like gut permeability measures for example (see here) and perhaps a little more data on the genetics and functioning of endogenous digestive enzyme functions also (see here and see here respectively). That other research has talked about probiotics as degrading gluten peptides too (see here) might also suggest a dual strategy research approach might be of some interest...

Music: Hole - Celebrity Skin.


[1] Saad K. et al. A Randomized, Placebo-controlled Trial of Digestive Enzymes in Children with Autism Spectrum Disorders. Clin Psychopharmacol Neurosci. 2015 Aug 31;13(2):188-93.

[2] Levy SE. et al. Children with autistic spectrum disorders. I: comparison of placebo and single dose of human synthetic secretin. Arch Dis Child. 2003 Aug;88(8):731-6.

---------- Saad K, Eltayeb AA, Mohamad IL, Al-Atram AA, Elserogy Y, Bjørklund G, El-Houfey AA, & Nicholson B (2015). A Randomized, Placebo-controlled Trial of Digestive Enzymes in Children with Autism Spectrum Disorders. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 13 (2), 188-93 PMID: 26243847

Thursday, 20 August 2015

Canada and the autism prevalence rate (yet again)

"At the end of 2013, the prevalence among children born in 2006 was 1 case of autism spectrum disorder per 46 children or 215.77 per 10 000."

That was the conclusions reached in the study by Lorine Pelly and colleagues [1] looking at "the incidence and 1-year cohort prevalence for autism spectrum disorders in children less than 15 years of age and living in the Avalon Peninsula at the time of diagnosis." The Avalon Peninsula by the way, is located in Canada.

Looking at data derived from the "Janeway Children’s Health and Rehabilitation Centre (St. John’s)" and specifically information pertinent to those with autism (this facility is apparently "the only child development centre in the region and is the only centre giving comprehensive autism spectrum disorder diagnoses to patients in this region") researchers set about looking at the numbers for autism diagnosis in the area. Autism spectrum disorder (ASD) diagnoses were based on DSM-IV criteria, confirmed through "multiple observations" and in most instances, involved data derived from the gold-standard assessment instrument that is ADOS (Autism Diagnostic Observation Schedule). Incidence and prevalence analyses were both undertaken.

So: "Between 2006 and 2010, 272 new cases of autism spectrum disorder were diagnosed within the study population." Most of these cases were male, and, get this, the median age of diagnosis was... 3.84 years. The lion's share of cases were autistic disorder (~47%) followed by autism spectrum disorder (27%) and then Asperger syndrome (20%). Complementing those diagnostic divisions and age at diagnosis was the fact that a module 1 ADOS was used for over 40% of assessments. The calculated incidence for 2006 was 10.1 per 10,000. This increased to 16.7 per 10,000 in 2010. The difference was statistically significant. Prevalence, as I've already said, was 1 in 46 in this cohort with males shouldering the largest risk.

Then, another important point emerges: "Our review found that many patients had at least one of the co-morbidities often associated with autism; the most prevalent were behavioural issues (n = 28), attention-deficit/hyperactivity disorder (n = 27) and anxiety disorder (n = 25)." It all sounds very ESSENCE-like if you ask me.

These are interesting data and add to previous studies looking at the autism numbers game in Canada (see here and see here). In that instance as in this, the numbers were increasing for whatever reason(s) and starting to look similar to the top-end CDC estimates from last year (2014). Pelly et al don't go into the specific hows and whys potentially linked to the increase in cases so I can't comment too much on that angle in their paper. Other recent publications talking about diagnostic substitution as one possible factor [2] in the increasing rate of autism makes a valid point but I dare say that things aren't so simple when it comes to the reasons behind the increase in different parts of the world [4]. Whether also such a increased rate of autism merits the term 'epidemic' is another issue covered recently in another paper [3] although I'm not getting too involved in that debate.

Music: Gossip - Standing In The Way Of Control.


[1] Pelly L. et al. Incidence and cohort prevalence for autism spectrum disorders in the Avalon Peninsula, Newfoundland and Labrador. CMAJ Open. 2015. July 29.

[2] Polyak A. et al. Comorbidity of intellectual disability confounds ascertainment of autism: Implications for genetic diagnosis. Am J Med Genet B Neuropsychiatr Genet. 2015 Jul 22.

