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Autism research and other musings

Paul Whiteley
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  • March 22, 2017
  • 04:08 AM

On genotype and environmental exposure patterns

by Paul Whiteley in Questioning Answers

I was rather interested to read the paper by Michela Traglia and colleagues [1] (open-access available here) concluding that: "maternal and fetal genetic make-up are important determinants of mid-gestational maternal circulating levels of some environmental organohalogens." Interested because, in these days of gene-environment interactions being applied to just about everything, the detail that is missing - which genes might potentially be linked to which environmental factors - has not yet been suitably addressed in the peer-reviewed science literature.So, based on data - "serum levels of a set of 21 organohalogens in a subset of 790 genotyped women and 764 children" - derived from participants included in the Early Markers for Autism (EMA) Project, researchers set about assessing how genetics might impact on environmental pollutant exposure profiles. Maternal blood samples were collected at around 15-20 weeks pregnancy. Children provided blood samples via the fabulous resource that is the newborn screening program, where: "Newborn blood spots were collected on filter paper 1-2 days after birth." Maternal samples were analysed for various environmental pollutants and both sets of samples were analysed for the genetic material they contained pertinent to whether "circulating mid-gestational levels of organohalogens would be driven by common maternal genetic determinants, and that these results could shed light on the observed associations between the organohalogens and ASD [autism spectrum disorder]."Results: yes, the authors "found evidence that a large proportion of maternal circulating levels of BB-153, BDE-47, -100, -153 [polybrominated congeners] and their sum was significantly controlled by common genetic factors." Those 'common genetic factors' typically referred to the presence of point mutations (SNPs) that litter everyone's genome and on occasion, can affect the function/production of specific biological processes. So: "Genome-wide association analyses identified significant maternal loci for p,p'-DDE... in the CYP2B6 gene and for BDE-28... near the SH3GL2 gene, both involved in xenobiotic and lipid metabolism." In other words, although the environmental pollutants measured are not great products in the first place (in terms of safety), a person's genetic make-up can influence how such products are eventually dealt with by the body and potentially onwards, what subsequent effects they might have.Additionally: "results suggest that the maternal circulating levels of some compounds were more highly influenced by fetal genetic factors than maternal genetics." This leads into another aspect of the current study whereby foetal genetic factors might also play a part in "controlling the toxicant disposition between mother and fetus." Specifically, authors noted that aspects of the individual genetics of a foetus (distinct from its mother) "contributed to the levels of BDE-100... and PCB187... near the potential metabolic genes LOXHD1 and PTPRD, previously implicated in neurodevelopment."And finally: "We confirmed that the serum levels of BDE-100, -153 and the total sum of PBDEs were significantly lower in mothers of ASD-affected children compared to mothers of control children." This is interesting in light of other discussions about PBDEs and autism in particular (see here). The authors do discuss various scenarios to account for their results not least that "transplacental transfer of organohalogens during pregnancy may be driven by the fetal genome expressed in placenta." Further analyses of the 'placentome' might therefore be indicated.To reiterate, this is interesting research. It tells us that many [adverse] environmental exposures, whilst typically to be avoided, don't act on the body in a uniform way as a function of differing genomes and differences in the ways that the body 'handles' such exposures. With autism in mind, this is not necessarily new news (remember paraoxonase gene variants and organophosphate metabolism [2] and air pollution and offspring autism?) but is a useful reminder. Such work also provides a template for looking at the myriad of other environmental factors put forward to influence autism risk and whether individual product safety is necessarily the only or most important factor when it comes to assessing relative risk profiles.I might finally also draw your attention to a recent interesting meta-analysis of the various environmental risk factors potentially linked to autism [3] (open-access) and another article talking about similar things [4] (open-access) (thanks Annabelle). Genes and environment, genes and environment...Music: Petula Clark sings the Beatles? Personally, I think it's better than the original...----------[1] Traglia M. et al. Independent Maternal and Fetal Genetic Effects on Mid-gestational Circulating Levels of Environmental Pollutants. G3 (Bethesda). 2017 Feb 24. pii: g3.117.039784.[2] D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.[3] Modabbernia A. et al. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Molecular Autism. 2017; 8: 13.[4] Parker W. et al. The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism. Journal of International Medical Research. 2017. Jan 20.----------Traglia M, Croen LA, Lyall K, Windham GC, Kharrazi M, DeLorenze GN, Torres AR, & Weiss LA (2017). Independent Maternal and Fetal Genetic Effects on Mid-gestational Circulating Levels of Environmental Pollutants. G3 (Bethesda, Md.) PMID: 28235828... Read more »

  • March 21, 2017
  • 03:57 AM

PACE trial recovery data and chronic fatigue syndrome - a reply

by Paul Whiteley in Questioning Answers

I'd encourage readers interested in the background to the response paper by Michael Sharpe and colleagues [1] to have a look at a previous blogging occasion when the topic of the PACE trial, chronic fatigue syndrome (CFS) and 'recovery' were discussed (see here).Suffice to say that this latest paper is a reply to one published by Carolyn Wilshire and colleagues [2] who concluded that: "The claim that patients [with CFS] can recover as a result of CBT [cognitive behaviour therapy] and GET [graded exercise therapy] is not justified by the data, and is highly misleading to clinicians and patients considering these treatments." Said discussions linking back to some quite extensive debates on how one should (and shouldn't) treat/manage conditions like CFS (see here).I wanted to highlight the latest Sharpe paper because (a) I anticipated a reply from these authors following the Wilshire paper criticism of their recovery paper [3], and (b) although the debates in this area have been quite extensive already, the use of the scientific peer-reviewed medium to discuss and even argue is an important avenue. The authors have a right to scientific reply.So how did Sharpe et al respond? Well the words 'recovery', 'threshold' and ''no generally agreed measure of recovery" when it comes to CFS form the crux of the response to the Wilshire paper. They address the issue of recovery thresholds that have been a real source of discussion in relation to the PACE trial secondary analysis concluding that: "No participant met our full criteria for recovery at baseline." They point out that whilst "13% of participants met the recovery criterion of being within the normal range... for physical functioning when entering the trial" physical functioning was but one measure they used to determine recovery.They also approach the topic of 'changing thresholds' when it came to the definition of recovery in the PACE trial. To quote: "We changed these thresholds for our detailed analysis plan because after careful consideration and consultation, we concluded that they were simply too stringent to capture clinically meaningful recovery." They also report that elements of their assessment - the PACE walking test - are "not comparable with data collected in other studies" as a function of their reliance on personal motivation/ability over and above the use of encouragement as in other studies.Finally, authors also talk about 'what other studies have found regarding recovery' when it comes to CFS. They note that their findings in relation to the use of standard medical care (SMC) for CFS in the PACE trial were similar to other reports [4]. They also point to research suggesting that the use of CBT in independent study for CFS show similar rates of recovery [5] to theirs originally reported. In other words, they make a case for their findings fitting in with some of the other literature on this topic.A quick trawl of PubMed with the terms 'chronic fatigue syndrome' and 'recovery' reveals that there is indeed quite a bit more to do in this area of science. To quote from one paper (a critical review) [4]: "Estimates of recovery ranged from 0 to 66 % in intervention studies and 2.6 to 62 % in naturalistic studies." What this tells us is that (a) how recovery is reported in relation to CFS is still in need of some clarification [6] and perhaps more importantly, agreed uniformity is still required in its assessment; (b) some of the measures used to form judgements of recovery when it comes to CFS are not necessarily fit for purpose [7] (bearing in mind not everyone agrees with this); and (c) further efforts need to go into looking at many more aspects of CFS recovery outside of just a reliance on the fatigue parameter (see here and see here for examples). In short, science does not really know what recovery looks like in relation to CFS [8] despite it seemingly happening for all manner of reasons...Where do we go from here? This is a difficult question to answer. It is doubtful that the response from Sharpe and colleagues is going to change too many opinions about PACE given the strength of feeling on the topic and the various goings-on that have occurred around debate in this area (see here). Still today, other comments on the PACE trial continue to emerge in the peer-reviewed domain [9] from notable CFS researchers and there are even calls to retract the original recovery paper (see here). Yes, there are lessons to be learned from the PACE trial (e.g. stick to your "original protocol thresholds", make your data 'open-access' and think about how to do this in the planning/recruitment stages of your trial, be mindful that short-term gains don't necessarily translate into long-term ones, work with the ME/CFS community (rather than labelling elements of them 'vexatious' or worse when they ask questions or request data) but I can't see how these factors will immediately and positively affect the lives of people living with CFS/ME here and now. That recommendations on the use of CBT for CFS have already altered in some parts of the world (see here) - "The strength of evidence on global improvement is downgraded from moderate to low when considering CBT separately from other counseling and behavioral interventions" - and are potentially likely to change here in Blighty perhaps signifies that science and medicine is moving on when it comes to this topic. Science should be doubling its efforts to expand its research boundaries when it comes to managing CFS outside of just a reliance on the [outdated?] psychosomatic model and indeed, it is...And on the topic of other CFS research avenues, I've already talked about a few interesting avenues on this blog (see here and see here and see here) mindful that when we talk about CFS/ME, we're probably not talking about just one entity (see here). Also alongside, that there seems to be an awful lot of 'over-represented' comorbidity accompanying quite a lot of CFS/ME (see here for example) to also contend with...Music: Lush Life (even if you don't know the song title, you might rec... Read more »

