A role for viral infection in the aetiology of coeliac disease?

"In this longitudinal study, we found that a higher frequency of enterovirus infections was associated with increased risk of coeliac disease."

So said the findings reported by Christian Kahrs and colleagues [1] (open-access available here) based on the results of their: "Case-control study nested within Norwegian birth cohort recruited between 2001 and 2007 and followed to September 2016."

Following the screening of some 47,000 infants for the 'genetics of coeliac disease' - HLA genotype DR4-DQ8/DR3-DQ2 - over 900 children were entered on to the study. This group were followed "with repeated blood and faecal samples from the age of 3 months" for quite a few years. Just over 500 participants who quite regularly donated blood samples, were asked if they wanted a screen for coeliac disease. Two hundred and twenty of them (or their parents/guardians) said 'yes please' and the study results were drawn from this group. Twenty seven of the 220 participants with those all-important coeliac risk genes were diagnosed with the condition. Twenty five of those 27 diagnosed with coeliac disease were matched against 50 of the no coeliac disease participants; matching was done "for duration of follow-up, date of birth, and county of residence." It was then just a case of looking at all the biological data that had been accrued from those blood and fecal samples to ascertain things like (a) "the time interval when cases seroconverted for coeliac disease markers" (i.e. when the antibodies diagnostic of coeliac disease began to be present) and (b) if and when enterovirus was detected in some of the samples (stool samples) via PCR (polymerase chain reaction).

Results: as shown in the supplementary material, the mean age at first presence of coeliac disease (CD) antibodies in the CD diagnosed sample (n=25) was around 42 months (when the first positive sample was recorded). Symptoms 'debut' was around an average age of 73 months and CD diagnosis was received on average at 87 months. Enterovirus was reported in both CD (n=25) and non-CD groups (n=49). Some 20% of the stool samples from the CD group were positive for some kind of enterovirus exposure compared with 16% of controls. Slightly more enterovirus positive stool samples were observed in the CD group (median 4 positive samples per child) than the control group (median 3 positive samples per child).

As per the opening quote to this post: "Enterovirus was found in 370 (17%) of 2135 samples and was significantly more frequent in samples collected before development of coeliac disease antibodies in cases than in controls." Further: "The association was restricted to infections after introduction of gluten." In other words, there seemed to be some evidence of a possible temporal connection between enterovirus and the development of CD, suggesting that enterovirus exposure and not gluten was the more important trigger for CD.

Mechanisms? Well, there's some speculation about that in the Kahrs paper and a: "plausible explanation is that enterovirus causes impaired barrier function, which in turn increases the risk of coeliac disease." Enterovirus causing impaired intestinal (gut) barrier function eh? Interesting, does that mean 'leaky gut' might have a viral origin in some cases? Mmm, that could have lots of implications...

Obviously more investigation is required in this area. The Kahrs study has some strengths in terms of the sample collection protocols and frequency and potentially establishing a temporal *link* between CD and enterovirus exposure. But there's still more to do: "unmeasured confounding factors or residual confounding can never be entirely ruled out in non-randomised studies." But don't let that take anything away from the potential importance of these findings.

And on the topic of prospectively following children who might be prone to develop coeliac disease, the study findings published by Lionetti and colleagues [2] are equally interesting. In particular, based on 23 of their 26 children who received a "potential diagnosis of CD" but nonetheless "continued a gluten-containing diet... 19 (83%) became antibodies negative at 1 year from the first biopsy and remained negative up to 10 years of follow-up." Could there be a tie-up with the Kahrs findings perhaps?

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[1] Kahrs CR. et al. Enterovirus as trigger of coeliac disease: nested case-control study within prospective birth cohort. BMJ. 2019 Feb 13;364:l231.

[2] Lionetti E. et al. Long-Term Outcome of Potential Celiac Disease in Genetically at-Risk Children: The Prospective CELIPREV Cohort Study. J Clin Med. 2019 Feb 5;8(2). pii: E186.

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Childhood lead (Pb) exposure and "greater psychopathology across the life course"

I've talked about the effects of lead (Pb) on cognition, behaviour and psychology before on this blog (see here and see here for examples). A (heavy) metal with no confirmed biological function, lead represents something that pretty much everyone should be avoiding exposure to, despite it still being used in everything from roofing materials to batteries. The findings reported by Aaron Reuben and colleagues [1] add further to the 'avoid lead' sentiments, and specifically how: "Childhood lead exposure may have long-term consequences for adult mental health and personality."

The aim of the Reuben paper was to conduct "the longest and largest psychiatric follow-up to date in a cohort of adults who were lead exposed and lead tested as children." Participants and their data came from "the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of health and behavior in a birth cohort." This study specifically drew on data from over 500 Dunedin study members who were tested for lead exposure around age 11 years and were followed up until their late 30s. A range of psychometric measures were employed in adulthood to complement participants' blood lead test results during childhood, including "(1) repeated clinical interviews assessing psychopathology symptoms across adulthood up to 38 years of age; (2) comprehensive, dimensional measures of psychopathology that account for severity, comorbidity, and reoccurrence; and (3) a broad measure of adult personality (Big Five Personality Inventory)... that did not rely on self-report." Importantly, researchers relied on a sample where "the extent of children's exposure to lead was unrelated to their socioeconomic origins."

Results: most of the cohort (over 90%) had tested blood lead levels above the 5 μg/dL level that the US CDC currently describes as a "reference value for clinical attention." This threshold value replaced the 10 μg/dL level that used to be thought to be important. Indeed within the Reuben cohort: "The mean (SD) blood lead level was 11.08 (4.96) μg/dL."

Researchers also observed that: "After adjusting for covariates, each 5-μg/dL increase in childhood BLL was associated with a 1.34-point increase... in general psychopathology." Covariates included "family socioeconomic status, maternal IQ, and family history of mental illness." This seemingly dose-dependent relationship looked to be quite important.

Onward: "study members with higher BLLs [blood lead levels] at 11 years of age were viewed in adulthood by their informants as more neurotic..., less agreeable..., and less conscientious" than those with lower levels. Personality it seems *might* also be affected by childhood lead exposure (at least partially). These and other factors lead Reuben et al to conclude that: "the association between lead exposure and psychopathology may begin to manifest broadly well before adulthood" and "early-life lead exposure in the era of leaded gasoline experienced by individuals who are currently adults may have contributed to subtle, lifelong differences in emotion and behavior that are detectable at least up to 38 years of age."

I know there are caveats to this type of observational work - "there was only one time point of lead testing" - and even controlling for some potential covariates does not mean that the total spread of covariates has been covered in this study. Personally, I'm not overly enthused by the whole personality types bit either; particularly in light of further revelations about some of the historical proponents of such an idea (see here). But taken as part of a wider series of research on lead exposure and psychopathology, the Reuben work is in line with other results on how an environmental factor can seemingly affect both development and psychopathology. And minus any sweeping generalisations about psychopathology and crime, the so-called 'lead-crime hypothesis' under the guise of biosocial criminology for example, doesn't exactly suffer as a result of the Reuben findings...