[3] Lilenfeld SO. et al. Fifty psychological and psychiatric terms to avoid: a list of inaccurate, misleading, misused, ambiguous, and logically confused words and phrases. Front. Psychol. 2015. August 3.

[4] Randall M. et al. Autism spectrum disorder: Presentation and prevalence in a nationally representative Australian sample. Aust N Z J Psychiatry. 2015 Aug 17. pii: 0004867415595287.

---------- Pelly, L., Vardy, C., Fernandez, B., Newhook, L., & Chafe, R. (2015). Incidence and cohort prevalence for autism spectrum disorders in the Avalon Peninsula, Newfoundland and Labrador CMAJ Open, 3 (3) DOI: 10.9778/cmajo.20140056

Wednesday, 19 August 2015

Breast milk protects against GI symptoms in high risk autism?

Happy house @ Paul Whiteley
"Late weaning and EBM [exclusive breast milk] were associated with protection against GI [gastrointestinal] symptoms in High-risk infants."

That was one of the conclusions presented in the paper by Alexander Penn and colleagues [1] who asked some pretty important questions when it comes to the increasingly strong relationship between bowel issues and autism spectrum disorder (ASD) (see here).

"Using questionnaires, diet history and gastrointestinal problems were tracked prospectively and retrospectively in 57 High-risk infants, and for comparison, in 114 Low-risk infants (infants from families without ASD history)." The main aims of this study were to examine whether those at an enhanced risk for autism by virtue of having a sibling already diagnosed were at any greater risk of presenting with functional bowel symptoms, and whether such bowel issues were "associated with diet and age at weaning from breast milk."

Early weaning - the introduction of solid foods to an infant - seemed to be more frequently present in high-risk infants with bowel issues as did "a no breast milk (NBM) diet" compared with an exclusive breast milk diet. This was particularly true for the bowel symptom constipation and especially for those who were weaned earlier than 6 months of age.

The authors suggest that their data indicate that weaning and breast milk diet practices might have some bearing for the presentation of bowel symptoms in those at high-risk for autism. Further: "The greater prevalence of GI symptoms in High-risk infants suggests that GI dysfunction during early infant development may be a part of the ASD endophenotype." That all sounds rather important.

I'm drawing back from making too many sweeping statements about this research bearing in mind the participant number, the use of the term 'high-risk' and elements of the questionnaire design of the study. There is quite a bit more research required in this area.

That all being said, I do think there are more than a few future studies that might come from such findings. So, thinking back to the paper by Afzal and colleagues [2] and the idea that "consumption of milk to be the strongest predictor of constipation" among their cohort diagnosed with autism, is the suggestion that more attention might be needed for specific elements of the diet such as cows milk. Added to the findings from Kushak and colleagues [3] (see here for a past post on this work) regarding lactose intolerance as being pretty rife in their cohort with autism (importantly, "not identified by clinical history"), and clues start to emerge alongside possible alternative strategies (see here and see here)...

Music: Stevie Wonder - Superstition.


[1] Penn AH. et al. Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. J Pediatr Gastroenterol Nutr. 2015 Jul 29.

[2] Afzal N. et al. Constipation with acquired megarectum in children with autism. Pediatrics. 2003 Oct;112(4):939-42.

[3] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

---------- Penn AH, Carver LJ, Herbert CA, Lai TS, McIntire MJ, Howard JT, Taylor SF, Schmid-Schönbein GW, & Dobkins KR (2015). Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. Journal of pediatric gastroenterology and nutrition PMID: 26230900

Tuesday, 18 August 2015

Neonatal hyperbilirubinemia and autism risk (again)

Tall ships @ Paul Whiteley
The paper by Luis Lozada and colleagues [1] (open-access) brings back into focus a topic that has graced this blog before (see here) with their observation that: "Children who develop ASD [autism spectrum disorder] are more likely to have an admission with a diagnosis of jaundice in the neonatal period and more likely to require treatment for this jaundice."

Jaundice, by the way, refers to a condition marked by yellowing of the skin and eyes as a result of the build up of a compound called bilirubin. For the newborn, elevations in bilirubin can have some really negative effects when accumulating in parts of the brain.