M Sharpe, T Chalder, AL Johnson, KA Goldsmith, & PD White. (2017) Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments?. Fatigue: Biomedicine, Health , 1-5. info:/10.1080/21641846.2017.1288629

  • March 20, 2017
  • 04:13 AM

ALSPAC says no to cat ownership - psychosis risk hypothesis but...

by Paul Whiteley in Questioning Answers

"While pregnant women should continue to avoid handling soiled cat litter, given possible T. gondii exposure, our study strongly indicates that cat ownership in pregnancy or early childhood does not confer an increased risk of later adolescent PEs [psychotic experiences]."So said the findings reported by Francesca Solmi and colleagues [1] (open-access) who brought a smile to any reader of the title of their paper: "Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort." For those who might not be aware of the hypothesis, cat ownership has been previously linked to 'adverse' psychological outcomes (see here) tied into some peer-reviewed evidence on one possible environmental factor linked to psychosis and conditions manifesting psychosis: Toxoplasma gondii.ALSPAC - Avon Longitudinal Study of Parents and Children - brought it's quite significant scientific prowess to bear on the question of whether "cat ownership in pregnancy and childhood (ages 4 and 10 years) was associated with psychotic experiences (PEs) in early (age 13, N = 6705) and late (age 18, N = 4676) adolescence, rated from semi-structured interviews." Having a cat in the house was not the only question asked by Solmi et al as the presence of other pets were also investigated: "dogs, rabbits, rodents, birds (all waves), and tortoises and fish (from 21 months)." PEs were assessed at approximate ages of 13 and 18 years old via responses to the "psychotic-like symptoms interview (PLIKSi), a semi-structured interviewer-rated screening assessment for PEs." Various other variables were also factored into the examination of any effect or not.Results: well, as per the opening sentence to this post, cat ownership did not seem to be related to later PEs. The potential caveat being that in some of their analyses there did seem to be a possible association - "Owning a cat at age 4 years was associated with higher odds of having PEs at age 13 years in univariable models" - but the significance of this association disappeared when adjustments for other potentially confounding variables were made. Obviously this kind of study can't control for every single potentially confounding variable but they did at least try.Why the disparity between these results and the previous ones suggestive of a possible connection between childhood cat ownership and later adverse psychological health? Well, an important point is made by Solmi and colleagues: "Our study was based on PEs in early and late adolescence, unlike other studies which were based on a clinical diagnosis of schizophrenia." In other words. psychotic experiences might be part and parcel of schizophrenia but not necessarily all that schizophrenia encompasses and not necessarily just enough to merit a diagnosis of schizophrenia. They do also go on to highlight how the previous report on the association may also not have included the range of potentially confounding variables that were included and controlled for in the current study as another possibility for the differences reported. Having said that [2]...Does the T. gondii - schizophrenia hypothesis fall as a result of the Solmi results? Probably not. Solmi et al hint that even though cat ownership probably isn't related to PEs, they do not totally debunk the idea that there may be a connection. They did not for example, look for the presence of contact with T. gondii in this particular study (others have) as per serological examination of participants. I say this bearing in mind that not every moggy is necessarily infected with T. gondii or anything else. Sweeping generalisations on all cats are not required.Music to close, and containing the lyric 'Caringosity killed the Kerouac cat', a chirpy little number from a band with quite a contentious name...----------[1] Solmi F. et al. Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort. Psychol Med. 2017 Feb 22:1-9.[2] Fuller Torrey E. et al. The antecedents of psychoses: a case-control study of selected risk factors. Schizophr Res. 2000 Nov 30;46(1):17-23.----------Solmi F, Hayes JF, Lewis G, & Kirkbride JB (2017). Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort. Psychological medicine, 1-9 PMID: 28222824... Read more »

  • March 18, 2017
  • 04:58 AM

HSV-2 gestational infection and offspring autism risk

by Paul Whiteley in Questioning Answers

"In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy."That was the conclusion reached in the paper published by Milada Mahic and colleagues [1] including the research tag-team that is Mady Hornig and Ian 'virus hunter' Lipkin in the list of contributing authors. Having already received some media attention (see here), it doesn't need much more from me but I do want to include a few details and relevant points in this blog entry.So, the Autism Birth Cohort was the starting point, and "442 mothers of children with ASD... and 464 frequency-matched controls" who all provided plasma samples "(903 samples acquired at midpregnancy and 878 acquired after delivery)." Said samples were analysed for IgG antibodies to ToRCH agents: "Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), and herpes simplex viruses 1 (HSV-1) and 2 (HSV-2)." Some of those viruses and parasites have previously been mentioned with [some] autism in mind (see here and see here and see here).Results: well, an important detail first: "Because rubella vaccination is part of the routine child vaccination schedule in Norway, almost all individuals had IgG antibodies to rubella virus." Indeed, other authors have speculated that rubella vaccination has actually "prevented substantial numbers" of autism as a knock-on effect of reducing the numbers of cases of congenital rubella syndrome [2]. Vaccination doing more than just saving lives eh?Next: "Our data suggest that the presence of high levels of anti-HSV-2 antibodies at midpregnancy increases the risk of ASD [autism spectrum disorder] in boys." The authors complemented this finding by some rather neat statistical wizardry whereby odds ratios were calculated based on "four different anti-HSV-2 reference levels (60, 120, 180, and 240 arbitrary units [AU]/ml)." Having said that: "High levels of antibodies, which are typically indicative of recent infection, were found in only a small number of subjects." They also reported "no statistically significant association with risk was found with high levels of HSV-2 antibodies at delivery" and saw nothing significant when it came to the other infections examined. These important points have been picked up in the NHS Choices entry on this study (see here).These are interesting findings and, as far as I can see, represent something quite novel to the quite vast autism research landscape (assuming you count maternal HSV-2 levels and not antibody levels in actual people diagnosed with autism). The reliance on data from an initiative like the Autism Birth Cohort ensured some rigour in terms of the diagnosis of autism [3] and with the reputations following Drs Hornig and Lipkin, one would have to be pretty brave to question their virus-hunting credentials also with autism in mind [4].Then to the million-dollar question: how might elevated HSV-2 antibodies during pregnancy affect offspring risk of autism? There is a familiar theme offered by the authors to this question as per statements like: "ASD risk associated with high levels of antibodies to HSV-2 is not specific to HSV-2 but instead reflects the impact of immune activation and inflammation on a vulnerable developing nervous system." I know some people still have a bit of a problem with the idea that something like maternal immune activation (MIA) might up the risk for various offspring outcomes [hint: if an article contains the word 'truth' in the title, step away] but please, stop with the 'it can never happen' generalisations and instead look to the existing peer-reviewed evidence on the topic [5]. Yes, science needs to do more on the topic of MIA and autism but clues are emerging all the time...Oh, and I'll be coming to research talking about another member of the herpesviruses in relation to autism quite soon on this blog.To close, operation hardtack and other videos (best viewed in full-screen mode).----------[1] Mahic M. et al. Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere. 2017. Feb 22.[2] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination - United States, 2001-2010. BMC Public Health. 2011; 11: 340.[3] Stoltenberg C. et al. The Autism Birth Cohort (ABC): A Paradigm For Gene-Environment-Timing Research. Molecular Psychiatry. 2010;15(7):676-680.[4] Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS One. 2008 Sep 4;3(9):e3140.[5] Careaga M. et al.  Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol Psychiatry. 2017 Mar 1;81(5):391-401.----------Milada Mahic, Siri Mjaaland, Hege Marie Bøvelstad, Nina Gunnes, Ezra Susser, Michaeline Bresnahan, Anne-Siri Øyen, Bruce Levin, Xiaoyu Che, Deborah Hirtz, Ted Reichborn-Kjennerud, Synnve Schjølberg, Christine Roth, Per Magnus, Camilla Stoltenberg, Pål Surén, Mady Hornig, & W. Ian Lipkin (2017). Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere : ... Read more »

Milada Mahic, Siri Mjaaland, Hege Marie Bøvelstad, Nina Gunnes, Ezra Susser, Michaeline Bresnahan, Anne-Siri Øyen, Bruce Levin, Xiaoyu Che, Deborah Hirtz.... (2017) Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere. info:/10.1128/mSphere.00016-17