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[1] Reuben A. et al. Association of Childhood Lead Exposure With Adult Personality Traits and Lifelong Mental Health. JAMA Psychiatry. 2019. Jan 23.

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"A fast reduction in HERV-H activity in ADHD patients undergoing MPH therapy"

Just in case the title of this post is not readily translatable, here's a key to help. HERV-H refers to human endogenous retrovirus H. ADHD means attention-deficit hyperactivity disorder. MPH therapy refers to the therapeutic use of methylphenidate, "widely used in the treatment of attention deficit hyperactivity disorder."

Putting all these concepts together are the findings reported by Cipriani Chiara and colleagues [1] following a research trend in recent years (see here). The general idea is that those fossil viruses, that we all carry in our genome as a result of our ancestral exposure to various viruses down the ages, might not be as dormant or 'junk' as many would believe. Being 'transcriptionally active', meaning that they could code for viral proteins, such HERVs have been *associated* with quite a few conditions and labels (see here and see here for examples). ADHD has also been mentioned with HERVs in mind (see here).

The Chiara results observing a "fast reduction in HERV-H activity in ADHD patients undergoing MPH therapy" were based on the examination of HERV-H expression in peripheral blood mononuclear cells (PBMCs) from those diagnosed with ADHD (N=7) first under drug-naïve conditions (without use of MPH) and then at intervals of 1 week, 8 weeks and 24 weeks of MPH use. Results were also compared with a small cohort of not-ADHD controls (I hate the use of the term 'healthy controls' (HC) despite the fact that: "None of them had a history of neurological or psychiatric disorders, learning disability, or infectious diseases"). Researchers observed a rapidly decreasing HERV-H 'relative' expression at all intervals of MPH use in their participant group with ADHD. The concluded that: "after 24 weeks of MPH therapy, HERV-H levels were comparable to those found in PBMCs from HC."

Alongside, although quite notably not reported in the study abstract, authors also looked at some of the clinical signs and symptoms of their participants with ADHD over the course of the study. Based on the use of the "long version of the Conners’ Parents Rating Scale-Revised questionnaire (CPRS-R)" they observed a corresponding trend of a reduction in scores (indicative of improvement) specifically focused on "the Conners’ parent oppositional (CP-O), the Conners’ parent inattention (CP-I), the parent hyperactivity/impulsivity (CP-H), and the Conners’ parent ADHD-Index (CP-AI)."

Putting the two findings together, the authors conclude that methylphenidate use *might* be something important to HERV-H expression in ADHD and *could* potentially explain part of the therapeutic action of the drug on ADHD.

Obviously one has to bear in mind issues such as correlation not being the same as causation alongside the relatively small participant numbers and the lack of any comparative data (say, from other interventions being used in the context of ADHD or following the use of MPH in non-ADHD populations). But the Chiara findings are interesting, and suggest some follow-up studies could be equally enlightening...

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[1] Chiara C. et al. The Decrease in Human Endogenous Retrovirus-H Activity Runs in Parallel with Improvement in ADHD Symptoms in Patients Undergoing Methylphenidate Therapy. Int J Mol Sci. 2018 Oct 23;19(11). pii: E3286.

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Regressive vs. non-regressive autism: limited chemical differences noted

The paper published by Antonio Gomez-Fernandez and colleagues [1] examining whether or not there may be some potentially important biological differences as a function of reported regression vs. no regression in autism provides the blogging fodder today. Not for the first time has the immune system and 'regressive autism' been mentioned in the peer-reviewed science literature (see here and see here), but the current work focuses on the examination of various immune system and other related compounds: in a seemingly well-defined cohort: "Analyses of plasma molecules, such as cathepsin, IL1β, IL6, IL8, MPO, RANTES, MCP, BDNF, PAI NCAM, sICAM, sVCAM and NGF."

"Fifty-four children (45 males and nine females) aged 2-6, who were diagnosed with ASD [autism spectrum disorder], and a control group of 54 typically-developing children of similar ages were selected." Authors relied on quite an extensive battery of assessments looking at behaviour, alongside their use of the DSM-5 diagnostic criteria for autism (see here). Also accompanying physical examination "with a special emphasis on neurological and nutritional status", authors garnered blood samples from participants (overnight fasting) for their immune system and related functioning evaluations.

"The group of ASD children was further divided into two subgroups based on the presence or absence of neurodevelopmental regression during the first two years of life, which was assessed using a five-item questionnaire following the guidelines used by the Autism Diagnostic Interview-Revised (ADI-R) for the evaluation of this process." The ADI-R has been previously discussed on this blog in relation to regression in autism (see here). And just in case you might not be totally convinced that regression can be part of a pathway to autism, here's some more evidence for you (see here)...

Results: "there were 20 children included in the AMR [neurodevelopmental regression] subgroup and 32 in the ANMR [without neurodevelopmental regression] subgroup; two children could not be classified in these subgroups because they were adoptees, allocated by a national adoption agency." Bearing in mind that we cannot rule out any recruitment bias that might have leaned towards including those with regressive autism on the Gomez-Fernandez study, the figure of approaching 40% of their cohort showing such a regressive profile is notable. I'd also draw your attention to the finding that the behavioural profile for the regressive group (AMR) was also significantly different from the non-regressive group (ANMR) insofar as perhaps painting a picture of greater [group] autism severity...

Interestingly, the study did not show too many immune system and other compound differences between those diagnosed with autism and the asymptomatic (for autism) control group. So: "No differences were found between the two groups in terms of the cytokine and adhesion molecule levels studied, except for NGF [nerve growth factor], in which the group of ASD children was found to have twice the plasma levels compared to the control group." NGF is no stranger to autism research, and other studies have come to a similar conclusion [2].

When it came to examining results based on comparing the regressive (AMR) and non-regressive (ANMR) groupings, things got slightly more interesting but again no complicated pattern of difference was noted. So, for the ANMR (non regression) grouping: "lower plasma levels of the NCAM adhesion molecule were detected compared to the levels in the AMR subgroup and the control group. This ANMR group also exhibited higher NGF levels than the typically-developing children, which could indicate an alteration in neuronal development." Again, adhesion molecules have been mentioned in other autism research (see here).

"In conclusion, the results of this study show that there is not a typical profile for the expression of relevant plasma cytokines, adhesion molecules or growth factors in children with ASD compared with that in typically-developing children." OK, there are caveats to the phrasing used by the authors; not least that the participant numbers were quite small in the Gomez-Fernandez study and the idea that within the very heterogeneous autism spectrum, there may be smaller groupings (phenotypes) that perhaps show a tendency to greater immune system and related 'issues' (see here). But there are also some strengths attached to the Gomez-Fernandez study; not least the study "benefits from a careful selection of children of similar ages, as well as the complete diagnosis of ASD with multiple tests, clinical follow-up and associated complementary tests."

