SHANK3, gut issues and (mouse) autism continued

"We conclude that apart from its well-known role in the CNS [central nervous system], SHANK3 plays a specific role in the GI [gastrointestinal] tract that may contribute to the ASD [autism spectrum disorder] phenotype by extracerebral mechanisms."

So said the findings reported by Ann Katrin Sauer and colleagues [1], and yet more evidence that issues with SHANK3 mentioned in relation to 'some' autism, may well (partly) explain much more than just behaviour (see here and see here).

The Sauer study was yet another mouse study. They specifically focused on the "Shank3αβ KO" mouse, where KO means knock-out, referring to the engineering of this mouse strain to mimic issues with the functioning and availability of SHANK3, "a known scaffolding protein of the postsynaptic density (PSD) of glutamatergic excitatory synapses." Said knock-out mice have been "reported to display ASD-like behavior with abnormal ultrasonic vocalization, repetitive self-grooming, and reduced interest in novel mice." I say this being careful to reiterate that we're talking about a mouse not human beings (see here).

On the basis of the observation that SHANK3 is expressed in the gut as well as brain and that GI issues are no stranger to autism (see here), researchers set about looking at how SHANK3 issues might also manifest as gut issues, and what this *could* mean for some autism. They observed some interesting things:

• "analysis of the GI tract of Shank3αβ KO mice revealed significantly altered gut morphology" which included, among other things, increased levels of ZONULIN1 ("a modulator of tight junctions and alterations"). Zonulin is something that I'm particularly interested in on this blog (see here and see here) on the basis of its *connection* to intestinal barrier function and the misnomer that is 'leaky gut' (see here).
• "The Microbiome of Shank3 KO Mice Is Altered." Bearing in mind the increasing importance of the gut microbiome to autism (see here), researchers reported some interesting difference between "Shank3αβ KO mice" and controls with regards to several different bacterial species. 
• Researchers describe how those gut morphology and gut bacterial differences seemed to be linked to alterations in the "expression of inflammatory markers" too as they talked about "signs of increased immune activation in the periphery and the brain." A familiar cytokine is mentioned - IL-6 - and quite a few avenues for further investigation.

The net result of all this work is to say that, yes, the SHANK3 mouse model *potentially* mimicking some of the behavioural signs and symptoms of autism does also appear to show some significant gut-related issues. No, this does not directly translate into issues for 'all human autism', but it does add further credence to the idea that the gut-brain axis is likely important to at least 'some autism'. Where also SHANK3 issues are identified as coinciding with 'human autism', one might also entertain the idea that gut issues should be screened and treated/managed. And there might be lots of ways to manage them (see here for one example)...

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[1] Sauer AK. et al. Altered Intestinal Morphology and Microbiota Composition in the Autism Spectrum Disorders Associated SHANK3 Mouse Model. Int. J. Mol. Sci. 2019; 20: 2134.

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A test "that distinguishes ASD fast response constipation from ASD persistent right-sided constipation"?

The quote heading this post - "A test that distinguishes ASD [autism spectrum disorder] fast response constipation from ASD persistent right-sided constipation" - comes from the findings reported by Stephen Walker and colleagues [1]. The Walker results continue a theme from this research group (see here) whereby some important data is being generated on how to treat some fairly prevalent bowel issues that seem to accompany quite a few diagnoses of autism (see here).

Much like other research from this authorship group, the research material examined was biopsy tissue - "ascending colon biopsy tissues" - provided by 35 children diagnosed with an autism spectrum disorder "and chronic constipation on a background of enterocolitis." I know some people don't like the word 'enterocolitis' in the context of autism (see here) but prejudices aside, there is nothing in the current research literature to suggest that a diagnosis of autism is somehow protective against the development of inflammatory bowel disease and/or its symptoms. Nothing.

Anyhow, 20 of those 35 children were categorised as 'slow responders' on the basis of showing "recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis" and 15 were defined as 'fast responders' as a function of experiencing "a sustained state of GI [gastrointestinal] symptomatic remission while on maintenance anti-inflammatory therapy." In effect the group was divided up into those whose bowel symptoms got better (n=15) and those whose bowel symptoms did not (even after multiple attempts) (n=20). Researchers analysed those biopsy samples with the expression of genes in mind as per other research occasions [2].

Results: "Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction)." Apologies for the long quote taken from the Walker paper, but they said it better than I ever could. The translation: gene expression data was different between the fast and slow responder groups.

Obviously more research is needed in this area with larger participant groups and perhaps using samples from other non-autism groups who present (or don't) with various types of bowel issues, whether sensitive to treatment or not. The cluster of genes that were used in the authors' modelling did all right when it came to talk of possible 'biomakers' - "The sensitivity (sensitivity = 0.88), specificity (specificity = 0.89), and kappa (kappa = 0.77) statistics all reflect a good strength of agreement between prediction and actual assignments" - but still need more work before any big claims are made.

There are a couple of other things to mention from the Walker results. So, results suggested that: "predominantly chronic constipation in fast responders is not only related to the inflammatory status of the right colon but is likely a direct consequence of this colonic inflammation." Inflammation perhaps equalling constipation? Interesting. And it not only offers lots more avenues for further study but also some important treatment options.

Next, the amino acid tryptophan was singled out as being potentially "especially significant." I've always been interested in the aromatic amino acids in relation to some autism (see here). Tryptophan is a particularly important aromatic amino acid because it's eventually metabolised into a whole slew of important compounds from serotonin (5-HT) to melatonin and beyond, with some interesting connections to autism (see here). Walker and colleagues mention how: "In the slow responder cluster of patients, there was a significant upregulation of transcripts in each of the metabolic degradation pathways for tryptophan, serotonin, and melatonin, suggesting that TRP [tryptophan] insufficiency (and therefore 5-HT insufficiency) may be an important factor in the sustained hypomotility seen in this patient cohort." There's some much more study that one could do in this area. Particularly when 'gut hypomotility' is a potential issue for quite a few people on the autism spectrum (see here).

There are other things to consider from the Walker paper - "A third relevant theme apparent from the slow response gene expression profile involves a number of pathways that converge in the mitochondria and impact mitochondrial function" - but I'll leave that for now (see here). Suffice to say that there is enough evidence emerging in the peer-reviewed domain to say that (a) pathological bowel problems are more than present alongside a diagnosis of autism, (b) said bowel issues also overlap with functional GI symptoms such as constipation in particular, (c) there are physiological reasons for such bowel issues outside of any psychobabble explanations, and (d) lots more research is required in this area without fear or favour pertinent to improving quality of life...

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[1] Walker SJ. et al. A molecular biomarker for prediction of clinical outcome in children with ASD, constipation, and intestinal inflammation. Sci Rep. 2019 Apr 12;9(1):5987.