  • March 17, 2017
  • 03:39 AM

Fatty acids and autism meta-analysed yet again (with a different result?)

by Paul Whiteley in Questioning Answers

OK I'm a little confused right now.Not so long ago I talked about the paper from Horvath and colleagues [1] (see here) concluding that "the limited data currently available suggest that ω-3 FA [omega-3 fatty acid] supplementation does not enhance the performance of children with ASD [autism spectrum disorder]." Such a conclusion was based on the application of a systematic review and meta-analysis of the available peer-reviewed literature up to August 2016.Now however, another systematic review and meta-analysis on the topic has emerged from Mazahery and colleagues [2] and reported something a little bit different: "Populations with ASD have lower n-3 LCPUFA status and n-3 LCPUFA supplementation can potentially improve some ASD symptoms." Don't you just love science!OK, so what could be the reason(s) for the differing conclusions reached by the reviews on this topic? Well, Mazahery and colleagues (the most recent review) actually conducted two meta-analyses: "meta-analysis 1 compared blood levels of LCPUFA and their ratios arachidonic acid (ARA) to docosahexaenoic acid (DHA), ARA to eicosapentaenoic acid (EPA), or total n-6 to total n-3 LCPUFA in ASD to those of typically developing individuals (with no neurodevelopmental disorders), and meta-analysis 2 compared the effects of n-3 LCPUFA supplementation to placebo on symptoms of ASD." Horvath et al only conducted one meta-analysis in their study roughly equivalent to meta-analysis 2 presented by Mazahery looking at the effects of fatty acid supplementation on the presentation of autism. Mazahery and colleagues also surveyed the literature up to May 2016 and found four randomised-controlled trials (RCTs) (N=107) whereas Horvath et al (who published earlier!) surveyed the literature up to August 2016 and found five RCTs (N=183). Indeed, it appears that based on that last 'difference' one might see how the grand 'top of the scientific hierarchy' meta-analysis is yet again, only as good as the data it contains. And a certain celebrity in science circles seems to agree...Where next I hear you ask? Well, I'd be tempted to follow the recommendations of Mazahery and colleagues when they suggest that: "Further research with large sample size and adequate study duration is warranted to confirm the efficacy of n-3 LCPUFA." Indeed, there are already studies to watch in this area. That and recognising that within the vast plurality that is the autisms it is not totally outside the realms of possibility that specific parts of the autism spectrum might be more vulnerable to fatty acid issues than others. Oh, and don't forget that outside of impacting autistic 'performance' (or not), fatty acid supplementation does seem to have other health-related properties too...----------[1] Horvath A. et al. ω-3 Fatty Acid Supplementation Does Not Affect Autism Spectrum Disorder in Children: A Systematic Review and Meta-Analysis. J Nutr. 2017 Jan 11. pii: jn242354.[2] Mazahery H. et al. Relationship between Long Chain n-3 Polyunsaturated Fatty Acids and Autism Spectrum Disorder: Systematic Review and Meta-Analysis of Case-Control and Randomised Controlled Trials. Nutrients. 2017 Feb 19;9(2). pii: E155.----------Mazahery H, Stonehouse W, Delshad M, Kruger MC, Conlon CA, Beck KL, & von Hurst PR (2017). Relationship between Long Chain n-3 Polyunsaturated Fatty Acids and Autism Spectrum Disorder: Systematic Review and Meta-Analysis of Case-Control and Randomised Controlled Trials. Nutrients, 9 (2) PMID: 28218722... Read more »

  • March 16, 2017
  • 03:44 AM

Autoimmune disease(s) and ADHD: birds of a feather?

by Paul Whiteley in Questioning Answers

"A personal history and a maternal history of autoimmune disease were associated with an increased risk of ADHD [attention-deficit hyperactivity disorder]. The previously reported association between type 1 diabetes and ADHD was confirmed. In addition, specific parental autoimmune diseases were associated with ADHD in offspring."So said the study results published by Nielsen and colleagues [1] including "a study population of 983,680 individuals followed from 1995 to 2012." Reliant once again on one/some of those marvellous Scandinavian population registries (every country should have them), researchers "investigated the association between a personal history and a family history of autoimmune disease and the risk of developing attention-deficit/hyperactivity disorder (ADHD)." Autoimmune disease refers to the development of symptoms when the body's own immune system fails to recognise 'self' as 'self' and starts attacking its own tissue(s). I might add that the authors on the Neilsen paper have some research history when it comes to the behavioural correlates of autoimmune disease (see here).Drawing on data for around 23,000 children diagnosed with ADHD, researchers reported a modest but significant 'risk' of ADHD being diagnosed where an autoimmune condition was reported. The presence of an autoimmune condition being diagnosed in mums also elevated the risk of offspring being diagnosed with ADHD (again modestly but significantly). Further: "a paternal history of autoimmune diseases was not significantly associated with ADHD in the offspring." Various types of autoimmune disease in the immediate family were potentially associated with offspring ADHD diagnosis: "a family history of thyrotoxicosis, type 1 diabetes, autoimmune hepatitis, psoriasis, and ankylosing spondylitis." This follows other population registry studies in this area [2].Based on the Nielsen and other data, I don't yet think we're in the realm of calling something as diverse as ADHD an autoimmune condition on the basis that autoimmune conditions tend to 'flock together' [3]. But I do think this adds to a growing body of literature talking about immune function and ADHD (see here for example) and some quite 'strong' data (see here). Hopefully without being too speculative, I'd also draw your attention to some interesting work talking about some possible reasons why autoimmunity might be over-represented when it comes to [some] ADHD on the basis of the expression of those fossil viruses that we all have and their 'super-antigen' and 'molecular mimicry' properties. Just one possibility among many...Music: Nana Mouskouri sings Hey Jude...----------[1] Nielsen PR. et al. Associations Between Autoimmune Diseases and Attention-Deficit/Hyperactivity Disorder: A Nationwide Study. J Am Acad Child Adolesc Psychiatry. 2017 Mar;56(3):234-240.e1.[2] Instanes JT. et al. Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases. Biol Psychiatry. 2017 Mar 1;81(5):452-459.[3] Assa A. et al. Large population study shows that adolescents with celiac disease have an increased risk of multiple autoimmune and non-autoimmune comorbidities. Acta Paediatr. 2017 Mar 1.----------Nielsen PR, Benros ME, & Dalsgaard S (2017). Associations Between Autoimmune Diseases and Attention-Deficit/Hyperactivity Disorder: A Nationwide Study. Journal of the American Academy of Child and Adolescent Psychiatry, 56 (3), 234-2400 PMID: 28219489... Read more »

  • March 15, 2017
  • 04:08 AM

The extra-intestinal effects of coeliac disease autoimmunity?

by Paul Whiteley in Questioning Answers

"In 3.5-year-old children, CDA [coeliac disease autoimmunity] is associated with increased reports of child depression and anxiety, aggressive behavior, and sleep problems when mothers are unaware of their child’s CDA status."So said the findings reported by Laura Smith and colleagues [1] (open-access available here) adding to an emerging body of peer-reviewed research suggesting that the archetypal 'gluten is the baddie' autoimmune condition known as coeliac disease might, when not managed, have effects well beyond the classical somatic presentations. Real gut-brain axis stuff in action, as also agreed in an editorial by the 'godfather' of coeliac disease research Prof. Alessio Fasano [2].Smith et al focused on data derived from the TEDDY study (no, really it was called TEDDY), an initiative "looking for the causes of type 1 diabetes mellitus (T1DM)." T1DM is also categorised as an autoimmune condition, where the body's defences fail to recognise 'self' as 'self' and attack it's own tissues. Researchers were able to access biological samples taken as part of the TEDDY study and screen for something called tissue transglutaminase autoantibodies (tTGA), part and parcel of the typical screening protocol for coeliac disease (CD). Where values were "persistently positive" for tTGA, the authors used the term 'celiac disease autoimmunity (CDA)' to illustrate not necessarily a diagnosis of CD but something potentially very close. The Achenbach Child Behavior Checklist (CBCL) was the questionnaire of choice for assessing child "behavioral and emotional functioning" between 3 and 5 years of age.Results: "At 3.5 years, 66 mothers unaware their child had CDA reported more child anxiety and depression, aggressive behavior, and sleep problems than 3651 mothers of children without CDA." The 'unaware' bit refers to the fact that some participants falling into the CDA grouping "were unaware their child was developing CDA" This number (n=66) was quite a bit smaller than the "already aware their child had CDA" grouping (n=440). For those aware of CDA: "The CBCL responses of mothers in the aware-CDA group were not significantly different from those of mothers in the no-CDA group."The authors also looked at whether instigation of a gluten-free diet (the treatment of choice when it comes to coeliac disease) had any effect on those who were already aware of CDA presence. The answer: "No differences were found in CBCL scores for aware-CDA mothers based on whether the child was on a gluten-free diet."These are important findings. As the authors note: "These results support previous studies documenting depression, anxiety, and sleep problems as possible manifestations of celiac disease." They also try and put their results into some context in terms of how "knowledge of the child’s CDA increases a parent’s sensitivity to physical discomforts of their child while providing an alternative explanation for any psychological symptoms the child exhibits." In other words, maybe there is an unwritten rule that young children with coeliac disease might be more prone to behavioural issues? They even go as far as suggesting that: "pediatricians may want to recommend tTGA testing in children <4 years of age with a family history of celiac disease if parents report child psychological symptoms."  More research is definitely indicated and I'll be coming to related studies soon enough...Music, and a catchy track that always seems to be playing outside my dojo (not great for the concentration I might add)...----------[1] Smith LB. et al. Psychological Manifestations of Celiac Disease Autoimmunity in Young Children. Pediatrics. 2017 Feb 20. pii: e20162848.[2] Fasano A. Celiac Disease, Gut-Brain Axis, and Behavior: Cause, Consequence, or Merely Epiphenomenon? Pediatrics. 2017. Feb 20.[3] Butwicka A. et al. Celiac Disease Is Associated with Childhood Psychiatric Disorders: A Population-Based Study. J Pediatr. 2017 Mar 7. pii: S0022-3476(17)30153-1.----------Smith LB, Lynch KF, Kurppa K, Koletzko S, Krischer J, Liu E, Johnson SB, Agardh D, & TEDDY study group. (2017). Psychological Manifestations of Celiac Disease Autoimmunity in Young Children. Pediatrics PMID: 28219962... Read more »

