Nicotine exposure and offspring ADHD (yet again)

The study findings reported by Andre Sourander and colleagues [1] talking about "an association with and a dose-response relationship between nicotine exposure during pregnancy and offspring ADHD [attention-deficit hyperactivity disorder]" continue an important research theme (see here and see here).

What was different about the Sourander results compared with some of the other studies in this area was their focus on the measurement of cotinine levels - cotinine being a biomarker for exposure to tobacco smoke - in mums-to-be as "measured by using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy and archived in the national biobank." Indeed, such a biological marker measurement protocol mimics other research from members of this authorship group when looking at maternal nicotine exposure and offspring risk of schizophrenia for example (see here).

Based on the analyses of samples from over a thousand participants born in the late 1990s and diagnosed with ADHD compared with samples from a similar number of non-ADHD control participants, researchers came to their possible *link* observation. They mention how the relationship between maternal cotinine levels and offspring ADHD diagnosis was statistically significant even when other important, potentially confounding, variables were taken into account. When categorising their maternal cotinine results into bands approximating light to heavy nicotine exposure and the possibility of a link with offspring ADHD diagnosis, researchers also reported something that looked like a dose-response relationship. Ergo, a biomarker of nicotine exposure during pregnancy *looked* to be potentially linked to offspring risk of ADHD.

Although important work, my first thought when reading this research was about how these results are 'set' within the context that historically, smoking rates or tobacco exposure rates during pregnancy were so much larger decades ago than they are now (see here), but ADHD is seemingly showing only quite a recent rise in numbers (see here). Although no expert on pregnancy tobacco consumption during the 20th century, I'm assuming that all those adverts about smoking being 'healthy' in the 1940s and beyond (see here) probably meant that quite a few women smoked during their pregnancy in the belief that it was 'healthy'. At the very least, it probably meant that they were exposed to a lot more second-hand tobacco smoke as a result of smoking being allowed in various public places and also more likely to be observed in the home environment. Surely then we would have seen an explosion of ADHD diagnoses at that point in time if the link was so simple? That is, assuming that the tobacco of today is the same as the tobacco of yesteryear.

I'm also intrigued that within the various potentially confounding variables which Sourander and colleagues adjusted for - "maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and child’s birth weight for gestational age" - there's another variable that could exert an effect on ADHD risk: relative age (see here and see here). Relative age refers to the observation that the youngest children in the school classroom compared to their older classmates, are more likely to be diagnosed with ADHD. It strikes me that alongside something like tobacco or nicotine exposure, so age and other effects could be important.

I'm not trying to poo-poo the link that Sourander and various other research teams have independently observed. I'm also not trying to downplay the harms that tobacco (nicotine) exposure can have for the unborn child. I merely suggest that with typically falling rates of (reported) tobacco exposure during pregnancy in many countries (see here) and increasing levels of childhood (and adulthood) ADHD being reported, there must be other factors at work in any such relationship (see here for example).

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[1] Sourander A. et al. Prenatal Cotinine Levels and ADHD Among Offspring. Pediatrics. 2019. Feb 25.

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Low grade inflammation in acute psychiatric inpatients

I was interested to read the findings reported by Emanuele Osimo and colleagues [1] (open-access available here) recently, and their observation that: "Evidence of low-grade inflammation was present in all major diagnostic groups, with prevalences ranging from 12 to 40% depending on the measure."

'Major diagnostic groups' included in the Osimo paper, included "acutely unwell psychiatric inpatients from all major ICD-10 diagnostic groups" covering labels such as psychotic disorder, schizophrenia, mood disorders, personality disorders and organic mental disorders.

Authors - including the notable name of Golam Khandaker who has published work previously covered on this blog (see here and see here for examples) - conducted an "anonymised search of the electronic patient records" for those hospitalised in a specialist mental health department for the treatment of a mental health / psychiatric condition between 2013 and 2016. Alongside, they had to have "a blood test result for CRP [C-reactive protein] or for WBC [total white cell count] [that] had been recorded on the electronic medical notes system within 14 days of admission" yielding almost 600 participants. In effect, a blood test pertinent to the measurement of compounds reflective of immune system processes such as inflammation.