[2] Walker SJ. et al. A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis. Sci Rep. 2016 Oct 21;6:35820.

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"Maternal infection during pregnancy may be responsible for some portion of autism..."

The quote heading this post - "Maternal infection during pregnancy may be responsible for some portion of autism..." - comes from the paper published by Benjamin al-Haddad and colleagues [1]. They continue a research theme observing that pregnancy infection may have some quite far-reaching effects on the unborn child and their subsequent risk for various conditions / labels / diagnoses (see here for example).

So: "A total of 1 791 520 Swedish children born between January 1, 1973, and December 31, 2014, were observed for up to 41 years using linked population-based registries." As per use of the term 'population-linked registries', this was another study originating in Scandinavia (this time in Sweden) and their important research registries (see here). The important variables being analysed were the presence of "fetal exposure to any maternal infection while hospitalized during pregnancy" and "diagnosis of autism, depression, bipolar disorder, or psychosis among offspring."

Results: "fetal exposure to any maternal infection increased the risk of an inpatient diagnosis in the child of autism... or depression" but not seemingly for bipolar disorder or psychosis. The magnitude of the risk could be described as 'notable' but perhaps not exceptional. 'Urinary tract infection' (UTI) is mentioned as one infection that seemed to increase the risk of offspring diagnosis; something that has been kinda hinted at in other research literature [2] outside of the classic 'acute psychosis and UTI' research that appears in the peer-reviewed literature (see here).

Mechanisms? Well, it doesn't take a genius to figure out that most infection has a bearing on immune system functions and onward concepts like inflammation. There's quite a long history of immune system 'issues' and inflammatory processes being potentially connected to labels like autism and depression (see here and see here respectively) that provide a template for further investigation. This, bearing in mind, that pregnancy is already a time of 'reprogrammed' immune function so that a mothers body can 'tolerate' the developing fetus. As good as any place to start for further investigations...

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[1] al-Haddad BJS. et al. Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero. JAMA Psychiatry. 2019. March 6.

[2] Hadjkacem I. et al. Prenatal, perinatal and postnatal factors associated with autism spectrum disorder. J Pediatr (Rio J). 2016 Nov - Dec;92(6):595-601.

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Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a fail

"B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS [Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]."

That was the conclusion reached in the paper by Øystein Fluge and colleagues [1]. Their findings based on the use of rituximab, "a drug that is often used to treat inflammatory diseases (for example, rheumatoid arthritis) and lymphoma" were not entirely unexpected (see here) as a familiar theme of small scale results [2] being 'positive' but not translating into gains during more methodologically-sound study was rehashed.

The Fluge paper also has an accompanying easy-read summary of the results [3] which really aids my job. The long-and-short of it was that over 150 patients diagnosed with ME/CFS were enrolled into the study. Most had been ill with ME/CFS for several years. They were randomly assigned to receive either rituximab or saline (control) over the course of 1 year. Said timing and dosage of rituximab started with "2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months." Participants completed various 'self-reported' questionnaires about their fatigue and functioning over a 2-year period alongside some more objective measurement of physical activity. Results were collated, and well, there was very little difference between rituximab and saline use noted when comparisons were made. What was notable in the published findings were the quite high rates of side-effects observed: "Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events" and over a third of those adverse events were considered 'possibly or probably related to' rituximab use.

What's more to say? Well, the discrepancy between these latest findings and other previous results suggests a couple of potentially important processes *might* be at work. First, the placebo response seems to be quite prominent in this patient group. I say that on the basis that the calculated placebo response among those receiving saline ranged between 25-50% across the various centres that recruited participants for this study. Other commentators (see here) have similarly mentioned how the placebo response seems to be typically quite high in ME/CFS, and how that might have also been on show in other studies too (see here). This could have lots and lots of implications for various intervention trials relevant to ME/CFS. Second, one has to consider that similar to various other labels that include some significant heterogeneity 'under them', there may be responders and non-responders [4] to consider in relation to the use of something like rituximab [5]. Third, and also quite important is to mention that although negative, these results don't invalidate the idea that immune function seems to have something of an important relationship with quite a few cases of ME/CFS (see here for example).

Having said all that, it is difficult to talk about further research on rituximab with ME/CFS in mind on the basis of the Fluge negative results. Not least because, like all medicines, there is a risk-benefit balance to be struck with such a preparation and failures using gold-standard experimental methodologies cannot be easily brushed under the scientific carpet...

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[1] Fluge Ø. et al. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Annals of Internal Medicine. 2019. April 2.

[2] Fluge Ø. & Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28.

[3] Patient Summary: Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Annals of Internal Medicine. 2019. April 2.

[4] Rekeland IG. et al. Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome. Clin Ther. 2018 Nov 28. pii: S0149-2918(18)30514-9.

[5] Morris MC. et al. Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome. Clin Ther. 2019 Mar 28. pii: S0149-2918(19)30112-2.

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"support the hypothesis that early life gut microbiota are associated with neurodevelopmental outcomes in childhood"

Question: "Is the gut microbiome in infancy associated with neurodevelopment in children at preschool age?" Answer: "findings appear to support the hypothesis that early life gut microbiota are associated with neurodevelopmental outcomes in childhood."

That was the about the sum of the findings reported by Joanne Sordillo and colleagues [1] and their analyses of "Ages and Stages Questionnaire, third edition (ASQ-3)" data and "microbiome analysis using 16S rRNA gene sequencing" of stool samples from over 300 infants who were taking part in something called the "Vitamin D Antenatal Asthma Reduction Trial (VDAART)."

The Sordillo paper is open-access so doesn't require any rehashing from me. A few details do however stick out. So: "findings suggest that the infant gut microbiome may be associated with subsequent development of communication, personal and social, and fine motor skills in typical developing 3-year-old children and with odds of possible developmental delays." The authors were specifically drawn to "Clostridiales (Lachnospiraceae genera and other, unclassified Clostridiales taxa)" as being important when it came to their stool analyses. Said bacteria seemed to be *associated* with various ASQ-3 data covering "poorer ASQ-3 communication... and personal and social... scores and with increased odds of potential delay for communication... and personal and social skills."

The word 'autism' is also mentioned in the Sordillo paper, alongside the idea that (1) "poor performance of children on the ASQ-3 (particularly on communication skills) at 16 to 30 months of age has been shown to be sensitive (but not specific) for diagnosis of ASDs [autism spectrum disorders]", and (2) "A number of cross-sectional studies comparing the gut microbiome of neurotypical children with that in children with ASDs have reported increased levels of Clostridiales in the gut microbiome of individuals with ASDs, including higher levels of Clostridium,... Clostridium histolyticum,... and Ruminococcus." Indeed, there's also mention of the Luna study [2] covered on this blog previously (see here).