Questions still remain. Perhaps an important one is the question around why some children show a regressive pattern of behaviour as part of their path to a diagnosis of autism? Yes, issues such as infection do seem to be part-and-parcel of the clinical profile for some (see here and see here for examples) and perhaps more detailed focus is required in such areas. But much like a group showing the opposite of regressive autism - those who seemed to 'grow out' of autism - currently thought to include as many as one in ten (see here), a wider range of biological as well as psychometric measures are required to help pick out potentially important mechanisms pertinent to the idea that autism is not necessarily 'hard-wired' for all...

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[1] Gomez-Fernandez A. et al. Children With Autism Spectrum Disorder With Regression Exhibit a Different Profile in Plasma Cytokines and Adhesion Molecules Compared to Children Without Such Regression. Front. Pediatr. 2018. September 26.

[2] Dinçel N. et al. Serum nerve growth factor levels in autistic children in Turkish population: a preliminary study. Indian J Med Res. 2013 Dec;138(6):900-3.

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Another blood test for autism?

"These results form the foundation for the development of a biochemical test for ASD [autism spectrum disorder] which promises to aid diagnosis of ASD and provide biochemical understanding of the disease, applicable to at least a subset of the ASD population."

OK, use of the word 'disease' in the context of autism is really, really not OK in this day and age. Researchers, peer reviewers and their publishing journals should be doing something about this kind of language. There are however some potentially important aspects to the work published by Daniel Howsmon and colleagues [1] worth talking about. Not least is their observation on how "folate‐dependent one carbon metabolism (FOCM) and transsulfuration (TS) pathways" that have been quite readily *associated* with autism might be linked to quite a bit more than just uncovering the biochemistry of at least some autism (see here for example).

Before progressing further into these findings, I note there has already been some media interest in them (see here) with a byline reading: "First physiological test for autism proves high accuracy in second trial." We'll see about that...

So, after quite a long introduction about 'biomarkers for autism' and how they "come with their own set of challenges before they reach clinical translation", authors report further results building on some of their previous work in this area [2] that I've already covered on this blog (see here). On that previous research occasion, the suggestion was that between 5 and 7 metabolites linked to folate and/or transsulfuration pathways provided a 'best fit' when it came to picking out children diagnosed with autism from those not diagnosed with autism.

This time around, there was an 'extension' to that work: "(a) By comparing univariate analysis with four different multivariate methods on FOCM/TS data for ASD biomarker development to ensure that the identified results are not restricted to FDA [Fisher Discriminant Analysis] and (b) to test and validate multivariate FOCM/TS biomarkers on data collected from a new cohort of ASD participants." The words 'training data' and 'validation data' are used quite a bit throughout the Howsmon article, illustrating how different statistical classification methods were initially applied to training data from the cohort used in their first paper, which were then tested on a new cohort of participants (n=154) diagnosed with an ASD. Given some of the names included on the authorship list, it's no surprise that participant data with regards to the metabolites being looked at were drawn from other studies looking at the possible clinical value of preparations like folinic acid (see here) and sapropterin (see here) with autism in mind.

When those different statistical classification methods were applied and data was crunched, a few observations were made. The headline result was that one model/method produced the best 'potential' biomarker results and it was the same/similar method to that previously discussed by the authors. To quote: "An FDA model using five variables was shown to slightly outperform the other models on this new validation data set." That being said, the accuracy rates (including false positive and false negative rates) hovering around the high 80%s have to take into account that two of the metabolites thought to be important on the last research occasion - % DNA methylation and 8‐OHG - "were not present in the validation set" on this research occasion. This is a pity and a weakness of the current study.

So, do we at last have a 'physiological test' with 'high accuracy' for picking out autism from not-autism? Erm, not quite yet. With all due respect to the authors, their data is interesting and does partially back up their original findings, but we're not quite there yet with regards to rolling out any sort of biological test for autism. Indeed, in these days of the plural 'autisms' (see here) and acknowledging that the diagnosis of autism rarely presents in some sort of diagnostic vacuum (see here) it could be worthwhile re-evaluating whether we're ever likely to see a 'one biological test to diagnose them all' situation.

Further investigations are however indicated and of course, this more recent information does add to the quite rich data already generated suggesting that quite a bit more focus on things like methionine, homocysteine, cysteine and glutathione in relation to autism could be an important research path to follow. I'm also minded to suggest that different research teams taking on a 'possible biomarker for autism' type research perhaps need to talk more to each other (see here) pooling findings, resources and perhaps participant groups too...

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[1] Howsmon DP. et al. Multivariate techniques enable a biochemical classification of children with autism spectrum disorder versus typically‐developing peers: A comparison and validation study. Bioengineering & Translational Medicine. 2018. May 14.

[2] Howsmon DP. et al. Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS Comput Biol. 2017 Mar 16;13(3):e1005385.

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Hypertensive disorders of pregnancy (HDP) and offspring autism and/or ADHD meta-analysed

"Pooled estimates from this systematic review and meta-analysis of 61 studies suggest that exposure to hypertensive disorders of pregnancy is associated with a small yet statistically significant increase in the odds of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring compared with no exposure."

So concluded the review and meta-analysis published by Gillian Maher and colleagues [1] that collected and analysed the current peer-reviewed research literature (up to June 2017) looking at hypertensive disorders of pregnancy (HDP) and offspring developmental outcomes. Continuing an important research theme (see here), authors observed something around "a 35% increased odds of ASD [autism spectrum disorder] compared with nonexposure" and that children were "30% more likely to have ADHD compared with unexposed offspring."

HDP according to Maher et al, covers quite a bit of diagnostic ground: "chronic hypertension (essential/secondary), white-coat hypertension, masked hypertension, transient gestational hypertension, gestational hypertension, and preeclampsia (de novo or superimposed on chronic hypertension)." The primary characteristic is "high blood pressure that either precedes pregnancy, is diagnosed within the first 20 weeks of pregnancy, or does not resolve by the 12-week postpartum checkup" [2].

There's little more to say about this area of research aside from the idea that findings "highlight the need for greater pediatric surveillance of infants exposed to HDP to allow early intervention that may improve neurodevelopmental outcome" and that more work on possible mechanism(s) need to be undertaken. On that last point the authors opine that "placental dysfunction, associated with HDP, may result in reduced placental perfusion and oxidative stress" or that: "Maternal inflammation may also play a key role." Both worthy areas for future research. The implication also, is that yet again, there may be some form of 'foetal programming' going on with regards to offspring autism that *could* be sensitive to intervention at some point...

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[1] Maher GM. et al. Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2018 Jun 6.

[2] Mammaro A. et al. Hypertensive Disorders of Pregnancy. Journal of Prenatal Medicine. 2009;3(1):1-5.