Smith LB, Lynch KF, Kurppa K, Koletzko S, Krischer J, Liu E, Johnson SB, Agardh D, & TEDDY study group. (2017) Psychological Manifestations of Celiac Disease Autoimmunity in Young Children. Pediatrics. PMID: 28219962  

  • March 14, 2017
  • 03:56 AM

Depression in parents of children with autism

by Paul Whiteley in Questioning Answers

"Mothers (OR 2.95, 95% CI 2.81-3.09) and fathers (OR 2.41, 95% CI 2.25-2.58) of children with ASD [autism spectrum disorder] were more likely to have a diagnosis of depression than parents of children without ASD."The paper by Cohrs and Leslie [1] is probably not going to win any awards for novelty when it comes to their findings that: "Autism Spectrum Disorder (ASD) in children can have secondary effects on the child's parents." It does however represent another important piece of evidence pertinent to the idea that 'caring for the carers' should be a mainstay of the support and services offered when a diagnosis of autism is received in the family.I did say in a post not so long ago that I would talk about the Cohrs/Leslie paper and there, I [briefly] have. Added to the body of literature talking about parental stress (and what we can do about it) in the context of autism, resources aplenty should be poured into this area. That and the fact that we already have some clues as to what areas of child rearing might be primary targets for intervention and support....----------[1] Cohrs AC. & Leslie DL. Depression in Parents of Children Diagnosed with Autism Spectrum Disorder: A Claims-Based Analysis. J Autism Dev Disord. 2017 Feb 18.----------Cohrs AC, & Leslie DL (2017). Depression in Parents of Children Diagnosed with Autism Spectrum Disorder: A Claims-Based Analysis. Journal of autism and developmental disorders PMID: 28214978... Read more »

  • March 13, 2017
  • 03:29 AM

Mitochondria support for mitochondrial activity in [some] autism

by Paul Whiteley in Questioning Answers

"This study examined the effect of common mitochondrial treatments on specific mitochondrial components in a group of children diagnosed with ASD [autism spectrum disorder], some of which also were diagnosed with co-morbid mitochondrial disease."That was the premise of the study results published by Leanna Delhey and colleagues [1] (open-access available here) and follows previous discussions suggesting that mitochondrial disease might not be totally unfamiliar to at least some autism (see here). Including some notable names on the authorship list previously linked to the area of mitochondrial functions in relation to autism (see here), the authors provide some important information about how specific mitochondrial function might be 'supported' by various interventions.I'm not on this occasion going to venture into all the details discussed by Delhey but I do want to pick out some interesting titbits. First, of the 127 children diagnosed with an autism spectrum disorder (ASD), we are told that "15% of the sample was clinically diagnosed with mitochondrial disease." Bearing in mind this particular cohort might not be totally representative of the autistic population at large, 15% is not an insignificant figure. What this tells us is that as and when a diagnosis of autism is received, screening for a possible mitochondrial disorder should be initiated (yes, an autism diagnosis is a starting point not the finishing line and the diagnosis rarely exists in a diagnostic vacuum).Next, various supplements were taken by participants, some of which have recognised effects on mitochondrial functions. Of particular note was the use of coenzyme Q10 (CoQ10) and carnitine; both of which have been discussed on this blog previously (see here and see here respectively) with the word 'mitochondrial' also being mentioned. Interestingly, a couple of other supplements are also included in the Delhey paper including fatty acids and folate; some of which I have to say, didn't immediately pop into my mind as being primarily mitochondrial-related (folate is though, still a hot topic when it comes to autism). The authors head into how said supplements might affect specific facets of mitochondrial function. It also reminded me that I really need to brush up on my knowledge of mitochondrial functions..."This study provides empirical support for common mitochondrial treatments and demonstrates that the relationship between activities of mitochondrial components might be a marker to follow in addition to absolute activities." I'd agree that there is the beginnings of a roadmap for further study based on the Delhey results. That and including important parameters related to the presentation of autism and how it may/may not be affected by treating underlying mitochondrial disorder, and the scene is set for further recognition of how indeed, autism rarely exists in a diagnostic vacuum...----------[1] Delhey LM. et al. The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder. J Clin Med. 2017 Feb 13;6(2). pii: E18.----------Delhey LM, Nur Kilinc E, Yin L, Slattery JC, Tippett ML, Rose S, Bennuri SC, Kahler SG, Damle S, Legido A, Goldenthal MJ, & Frye RE (2017). The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder. Journal of clinical medicine, 6 (2) PMID: 28208802... Read more »

Delhey LM, Nur Kilinc E, Yin L, Slattery JC, Tippett ML, Rose S, Bennuri SC, Kahler SG, Damle S, Legido A.... (2017) The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder. Journal of clinical medicine, 6(2). PMID: 28208802  

  • March 11, 2017
  • 04:19 AM

B vitamins for schizophrenia?

by Paul Whiteley in Questioning Answers

I'd like to briefly draw your attention to the results - systematic review and meta-analysis results - published by Joseph Firth and colleagues [1] observing that "certain vitamin and mineral supplements may reduce psychiatric symptoms in some people with schizophrenia" and specifically that certain B vitamins might be something to consider.Such results come from a research team who are making significant waves in the field of meta-analyses and systematic reviews for all manner of different [important] topics. The additional inclusion of one Jerome Sarris to the authorship team adds a 'nutritional medicine as mainstream in psychiatry' touch to proceedings.Drawing on data from 18 clinical trials - randomized controlled trials (RCTs) - cumulatively including over 800 participants, researchers reported that: "vitamin B supplementation (including B6, B8 and B12) reduced psychiatric symptoms significantly more than control conditions." Dose seemed to be important (higher doses appeared to be more effective than lower doses) as did timing of vitamin 'intervention'. Authors also indicated that subgroups of people with schizophrenia might be 'better responders' to this type of intervention, suggesting that either individual genetic differences or possibly nutritional deficiency before intervention might count in terms of effectiveness of B vitamin use. I was wondering whether those last points might tie into other discussions on this blog referencing genotype, B vitamins and [some] schizophrenia (see here).In the context of the rise and rise of plurality in psychiatry ('the schizophrenias' and 'schizophrenia does not exist: discuss') there are some important research directions to be followed on the basis of the Firth findings. Identifying those people on the schizophrenia spectrum who might be potential best responders to this type of nutritional intervention is a research priority. Closely followed by further investigations on the hows-and-whys of such intervention potentially being useful. In that final respect, the peer-reviewed literature has already provided a few ideas for starters (see here and see here for examples).To close, "I've got a good idea..."----------[1] Firth J. et al. The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychological Medicine. 2017. Feb 16.----------Firth J, Stubbs B, Sarris J, Rosenbaum S, Teasdale S, Berk M, & Yung AR (2017). The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis. Psychological medicine, 1-13 PMID: 28202095... Read more »

  • March 10, 2017
  • 02:37 AM

I would walk 500 miles... or maybe just 8 miles (a day).