Obviously there are caveats to the Sordillo findings; not least that this all about looking at two variables (ASQ-3 scores and stool bacterial content) and marrying them together at some quite specific time points. I'd for example, be interested to see whether further follow-up studies saw a continuation of the trends described in this paper perhaps covering examination of multiple stool samples taken over different testing occasions. Also going back to the 'autism' suggestion, the authors note that they "did not have data on clinical diagnoses of ASDs for our analysis" so one has to be a little bit careful with any suggestions there too.

Still, such work is important and further contributes to the idea that the brain probably isn't the only place to look when considering things like cognitive and behavioural development (see here). Indeed, as mentioned previously on this blog (see here), a possible role for inflammation 'impairing' social cognitive processes might not be a million miles away from the Sordillo findings on the basis that the new triad - gut bacteria, intestinal permeability, gut immune function - might be really quite important for lots of processes. And then there is another question to consider: if one is able to 'alter' the gut bacterial make-up at an early age, can one potentially affect behavioural and/or developmental outcomes? I say that in the context that something similar has been talked about before (see here).

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[1] Sordillo JE. et al. Association of the Infant Gut Microbiome With Early Childhood Neurodevelopmental Outcomes. JAMA Netw Open. 2019; 2: e190905.

[2] Luna RA. et al. Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder. Cellular and Molecular Gastroenterology and Hepatology. 2017; 3: 218-230.

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"Maternal diabetes, especially GDM, is probably a risk factor for ADHD"

It's coincidental that as I write this post about the findings reported by Lifeng Zhao and colleagues [1] talking about how "Maternal diabetes, especially GDM [gestational diabetes mellitus], is probably a risk factor for ADHD [attention-deficit hyperactivity disorder]" so the BBC news website highlights how screening for gestational diabetes here in Blighty is still a bit of a hit-and-miss affair (see here).

That news report mentions how about a quarter of those mums-to-be who are most at risk of developing pregnancy diabetes - "having a high BMI [body mass index] or being of South Asian or Black Caribbean ethnicity" - did not get screened at all. Left untreated, gestational or pregnancy diabetes can increase the risk of various adverse events including "a baby that grows larger than usual, leading to problems in labour; premature birth; pre-eclampsia and stillbirth."

The Zhao findings - a meta-analysis - continue a theme suggesting that exposure to maternal diabetes, including pregnancy diabetes, seems to increase the risk of various other developmental and behavioural diagnoses also being present in offspring. The primary source material of this blog - autism - has been talked about on various occasions as being one of those developmental/behavioural diagnoses (see here and see here). That ADHD is quite often mentioned in the diagnostic mix when it comes to autism (see here) is another point to make.

The basics of the Zhao paper: a search of the peer-reviewed science literature was undertaken revealing nine studies that fitted the inclusion criteria including "7,218,903 participants." The quality of most studies was ranked as high. The results were interesting in that researchers "did not find significant association between maternal diabetes and ADHD risk (OR: 1.20, 95% CI: 0.96–1.49)." This observation is slightly at odds with the quote titling this post, which Zhao et al put down to the "high heterogeneity" detected among the included studies and their subgroup analysis of case-control studies (n=3).

Also... when it came to looking at another type of study - a cohort study (n=6) - "the meta-analysis demonstrated that maternal diabetes increased the risk of ADHD in offspring by 40%." Further, and bearing in mind the description 'diabetes' covers quite a bit of diagnostic ground, authors zoomed in on one particular 'type of diabetes', that called gestational diabetes (GDM) and looked at any effect. This is where things got a little more interesting as their results, based on four studies, indicated that "GDM exposure increased the risk of ADHD for children by 164%" in Caucasian children. Ergo, although a little mixed, the existing research literature at the time of analysis indicated that maternal diabetes during pregnancy, particularly GDM, *might* have some important effect on risk of offspring ADHD.

I'm not going to say much more at this point in time in terms of potential mechanisms that *might* elevate the risk of ADHD in offspring exposed to pregnancy diabetes. It's likely to be pretty complicated. Given also that GDM appears more often than not alongside other conditions (see here), it's not going to be easy to tease apart what might be the more important issues. Is it inflammation? Is something to do with blood sugar or insulin? At the moment, we just don't know enough...

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[1] Zhao L. et al. The association of maternal diabetes with attention deficit and hyperactivity disorder in offspring: a meta-analysis. Neuropsychiatr Dis Treat. 2019;15:675–684.
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The gastrointestinal (GI) effects of a gluten- and casein-free diet in autism (continued)

It took a few attempts for me to get this blog post discussing the the paper by Carlo Alessandria and colleagues [1] right. The reasons? Well, predominantly it was because I'm no expert when it comes to the gastrointestinal (GI) tract and autism and, in particular, some of the intricacies of the clinical findings in that context. Don't get me wrong, I am a very keen observer of the peer-reviewed science literature on the bowel and autism (see here and see here  and see here for examples) but I'm no gastroenterologist.

What I did take away from the Alessandria findings is that science is continually looking at the possibility of a link between the various GI issues identified in cases of autism and the still-important peer-reviewed literature on how use of a gluten- and/or casein-free diet (GCFD) seems to have a positive impact for some people on the autism spectrum (see here). Indeed, that there may be lots more to see when it comes to a gut-diet-behaviour interface in relation to (some) autism...

So, slowly does it. First, the aim of the Alessandria study: "evaluating the distribution of human leukocyte antigen (HLA)-DQ2/DQ8 typing among patients with ASD [autism spectrum disorder] with GI symptoms, together with its correlation with duodenal histology and response to GCFD."

HLA-DQ2/DQ8 'typing' are words more commonly found in relation to the prototypical 'dietary gluten can affect health' condition that is coeliac disease. They describe some of the genetics of coeliac disease (CD), and are key components involved in risk for the condition and perhaps other diagnoses of a similar autoimmune ilk. From the 150 or so participants - "with ASD with GI symptoms referred to our outpatient clinic" - who were screened for HLA-DQ2/DQ8, around half were positive (72/151). But researchers did not just stop there. Alongside they also screened for "CD-specific antibodies" (see here and see here for the flavour of what this includes) and concluded that "134 (89%) were negative." To summarise, around half of participants with autism and bowel symptoms possessed the genetics of coeliac disease. But, only around 10% showed a pattern of antibodies related to CD indicative of an immune response to gluten as well as other issues (see here).