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Early lead (Pb) exposure and risk of ADHD: yet more 'nothing good comes from exposure to lead'

Lead (Pb) is a metal that has cropped up more than once on this blog (see here and see here and see here) in relation to early exposure and it's *possible* links to various childhood behaviour(s). As per part of the title of this post - 'nothing good comes from exposure to lead' - there really does seem to be very little good to say about exposure to lead (see here) given an apparent lack of any (advantageous) biological role when it comes to the human body. In short, we should be doing everything we can to ensure that exposure levels for everyone, particularly the very youngest, are kept to an absolute minimum...

The study results published by Yuelong Ji and colleagues [1] add to a pretty large peer-reviewed research literature observing a possible connection between biological lead levels "in early childhood" and risk of childhood psychopathology. They concluded that: "Elevated early childhood blood lead levels increased the risk of ADHD [attention-deficit hyperactivity disorder]."

The source material for the Ji study was the Boston Birth Cohort (a research initiative that has cropped up before on this blog) and specifically the examination of blood lead levels in conjunction with "physician-diagnosed ADHD" in some 1500 infants: "299 ADHD, 1180 neurotypical." Various other co-variates were also included in the statistical mix and sex/gender was analysed as an independent variable. And before you mention it, yes, as per my other musings on the word 'neurotypical' in the context of autism (see here), I'd prefer another term to denote not-ADHD such as er, 'not-ADHD'.

Results: approaching 1 in 10 of the cohort had elevated blood lead levels defined as a value between 5-10 µg/dL. This is quite worrying, particularly as various agencies have started to reduce the cut-offs/definition of a 'safe' level of lead in recent years (see here). For the 8.9% of the cohort with such blood lead levels, authors noted that this was "associated with a 66% increased risk of ADHD." Boys also seemed to be particularly vulnerable to the effects of elevated blood lead levels in relation to ADHD: "Among boys, the association was significantly stronger."

What else?  Well, bearing in mind the observational methodology employed in the Ji study, authors noted that the relationship between blood lead levels and ADHD also seemed to be mediated by other factors. So, the "risk of ADHD in boys was reduced by one-half if the mother had adequate high-density lipoprotein levels or low stress" where high-density lipoprotein (HDL) typically refers to the 'good type of cholesterol' (bearing in mind that biology is rarely so black-and-white) and 'low stress' refers to stress during pregnancy. In effect, whilst early lead exposure (or blood lead levels) may be important when it comes to risk of ADHD, other factors also seem to play a role; some potentially protective, others not so much (see here for example). This is something that has been noted in other studies looking at other heavy metals and neurodevelopmental outcomes (see here).

In conclusion, still nothing good comes from (early) exposure to lead...

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[1] Ji Y. et al. A Prospective Birth Cohort Study on Early Childhood Lead Levels and Attention Deficit Hyperactivity Disorder: New Insight on Sex Differences. J Pediatr. 2018 May 8. pii: S0022-3476(18)30488-8.

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ALSPAC does... prenatal mercury exposure and autism or autistic traits

The ALSPAC - Avon Longitudinal Study of Parents and Children - mentioned in the title of this post is something of quite a regular feature on this blog (see here and see here for examples).

On this particular blogging occasion I'm heading into the findings reported by Jean Golding and colleagues [1] who utilised this fabulous research resource to examine whether "prenatal exposure from total maternal blood Hg [mercury] in the first half of pregnancy is associated with the risk of autism or of extreme levels of autistic traits." They concluded that there were "no adverse effect of prenatal total blood Hg on autism or autistic traits provided the mother ate fish."

OK, mention of the heavy metal mercury in the context of autism and/or autistic traits can be a touchy subject for some. I'm talking about the various 'discussions' that have taken place both in the lay and peer-reviewed science arenas concerned with the exposure patterns relevant to mercury in the context of autism (see here and see here). This, on the basis that mercury exists in several 'forms', and those different forms have different potential exposure routes.

Golding et al relied on some of the gold-standard analytical methods for the analysis of whole blood Hg collected in the most part "at < 18 weeks gestation": "inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS)." Variations on this method - ICP mass spectrometry - have been previously reported on in the context of mercury and autism research (see here and see here). Alongside, they looked at measured levels of mercury in relation to various behavioural and other variable groupings: "(1) direct comparison of 45 pregnancies resulting in children with diagnosed autism from a population of 3840, (2) comparison of high scores on each of the four autistic traits within the population at risk (n~2800), and (3) indirect measures of association of these outcomes with proxies for increased Hg levels such as frequency of fish consumption and exposure to dental amalgam (n > 8000)." They however cautioned that: "Although we accounted for several important confounders which are relevant to Hg levels and autism, the possibility of unmeasured confounding cannot be ruled out." I can think of one potential confounder that was not seemingly included in their list outside of fish consumption and dental amalgams but ho-hum...

Alongside their overall 'no relationship' results, a few other details are noteworthy. First: "all correlations indicated that with increasing levels of [maternal] mercury, the signs of autism [in offspring] were slightly less, but none were statistically significant." Interesting idea - higher maternal levels of mercury during pregnancy 'correlates' with 'less' autistic traits in offspring in childhood - but to reiterate, not statistically significant. Second was that 'provided the mother ate fish' detail attached to the main findings. So: "we have shown a differential relationship between the social cognition trait and prenatal Hg exposure, such that there was a significant difference in apparently protective effects contingent upon whether the mother ate fish." The authors opine as to what it is about fish consumption that might "counteract any possible adverse cognitive and behavioral differences that may be caused by prenatal exposure to Hg" including "the beneficial components of fish such as the omega-3 fatty acids, iodine, and vitamins D and B2." This in the context that omega-3 fatty acids have some research form in relation to autism (see here) as does the sunshine vitamin/hormone that is vitamin D (see here).

One has to be slightly careful with the Golding results given the focus on prenatal exposure, and prenatal exposure at only one early point in pregnancy, as well as also not actually looking at mercury levels in the children themselves. The current results say nothing for example, about any possible direct or acquired role for mercury in relation to autism as per other findings published during the same period [2]. Neither do they offer any additional information on the idea that exposure issues to such heavy metals may be only one part of the story, and that the biological processes involved in removing such heavy metals may be somehow perturbed in relation to some autism (see here).

But... set within the idea that prenatal mercury exposure may be linked to the 'etiology' of at least some autism, the Golding findings represent pretty strong evidence suggestive of no connection.

Music to close, and could I recommend the soundtrack to Sonic 3 while you work?

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[1] Golding J. et al. Prenatal mercury exposure and features of autism: a prospective population study. Molecular Autism. 2018; 9: 30.

[2] Qin YY. et al. A comparison of blood metal levels in autism spectrum disorder and unaffected children in Shenzhen of China and factors involved in bioaccumulation of metals. Environ Sci Pollut Res Int. 2018 Apr 22.

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Immunoadsorption and ME/CFS: observations from a small proof of concept study

Immunoadsorption refers to "an alternative blood purification technique... used to eliminate pathogenic antibodies." I'll freely admit that I don't know an awful lot about this procedure, so approach the findings reported by Carmen Scheibenbogen and colleagues [1] with a degree of naivety with regards to 'usefulness' and also important issues such as safety.