by Paul Whiteley in Questioning Answers

"Desk-bound workers should ‘walk EIGHT miles a day’ to slash risk of heart attacks or stroke" went one headline talking about the findings reported by William Tigbe and colleagues [1]. Drawing on data from over 110 postal workers - "(55 office-workers, 5 women, and 56 walking/delivery-workers, 10 women)" - who wore "activPAL physical activity monitors for seven days", researchers observed some potentially important trends.Alongside wearing their activity monitors, participants were also assessed on the basis of weight, height, and blood pressure; also providing blood samples pertinent to analyses for cholesterol and triglycerides. Such collected data were used to assess cardiovascular risk based on the PROCAM risk calculator.Results: those who were described as office workers and had a 'desk job' were generally larger at the waist and showed a slightly larger body mass index (BMI) score. They were also deemed to have an elevated risk of cardiovascular disease (over 10 years) compared with the walking/delivery workers. These observations were discussed in terms of the sedentary behaviours associated with their desk job. By contrast, those who delivered post (i.e. were active for large parts of the day) fared quite a bit better than their desk-bound colleagues, bearing in mind that all study participants were fairly healthy to begin with in terms of being non-smokers for example and not being in current receipt of blood pressure or glucose lowering medicines at time of study.The 'walk 8 miles a day' headline that followed the Tigbe study was derived from the observation(s) that: "Those with no metabolic syndrome features walked >15 000 steps/day, or spent >7 h/day upright." Metabolic syndrome refers to a collection of symptoms - "a combination of diabetes, high blood pressure and obesity" - that increases the risk of adverse events associated with cardiovascular (dys)function. It seems that being active, or at least not being sedentary, is important for our health - a shocker indeed!I've covered some of the other research in this area before (see here and see here for examples) and so the Tigbe results really don't come as a surprise. The strengths of the study are multiple in terms of objective measuring of activity (not reliant on the 'how much activity/exercise did you do today' type questionnaires) and all those biochemical measurements taken for participants to complement such findings. Yes, the sample size is OK but not particularly large and yes, these were pretty healthy participants to start with, but the results are nonetheless important.Obviously one has to be a little careful so as not to imply that being active is the only thing that leads to good health and wellbeing. Science has already heard about how 'you can't outrun a bad diet' [2] and for some people, walking 15,000 steps every day or even standing up for 7 hours a day is going to be a big ask. But as part of a package of 'interventions' to potentially ward off metabolic syndrome or related issues [3], the idea that we should all be quite a bit more active is one that really should be given a lot more consideration...Music to close, and with the title to this post, what else could I offer?----------[1] Tigbe WW. et al. Time spent in sedentary posture is associated with waist circumference and cardiovascular risk. Int J Obes (Lond). 2017 Jan 31.[2] Malhotra A. et al. It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet. Br J Sports Med. 2015 Aug;49(15):967-8.[3] Alexander DD. et al. A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clinic Proceedings. 2017; 92: 15-29.----------Tigbe WW, Granat MH, Sattar N, & Lean ME (2017). Time spent in sedentary posture is associated with waist circumference and cardiovascular risk. International journal of obesity (2005) PMID: 28138134... Read more »

  • March 9, 2017
  • 03:06 AM

"Relatives of individuals with ASD were at higher risk of ADHD"

by Paul Whiteley in Questioning Answers

"Individuals with ASD [autism spectrum disorder] and their relatives are at increased risk of ADHD [attention-deficit hyperactivity disorder]."So said the paper published by Laura Ghirardi and colleagues [1] (open-access) who studied "1 899 654 individuals born in Sweden between 1987 and 2006" and identified some 28,000 cases of ASD and 82,000 cases of ADHD "with 13 793 individuals... being comorbid cases."Results: "Individuals with ASD were at higher risk of having ADHD, compared with those who did not have ASD (OR=22.33, 95% CI: 21.77–22.92)." This is not a particularly surprising finding given what is already emerging in peer-reviewed science and clinical circles about autism rarely appearing in some sort of diagnostic vacuum (see here). The authors also report that: "the prevalence of ASD–ADHD comorbidity was higher in males (1.01%) than in females (0.43%)."Looking further at various degrees of familial relationship starting with monozygotic (MZ) twins - twins sharing the same genome - outwards to full- and half-cousins, authors reported a sort of sliding scale of risk on the association between autism and ADHD. So: "monozygotic twins of ASD cases had an increased risk of having ADHD" which was a higher risk than that noted for dizygotic (non-identical twins). Next on the list of heightened risk of ADHD where another family member was diagnosed with autism was a full sibling (actually, the calculated risk was slightly higher for full siblings over dizygotic twins) and then maternal and paternal half siblings respectively. The authors note that: "The pattern of within-family associations between ASD and ADHD across different types of relatives reflected the decreasing genetic resemblance among them." This potentially signifies quite a substantial role for genetics when it comes to the co-occurrence of autism and ADHD as per other important data [2] (assuming that environmental - non-genetics - factors don't impact on pregnancy or before pregnancy processes related to sperm and egg for example).Where next? Well, the pathway(s) potentially linking autism and ADHD still requite a lot more investigation. With my continued interest in how autism and ADHD might 'set someone up' for later mental health issues (see here and see here for examples) I'd be inclined to widen the range of diagnoses/labels that might also need examination pertinent to processes involved. Assuming also that genes for autism or ADHD might not necessarily be just genes for autism and ADHD (see here), an open mind needs to be kept of what could be potentially involved, as per the whole immune system link for example (see here). I'd also be inclined to suggest that the Ghirardi findings suggest greater examination a possible new dimension when it comes to concepts like the broader autism phenotype (BAP) (see here) too (including signs and symptoms based around sensory profiles [3]).Music to close: The Flaming Lips - She Don't Use Jelly.----------[1] Ghirardi L. et al. The familial co-aggregation of ASD and ADHD: a register-based cohort study. Mol Psychiatry. 2017 Feb 28.[2] Sokolova E. et al. A Causal and Mediation Analysis of the Comorbidity Between Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). J Autism Dev Disord. 2017 Mar 2.[3] Bijlenga D. et al. Atypical sensory profiles as core features of adult ADHD, irrespective of autistic symptoms. European Psychiatry. 2017. Feb 21.----------Ghirardi L, Brikell I, Kuja-Halkola R, Freitag CM, Franke B, Asherson P, Lichtenstein P, & Larsson H (2017). The familial co-aggregation of ASD and ADHD: a register-based cohort study. Molecular psychiatry PMID: 28242872... Read more »

Ghirardi L, Brikell I, Kuja-Halkola R, Freitag CM, Franke B, Asherson P, Lichtenstein P, & Larsson H. (2017) The familial co-aggregation of ASD and ADHD: a register-based cohort study. Molecular psychiatry. PMID: 28242872  

  • March 8, 2017
  • 03:09 AM

Blocking FRAAs and thyroid function in autism (continued)