Using a case-control study design based on data derived from the "TRICARE Management Activity’s Military Health System (MHS) database", authors set about assessing whether there was a heightened risk of autism (ASD) "among infants with a history of neonatal unconjugated hyperbilirubinemia (jaundice)." Participant numbers were in the thousands: "A total of 2917 children with ASD and 8751 matched controls were included in the study."

Using two definitions of jaundice and hence bilirubin exposure - "a diagnosis of jaundice during the hospital stay associated with birth, or during an admission within the first month of life" and/or "any phototherapy or exchange transfusion procedure in the first month of life" - authors reported that: "A history of admission with a diagnosis of neonatal jaundice was present in 640 (21.9%) of children with ASD compared with 1614 (18.4%) of controls." Further: "A procedural treatment for jaundice was documented in 107 (3.7%) of children with ASD and 221 (2.5%) of controls." On the basis of these figures and some statistical analysis, they concluded that there may be an association between bilirubin and autism (ASD). That being said, such an association was not uncomplicated. When for example, they undertook a separate analysis of those children who were born preterm - that is born before 37 weeks - the association between autism and jaundice lost its statistical significance.

These data are interesting and mirror other findings (see here) with equally large participant numbers. As the authors indicate, there are some important methodological strengths to their study that add to quality of the study findings. The one down side to the study however was the fact that the authors "did not have bilirubin levels available", so any efforts looking at "a specific dose–response relationship with ASD" are research fodder for another day.

Insofar as the possible mechanism of effect going from neonatal jaundice to autism risk, the neurotoxin angle to bilirubin is a preferred explanation for Lozada et al. As they note: "There is biologic plausibility to suggest an association between bilirubin and ASD" in terms of parts of the brain vulnerable to bilirubin toxicity and what has been identified in the large (very large) peer-reviewed literature talking about brain architecture and [some] autism. Mention is also made about the concept of BIND (bilirubin-induced neurologic dysfunction) and the possibility of an overlap with some of the core and peripheral signs and symptoms of autism.

Accepting that any link between bilirubin and autism is likely to be a complex process, the only thing I would perhaps add to speculations would be the possible intersection with the concepts of sulphation and glucuronidation - important metabolic mechanisms that have been suggested to be disrupted in some cases of autism (see here and see here respectively). I would be interested to see whether any underlying issues with such metabolic pathways might intersect with jaundice and the metabolism of bilirubin and onwards autism risk...

Music: Blackbird - The Beatles.


[1] Lozada LE. et al. Association of Autism Spectrum Disorders With Neonatal Hyperbilirubinemia. Global Pediatric Health. 2015; 2: 2333794X15596518.

---------- Lozada, L., Nylund, C., Gorman, G., Hisle-Gorman, E., Erdie-Lalena, C., & Kuehn, D. (2015). Association of Autism Spectrum Disorders With Neonatal Hyperbilirubinemia Global Pediatric Health, 2 DOI: 10.1177/2333794X15596518

Monday, 17 August 2015

Sibling death by defenestration: a case report

The case report published by Osman Sabuncuoglu and colleagues [1] (open-access) highlighting the extremes of certain high-risk behaviours potentially associated with autism is the topic of today's brief post.

Detailing the very saddest of outcomes whereby a young boy diagnosed with autism and "aggression, violence and poor behavioral control" threw his 18-month old sister out of a window (defenestration) causing her death, the authors draw attention to several issues tied into the extremes of aggression appearing alongside autism and the legal implications of such behaviour under such circumstances.

The authors describe how due to the gravity of the issues faced by the autistic child (including a degree of learning disability) "the child had no preconception of consequences of his behavior" already with a history of violence towards caregivers before the very unfortunate episode with his sister. The subsequent criminal investigation carried out on this incident was eventually dropped "on the grounds of incompetence due to insanity and being below the age of criminal responsibility."