As per the opening sentences to this post, and using CRP and/or WBC as a measure of inflammation, authors identified some quite notable prevalences of low-grade inflammation in their patient group. So: "The prevalence of inflammation in the major ICD-10 diagnostic groups of psychotic disorders (F20–29), mood disorders (F30–39), neurotic disorders (F40–48) and personality disorders (F60–69) was 32%, 21%, 22% and 42%, respectively." Various other variables also seemed to be *associated* with the presence of such inflammation too. Authors note for example that: "Patients with medical comorbidities were more likely to be inflamed" alongside various other factors also potentially exerting an effect: "older age, black ethnicity, being single, self-harm, diagnoses of schizophrenia, bipolar disorder, current treatments with antidepressants, [and] benzodiazepines" were all associated with low-grade inflammation.

Such findings add to the ever-growing amount of research that suggests a role for the immune system in relation to various psychiatric / behavioural diagnoses (see here). Further, that with a little more focus on the somatic as well as the psychiatric (see here) when it comes to such conditions, potentially relevant clues may emerge pertinent to treatment options. I might finally also draw your attention to some work previously discussed on this blog dealing with the idea that inflammation *might* have the ability to affect social cognitive processing (see here). Such a finding, focused on symptoms rather than labels, could offer a few alternative directions for intervention given the widespread nature of social cognitive issues across a wide variety of psychiatric conditions.

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[1] Osimo EF. et al. Prevalence and correlates of low-grade systemic inflammation in adult psychiatric inpatients: An electronic health record-based study. Psychoneuroendocrinology. 2018 Mar 1. pii: S0306-4530(17)31581-0.

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ATEC (Autism Treatment Evaluation Checklist) still rising

The paper by Shreyas Mahapatra and colleagues [1] (open-access available here) provides the blogging fodder today and some important data relating to an important instrument in autism research circles: the Autism Treatment Evaluation Checklist (ATEC).

I'm a fan of the ATEC. Not only because it was one of the first instruments specifically devised to look at measuring changes to autistic symptom severity but also because it's freely available to use. No royalty payments required; free and open for anyone and everyone to use.

Devised by the late Bernard Rimland and Stephen Edelson of the Autism Research Institute (ARI), the ATEC was born out of the need for researchers and non-researchers alike to measure how autism / autistic features can, on some occasions, fluctuate, specifically in response to intervention. It's perhaps no coincidence that the ARI also holds some important data on parent ratings of how useful certain interventions were reported to be when it comes to autism (see here). Although probably not loved by all, such ratings - derived from those who probably know their children best - provide an important rough-and-ready measure of what intervention options perhaps need a little more investigation and which should probably be avoided. The fact that they're based on the reports of over 27,000 parents also helps matters too...

Anyhow, one thing that did seem to be missing from the increasing interest (see here and see here) in the ATEC is data on "the norms on the longitudinal changes in ATEC in the “treatment as usual population." The Mahapatra paper sought to partially remedy that situation based on an "observational cohort who voluntarily completed ATEC evaluations over the period of four years from 2013 to 2017."

Based on observations for some 2600-odd children (mostly males) all of whom scored 20 or above on the ATEC total score, researchers provided some important baseline data. They for example, show how total ATEC scores, a measure of autism severity, seem to change / fluctuate as children age (see Table 1). They also show how subscale scores - Speech / Language / Communication, Sociability, Sensory / Cognitive awareness, Health / Physical / Behavior - move around as a function of 'starting position' and age too. In short, it provides researchers and non-researchers alike some data on what might be expected to happen to the presentation of autism based on ATEC scoring.