Authors report preliminary findings from their 'proof of concept' study, using immunoadsorption (IA) on a small group of adults (N=10) diagnosed with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS / ME) who also presented with "infection-triggered disease onset, disease severity according to the Bell scale of ≤ 50 of 100, and elevated levels of ß2 antibodies." The Bell scale by the way, seems to refer to a scale developed by David Bell with scores ranging from 0 to 100 to denote fatigue symptoms, post-exertional malaise (PEM) and 'ability to work full-time'. A lower score denotes more severe symptoms. The description "elevated levels of ß2 antibodies" refers to antibodies against ß2 adrenergic receptors; receptors which are found throughout the body and are involved in various biological tasks including smooth muscle relaxation and regulating certain cardiac functions. As the authors note: "Antibodies to ß2... receptors had been reported in various other diseases including dilatative cardiomyopathy, postural tachycardia, regional pain syndrome, Alzheimer, Sjögren’s syndrome, asthma and others." The 'antibodies' bit implies that the body is failing to recognise these receptors as 'self' and instead wrongly mounts an immune response against them.

Scheibenbogen et al mention that during their other studies on ME/CFS [2] they noted "a sustained decline of pretreatment elevated ß2 antibody levels in clinical responders to rituximab treatment." The rituximab bit refers to some initially encouraging results [3] from the use of this treatment that, unfortunately, do not seem to have weathered more rigorous scientific scrutiny (see here). Authors further hypothesised that IA might be a route to "removing autoantibodies" and specifically those "elevated antibodies against β2."

Results: "Prior to IA all patients had elevated antibodies against β2, in addition 7 patients against ß1 adrenergic receptors and 6 patients against both M3 and M4 acetylcholine receptors." Autoantibodies in many of the participants included for study went beyond just those against β2.

Following quite a few cycles of IA - "IA was conducted in 5 cycles on days 1–3 and 6–7 with 2 to 2.5-fold plasma volume filtered" - authors reported that: "Levels of ß2 adrenergic antibodies were low to undetectable in 9 of 10 patients." This is kinda what would be expected following IA (bearing also in mind that: "After the 5th IA cycle all patients received 25 g IgG i.v." also known as IVIG).

Insofar as the clinical course of participants' presented symptoms, well, it was a bit of a mixed bag. So: "A rapid improvement of several symptoms was reported by 7 of these 9 patients during IA. However, none of the patients completely recovered and 5 patients had worsening of fatigue towards the end of treatment despite improvement of other symptoms." I'm happy to report that the authors did utilise the wonderful technology headed under the term actigraphy (activity monitoring) as per their assessing participants step counts "by a Vivofit activity tracker." Such objective activity monitoring is sadly lacking from many other studies on ME/CFS (see here for example). Again however, the step counts reflect an initial 'good start' for IA followed by a not-so-good finish...

"Taken together, this pilot study provides evidence that IA can effectively remove ß2 and M3/M4 autoantibodies in CFS/ME and can result in rapid moderate to marked symptom improvement." I wouldn't disagree with the authors' conclusions but would perhaps suggest that the current results as they stand don't yet provide authoritative evidence for a beneficial effect of IM in the longer term. More [controlled] study is required.

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[1] Scheibenbogen C. et al. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS One. 2018 Mar 15;13(3):e0193672.

[2] Loebel M. et al. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. 2016; 52: 32-39.

[3] Fluge Ø. et al. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS One. 2015 Jul 1;10(7):e0129898.

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Mercury levels and autism meta-analysed

"Indeed, if someone is looking for yet another systematic review and meta-analysis topic, there you go - you're welcome." Those are my words on a previous blogging occasion earlier this year discussing yet another peer-reviewed article on the topic of heavy metals and autism (see here). The findings reported by Tina Jafari and colleagues [1] have seemingly done just that with their meta-analysis of the collected science literature up to June 2017 looking at assessing the "relationship between ASD [autism spectrum disorder] and mercury levels in hair, urine, blood, red blood cells (RBC), and brain."

OK, I know that mention of mercury in the context of autism can be a bit of hot potato in terms of the different types of mercury and their potential sources (see here). I don't want to get into any specific debates on wheres-and-hows in this post but rather focus on what the peer-reviewed science currently says (see here). Jafari et al describe how from the 40+ articles they included for analysis, several themes emerged: (1) blood and brain levels of mercury seemed to be generally elevated in cases of autism vs. controls, and (2) hair levels were typically lower in autism vs controls. Urinary mercury levels were described as "not significantly different" comparing autistic and non-autistic groups although I'll draw your attention to some 'technical talk' in this area that could potentially affect any results produced (see here).

The authors go on to talk about how "detoxification and excretory mechanisms are impaired in ASD patients which lead to accumulation of mercury in the body" which - minus sweeping generalisations - is a conclusion that I've pretty much settled on when talking about some of the findings in this area down the years. There are likely many mechanisms involved in the removal of heavy metals such as mercury from the body but one group in particular, the intersecting "redox and methylation" pathways [2] stand out in view of other research on glutathione levels and autism for example (see here). Other research has pointed to other biological mechanisms that may be worth research consideration [3].

What can and should be done in this area? Well minus any medical or clinical advice given or intended, there are protocols in place as and when mercury poisoning is diagnosed in the general population. There is no reason to assume that these same protocols shouldn't be followed if and when mercury poisoning is diagnosed alongside autism or ASD save any further health inequalities appearing. Autism science needs to also continue it's interest in this area and perhaps make move towards what can be done for example, to 'prop up' biological mechanisms that aid in the detoxification of things like mercury. This may take the form of some rather peculiar research directions (see here) but nonetheless is an area that could potentially be important. Finally, there is the idea that if there are biological issues associated with the removal of several heavy metals including mercury in cases of autism, greater focus on 'avoidance' might also be important. I say this on the basis of findings such as those by Jia Ryu and colleagues [4] who for example, observed that "blood mercury levels at late pregnancy and early childhood were associated with more autistic behaviors in children at 5 years of age." Yes, correlation is not the same as causation, but can we/should we take the chance that the two are connected particularly knowing how detrimental heavy metals can be to human health?

Music to close: Ain't That A Shame by Fats. RIP.

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[1] Jafari T. et al. The association between mercury levels and autism spectrum disorders: A systematic review and meta-analysis. J Trace Elem Med Biol. 2017 Dec;44:289-297.

[2] Hodgson NW. et al. Decreased glutathione and elevated hair mercury levels are associated with nutritional deficiency-based autism in Oman. Exp Biol Med (Maywood). 2014 Jun;239(6):697-706.

[3] Gump BB. et al. Background lead and mercury exposures: Psychological and behavioral problems in children. Environmental Research. 2017; 158: 576-582.