Treading carefully so as not to make any sweeping generalisations about the very heterogeneous autism spectrum, the Sabuncuoglu report highlights how aggression can manifest alongside [some] autism and brings into focus the plight of quite a few families dealing with such issues day to day. Judging by the lack of peer-reviewed literature on this topic, I am assuming that the extent and effects of the aggression detailed by Sabuncuoglu is thankfully pretty rare(?) (in terms of endangering life for example) but that isn't to say that it hasn't happened before (see here).

"The most distinctive symptoms that led to the death of the sibling seem to be a high level of aggression, low level of impulse control and severe form of disability." Alongside the idea that there may be various strategies that can be employed to potentially off-set such variables (see here and see here for examples), I'd be minded to suggest that further investigations on such factors such be a research priority in terms of improving quality of life for those presenting with such issues and their family and loved ones.


[1] Sabuncuoglu O. et al. Sibling death after being thrown from window by brother with autism: defenestration an emerging high-risk behavior. Case Reports in Psychiatry. 2015. July 21.

---------- Osman Sabuncuoglu, Mustafa Yasin IRMAK, Nagehan Ucok Demir, Duygu Murat, Can Tumba, & Yuksel Yilmaz (2015). Sibling death after being thrown from window by brother with autism: defenestration an emerging high-risk behavior Case Reports in Psychiatry

Saturday, 15 August 2015

Delivering medicines in psychiatry the transdermal way: application to autism

The real iron man
Pharmaceutical technology, and specifically the various research strategies looking at the way that medicines are delivered to the body, is probably not a topic high on most people's list of interests. This area is generally not 'sexy' research insofar as producing headlines about almost miracle interventions for condition X or label Y. Instead, we take for granted that the tablet or capsule we have been given has been formulated and tested or that the nicotine patch that you may be wearing includes some pretty comprehensive physics, chemistry and biology behind its development.

In order to raise the profile - even champion the role - of pharmaceutical technology, I'm briefly bringing the paper from Jonathan Stevens and colleagues [1] to your attention, reviewing the literature "related to transdermal delivery systems from the perspective of clinical practice and research related to their use in the treatment of psychiatric conditions." Transdermal delivery by the way, refers to the various ways and means that medicines can be formulated to pass through the skin and into general circulation. This method has significant advantages insofar as bypassing the gastrointestinal (GI) tract and the first pass effect among other things. This might also be important from the point of view of those trillions of wee beasties that call our gut home [2].

I've covered some of the ways and means that transdermal drug delivery might impact / has impacted on conditions like autism before on this blog. This has included the very preliminary suggestion that transdermal nicotine patches might impact on individual cases of aggression comorbid to autism (see here) and some of my own research (see here) looking into the now controversial suggestion that dermal preparations of low dose naltrexone might be useful for various conditions [3].

Insofar as some of the other research talking about transdermal preparations and autism, there are a few studies to quickly direct you towards. The trial by Kern and colleagues [4] is worth mentioning in view of their use of transdermal glutathione with autism in mind and effects "improving some of the transsulfuration metabolites." Glutathione is something of an elephant in the room when it comes to at least some cases of autism (see here). There is also the older study by Fankhauser et al [5] to consider, describing the use of transdermal clonidine in cases of autism. I'm not necessarily advocating clonidine for autism (despite there being some indications for some use) but what this research does suggest is that various medicines currently used to manage some core and peripheral aspects of autism are perhaps ripe for re-formulation in order to better control drug delivery and potentially increase important issues such as compliance to specific medication  regimes. Dare I also mention the use of transdermal secretin [6] when it comes to autism too?

I do think we are going to see more and more about transdermal drug delivery systems being used when it comes to autism and beyond in future times. Coupled to other drug delivery methods such as via the nasal route (think oxytocin and autism... carefully) and the days of pill-popping and even painful injections (all hail micro-needles) may well be numbered.

Music: The Cure - Boys Don't Cry. Well, only at the football (soccer) match and/or when watching Watership Down.


[1] Stevens JR. et al. The Use of Transdermal Therapeutic Systems in Psychiatric Care: A Primer on Patches. Psychosomatics. 2015 Apr 1. pii: S0033-3182(15)00060-2.

[2] Swanson HI. Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry? Drug Metab Dispos. 2015 Aug 10. pii: dmd.115.065714.

[3] Bouvard MP. et al. Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Psychiatry Res. 1995 Oct 16;58(3):191-201.