by Paul Whiteley in Questioning Answers

Readers of this post are advised to check out a previous blogging occasion describing how 'FRAAs - folate receptor alpha autoantibodies - may correlate with reduced thyroid function in cases of autism' before heading into this entry on the recent paper published by Richard Frye and colleagues [1].You're back already? OK, well just in case you didn't read that last entry (😉), it's worthwhile first noting that: "Folate receptor α (FRα) autoantibodies (FRAAs) are prevalent in autism spectrum disorder (ASD). They disrupt the transportation of folate across the blood-brain barrier by binding to the FRα. Children with ASD and FRAAs have been reported to respond well to treatment with a form of folate known as folinic acid, suggesting that they may be an important ASD subgroup to identify and treat." Those are author words not mine (as is the clinical intervention mention).The 'thyroid' addition to their recent paper follows that previous paper by the authors [2] stating that: "blocking FRAAs are associated with reduced thyroid function and suggest that thyroid function should be examined in children with ASD who are positive for the blocking FRAAs."This time around the authors examined "blocking and binding FRAAs and thyroid stimulating hormone (TSH), free T4 (FT4), total T3 (TT3), reverse T3 (rT3), thyroid releasing hormone (TRH) and other metabolites" in 87 children diagnosed with an ASD. Some of their cohort had more than one measure of FRAAs, TSH and FT4.Results: "TSH, TT3 and rT3 were above the normal range in 7%, 33% and 51% of the participants and TRH was below the normal range in 13% of the participants." Further: "TSH concentration was positively and the FT4/TSH, TT3/TSH and rT3/TSH ratios were inversely related to blocking FRAA titers." The observation that levels of thyroid stimulating hormone (TSH) were positively correlated with blocking FRAA titers follows the same pattern as the previous findings reported by authors. Elevations in TSH normally imply that the 'thyroid is struggling' and potentially leaning towards hypothyroidism; the correlation with FRAA titers *could* imply that those blocking antibodies might be part and parcel of why the thyroid is struggling. Ergo: "This study suggests that thyroid dysfunction in ASD may be related to the blocking FRAA."Accepting that 'FRAA autism' (if I can call it that) is not a universal label to be applied to the autism spectrum (see here) the combined results in this area (with and without the thyroid bit added on) make for interesting reading. Not only do they offer yet another strand to the saying 'an autism diagnosis is the starting not finishing point' when it comes to assessments, but the possible intervention angle also comes to the forefront (see here).What else would I like to see in this area? Well, quite a bit more work on thyroid function and autism could be a good starting point, outside of the maternal thyroid function (autoimmunity) and offspring risk bit (see here). Given that also all those thyroid metabolites are reliant on iodine (the number referring to the number of thyroid units chemically attached), there could be quite a bit more to see when it comes to iodine and [some] autism too (see here). Then another research question: what happens to thyroid function as and when something like folinic acid is used? Science already has some idea that folinic acid - under double-blind, placebo-controlled conditions - might be useful for aspects of some autism (see here). Could we learn from other studies looking at folinic acid where thyroid function has been mentioned? [3] I daresay we could...To close, science is great. Especially when it talks about case reports like this...----------[1] Frye RE. et al. Thyroid dysfunction in children with autism spectrum disorder is associated with folate receptor alpha autoimmune disorder. J Neuroendocrinol. 2017 Feb 15.[2] Frye RE. et al. Folate Receptor Alpha Autoantibodies Modulate Thyroid Function in Autism Spectrum Disorder. NAJ Med Sci. 2014; 7: 53-56.[3] Blehaut H. et al. Effect of leucovorin (folinic acid) on the developmental quotient of children with Down's syndrome (trisomy 21) and influence of thyroid status. PLoS One. 2010 Jan 11;5(1):e8394.----------Frye RE, Wynne R, Rose S, Slattery J, Delhey L, Tippett M, Kahler SG, Bennuri SC, Melnyk S, Sequeira JM, & Quadros E (2017). Thyroid dysfunction in children with autism spectrum disorder is associated with folate receptor alpha autoimmune disorder. Journal of neuroendocrinology PMID: 28199771... Read more »

  • March 7, 2017
  • 04:23 AM

Herbal medicines 'for' ADHD systematically reviewed

by Paul Whiteley in Questioning Answers

The paper by Dennis Anheyer and colleagues [1] (open-access available here) is offered up for your reading consumption today, and the results of a review of the available published science - "Only randomized controlled trails (RCT)" (authors' spelling mistake not mine) - looking at the use of herbal medicines for the treatment/management of attention-deficit hyperactivity disorder (ADHD).OK I know some people read the term 'herbal medicine' and automatically think 'woo'. If I instead use the term 'pharmacognosy' to denote how plants and herbs are the starting material for quite a few active ingredients included in various medicines (and related products!), you can perhaps see that a little more scientific respect is required for our cumulative flora. Respect and caution I should perhaps say...Anheyer et al boiled the literature on this topic down into 9 studies fulfilling their eligibility criteria, covering a variety of herbal medicines. These included: Melissa officinalis, Valeriana officinalis, Passiflora incarnata, evening primrose oil, Gingko biloba, Pycnogenol and St. John’s Wort.  They concluded that based on their examination of the collected literature "no concrete recommendations for use can be made so far."But that's not to say that there weren't some potentially encouraging 'green shoots' to be seen in the literature reviewed. The "potential efficacy of pine bark extract [pycnogenol] in the therapy of ADHD" was mentioned, as the 'bark with bite' (see here) got something of a thumbs-up (or at least, not a thumbs down). Researchers also suggested that: "Low evidence could be found for Melissa officinalis, Valeriana officinalis and Passiflora incarnata" as part of a mixture (compound herbal preparation) indicating that more research might be indicated.It's also worth pointing out that within the studies examined by Anheyer and colleagues, the safety profiles of the herbal medicines used were typically good in relation to reported side-effects over the duration of their study. Only one 'serious event' was recorded as far as I can see when it came to the use of evening primrose oil and a participant who "developed severe diarrhea" (although even this event may not have been directly due to the remedy given).Where next I thought I heard you ask? Well, assuming one can get around any issues with the term 'herbal medicine' I'd like to think that further investigations could be attempted on some of the more favourable herbal medicines identified in this and other reviews [2] and what the active ingredients and relevant biological processes might be. Allied to the increasingly important data on how something like certain fatty acids might be an intervention option for some with ADHD (see here), there is potentially still much we can learn from applying the science of pharmacognosy to a label like ADHD.But, as I've said before, treat your herbal medicines (and other nutritional supplements) as what they are - medicines - and just be careful [3] particularly when other medicines might also be administered at the same time.----------[1] Anheyer D. et al. Herbal medicines in children with attention deficit hyperactivity disorder (ADHD): A systematic review. Complement Ther Med. 2017 Feb;30:14-23.[2] Sarris J. et al. Complementary medicines (herbal and nutritional products) in the treatment of Attention Deficit Hyperactivity Disorder (ADHD): a systematic review of the evidence. Complement Ther Med. 2011 Aug;19(4):216-27.[3] Mouly S. et al. Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John's Wort? Pharmacol Res. 2016 Sep 28. pii: S1043-6618(16)30991-4.----------Anheyer D, Lauche R, Schumann D, Dobos G, & Cramer H (2017). Herbal medicines in children with attention deficit hyperactivity disorder (ADHD): A systematic review. Complementary therapies in medicine, 30, 14-23 PMID: 28137522... Read more »

  • March 6, 2017
  • 04:25 AM

"Logical fallacies in animal model research"

by Paul Whiteley in Questioning Answers

A paper which is a bit 'out of left field' is presented for your reading pleasure today and how one should be rather careful about how animal research - "with focus on animal models of mental illness" - is translated into relevance to humans [1].The paper by Espen Sjoberg is pertinent to various diagnostic labels including depression and schizophrenia. I would perhaps disagree with the author including autism under the specific heading of 'mental illness' (bearing in mind various mental health diagnoses can follow an autism diagnosis), but the discussions on how we should all be a little cautious about translating findings from animal research to real people ring as true for autism as they do for the other conditions discussed.The paper is open-access but a few choice phrases are worth highlighting from the 'what can we do about this ' section of the Sjoberg paper in these days of animal models of [insert condition name here].So: "Avoid making inferences about the animal’s thoughts, feelings, inner motivation, or understanding of the situation. We can report what the animals did, and what this means in the context of our hypothesis, but take care not to make assumptions of the inner workings of the animal." I note the words 'theory of mind' (ToM) are mentioned in another section of the paper which is interesting and potentially relevant to autism research history...Onwards: "No matter how validated an animal model is, we cannot be certain that a newly observed effect also applies to humans." The valproate model of autism is specifically mentioned in the Sjoberg text - where prenatal exposure to valproate may have implications for offspring development - but is not the only rodent model of autism (see here). The implication is that one has to be be mindful that just because findings might talk about intestinal inflammation associated with the valproate mouse model of autism for example (see here), this does not make them directly applicable to real people without looking at real people (who were prenatally exposed to valproate). The caveat being: "Remember that the strength of an animal model is to generate new knowledge and hypotheses relevant to the target group, including the assessment of potentially useful treatments, but that these new possibilities are only hypothetical once they are discovered."Finally: "Replicating an experiment in order to establish interval validity and reliability of an animal model is essential." Replication is a cornerstone of reliable science and so, where possible, when one finds and reports on a specific aspect of an animal model of some label or other, the experiment should be [independently] replicated. The author even goes further, bringing in another couple of 'R' words: reproduction and reconstruction ("A reconstruction involves redesigning an experiment, while maintaining the original hypothesis, in order to accommodate different species").The bottom line: don't over-hype your [animal research] findings if you've only looked at animal models and are presenting novel findings. In particular, make sure you write any press release mindful of what you were studying and how applicable the results may/may not be (outside of animals)...Music to close: an old favourite of this blog, Weezer and The Fonz...----------[1] Sjoberg EA. Logical fallacies in animal model research. Behavioral and Brain Functions. 2017; 13: 3.----------Sjoberg EA (2017). Logical fallacies in animal model research Behavioral and Brain Functions : 10.1186/s12993-017-0121-8... Read more »

Sjoberg EA. (2017) Logical fallacies in animal model research. Behavioral and Brain Functions. info:/10.1186/s12993-017-0121-8