But it's not by any means a perfect start. As the authors point out: "In the selection of participants for inclusion in this study, a baseline of ASD [autism spectrum disorder] diagnosis could not be established as child’s diagnosis is not part of ATEC questionnaire" indicating that not every child who participated might have had a diagnosis of autism or ASD. There were other methodological 'issues' too that need to be kept in mind.

I'm still however happy to talk about the ATEC and its potential usefulness to lots more autism studies aside from that already discussed in the peer-reviewed literature. Assuming also that ATEC has some overlap with other more standardised measures used in autism research [2] I think the future continues to look rather rosy for this rather important instrument.

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[1] Mahapatra S. et al. Autism Treatment Evaluation Checklist (ATEC) Norms: A "Growth Chart" for ATEC Score Changes as a Function of Age. Children (Basel). 2018 Feb 16;5(2). pii: E25.

[2] Geier DA. et al. A Comparison of the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS) for the Quantitative Evaluation of Autism. J Ment Health Res Intellect Disabil. 2013 Oct;6(4):255-267.

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Bone health and autism continued

It's been a while since I last wrote about the topic of bone health and autism (see here). On that particular occasion, it was the work by Ann Neumeyer and colleagues [1] that provided the blogging fodder and the observation that: "BMD [bone mineral density] is lower in peripubertal boys with ASD [autism spectrum disorder]." BMD is important because of a possible association between lower BMD and risk of fracture or indeed, something more pathological.

Today I continue with this topic as per further work from Neumeyer and colleagues [2] looking to "examine macro- and micronutrient intakes and self-reported physical activity in boys with ASD compared to TDC [typically developing controls] and the relationship of these variables with BMD."

Based on data from nearly 50 boys aged 8-17 years of age (25 diagnosed with ASD and 24 not-autism controls), researchers once again relied on the technique known as dual-energy x-ray absorptiometry (DXA) for the measurement of bone mineral density. Various measures were taken from various parts of the body -"whole body less head, hip, and spine." Alongside, food diaries provided a rough-and-ready measure of food intake, self-reported physical activity (that's self-reported) did what it said on the tin, and fasting levels of 25(OH) vitamin D and calcium were garnered. I'll come back to some of the pros-and-cons of some of these measures shortly.

Results: consistent with the peer-reviewed data that has come before, BMD z scores at the lumbar spine, femoral neck, total hip, and whole body less head were lower in those with autism compared with control participants. A BMD z score by the way, is basically a comparison of BMD with that of standardised data (i.e. an average person of the same sex and age). Added to such results, authors also observed that less calorie intake was present in the ASD group (again compared with controls) and a "lower proportion of ASD participants were categorized as "very physically active" (27% vs 79%; P<0.001)." Interestingly however: "Body mass index and serum vitamin D and calcium levels were similar."

I was rather intrigued by the Neumeyer results. Not least that vitamin D and calcium levels were 'similar' in the autism and control groups. As I've discussed before on this blog, there have been calls for preferential screening for these biological parameters as and when an autism diagnosis is received (see here) in light of other findings (see here). The Neumeyer observations perhaps reflect a wider need for such screening.

The use of self-report as a measure for physical activity, whilst useful, is slightly outdated in these times of actigraphy. Wearable technology to measure activity and rest cycles is cheap and abundant these days and, as I've mentioned on other occasions, really should be the research industry standard. I'm not saying people might not be accurate in reporting their short-term physical activity but...

I do think there are some additional 'where next?' things to consider when it comes to future work looking at BMD and autism. Noting for example, that both dietary and malabsorptive issues seem to be able to influence BMD [3] there are additional parameters to be looked at. Given previous peer-reviewed reports on lactose issues being present in relation to autism (see here), this could feature in future work. Although still possessing the ability to furrow brows in certain quarters, the observation of issues with intestinal permeability ('leaky gut') in relation to some autism (see here) also could be an additional parameter to examine. I daresay also that some initial chatter about a compound called zonulin potentially serving as a 'biomarker of impaired gut barrier function' in relation to some autism (see here) might also be revealing. And then there is the important issue of epilepsy / seizure disorder often being comorbid with autism (see here), and how certain [important] intervention measures for said issues might affect parameters such as vitamin D (see here) and what that might mean for long-term bone health...