[4] Ryu J. et al. Associations of prenatal and early childhood mercury exposure with autistic behaviors at 5 years of age: The Mothers and Children's Environmental Health (MOCEH) study. Science of The Total Environment. 2017; 605-606: 251-257.

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Quarter of kids with autism with iron deficiency but...

Iron (Fe) is something that I've always been a little bit interested in on this blog with specific regards to autism (see here). Outside of the typical 'helping to produce red blood cells' bit, I've always been intrigued by the potential behavioural and cognitive effects following issues with suitable iron supplies. My particular interest in an enzyme that relies on iron as a co-factor (see here) is also worthwhile noting...

A new paper by Serkan Gunes and colleagues [1] (open-access) continues the important theme of iron and autism suggesting that various iron-related parameters might be sub-optimal in relation to the autism spectrum but also with a possible confounding effect of comorbidity in relation to the presence of iron deficiency anemia (IDA) and autism.

Looking at 100 children and young adults diagnosed with an autism spectrum disorder (ASD) and 100 not-autism (I hate the term "healthy controls") controls, researchers surveyed both blood samples and behaviour using a variety of measures. Alongside just having a diagnosis, participants with autism were also subject to various measures covering autistic behaviours, "intellectual evaluation" and various behavioural schedules in-between. Various iron-related parameters were studied: serum ferritin ("as an indicator for ID [iron deficiency] since it is a precursor for ID and represents iron levels in body tissues including brain") and then hemoglobin, hematocrit, iron, ferritin, MCV (mean corpuscular volume), and RDW (red blood cell distribution width).

Results: as per the title of this blog post, 25% of participants fell into the range of iron deficiency (ID). Perhaps a little more seriously, some 13% also presented with iron deficiency anaemia (IDA). This compared with 15% and 6% of the control group respectively. The 'but...' in the title of this post reflects the fact that saying a quarter of children with autism might have ID sounds dramatic but perhaps not so dramatic when it compares with that 15% of controls; hence the lack of significant difference between the groups. Having said that, it is worthwhile noting that controls in this study were not necessarily children and young adults just plucked at random: "For the control group, 100 children (an equal number with patients), who referred to the department [child and adolescent psychiatry department] for counseling about child development, school adjustment and performance, teenage problems, family and friend relations, were recruited."

Then: "Hemoglobin, hematocrit, iron, and MCV (p < 0.05) levels were found to be lower in children with ASD."

Finally, taking into account age (comparing those with autism under 6 years (n=46) with those over 6 years (n=54)) and the presence of learning (intellectual) disability (n=58) vs. those with none (n=42) and autism severity (mild-moderate ASD (n=50) vs. severe ASD (n=50)), some other interesting trends were observed. "Hemoglobin, hematocrit, and MCV (p < 0.05) levels were found to be significantly lower in preschool ASD patients" and "Hemoglobin and hematocrit (p < 0.05) levels were significantly lower in ASD patients with intellectual disability."

What can we conclude from the Gunes paper? Well, I don't want to belittle the various issues with iron detected in either group included for study. If ID or more seriously IDA is detected, remedial measures need to be adopted to correct such issues irrespective of a diagnosis of autism or anything else. Insofar as the relationship(s) between iron parameters and autism, the Gunes papers reiterates that this is likely to be complex and not necessarily just exclusive to autism. Perhaps the most accurate thing I can say is that yet again, a diagnosis of autism or ASD is seemingly protective against nothing when it comes to comorbidity and [preferential] screening is once again implied. Oh, and when it comes to trying to predict those people on the autism spectrum who might be at greatest risk of iron deficiency et al, the findings published by Sidrak and colleagues [2] offer some possible variables: "problems sucking, swallowing or chewing...; poor eating behaviour...; and inadequate amounts of meat, chicken, eggs or fish."

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[1] Gunes S. et al. Iron deficiency parameters in autism spectrum disorder: clinical correlates and associated factors. Italian Journal of Pediatrics. 2017; 43: 86.

[2] Sidrak S. et al. Iron deficiency in children with global developmental delay and autism spectrum disorder. J Paediatr Child Health. 2014 May;50(5):356-61.

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Blood heavy metal levels and autism (yet again)

"Data showed that the children with ASD [autism spectrum disorder] had significantly (p < 0.001) higher levels of mercury and arsenic and a lower level of cadmium."

And... "It is desirable to continue future research into the relationship between ASD and heavy metal exposure."

Those sentences come from the study by Huamei Li and colleagues [1] continuing a research theme regarding (generally) elevated levels of heavy metals being detected in those on the autism spectrum (see here). Yes, I know that this kind of research is not always met with great appreciation (see here) but the suggestion that the heavy metal burden seems to be quite a bit higher in the autistic population is not something that can just be ignored. More so when it might actually be treatable (with no medical or clinical advice given or intended)...

There are numerous other examples in the peer-reviewed science literature that I could give where the heavy metal burden has been found to be elevated in relation to autism. Indeed, if someone is looking for yet another systematic review and meta-analysis topic, there you go - you're welcome. Personally, I think we've reached the point where the questioning needs to move on to (a) the possible sources of those heavy metals and (b) whether 'exposure amount' is the sole reason for the elevations in relation to autism over and above issues with the biology around 'detoxifying' said metals. Answers are not likely to be simple but questioning has to continue...

To close, he was always my favourite James Bond...

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[1] Li H. et al. Blood Mercury, Arsenic, Cadmium, and Lead in Children with Autism Spectrum Disorder. Biol Trace Elem Res. 2017 May 8.

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Li H, Li H, Li Y, Liu Y, & Zhao Z (2017). Blood Mercury, Arsenic, Cadmium, and Lead in Children with Autism Spectrum Disorder. Biological trace element research PMID: 28480499

Folate-dependent one carbon metabolism and transsulfuration pathways: biomarkers for autism?

I found it a little unusual that the findings reported by Daniel Howsmon and colleagues [1] (open-access) talking about "multivariate statistical analysis presented herein [provided] unprecedented quantitative classification results for separating participants into ASD [autism spectrum disorder] and NEU [neurotypical] cohorts based solely on biochemical data" merited a rapid reply in a prominent science magazine pouring cold water on the results (see here). Not least because one of the commentators interviewed in said science magazine article is also not seemingly immune when it comes to sweeping claims being made on the basis of preliminary research findings about autism (see here as per the previous headline: 'Super-parenting' improves children's autism).

No mind, the Howsmon paper - including a notable research name on the authorship list - mentions a few important compounds and biological processes in their discussions on: "Stepping towards this goal of incorporating biochemical data into ASD diagnosis." The sorts of things covered included various biological 'markers' pertinent to folate-dependent one-carbon metabolism (FOCM) and transsulfuration (TS) some of which have been fodder for this blog previously (see here and see here for examples). Researchers looked at these various compounds in blood samples from some 80 children diagnosed with an ASD and compared levels with 47 siblings and 76 age-matched controls. They applied some nifty statistics to try and determine whether any combination of the 24 analytes examined might be potential biomarker-material for an autism diagnosis. You'll note that once again the quite problematic binary description of 'neurotypical' was used to define 'not-autism' leading onwards to the inevitable questions: 'what is neurotypical?' and 'what are the boundaries of being neurotypical?' Sensible [evidence-based] answers on a postcard please.