And there was more: "Patients were prescribed a 6-month GCFD, and then clinically reassessed." This is where another 'assessment' also becomes relevant to the Alessandria findings. As part of their clinically indicated procedures, participants also underwent endoscopy. This allowed researchers to both look at the inner workings of some of the GI tract and also potentially take biopsy samples. At baseline, before any diet was put in place, they observed that: "56 (37%) showed duodenal microscopic inflammation." 'Duodenal' refers to the duodenum, a part of the GI tract fairly close to the exit of the stomach. Inflammation means just that. And something interesting seemed to connect such bowel findings and dietary response: "Response to diet was related to the presence of histological duodenal alterations at baseline (odds ratio 11.323, 95% confidence interval 1.386-92.549 for Marsh 2 pattern)." In other words, and accepting that correlation is not the same as causation, issues identified in the duodenum - "duodenal histology" - seem to be a possible predictor of response to a gluten- and casein-free diet in relation autistic people.

There is a need for lots more study in this area. Alessandria and colleagues reported their observations on the basis of patients presenting at their clinic with medical needs. This was not a clinical trial in the respect of being randomised (e.g. receiving a diet or not or some other medication to treat such identified bowel issues) or being blinded (researchers and patients not knowing who got what intervention). Knowing a little bit about the use of a GCFD in the context of autism (see here) I'm also acutely aware that 6 months following such a diet is a long time. Even with the best will in the world, some people will not be able to follow such a restrictive diet day-in, day-out. There are issues.

But the Alessandria results are important and promising. They provide a template for further study and an addition to the wealth of biologically-based information on who, on the autism spectrum, might be a 'best candidate' for dietary intervention which excludes gluten and/or casein. I know some people might start up with the 'it's too invasive' arguments in relation to the use of endoscopic and indeed, colonoscopic inquiry when it comes to autism. My counter-argument is that if physicians were presented with a child or adult who did not have autism yet had the same bowel problems as this and other cohorts, would they not be afforded the best healthcare available to them including such inquiry? And why then should a diagnosis of autism but exclusionary to accessing such healthcare? Oh, and it's worth mentioning that at least one of the authors on the Alessandria paper has talked about how technology might eventually make such invasive techniques that little less invasive [2]. Indeed, they've also talked about what else aside from a gluten- and casein-free diet might be clinically indicated for some people on the autism spectrum [3] too with GI issues in mind...

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[1] Alessandria C. et al. HLA-DQ Genotyping, Duodenal Histology, and Response to Exclusion Diet in Autistic Children With Gastrointestinal Symptoms. J Pediatr Gastroenterol Nutr. 2019 Feb 7.

[2] Balzola F. et al. Panenteric IBD-like disease in a patient with regressive autism shown for the first time by the wireless capsule enteroscopy: another piece in the jigsaw of this gut-brain syndrome? Am J Gastroenterol. 2005 Apr;100(4):979-81.

[3] Campion D. et al. The role of microbiota in autism spectrum disorders. Minerva Gastroenterol Dietol. 2018 Dec;64(4):333-350.

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"parental asthma was associated with slightly elevated risk of ASD in offspring"

The paper by Tong Gong and colleagues [1] provides the blogging fodder today and the finding that "parental asthma was associated with slightly elevated risk of ASD [autism spectrum disorder] in offspring."

As unusual as it might sound to some people that a condition primarily affecting the lungs *might* show a connection to a developmental diagnosis in offspring, this is not the first time that asthma and autism has been talked about on this blog (see here and see here). Granted, much of that previous peer-reviewed research has been looking at the possible *connection* between asthma and autism diagnosed in the same person (albeit not necessarily always describing a link). But there is some research history connecting the two labels. Indeed, one of the primary comorbidities that can follow a diagnosis of autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger *association* with asthma (see here).

Gong et al set out to investigate a few important issues: "the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to β2-agonists, other asthma medications and offspring ASD." It would be difficult to describe the Gong study as 'underpowered' given that their use of those fabulous Scandinavian population registries - this time in Sweden - covering "all children (N=1,579,263) born in Sweden 1992-2007." From the total population, researchers identified some 22,000 children diagnosed with an ASD. They looked at their exposure to "parental asthma or prenatal asthma medications" and compared the data with other populations (not diagnosed with autism) including various degrees of siblings and extended family members.

As per the title of this post, a possible *association* was revealed between parental medical history of asthma and offspring risk of a diagnosis of ASD. Asthma in either parent seemed to show a connection, but maternal asthma showed the stronger connection. Also: "The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half-siblings... full-cousins... and half-cousins." This suggests that familial factors were not 'confounding' factors. Another detail is important to mention: "Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD." This is an important detail. It mirrors the findings reported in the paper by Su and colleagues [2] looking at another Scandinavian cohort, and their conclusion: "children born to women who used β2AA [β2-adrenoreceptor agonist] during pregnancy have an increased risk of ASDs in later life" with the caveat that risk of offspring autism was "more likely due to underlying maternal diseases rather than the exposure to β2AA itself."

Implications? Well, several. Not least that more study is required looking at the biological and genetic links between autism and asthma. Y'know, something along the lines of the fact that 'autism genes are probably not just genes for autism' (see here) and how autism has been previously studied in the context of lung architecture too (see here).

What else? How about examining the possibility of some shared biological mechanisms also at work? Perhaps start with inflammation for example [3] and work through other potential immune-related issues as well (see here). And how about also thinking about the possibility of shared 'exposure' events being potentially important? Asthma is a condition affecting the lungs. Something like air pollution is therefore a prime suspect when it comes to the development and continuation of the condition. Likewise, air pollution is no stranger to the autism peer-reviewed research landscape (see here for example). Is it possible that air pollution might be implicated in asthma and autism?

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[1] Gong T. et al. Parental asthma and risk of autism spectrum disorder in offspring: a population and family based case-control study. Clin Exp Allergy. 2019 Feb 11.

[2] Su X. et al. Prenatal exposure to β2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring. Pharmacoepidemiol Drug Saf. 2017 Jul;26(7):812-818.

[3] Murdoch JR. & Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1-2):24-39.

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"serum levels of certain endocannabinoids are substantially decreased in people with ASD"

The quote titling this post - "serum levels of certain endocannabinoids are substantially decreased in people with ASD [autism spectrum disorder]" - comes from the paper published by Adi Aran and colleagues [1]. It adds to previous study on this topic (see here) and continues a research theme from members of this authorship team where the word 'cannabis' is being discussed - in the peer-reviewed science domain - in the context of [some] autism (see here).

Distinct from the last time authors' research appeared on this blog talking about the feasibility of "Cannabidiol-Rich Cannabis" 'for autism' [2], the name of the research game this time around was to assess "the circulating levels of several endocannabinoids and delineate the correlations between their levels and disease characteristics in a large group of children with ASD and their matched controls with typical development." Researchers mention how previous studies in this area "were not designed to comprehensively characterize the involvement of the ECS [endocannabinoid system] in the pathogenesis of ASD" in quite a sweeping blow to some of the other research in this area.