  • March 4, 2017
  • 04:43 AM

Fatigue in adults with a 22q11.2 deletion syndrome

by Paul Whiteley in Questioning Answers

The genetic condition called 22q11.2 deletion syndrome (22q11.2DS) has, on occasion, provided some research fodder for this blog (see here and see here). The reason for its inclusion here has tended to be around the 'overlap' in the presentation of 22q11.2 and autism/autistic features and the importance of appropriate screening as and when an autism diagnosis is received (see here). Remember: receipt of an autism diagnosis is a starting point not the finishing line.Today I'm once again talking about 22q11.2 and specifically the results reported by Vergaelen and colleagues [1] on the need for more research/investigation on fatigue as a potentially important symptom when it comes to 22q11.2. This work links into another area of interest to this blog: chronic fatigue (syndrome) (CFS).OK, just for the record I'd like to point out that fatigue is not the same as chronic fatigue syndrome (indeed, as mentioned in a recent post, 'chronic disabling fatigue' is also not the same as chronic fatigue syndrome). Vergaelen et al relied on data from 29 people (adults) diagnosed with 22q11.2 who completed "the multidimensional fatigue inventory (MFI) measuring severity of fatigue." Results from the self-report schedule were "compared with published population norms" and suggested that: "Subscales and total MFI scores were significantly higher in adults with 22q11.2DS." Authors also noted that the presence of fatigue seemed to also affect scores on quality of life and depression in their cohort and recommend "a systematic clinical examination to exclude underlying somatic or psychiatric causes of fatigue."There's little more to say on this topic aside from reiterating the point that further clinical examinations should be undertaken to assess the possible hows and whys of fatigue presenting alongside 22q11.2 deletion syndrome. Given for example, previous work suggesting that mitochondrial disease might manifest as fatigue (as part of CFS that is) (see here) and some work linking "some 22q11DS genes implicated in mitochondrial function" [2] that is one option to consider among [likely] many.Music: and if like me, you watched the trailer to the new 'Logan' film and asked who 'sings that song?', well it was Johnny Cash and Hurt.----------[1] Vergaelen E. et al. High prevalence of fatigue in adults with a 22q11.2 deletion syndrome. Am J Med Genet A. 2017 Feb 12.[2] Devaraju P. & Zakharenko SS. Mitochondria in complex psychiatric disorders: Lessons from mouse models of 22q11.2 deletion syndrome: Hemizygous deletion of several mitochondrial genes in the 22q11.2 genomic region can lead to symptoms associated with neuropsychiatric disease. Bioessays. 2017 Feb;39(2).----------Vergaelen E, Claes S, Kempke S, & Swillen A (2017). High prevalence of fatigue in adults with a 22q11.2 deletion syndrome. American journal of medical genetics. Part A PMID: 28190295... Read more »

Vergaelen E, Claes S, Kempke S, & Swillen A. (2017) High prevalence of fatigue in adults with a 22q11.2 deletion syndrome. American journal of medical genetics. Part A. PMID: 28190295  

  • March 3, 2017
  • 02:56 AM

Poverty status and autism, ADHD and asthma

by Paul Whiteley in Questioning Answers

The paper by Christian Pulcini and colleagues [1] talking about poverty status potentially influencing "parent-reported lifetime prevalence and comorbidities" when it comes to three target conditions (autism, attention-deficit hyperactivity disorder [ADHD] and asthma) should have been a call to action. Concluding that "poor and near poor children had a higher lifetime prevalence of asthma and ADHD, but not ASD [autism spectrum disorder]" [2], some of the findings have instead attracted criticism based on the content of the abstract (see here); specifically the line: "the lifetime prevalence of ASD rose almost 400%."Poverty and diagnosis is a topic that I've covered before on this blog (see here for example) and how not every research study has linked poverty (measures of poverty) to something like autism and/or ADHD. At least that is, when taking into account "elevated emotional problems among children with ASD + ADHD" [3].On this most recent occasion, Pulcini et al drew on data derived from the "National Survey of Children's Health [NSCH] for years 2003, 2007, and 2011-2012" and specifically "trends in parent reported lifetime prevalence and comorbidity among children with asthma, ADHD, and ASD" taking into account variables like poverty status. The NSCH initiative has again, been talked about previously on this blog (see here and see here) in terms of parent-reported prevalence of autism and parent-reported epilepsy appearing alongside autism. It's a good rough-and-ready measure of what estimated prevalence rates might look like (with the need for further, more detailed study).This time around the authors illustrated that - yet again - the only way is up when it comes to estimated prevalence rates for all the 'target' conditions examined. I don't think anyone should be too surprised at such findings given data from other studies in other geographic areas (see here) specifically with the autism spectrum in mind. I'm not going to head into the debate about whether the 400% increase figure is right or wrong but will note previous findings [4] that suggested that: "differential survey measurement error over time was not a major contributor to observed changes in the prevalence of parent-reported ASD. Rather, much of the prevalence increase from 2007 to 2011–2012 for school-aged children was the result of diagnoses of children with previously unrecognized ASD." This for when data from the 2007 and 2011-2012 surveys were contrasted (not the 2003 survey).The contribution of poverty or near poverty was not to be sniffed at when it comes to those ADHD and asthma diagnoses. This is perhaps even more important when one considers that these two labels might be rather more 'entangled' than many people might have previously realised (see here). That a poverty and ADHD link might also generalise to somewhere like here in the UK is also worth noting (see here) and implies that quite a bit more research is needed to answer the question: why? With regards to autism (ASD), the observation that the "rise in ASD was associated with being nonpoor"adds to an on-going debate, with some studies saying yes, we agree, and other studies saying no, we don't (see here). In short, it is slightly more complicated when it comes to how social factors might affect autism rates.Music: Three steps to heaven.----------[1] Pulcini CD. et al. Poverty and Trends in Three Common Chronic Disorders. Pediatrics. 2017 Feb 13. pii: e20162539.[2] Dreyer BP. Congress Should Adopt a “Do No Harm to Children” Standard in Changes to Public Health Insurance. Pediatrics. 2017. Feb 2017.[3] Flouri E. et al. Poverty and the Growth of Emotional and Conduct Problems in Children with Autism With and Without Comorbid ADHD. J Autism Dev Disord. 2015 Sep;45(9):2928-38.[4] Blumberg SJ. et al. Changes in Prevalence of Parent-reported Autism Spectrum Disorder in School-aged U.S. Children: 2007 to 2011–2012. Natl Health Stat Report. 2013 Mar 20;(65):1-11.----------Pulcini CD, Zima BT, Kelleher KJ, & Houtrow AJ (2017). Poverty and Trends in Three Common Chronic Disorders. Pediatrics PMID: 28193790... Read more »

Pulcini CD, Zima BT, Kelleher KJ, & Houtrow AJ. (2017) Poverty and Trends in Three Common Chronic Disorders. Pediatrics. PMID: 28193790  

  • March 2, 2017
  • 03:11 AM

Subgroups in autism (without intellectual disability)

by Paul Whiteley in Questioning Answers

"Children with ASD [autism spectrum disorder] without ID [intellectual disability] could be differentiated into Moderate and Severe Social Impairment subgroups when core ASD symptoms were more closely examined."So said the findings reported by Felicity Klopper and colleagues [1] looking at an important part of the autism research scene related to the 'plurality' of the term autism and the seemingly vast range of presentations included under the label. Reliant on data obtained from "the ‘gold standard’ ASD diagnostic instruments" (including the ADOS and ADI), researchers looked at the "presence of phenotypic subgroups" in their cohort.As per the opening sentence to this post, there were some differences to be seen in the cohort, and in particular, how social interaction issues might be a key part of any differentiation. The authors talk about how social interaction issue differences seemed to tie into other core behavioural features such as communication and the presence of restricted/repetitive behaviours. They concluded: "both categorical and dimensional approaches may be useful in classifying ASD, with neither alone being adequate."It is not necessarily new news that the label of autism is good for diagnosis but seemingly says little about the range of presentation included under the heading (see here for example). Indeed, in these days of ESSENCE I might forward the view that even the label autism might be part of a wider heterogeneous presentation (see here) and one should further expand those subgroup notions at the label as well as symptom level. The focus on overt behaviour (as assessed by those gold-standard instruments) in the Klopper study is but one part of looking at such 'heterogeneity' (see here for example) as the authors argue that: "The dissociated profiles of ASD features could represent different underlying neurobiological mechanisms for each subgroup." At least one of the authors on the Klopper paper probably, more than most, realises that fact (see here).There are other key areas to this focus on the presentation of autism that also need to be factored in: sex differences and comorbidity profiles. Specifically, the growing realisation that girls and boys on the autism spectrum probably show subtle differences in presentation (see here) and, minus any sweeping generalisations, should be considered in future studies in this area. Oh, and keep in mind that those diagnosed with autism with an intellectual disability (ID) could also be 'sub-grouped' according to symptom presentation too with similar caveats. The question is: how many sub-groups of autism will we eventually end up with?Music, and because Spring has Sprung... In Bloom.----------[1] Klopper F. et al. A cluster analysis exploration of autism spectrum disorder subgroups in children without intellectual disability. Research in Autism Spectrum Disorders. 2017; 36: 66-78.----------Felicity Klopper, Renee Testa, Christos Pantelis, & Efstratios Skafidas (2017). A cluster analysis exploration of autism spectrum disorder subgroups in children without intellectual disability Research in Autism Spectrum Disorders : 10.1016/j.rasd.2017.01.006... Read more »

