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.

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[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.

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ResearchBlogging.org 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).

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[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.

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ResearchBlogging.org 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.

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[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.

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ResearchBlogging.org 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.

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[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.

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ResearchBlogging.org 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).

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[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.

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ResearchBlogging.org 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.

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[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.

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ResearchBlogging.org 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.

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[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.

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ResearchBlogging.org 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