Results: "FDA [Fisher Discriminant Analysis] on seven metabolites allows sufficient separation such that a linear classifier can correctly resolve 96.9% of participants." But actually this was not the whole story as the authors also report that five compounds/variables - GSSG, tGSH/GSSG, Nitrotyrosine, Tyrosine, and fCysteine - provided the best 'fit' when it came to potentially picking out children with autism. You might note that some of those 'famous five' have some autism research history (see here). The authors similarly note that: "these variables are affected by high quality vitamin supplementation that also decreases ASD severity in at least a subset of cases." Mmm.

There is definitely more science to do in this area. Biomarkers in relation to autism have come and gone down the years (see here for example) and I'm not altogether sure that using the label 'autism' as a starting point for this kind of research is necessarily the best idea (see here). Outside of just the heterogeneity and plurality - the autisms - associated with the label autism, there are other considerations to take on board such as the impact of all that over-represented comorbidity too (something that continues to 'mess around' with various 'autism is linked to..' studies).

But that shouldn't stop further efforts in this area including those also looking to expand into the 'genetics' of folate metabolism alongside the biochemistry, as per everyone's favourite scrabble word 'MTHFR' (see here) and its [meta-analysed] potential contribution to some autism. I agree that we are not quite there when it comes to folate metabolism as providing a generic biomarker or set of biomarkers for autism, but there again, the authors never said that it definitively did: "it should be noted that these studies should be replicated and empirically tested on a wider scale before more definite conclusions can be drawn." Too true but the Howsmon results represent an interesting first attempt...

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[1] Howsmon DP. et al. Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS Comput Biol. 2017 Mar 16;13(3):e1005385.

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Howsmon DP, Kruger U, Melnyk S, James SJ, & Hahn J (2017). Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS computational biology, 13 (3) PMID: 28301476

Hyperuricemia present in both medicated and unmedicated kids with autism

I was intrigued to read the findings reported by Natchaya Vanwong and colleagues [1] talking about the presence of hyperuricemia - an excess of uric acid in the blood - in their cohort of children and young adults diagnosed with an autism spectrum disorder (ASD). Intrigued not only because the authors discuss how the use of the atypical antipsychotic risperidone might *correlate* with elevations of uric acid but also how: "Hyperuricemia was present in 44.70% of risperidone-naïve patients with ASD."

Uric acid, more readily associated with the condition gout, has been mentioned before on this blog in the context of autism (see here) and other conditions/states (see here) not totally unfamiliar to autism. It's therefore not necessarily new news that elevations of the stuff might have been found again. The Vanwong study looked at uric acid levels in "127 children and adolescents with ASD treated with risperidone and 76 age-matched risperidone-naïve patients with ASD" alongside a few other biological parameters. They concluded that yes, quite a few participants in their cohort presented with hyperuricemia "defined as the level of uric acid concentration in the blood >5.5 mg/dL" bearing in mind no 'not-autism' control group was included for direct study (including those not diagnosed with autism but in receipt of risperidone).

Implications following the Vanwong study? Well, bearing in mind that gout is traditionally seen as a disease of middle-to-older age, the first thing would be to screen for gout in those with high uric acid levels and keep monitoring just in case gout develops. Next up would be to perhaps also look at some of the "rare inherited genetic disorders that cause hyperuricemia" and whether they might 'overlap' with the presentation of autism; y'know in the context that 'autism genes are probably not just genes for autism' and all that. At this point, I'm also minded to remind readers of the important (but often forgotten work) by Mary Coleman and Ted Page [2] on the topic of autism and uric acid, bringing in purine metabolism 'issues' as something potentially important to some autism (uric acid comes about as a consequence of the metabolism of purines). This, in the context of the autisms (plural)...

Insofar as the potential correlation posed between uric acid and risperidone usage, a word of caution is perhaps warranted but big words about 'risperidone causing hyperuricemia' are not required at this point in time without further study. Remember: "Hyperuricemia was present in 44.70% of risperidone-naïve patients with ASD and 57.50% of ASD patients treated with risperidone." I say this mindful that there are biological parameters that do need careful inspection when such antipsychotic therapy is put in place (see here) but the data is not yet so convincing when it comes to uric acid elevations and risperidone use.

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[1] Vanwong N. et al. Hyperuricemia in Children and Adolescents with Autism Spectrum Disorder Treated with Risperidone: The Risk Factors for Metabolic Adverse Effects. Front. Pharmacol. 2017. 5 Jan.

[2] Page T. & Coleman M. Purine metabolism abnormalities in a hyperuricosuric subclass of autism. Biochim Biophys Acta. 2000 Mar 17;1500(3):291-6.

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Vanwong N, Srisawasdi P, Ngamsamut N, Nuntamool N, Puangpetch A, Chamkrachangpada B, Hongkaew Y, Limsila P, Kittitharaphan W, & Sukasem C (2017). Hyperuricemia in Children and Adolescents with Autism Spectrum Disorder Treated with Risperidone: The Risk Factors for Metabolic Adverse Effects. Frontiers in pharmacology, 7 PMID: 28105014

"no evidence that the probiotic formulation is effective in treating low mood"

I'm a great believer in balance when it comes to this blog and its content. As enthusiastic as I might be about a particular topic or topics, I don't want to lose sight of the fact that peer-reviewed science is a messy business and often filled with contrary findings.

With 'contrary' in mind, I want to talk today about a paper by Amy Romijn and colleagues [1] detailing the results of a double-blind, randomised, placebo-controlled trial of a probiotic mix which contained "freeze-dried L. helveticus R0052 (strain I-1722 in the French National Collection of Cultures of Microorganisms [CNCM], Institut Pasteur, Paris, France) and B. longum R0175 (CNCM strain I-3470) bacteria at a dosage of three billion colony-forming units (⩾3 × 109 CFU) per 1.5 g sachet" with a sample of participants selected for 'low mood'. Probiotics, just in case you don't know, are those various live bacteria and yeasts that are supposed to confer some health benefit.

The reason for this study? Well, as the authors note, the specific probiotics under study were "previously found to improve emotional behaviour in animals and psychological outcomes and humans" as per other findings [2]. So with [prospective] trial registration (see here) in hand, researchers set out to look at what 8 weeks worth of probiotics might do for 'low mood' and other psychological parameters when pitted against a placebo formulation (that contained only the excipients included in the probiotic formulation). Blood samples were also provided by participants at baseline (before intervention) and at 8 weeks post-intervention "to measure levels of high-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6, TNF-α, vitamin D and BDNF."