Felicity Klopper, Renee Testa, Christos Pantelis, & Efstratios Skafidas. (2017) A cluster analysis exploration of autism spectrum disorder subgroups in children without intellectual disability. Research in Autism Spectrum Disorders. info:/10.1016/j.rasd.2017.01.006

  • March 1, 2017
  • 03:13 AM

Sex and age might affect comorbidity profiles in autism

by Paul Whiteley in Questioning Answers

The paper by Supekar and colleagues [1] provides some food for thought today specifically with the idea that comorbidity profiles accompanying autism might be influenced by age and gender in mind.To quote: "These results highlight crucial differences between cross-sectional comorbidity patterns and their interactions with sex and age, which may aid in the development of effective sex- and age-specific diagnostic/treatment strategies for ASD [autism spectrum disorder] and comorbid conditions."From a starting point assuming that the diagnosis of autism rarely exists in some sort of diagnostic vacuum (see here), researchers set about looking at comorbidity patterns for quite a few conditions/labels "using cross-sectional data from 4790 individuals with ASD and 1,842,575 individuals without ASD." The sorts of things that looked for were not uncommon to discussions about comorbidity accompanying autism on this blog (epilepsy, attention-deficit hyperactivity disorder (ADHD) and "bowel disorders" for example). The variables of sex (gender) and age were also included in the research mix.Bearing in mind that sweeping generalisations about autism comorbidity profiles are not required, the authors highlighted a couple of important points. First: "Epilepsy, ADHD, and CNS/cranial anomalies showed exceptionally large proportions in both male (>19%) and female (>15%), children/adolescents with ASD. Notably, these prevalence rates decreased drastically with age in both males and females." This is interesting. With a rather large research gap quite visible when it comes to the concept of ageing and autism (see here), the author's data seems to be suggesting that the burden of comorbidity (some comorbidity) might decline as people diagnosed on the autism spectrum get older. Yes, the words "cross-sectional comorbidity" are important (more longitudinal study is required where people are 'followed' as they age) and there is no doubt that intervention to manage diagnoses such as epilepsy (and/or seizure disorder) probably plays a hand in presentation, but more investigation is certainly required.Next: "the prevalence of schizophrenia increased with age affecting a disproportionately large number of older (≥35 year) adult males (25%), compared to females (7.7%), with ASD." Two points are made here: (a) rates of schizophrenia might be affected by sex, and (b) age might play a role in the presentation of schizophrenia in the context of autism. This follows a theme re-emerging over these past few years suggesting that the autism and schizophrenia spectrums might not be as separate and independent as many might believe (see here and see here). Quite a lot of [research] focus has been directed at some of the signs and symptoms of schizophrenia with [some] autism in mind (see here for example) and perhaps queries whether history was 'too quick' to try and distance the two labels from each other (were Mildred Creak and colleagues correct?). Given the significant issues potentially linked to a diagnosis of schizophrenia (see here) in terms of health inequality and the like (something also sadly not unfamiliar to autism too), the onus should surely be to screen (and keep screening) for schizophrenia when autism is present into adulthood? Said screening could be preferentially driven by the Supekar findings taking into account that caveat about not over-generalising findings.I'm gonna stop there with discussing these results so as not to over-analyse the findings. The important take-away point is that autism is generally not a 'stand-alone' condition and that age and gender might have some important roles to play when it comes to at least some comorbidity.Music: something lively I think so increase the volume please...----------[1] Supekar K. et al. The influence of sex and age on prevalence rates of comorbid conditions in autism. Autism Res. 2017 Feb 11.----------Supekar K, Iyer T, & Menon V (2017). The influence of sex and age on prevalence rates of comorbid conditions in autism. Autism research : official journal of the International Society for Autism Research PMID: 28188687... Read more »

Supekar K, Iyer T, & Menon V. (2017) The influence of sex and age on prevalence rates of comorbid conditions in autism. Autism research : official journal of the International Society for Autism Research. PMID: 28188687  

  • February 28, 2017
  • 02:42 AM

Premature mortality in intellectual disability in Australia (and England)

by Paul Whiteley in Questioning Answers

"Adults with ID [intellectual disability] experience premature mortality and over-representation of potentially avoidable deaths."The paper by Julian Trollor and colleagues [1] (open-access available here) provides some sombre reading today, as once again the topic of early mortality is raised on this blog. Looking at several measures - the "Age Standardised Mortality Rate (ASMR), Comparative Mortality Figure (CMF), years of productive life lost (YPLL) and proportion of deaths with potentially avoidable causes" - authors paint a depressing picture of a 'mortality gap' between those diagnosed with a learning (intellectual) disability and the wider, general population.I don't want to trawl through the Trollor paper in great detail given that it is open-access for all to see, but a few points are worthwhile raising. So, based on data from some 20,000 adults (aged 20 or over) registered with an intellectual disability (ID) in New South Wales (NSW) in Oz, there were 732 deaths reported (4%) "equivalent to a crude death rate of 5.9 deaths per 1000 people per year." The median age at death was 54 years and about 60% of deaths were in men. A control cohort consisting of adults from NSW was used as a comparator where "a crude death rate of 9.1 deaths per 1000 person years" was calculated. The median age at death however, for the control group, was 81 years. When looking at death rates between the groups according to age banding (20-44 years, 45-64 years, 65+ years) authors noted that: "People with ID in the 20–44 years age category had four times the death rate of the comparison group."Looking at the causes of death between the ID and control groups, authors noted some potentially important trends. So: "Cause of death in [the] ID cohort was dominated by respiratory, circulatory, neoplasm and nervous system." This bearing in mind that cause of death was not available for everyone diagnosed with an ID (only 87%). Such causes were not wildly different from those noted in the control population but when it came to 'potentially avoidable deaths' the ID group were placed at some quite notable disadvantage, with 31% of deaths falling into this category (revised up to 38% depending on the 'death classification' used) compared with 17% in the general population. Readers should also note that: "Potentially avoidable deaths are deaths from conditions that are preventable through individualised care and/or treatable through existing primary or hospital care for persons aged under 75 years and which are avoidable in the context of the present health system."As you can see, there are some quite shocking details noted in the Trollor paper. The emerging picture that some of the most vulnerable people in society (certainly in Australia) are (a) at risk of dying earlier than the general population and (b) at greater risk of suffering a 'potentially avoidable death' is one that no-one should be proud of. And just in case you though the results might not be generalisable to other parts of the world... you're wrong [2] (open-access here) as data from England reveals that: "Mortality rates for people with ID were significantly higher than for those without. Their all-cause standardised mortality ratio was 3.18. Their life expectancy at birth was 19.7 years lower than for people without ID." Truly shocking.What can society do about such a state of affairs? Well, potentially lots (and it doesn't take monumental shifts to achieve better outcomes either). "Particularly stark is the large proportion ofpotentially avoidable deaths due to infections. Such deaths suggest that people with ID experience delays, difficulties or differences in accessing specific and effective interventions for infections. Medical assistance must be sought assertively in individuals who manifest symptoms, but this is made difficult as patients with ID may not readily report symptoms, and some providing direct carelack skills in early identification of relevant physical signs. Primary care providers should consider careful assessment, proactive treatment and close monitoring of progress if there are infections in this population." Sorry for the large chunk of replication text there but several important themes are laid out by Trollor, some of which overlap with other work in relation to autism for example (see here). Not least is the need for 'proactivity' on the part of clinicians and other professionals, potentially dealing with a group who may not be able to readily communicate their physical state for example and so shifting the responsibility on medical care being inspective and proactive. This means regular health screening and, at the basic level, understanding that a diagnosis of ID (or autism or schizophrenia [3]) does not seemingly provide any protection against the development of life-threatening illness or other conditions becoming evident.I close with an article discussing another part of the reason why people with ID are being placed at an unacceptably high risk of early death: when those who are supposed to provide care, fail.----------[1] Trollor J. et al. Cause of death and potentially avoidable deaths in Australian adults with intellectual disability using retrospective linked data. BMJ Open. 2017. Feb 7.[2] Glover G. et al. Mortality in people with intellectual disabilities in England. J Intellect Disabil Res. 2017 Jan;61(1):62-74.[3] Hjorthøj C. et al. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry. 2017 Feb 22. pii: S2215-0366(17)30078-0.----------Trollor J, Srasuebkul P, Xu H, & Howlett S (2017). Cause of death and potentially avoidable deaths in Australian adults with intellectual disability using retrospective linked data. BMJ open, 7 (2) PMID: 28179413... Read more »

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