So, endocannabinoids are part of a system that is involved in various important biological processes [3]. As the name suggests there's an overlap between 'endogenous cannabinoids' and some of the chemical components seen in cannabis that provides as good an answer as any as to why cannabis use/misuse is the continuing issue that it is in a population sense. Authors talk about their study focusing on various endocannabinoids: AEA (anandamide), 2-AG (2-arachidonoil-glycerol), AA (arachidonic acid), PEA (N-palmitoylethanolamine), and OEA (N-oleoylethanolamine). They report how said compounds in serum samples were "analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD... and 93 age- and gender-matched neurotypical children." Please don't however get me started on the nonsense that is the word 'neurotypical' (see here). Various other behavioural, psychometric and demographic data were also collected and thrown into the statistical mix.

Results: "Serum levels of the main endocannabinoid AEA and its structurally related compounds OEA and PEA were lower in children with ASD versus age-, gender-, and BMI [body mass index]-matched control group of typically developed children." Nothing particularly new there, as the lower levels of anandamide for example, mimic those reported by Karhson and colleagues [4]. Researchers also mentioned how their findings *might* also have some other potential: "circulating AEA, OEA, and PEA might be used to identify a biologically homogeneous subgroup of ASD, predict response to treatments and adverse reactions to medications, and assist in the development of novel drugs that target specific core symptoms of ASD." Interestingly, some of these 'options' have already been explored [5] in humans and also some animal models [6] with autism in mind.

As to the biochemical *links* between the Aran findings and indeed, the ECS more generally with autism, well, there's still a way to go to decipher them all yet. There are clues emerging [7]; clues that intersect with other important autism-relevant concepts like inflammation among other things. I note also the authors mention how their findings "support the rationale in the ongoing and emerging clinical trials of CBD [cannabidiol] in ASD" (see here) and some results to come.

I'm well and truly [cautiously] interested...

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[1] Aran A. et al. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Molecular Autism. 2019; 10:2.

[2] Aran A. et al. Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study. J Autism Dev Disord. 2018 Oct 31.

[3] Lu HC. & Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2015;79(7):516-25.

[4] Karhson DS. et al. Plasma anandamide concentrations are lower in children with autism spectrum disorder. Mol Autism. 2018 Mar 12;9:18.

[5] Antonucci N. et al. Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases. Case Rep Psychiatry. 2015;2015:325061.

[6] Servadio M. et al. Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid. Transl Psychiatry. 2016 Sep 27;6(9):e902.

[7] Brigida AL. et al. Endocannabinod Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations. Int J Mol Sci. 2017;18(7):1425. Published 2017 Jul 3.

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"Zika Virus as a Possible Risk Factor for Autism"?

The paper by Vianna and colleagues [1] provides the blogging fodder today, discussing a potentially important topic around whether "the fetal brain infection caused by ZIKV [Zika virus] could predispose to ASD [autism spectrum disorder]."

Just before anyone gets the impression that a *link* has been found between Zika virus exposure and autism or autism spectrum disorder (ASD), I'm going to say no, not yet. The current peer-reviewed evidence at the time of writing this post has not identified autism as an outcome following exposure to the Zika virus. That's not to say that various other neurodevelopmental issues have not been associated with Zika virus exposure (see here for example) or that Zika virus exposure might not have biological consequences akin to that noted in some autism [2]. But as far as I'm aware, there is no peer-reviewed science yet suggesting that autism is for example, over-represented among those exposed to Zika virus in-utero. Not yet anyway.

Nonetheless, Vianna et al go through a number of lines of evidence suggesting how autism *could* be an outcome of Zika virus exposure. They start by talking about how Zika virus exposure during pregnancy can have a devastating effect on the developing child (see here) as a function of its teratogenic status. Severe microcephaly (small head size), a cardinal feature linked to infants' Zika virus exposure during pregnancy, has notable effects on the brain and its development, and is one of the more noticeable effects associated with Zika virus exposure in-utero. But further: "this phenotype is now considered only “the tip of the iceberg” and there is a spectrum of less severe abnormalities after congenital Zika infection."

Authors go on to talk about how pregnancy is a time of 'change' when it comes to maternal immune system functions, as a reprogrammed immune system has to become 'tolerant' of the developing foetus. Such reprogramming means that the foetus can survive and thrive. It also however means that the maternal immune system might be more susceptible to certain infections, where for example "opportunistic infections... take advantage." This is also the point where autism enters into the conversation, and the idea that exposure to various infections (viral and bacterial) occurring during pregnancy "can alter [offspring] brain development and are associated with alterations, such as brain calcifications, microcephaly, and neurodevelopmental disorders." I've covered a few possible examples on this blog with autism in mind (see here and see here).

Putting all this together, as well as talking about some of the immune system chemistry that *might* link Zika virus exposure and autism, and the authors come up with a model of 'neuroimmunomodulation' talking about "an ineffective anti-viral response" and increased levels of pro-inflammatory cytokines as being potentially important. I'll also provide another quote from Vianna which is similarly intriguing: "Moreover, in the case of ZIKV, previous infections with other flaviviruses, such as dengue virus and yellow fever, may trigger a secondary immune response of differential magnitude given the great molecular similarity of some immunogenic epitopes among these correlated viruses."

Reiterating that there is currently no link between Zika infection and risk of autism, I do find the Vianna paper interesting. It offers some testable hypotheses that could examined in the lab and beyond. It also provides some further support for the various surveillance and monitoring initiatives that remain in place with regards to Zika virus and the promise of further important data to come from them.

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[1] Vianna P. et al. Zika Virus as a Possible Risk Factor for Autism Spectrum Disorder: Neuroimmunological Aspects. Neuroimmunomodulation. 2019 Jan 10:1-8.

[2] Beys-da-Silva WO. et al. Zika Virus Infection of Human Mesenchymal Stem Cells Promotes Differential Expression of Proteins Linked to Several Neurological Diseases. Mol Neurobiol. 2018 Oct 30.

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"maternal obesity and overweight were significantly associated with [offspring] increased ASD risk"

The title heading up this brief post - "maternal obesity and overweight were significantly associated with [offspring] increased ASD [autism spectrum disorder] risk" - comes from the results published by Xian-Yang Lei and colleagues [1].

Under systematic review and meta-analysis conditions, researchers basically found what many people had suspected for quite a while, insofar as maternal weight, before or during pregnancy, being a 'risk factor' for an offspring diagnosis of autism or ASD. They arrived at their conclusion based on "13 eligible studies for meta-analysis (involving 943,293 children and 30,337 cases)" which collectively found that "both maternal obesity... and maternal overweight... were significantly associated with ASD, while maternal underweight was not associated with ASD." Researchers also looked at paternal weight as a possible risk factor for offspring autism but found no statistical association between paternal obesity, overweight or underweight based on the available data (limited to only three studies).