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[1] Neumeyer AM. et al. Bone density in peripubertal boys with autism spectrum disorders. J Autism Dev Disord. 2013 Jul;43(7):1623-9.

[2] Neumeyer AM. et al. Nutrition and Bone Density in Boys with Autism Spectrum Disorder. J Acad Nutr Diet. 2018 Feb 3. pii: S2212-2672(17)31749-5.

[3] Di Stefano M. et al. Lactose malabsorption and intolerance and peak bone mass. Gastroenterology. 2002 Jun;122(7):1793-9.

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Zonulin (testing): "its clinical utility questionable"

The quote making up part of the the title of today's post is taken from the paper by Aristo Vojdani and colleagues [1] (open-access available here) providing some well needed analysis of a compound of some interest for various clinical areas: zonulin.

Just in case you weren't familiar with all-things zonulin, this is a compound that has found some scientific favour when it comes to the concept of intestinal barrier function being perturbed in several diagnoses [2]. I must admit to being pretty interested in some quite recent research talking about zonulin in the context of 'some' autism (see here) based on the idea that intestinal barrier function might not be 'optimal' for some people diagnosed with an autism spectrum disorder (ASD) and what implications that might have (see here and see here).

Vojdani - who is also no stranger to autism research - cautions that the inevitable testing 'free for all' that has ensued as zonulin has risen up the scientific ranks might not be all good, as they pitted the direct measurement of serum zonulin levels against "antibodies against zonulin" to see which measure might provide the most accurate results. Antibodies against zonulin by the way, meant IgA and IgG antibodies against zonulin and was carried out "using enzyme-linked immunosorbent assay methodology."

Results: based on the analysis of over 70 blood samples from "18 volunteers at intervals of 0, 6, 24, and 30 h[ours]" authors noted that a third of participants (6/18) had low levels of serum zonulin "very close to the detection limit of the assay." We are told over the course of the hours, levels of serum zonulin "did not significantly fluctuate" in their trace amounts in this group. For the other 12 participants, it was a slightly different story as "significant fluctuation in zonulin levels was observed in almost all 12 of these subjects at the 6-, 24- or 30-h blood draws." When it came to those antibodies against zonulin, the clinical picture appeared to be slightly more calm as data showed that "both IgG and IgA antibody levels from blood obtained at 0, 6, 24, and 30 h were highly stable with variations of less than 10%." On that basis, the authors recommend that a single measurement of zonulin itself may not be a suitable indicator "for assessment of intestinal barrier integrity."

There was also another part to the Vojdani study looking at serum zonulin levels in "30 healthy controls along with 30 patients with known celiac disease." Coeliac or celiac disease (CD) is the archetypal gluten-related autoimmune condition and has some connection to zonulin. Results for this part of the study indicated a significant group difference between CD and non-CD groups where serum zonulin levels were higher in those with CD. When comparing serum zonulin levels against those antibodies to zonulin in the CS vs no-CD groups, authors reported "detection of antibodies against zonulin in 67% of patients with CD while zonulin level elevations were detected in only 33%." They suggested that these results could be due to "zonulin fluctuation in the blood and its removal by the immune system."

These types of results are interesting and help to add some 'detail' to big, sometimes sweeping, scientific findings with an emphasis on the technology and techniques used to measure such compounds. In the context of the Esnafoglu paper [3] that was the source material for my blogpost on zonulin and autism, there may be lessons to be learned as per their use of an enzyme-linked immunosorbent assay to analyse for serum zonulin levels in that particular cohort. That being said, a comparison of the range of zonulin levels reported in their autism cohort "(ASD (122.3 ± 98.46 ng/mL) compared with the healthy controls (41.89 ± 45.83 ng/mL)" compared with the Vojdani results (CD mean = 8.5 ng/mL vs. controls mean = 3.7 ng/mL ) shows that there may be quite a bit more to see when it comes to zonulin and [some] autism outside of just testing factors.