Results: "Intent-to-treat analysis (n = 79) showed no significant group differences on any outcome measure." The scores for the groups - probiotic (n=40) & placebo (n=39) - did not seem to differ significantly on any of the measures used during the trial. Indeed, when taking into account individual scores on the primary outcome measures called the Montgomery–Åsberg Depression Rating Scale (MADRS) - something used to measure "the severity of depressive episodes" - the results actually (non-significantly) seemed to favour the placebo in terms of those who "showed a ⩾60% change on the MADRS (responders)."

Insofar as adverse effects, well taking this probiotic probably won't do any harm if we rely on the Romijn findings, as authors describe "three serious adverse events over the course of the trial, all of which were suicide attempts by one participant from the placebo group. There were no serious adverse events in the probiotic group."

But all was not completely negative when it came to the trial as a little gem was potentially uncovered: "Among those randomized to the probiotic group, those who had high vitamin D at baseline showed greater improvement in mood and functioning than those who had low vitamin D at baseline." Without trying to make mountains out of molehills, the authors speculate that: "the vitamin D status of the host could have an effect on the relationship between the gut microbiota and the immune system: low vitamin D could limit response to probiotic treatment as any changes to the microbiome composition would not necessarily be translated to the immune system." A rather interesting sentiment given the increasingly vocal link between vitamin D and depression for example in the research literature (see here).

These results do represent a bit of a set-back for the idea of psychobiotics [3] but I'm not ready to poo-poo the whole area just yet. Among the various caveats raised by the study authors (samples size, length of intervention, etc) it is possible that 'low mood' over and above something a little more clinically 'transforming', might not be a suitable target for such intervention (indeed, other research might also be relevant [4]) despite the fact that other research on subclinical psychological symptoms have been seemingly affected by probiotic administration (see here). The specific formulation used might also be a factor as the authors quite correctly suggest that: "It is important that the results of the current study are not generalized to all potential probiotic strains." Baby and bathwater eh?

But these results stand, and given some important names on the authorship list (see here), this is one study that cannot and should not be just swept under the scientific carpet...

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[1] Romijn AR. et al. A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. Aust N Z J Psychiatry. 2017 Jan 1:4867416686694.

[2] Messaoudi M. et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011 Mar;105(5):755-64.

[3] Dinan TG. et al. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013 Nov 15;74(10):720-6.

[4] Kleiman SC. et al. The Gut-Brain Axis in Healthy Females: Lack of Significant Association between Microbial Composition and Diversity with Psychiatric Measures. PLoS One. 2017 Jan 19;12(1):e0170208.

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Romijn AR, Rucklidge JJ, Kuijer RG, & Frampton C (2017). A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. The Australian and New Zealand journal of psychiatry PMID: 28068788

ADHD and vitamin levels

"ADHD [attention-deficit hyperactivity disorder] patients were overrepresented in the group with low levels of some vitamins, possibly indicative of inadequate dietary intake of these micronutrients in a subgroup of patients. It is important to identify these patients in dietary intervention trials of ADHD."

So said the study findings reported by Elisabeth Toverud Landaas and colleagues [1] (open-access) providing some potentially important data on how nutritional factors might intersect with the diagnosis of ADHD. So: "Owing to the important and neurologically relevant functions of vitamins and the lack of studies exploring this topic in ADHD, we measured serum levels of the major vitamin classes in a sample of adult ADHD patients and controls to determine whether vitamin levels are associated with ADHD diagnosis and psychiatric symptoms." Said participants (n=133) were young adults and most were listed as having ADHD according to a "Norwegian national registry of adult ADHD patients." Vitamin levels were assessed from blood samples and compared with results for 131 control participants as per other studies on this cohort from this authorship group [2]. It's worth pointing out that samples were in deep freeze storage for between 2-9 years between collection and thawing for analysis.

Various vitamins were measured in those samples (vitamins A, B6, , B9, B12 and D to name a few) alongside levels of cotinine "to assess [tobacco] smoking status." The analytical assay(s) of choice was, in the most part, a familiar one to this blog: liquid- or gas chromatography-tandem mass spectrometry.

Results: "The concentrations of vitamins B2, B6 and B9 were all significantly lower in the ADHD group." When results were analysed according to percentiles based on blood levels of the various vitamins results similarly showed that those with ADHD were 'over-represented' in the lower levels bandings of those previously described vitamins. Smokers, as defined by a "widely used cut-off of 80 nmol/L" of blood cotinine, were also over-represented in the ADHD group (66%) compared with control participants' samples (12%). The authors reported that: "vitamin B6 and B9 levels were significantly higher in non-smoking ADHD patients compared with smokers" suggesting that lifestyle choices may play a role in some of the results obtained. Finally, when it came to looking at any possible association(s) between measured vitamin levels and behaviours pertinent to ADHD (derived from responses to the Adult ADHD Self-report Scale (ASRS), the authors report some preliminary observations but I'd like to see a little more data before anything further is made of this.

These are interesting results (aren't they always!). I note that the authors make reference to the findings reported by Julia Rucklidge and colleagues on a vitamin-mineral mix for ADHD (see here) and the idea that correcting vitamin deficiencies might have effects beyond just the somatic. There are however caveats to the latest results: "The reason why we observed association between lower levels of some vitamins and ADHD is uncertain and probably multifactorial. Regrettably, we do not have information on lifestyle and nutrient intake from the participants to help in the interpretation of our observations. It is reasonable to think that differences in dietary factors may partly be responsible for the differences." Indeed.

There is also one final observation to touch upon in the Landaas results concerning the vitamin/hormone of the hour: vitamin D. Although there was no overall difference in vitamin D concentrations in the ADHD and not-ADHD group samples, the authors did observe that: "for vitamin D, ADHD patients were significantly overrepresented both in the lowest and highest 10th percentile groups." Bearing in mind past research has suggested that ADHD might be yet another diagnosis/label where vitamin D deficiency might be a feature (see here) it is pertinent that the authors suggest: "One reason for the overabundance of ADHD patients in the highest 10th percentiles of vitamin D may thus be that relatively more ADHD patients take vitamin D supplements, either as part of an experimental treatment of symptoms or as a consequence of a diagnosed vitamin D deficiency."

Finally: "It is possible that low levels of certain vitamins may contribute to ADHD symptoms. Dietary intervention trials have shown promising effects in ADHD. Thus, identification and correction of low vitamin levels could be beneficial in treatment of ADHD. Further studies are warranted for replication and for examination of the underlying mechanisms."

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[1] Landaas ET. et al. Vitamin levels in adults with ADHD. BJPsych Open. 2016 Dec 13;2(6):377-384.

[2] Aarsland TI. et al. Serum concentrations of kynurenines in adult patients with attention-deficit hyperactivity disorder (ADHD): a case-control study. Behav Brain Funct. 2015 Nov 5;11(1):36.

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Landaas ET, Aarsland TI, Ulvik A, Halmøy A, Ueland PM, & Haavik J (2016). Vitamin levels in adults with ADHD. BJPsych open, 2 (6), 377-384 PMID: 27990293