Mindful of the potential for 'stigma' to set in with such investigation, and likewise being careful not to generalise too much from such findings, the Lei results point to both the requirement for more research in this area and a possible 'intervention' route towards reducing the risk of offspring autism: "pre-pregnancy weight control is suggested." I've covered this topic numerous times on this blog (see here and see here and see here for examples) and have concluded that whilst correlation is not the same as causation and that pre- and peri-pregnancy weight is often intricately tied into other features of the condition known as metabolic syndrome, immune function and in particular inflammation, are perhaps important areas for further assessment. Research should perhaps head in that direction, and see what further crops up...

And as if to further prove the point [2]...

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[1] Lei XY. et al. Association between parental body mass index and autism spectrum disorder: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2018 Nov 23.

[2] Windham GC. et al. Maternal Pre-pregnancy Body Mass Index and Gestational Weight Gain in Relation to Autism Spectrum Disorder and other Developmental Disorders in Offspring. Autism Res. 2018 Dec 21.

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Pioglitazone for autism?

Enjoyed Christmas? Welcome back. Onward...

"Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors."

So said the findings reported by Lucia Capano and colleagues [1] (open-access) describing preliminary efforts to "elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5–12 years old" taking the hypoglycemic medicine called pioglitazone. The results obtained from this phase II pilot study - "a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone" - suggest that further research on this medicine in the context of autism is warranted.

Capano et al provide quite a lot of information about the whys-and-wherefores of pioglitazone use in the context of autism. They talk about immune system 'issues' and inflammation being no strangers to autism research. They talk about various findings in relation to immune signalling and autism, drawing on data from several investigations that have looked at compounds like the cytokines and chemokines. Pioglitazone fits into this story by way of it being "an agonist of peroxisome proliferator activated receptor (PPAR)-ϒ." Activation of PPAR-ϒ leads to "insulin sensitization and enhances glucose metabolism." It also seemingly has an anti-inflammatory role to play too. Through the use of  pioglitazone ramping up the action of PPAR-ϒ, so researchers opined that this could be useful for some people diagnosed with autism where immune system and behaviour might meet...

Unlike other trials of pioglitazone in the context of autism [2], the Capano study was more exploratory than 'gold-standard' in it's design. It did however include both behavioural and biological components, where various behavioural outcome measures were included alongside the describing of various "research bloodwork" that included various cytokines ("IL1-β, IL-10, and TNF-α in plasma; IL-6 in serum") that have been discussed in other studies with autism in mind (see here for example).

Alongside those initial results mentioned in the opening sentence of this post, there are a few other important points to make. So: "Overall, pioglitazone was well tolerated." Welcome news indeed. Researchers also noted that: "There were no serious adverse events (SAEs) in any of the doses within the range tested (0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg)." This is important in the context that all medicines have the propensity for 'adverse effects' for some people, and pioglitazone is no different. Given also the focus on medication and weight gain in the context of autism (see here for example), it's a bit of relief to see that, for the study period at least, authors reported that: "BMI [body mass index] did not change significantly during the study."

I'm not going to go to heavily into the behavioural changes noted over the study period on this occasion, because these are preliminary and one has to be careful with any interpretation. I do however want to mention some of the biological results; namely: "Significant changes with treatment occurred with both IL-6 and IL-10" and "IL-1β and TNF-α did not change significantly with treatment." The authors note that the IL-6 and IL-10 findings - "decreasing IL-6 and increasing IL-10" - were "consistent with the known effect of PPAR-gamma agonists like pioglitazone." This is an interesting finding.

Cumulatively, such results suggest that quite a bit more research focus is needed on pioglitazone in the context of [some] autism. But for now, it looks quite promising (again [3])...

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[1] Capano L. et al. A pilot dose finding study of pioglitazone in autistic children. Molecular Autism. 2018; 9: 59.

[2] Ghaleiha A. et al. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism. Psychiatry Res. 2015 Sep 30;229(1-2):181-7.

[3] Boris M. et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation. 2007;4:3.

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"abnormally high extra-axial cerebrospinal fluid (CSF) volume" and autism

"Increased extra-axial CSF [cerebrospinal fluid] volume is a reliable brain anomaly that has now been found in three independent cohorts, comprising both high-risk and normal-risk children with autism spectrum disorder."

So concluded the findings reported by Mark Shen and colleagues [1] following their study results - "case-control MRI study" results - enquiring whether "increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder, whether extra-axial CSF remains abnormally increased beyond infancy, and whether it is present in both normal-risk and high-risk children with autism."

This latest study from Shen et al follows a research theme [2], a quite long running research theme [3] by all accounts, observing that extra-axial CSF volume might be important to at least some autism. Increased extra-axial CSF volume is described as a brain anomaly insofar as representing a larger than expected volume of cerebrospinal fluid 'coating' the brain, or at least filling the extra-axial space sitting on top and around the brain. It's perhaps not surprising that this work has also included the words 'brain enlargement' in discussions given the physical effect that such increased volume might have.

This latest chapter in the extra-axial CSF volume research comes from a familiar research initiative - the UC Davis MIND Institute Autism Phenome Project - "a longitudinal analysis of children diagnosed with autism spectrum disorder and age-matched typically developing children." The Autism Phenome Project (APP) has already been discussed a few times on this blog for various research reasons (see here and see here). The APP also has something of an interest in brain enlargement appearing alongside regression too (see here). This time around "159 children with autism spectrum disorder (132 male, 27 female) and 77 with typical development (49 male, 28 female) underwent MRI scans." Researchers were looking at extra-axial CSF volume as well as things like brain volume and head circumference. Alongside, various other behavioural measures and questionnaires on things like sleep were included.

"The autism spectrum disorder group had an average of 15·1% more extra-axial CSF than controls after accounting for differences in brain volume, weight, age, and sex." Further: "Both extra-axial CSF volume... and brain volume... uniquely contributed to enlarged head circumference in the autism spectrum disorder group." Authors also reported that: "Increased extra-axial CSF volume was associated with greater sleep disturbances... and lower non-verbal ability."

As per the opening quote to this post, this is not the first time that some of those findings have been reported in the science arena and I very much doubt that it will be the last time either. The authors also talk about such MRI findings in light of "normal risk (ie, from simplex families) or high risk (ie, from multiplex families)" for autism and applying "a previously validated machine learning algorithm based on extra-axial CSF volume, brain volume, age, and sex" but I'd like to see a lot more data before venturing further into these aspects. Not least, data covering the question of 'why?'. From the previous studies in this area, some hypotheses have been put forward, for example: "[as] CSF circulates through the developing brain, it removes inflammatory cytokines and proteins secreted by neurons that can otherwise accumulate and have a pathological effect on brain development." Such a hypothesis needs further research but is perhaps complementary to other discussions about 'neuroinflammation' in the context of autism (see here).