Just before I go, I do have one possible suggestion which might help matters in the area of zonulin measurement. Being quite a big fan of techniques such as mass spectrometry over other analytical methods and bringing in other recent data suggesting that *some* immunoassay kits purposed for zonulin analysis might be missing the mark [4], I'm minded to suggest that a more direct analysis of something like serum zonulin in various groups could be warranted based on mass spec and related techniques including those diagnosed with CD and autism (or even both)...

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[1] Vojdani A. et al. Fluctuation of zonulin levels in blood vs stability of antibodies. World J Gastroenterol. 2017 Aug 21;23(31):5669-5679.

[2] Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012;1258(1):25-33.

[3] Esnafoglu E. et al. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects. J Pediatrics. 2017. May 11.

[4] Scheffler L. et al. Widely used commercial ELISA for human Zonulin reacts with Complement C3 rather than preHaptoglobin2. bioRxiv preprint. 2017. Jun 30.

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Quality of life and autism: meta-analysed

"Quality of life of adults on the autism spectrum is lower than that of typically developing adults, when measured with tools designed for the general population."

That was one of the primary conclusions reached by Michael Ayres and colleagues [1] as per their systematic review of the peer-reviewed research looking at quality of life for adults on the autism spectrum and how said quality of life (QoL) is measured. Covering a topic that has received some significant airtime on this blog (see here), authors noted the available literature is generally consistent with the notion that for quite a few people, a diagnosis of autism or autism spectrum disorder (ASD) brings significant challenges that impact on how one feels/interprets their life experience. I know not everyone will necessarily agree with such sentiments but that is what the available science literature suggests (see here also).

The associated finding that there are currently "no comprehensive autism spectrum disorder-specific quality of life measurement tools validated for use with representative samples of adults on the autism spectrum" is also an important one. My first thought was that such a 'gap' might be partially plugged as and when the ICF core sets for autism are finally agreed upon (see here and see here for more information) and put into practice. More than that however, I hark back to my previous mega-post on QoL and autism and the idea that QoL is often a very subjective thing and indeed, is a dynamic concept, that can readily change as a function of nature and nurture. Any such measurement tools need to keep this in mind alongside how facets of autism and important comorbidities can wax and wane as a function of maturation for example and how said changes might impact on QoL (see here). They also need to bear in mind that proxy reporting when required, may not be the most accurate way of reporting [2].

The bottom line however is that QoL is affected by a diagnosis of autism, either directly or indirectly. I might add that, minus any sweeping generalisations or 'blame', QoL issues in the context of autism are also not confined to the person but potentially also significant others (see here). The next [complicated] question being: what can be done to improve QoL in the context of autism? [3] (ensuring that all aspects of the autism spectrum are included in that question) and keeping in mind that 'a good outcome' might mean different things to different people [4] as it might with other age-groups [5].

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[1] Ayres M. et al. A systematic review of quality of life of adults on the autism spectrum. Autism. 2017 Aug 1:1362361317714988.

[2] Flynn S. et al. Measurement tools for mental health problems and mental well-being in people with severe or profound intellectual disabilities: A systematic review. Clin Psychol Rev. 2017 Aug 11;57:32-44.

[3] Hwang YIJ. et al. Aging well on the autism spectrum: the perspectives of autistic adults and carers. Int Psychogeriatr. 2017 Aug 11:1-14.

[4] Lounds Taylor J. When is a good outcome actually good? Autism. 2017 Aug 1:1362361317728821.

[5] McConachie H. et al. Parents Suggest Which Indicators of Progress and Outcomes Should be Measured in Young Children with Autism Spectrum Disorder. J Autism Dev Disord. 2017. Aug 31.

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