[4] Kern JK. et al. A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit. 2011 Dec;17(12):CR677-82.

[5] Fankhauser MP. et al. A double-blind, placebo-controlled study of the efficacy of transdermal clonidine in autism. J Clin Psychiatry. 1992 Mar;53(3):77-82.

[6] Ratliff-Schaub K. et al. Randomized controlled trial of transdermal secretin on behavior of children with autism. Autism. 2005 Jul;9(3):256-65.

---------- Stevens, J., Justin Coffey, M., Fojtik, M., Kurtz, K., & Stern, T. (2015). The Use of Transdermal Therapeutic Systems in Psychiatric Care: A Primer on Patches Psychosomatics DOI: 10.1016/j.psym.2015.03.007

Friday, 14 August 2015

Coenzyme Q10 and NADH supplementation for Chronic Fatigue Syndrome continued

In a previous post on this blog I briefly discussed the research paper from Jesus Castro-Marrero and colleagues [1] suggesting that "oral CoQ10 [Coenzyme Q10] (200 mg/day) plus NADH [nicotinamide adenine dinucleotide (NADH)] (20 mg/day) supplementation" might be something useful for some people diagnosed with Chronic Fatigue Syndrome (CFS).

Enter then a new paper from Castro-Marrero and colleagues [2] (open-access available here) building on the original findings by suggesting that "CoQ10 plus NADH supplementation for 8 weeks is safe and potentially effective in reducing max HR [maximum heart rate] during a cycle ergometer test and also on fatigue in CFS." The max HR by the way, is a measure of cardiovascular function as part of exercise performance. A cycle ergometer test is all about testing parameters such as max HR using a stationary bicycle.

"A proof-of-concept, 8-week, randomized, double-blind, placebo-controlled trial was conducted" whereby either CoQ10 plus NADH was given (n=39) or a placebo (n=34) over the study period. Baseline and end of study max HR was tested alongside self-reported changes to "fatigue, pain and sleep problems" based on scoring using the Fatigue Impact Scale (FIS) among other things.

Based on an intention-to-treat (ITT) analytical strategy, authors reported that: "statistically significant differences were observed in CoQ10 + NADH group during the study, with a reduction in max HR after 8 weeks of treatment compared with baseline max HR." That being said, when comparing max HR from baseline to 8 weeks between the groups (CoQ10+NADH vs placebo), no statistically significant group differences were noted despite a trend towards greater max HR reduction in the experimental group. Insofar as other biological parameters also measured over the course of the study period ("VO2, VCO2, maximal workload, respiratory quotient and arm systolic and diastolic blood pressure") no significant differences were noted between baseline and end of study.

Fatigue scores showed a similar trend in terms of intra- and inter-group comparisons. So, for the CoQ10+NADH group, comparisons between baseline, week 4 and week 8 scores suggested significant reductions in total FIS scores. When it came to comparisons with the placebo group however, no significant differences were reported (indeed, the placebo group also showed a reduction in FIS total scores at least between baseline and week 4). The authors suggest that a lack of study power might have contributed to the lack of significant effects when comparing the experimental and placebo groups.

These are interesting results and from an intra-group perspective (comparing across different testing occasions) suggest that there may be more to see from this preparation on this patient group. Bearing in mind the emphasis on actually looking at physiological parameters such as max HR and as the authors note: "the use of strict inclusion criteria based on 1994 CDC case definition ensures that the participants were appropriately selected and without confounding comorbidities" further research is indicated to further assess such claims and determine specific biological mechanisms pertinent to any effect.

Music: Ike & Tina Turner - River Deep Mountain High.


[1] Castro-Marrero J. et al. Does oral Coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in Chronic Fatigue Syndrome? Antioxid Redox Signal. 2014 Nov 11.

[2] Castro-Marrero J. et al. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. Clin Nutr. 2015 Jul 17. pii: S0261-5614(15)00189-2.

---------- Castro-Marrero J, Sáez-Francàs N, Segundo MJ, Calvo N, Faro M, Aliste L, Fernández de Sevilla T, & Alegre J (2015). Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. Clinical nutrition (Edinburgh, Scotland) PMID: 26212172