We await further investigations.

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[1] Shen MD. et al. Extra-axial cerebrospinal fluid in high-risk and normal-risk children with autism aged 2-4 years: a case-control study. Lancet Psychiatry. 2018 Sep 27. pii: S2215-0366(18)30294-3.

[2] Shen MD. et al. Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism. Biol Psychiatry. 2017 Aug 1;82(3):186-193.

[3] Shen MD. et al. Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder. Brain. 2013;136(9):2825-2835.

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"C-Reactive Protein as a Peripheral Biomarker in Schizophrenia"

The results of the 'updated systematic review' published by Guillaume Fond and colleagues [1] looking at the "relationships between elevated blood C-reactive protein (CRP) levels and schizophrenia (SZ) onset risk, illness characteristics and treatments, cognition and physical health" provides the blogging fodder today.

Fond (a name not unfamiliar to all-things schizophrenia) et al dip into a topic with more than its fair share of research 'uncertainty' (see here and see here for examples) on whether or not C-reactive protein (CRP), a marker of systemic inflammation, shows a connection to schizophrenia. On this particular research occasion, no new data is added to the debate, but rather authors looked at the collected peer-reviewed data (up to November 2017) to see if any 'general opinions' could be discerned from the collected works.

Results: based on over 50 studies included in their review, authors concluded that it was 'reasonable' to assume that high-sensitivity CRP (hs-CRP) may be a marker for 'schizophrenia onset risk'. The caveat to that statement is that CRP is probably not something 'schizophrenia-specific' in terms of elevations of CRP being indicative of a inflammatory state. So increased hs-CRP may well be a risk factor for "increased positive symptoms, cognitive impairment, hypovitaminosis D, microbiota disturbances, cardiovascular and metabolic syndrome risk in SZ subjects, and increased nicotine dependence in SZ smokers."

I'm pretty happy with the Fond results and interpretation as they stand. They suggest that CRP probably does show some sort of connection to schizophrenia and onward, points to an immune system connection to at least some cases (see here and see here). At the same time, they also imply that certain other observations around schizophrenia - such as a link with certain physical health issues (see here) and/or vitamin D deficiency (see here) - probably also contribute to the elevations of CRP noted in relation to cases of schizophrenia. They also imply that moves to reduce levels of CRP in relation to schizophrenia may well have various other 'knock-on' effects on those other risk factors associated with the condition/diagnosis. This 'double hit' effect could be quite useful.

And with that last sentence in mind, and accepting that consistently high levels of CRP are probably good for no-one, the next question: what can we do about elevated CRP levels in relation to schizophrenia and further, the immune system issues also being co-expressed? Lots, is my impression; perhaps also learning from other labels where immune function (and dysfunction) has been noted [2] and intervention is similarly indicated.

And there's more to come from this authorship group on this blog soon...

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[1] Fond G. et al. C-Reactive Protein as a Peripheral Biomarker in Schizophrenia. An Updated Systematic Review. Front. Psychiatry. 2018. Aug 23.

[2] Marchezan J. et al. Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy. Neuroimmunomodulation. 2018 Sep 5:1-20.

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The FACE-SZ initiative: inflammation and latent Toxoplasma infection in schizophrenia

The FACE-SZ initiative mentioned in the title of this post refers to the National FondaMental Expert Center (FACE-SZ) Cohort, a French collaboration designed to further knowledge about schizophrenia (SZ). The year 2018 has already been quite a year for peer-reviewed publications stemming from this initiative (see here), previously covering some really important topics.

Today I'm discussing two papers from the FACE-SZ scheme: the first from Guillaume Fond and colleagues [1] covered the issue of latent Toxoplasma infection and schizophrenia, and the second also from Fond and colleagues [2] observed that peripheral low-grade inflammation seemed to be something over-represented when it came to "ultra resistance to treatment in schizophrenia (UTRS)." The common ground between the papers is the immune system and how 'activation' of the immune system *might* have some important connections to the presentation of schizophrenia (see here).

Toxoplasma infection is a topic that has been mentioned in the context of schizophrenia before (see here). The causative agent of such infection - Toxoplasma gondii - is most definitely one of Nature's survivors; even to the point of potentially 'making' mortal enemies 'attracted' to waste products of the other (see here). There's still some debate about the hows-and-whys of T.gondii and Toxoplasma infection in relation to schizophrenia, but the collected data is not easily ignored when it comes to an over-representation of infection in the context of schizophrenia and its symptoms (see here and see here).

The first Fond paper [1] reports data from a cohort of some 250 people diagnosed with schizophrenia and "included between 2015 and 2017 in the national FondaMental Expert Center (FACE-SZ) Cohort." Alongside looking for the presence of Toxoplasma infection - "Latent Toxoplasma infection was defined by T. gondii IgG ratio ≥0.8, equivalent to ≥10 international units" - researchers also looked for signs of peripheral inflammation as per their measurement of everyone's favourite pentraxin: highly sensitive C reactive protein (CRP). I should also mention that CRP also has quite a peer-reviewed publication history when it comes to schizophrenia (see here) albeit not always in agreement (see here).

They reported that almost three-quarters of their cohort (184/250) showed signs of latent Toxoplasma infection, equating to Toxoplasma being "almost 3 times more frequent in SZ population compared to general population in France." Not only that but such infection seemed to correlate with some important clinical measurements of schizophrenia, and "Treatments with Anti-Toxoplasmic Activity (TATA)" also correlated with lower depressive symptoms.

The second Fond paper [2] focused on 'chronic low-grade peripheral inflammation' as again, high sensitivity CRP (hs-CRP) was the analyte of choice. The focus this time around was on a sub-group classified as showing "ultra resistance to treatment in schizophrenia (UTRS)" and to see if the such inflammation was *associated* with such cases. Including a starting participant number of over 600 people all diagnosed with schizophrenia, researchers reported that about 10% fell into that UTRS grouping. Among this 10%, they reported something of important relationship between UTRS and levels of CRP as a marker of inflammation. Such a relationship also held when taking into account other, potentially influential variables: "adjustment for age, sex, current daily tobacco smoking, metabolic syndrome and antidepressant consumption." The authors opine that further studies should be directed to look at whether 'treating' such low-grade inflammation *might* have an important effect on some of the presented symptoms of schizophrenia.

Taken together, I'm hoping that readers can see the value of the FACE-SZ initiative, and what it could mean for research looking at the possible aetiology and pathology of at least some cases of schizophrenia. Yes, I appreciate that genetics and environment are going to be important to schizophrenia (as they seem to be for just about every behavioural/psychiatric label) but with that immune system 'connection' there could be lots of research opportunities including some potentially novel treatments to be examined. Once again, the immune system seems to be doing an awful lot more than just playing protector against various pathogens...

To close, and noting the mention of T.gondii in today's post, the news doesn't seem to be all that great when it comes to cat ownership...

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[1] Fond G. et al. Latent toxoplasma infection in real-world schizophrenia: Results from the national FACE-SZ cohort. Schizophr Res. 2018 May 27. pii: S0920-9964(18)30265-2.

[2] Fond G. et al. Chronic low-grade peripheral inflammation is associated with ultra resistant schizophrenia. Results from the FACE-SZ cohort. Eur Arch Psychiatry Clin Neurosci. 2018 May 28

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Vitamin D impacts on intestinal inflammation in 'active' ulcerative colitis: an autism research agenda item?

The results reported by Mayur Garg and colleagues [1] are slightly outside of the typical remit of this blog primarily focused on autism research, but give me a minute or two and I'll hopefully bring them back into the [research] fold.

Garg et al published findings looking at what effect (if any) a quite large dose of vitamin D delivered over 8 weeks might have in relation to a small group of participants "with active UC [ulcerative colitis],... with inactive UC and... non-IBD [inflammatory bowel disease] controls." They concluded that said intervention - "40,000 [international] units cholecalciferol weekly for 8 weeks" - (a) was associated with an increase in functional levels of vitamin D as would be envisaged, (b) *correlated* with a reduction in one measure of inflammation commonly used to grade the activity of UC (faecal calprotectin) and (c) did not seem to significantly impact on various measures examined in inactive and/or non-IBD participants. They concluded that: "Vitamin D supplementation was associated with reduced intestinal inflammation in patients with active UC" with the requirement for much more investigation in this area.

What's the possible autism link? Well, minus too many sweeping generalisations, there may be quite a few. First are the observations that IBDs such as UC may well be 'over-represented' when it comes to the label of autism (see here and see here). I know such findings might have the ability to furrow brows when it comes to autism research history (see here for example) but there is a clinical need for greater screening (and treatment) efforts when it comes to such IBDs in the context of autism. I'd also mention that faecal calprotectin in a 'low-grade intestinal inflammation' sense, has been discussed before on this blog (see here). Second, vitamin D is also a topic of growing interest when it comes to autism (see here and see here for examples). We can um-and-ah about whether such reports of deficiency/insufficiency in the context of autism are 'autism-specific' or just following the trends noted in various other populations (see here and see here). But that does not alter the vitamin D findings observed across various populations and studies with autism in mind. Adding the two observations together in the context that vitamin D deficiency is likely to affect more than just bone metabolism (something else noted in relation to some autism) and one arrives at the possibility that autism + inflammatory bowel disease (specifically UC, and active UC) *might* be something to look at with vitamin D supplementation in mind. Might...

Music, and my brood have finally bumped into the Greatest Showman, and one song seems to be a particular favourite...

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[1] Garg M. et al. The effect of vitamin D on intestinal inflammation and faecal microbiota in patients with ulcerative colitis. J Crohns Colitis. 2018 May 3.

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"CFS symptoms resemble a hypothyroid state" but...

I am a little late getting to the paper published by Begoña Ruiz-Núñez and colleagues [1] observing that, at least for some diagnosed with chronic fatigue syndrome (CFS), clinical findings related to thyroid function might "resemble a mild form of “non-thyroidal illness syndrome” and “low T3 syndrome” experienced by a subgroup of hypothyroid patients receiving T4 monotherapy." But I did get here eventually. Before heading into this paper, I'm gonna link to one of the 'already prepared' discussions on the Ruiz-Núñez findings (see here). My analysis is pretty similar but not entirely the same...

So: "We studied 98 CFS patients (21–69 years, 21 males) and 99 age- and sex-matched controls (19–65 years, 23 males)" was the starting point, as participants provided blood samples and 24-hour urine samples onward to various analyses being carried out. This included: "the measurement of routine hematological parameters [Hb, hematocrit, WBC, red blood cells (RBC), and thrombocytes]" and more specifically: "parameters of thyroid function, low-grade inflammation and gut wall integrity..., together with secondary markers of inflammation." Those 'parameters of thyroid function' included various measures of free and total levels of T3 and T4 required to ascertain the presence of "low-T3 syndrome." I was impressed to see that a measure of gut wall integrity was also on the research menu in the form of plasma zonulin levels being included (albeit analysed via ELISA and bearing in mind the issues that have emerged with that particular method).

Results: "Chronic fatigue syndrome patients exhibited lower FT3, TT4, TT3, %TT3, SPINA-GD, and SPINA-GT, lower ratios of TT3/TT4, FT3/FT4, TT3/FT3, and TT4/FT4; and higher %rT3 and rT3/TT3 ratio." These findings were based on 'group' comparisons with those sex-matched not-CFS controls, and point to some 'issues' with thyroid function in general. Coupled to other thyroid related findings, the Ruiz-Núñez suggest that lower levels of thyroid hormones were detected but "distinct from thyroidal disease" typical levels of thyroid-stimulating hormone (TSH) were also reported. TSH is the stuff that tells the thyroid gland to make thyroid hormone (thyroxine (T4)), where T4 is, in effect, the starting material for T3 (triiodothyronine). Where there are suitable levels of TSH but lower levels of T4 and/or T3, one gets the impression that it's more about what's 'happening' to T3 and T4 over and above issues with their production. Indeed, the collected findings led authors to talk about that 'low T3 [triiodothyronine]syndrome' as being potentially pertinent to their findings in relation to CFS. Going back to those plasma zonulin findings, and there is just a sentence from Ruiz-Núñez and colleagues: "Zonulin, a parameter of intestinal permeability... was lower in CFS patients as compared to controls" but not much else.

I'm not particularly au fait with all the details of low T3 syndrome in the context of CFS or anything else so can't really add too much more. From what I gather, this is not a CFS-exclusive condition but does seemingly tap into talk about CFS being reflective of a "hypometabolic state" (see here). Questions about how to 'treat' such thyroid-related issues in the context of CFS remain unanswered, despite authors talking about "trials with, e.g., T3 and iodide supplements" being potentially indicated. I say this bearing in mind that the focus on biochemistry in the Ruiz-Núñez paper could perhaps, have been complemented by a little more on the presentation of clinical symptoms too.

In short, quite a bit more investigation in this area is indicated...

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[1] Ruiz-Núñez B. et al. Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study. Front. Endocrinol. 2018. Mar 20.

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