"mitochondrial dysfunction is involved in the pathobiology of GWI [Gulf War Illness]"

Among the various research distractions that I take on this blog away from the core material of autism science, one condition/diagnosis/state continues to particularly intrigue me: Gulf war syndrome or Gulf war illness (GWI).

I've covered this topic a few times on this blog (see here and see here and see here for examples); specifically how the hostile environment of the Persian Gulf during the 1990-1991 Gulf War perhaps aligns with this conflict being labelled as 'one of the most toxic wars in human history' (see here). If you think I'm overplaying that last sentence have a look at what was housed at one facility in Iraq under Saddam Hussain and then understand the nature of some of the compounds to which combatants were potentially exposed to.

The [small scale] findings reported by Yang Chen and colleagues [1] (open-access) adds to the still-growing research base suggesting that for the 25%+ soldiers who returned from theatre in ill-health, the biological nature of their symptoms is both wide-ranging and complex. The authors concluded that: "veterans with GWI exhibit greater mtDNA [mitochondrial DNA] damage which is consistent with mitochondrial dysfunction."

Looking at "21 cases of GWI (CDC and Kansas criteria) and 7 controls" (I told you it was 'small scale') researchers looked in blood samples in order to "quantify mitochondrial and nuclear DNA lesion frequency and mitochondrial DNA (mtDNA) copy number (mtDNAcn)" as well as to provide some information on "mitochondrial complex I and IV enzyme activities." In effect, covering both genetic and biological presentation in relation to any possible mitochondrial dysfunction (mitochondria being the 'powerhouse' of the cell).

"This study provides the first direct biological evidence of mtDNA damage in the blood of veterans with GWI." I'm always a little cautious when a study claims to provide 'first evidence' of anything but a quick search of PubMed seems to confirm that mitochondrial DNA (mtDNA) has not been discussed in the research literature before. Although not an expert on mtDNA or anything, the details being discussed by Chen et al point to an excess of mitochondrial and nuclear DNA damage in the GWI group compared with the small control group. This is however, not the first time that mitochondrial dysfunction has been discussed in the context of the GWI as per other peer-reviewed research outings [2].

"Mitochondrial dysfunction among veterans with GWI may help explain, in part, the persistence of this illness for over 25 years." This is an important observation made by the authors. Drawing on data from another area of [overlapping] research - chronic fatigue syndrome (CFS) - it's worthwhile noting that some fatigue-related conditions do have a mitochondrial element to them (see here) even if not universally linked to mtDNA (see here). The fact that this group with GWI did show some evidence of mtDNA damage begs the questions: how and why?

Minus any sweeping statements or the like, I would draw your attention to one particular 'toxic exposure' seen in the Gulf War - depleted uranium tipped munitions - and some research suggesting that particular radioactive particles emitted from something like depleted uranium might very well be able to impact on mitochondrial DNA [3]. I'm not saying this is 'truth', just a testable hypothesis in the context of GWI.

Of course, further investigations are required in this area, both larger in scale and also carried out by other, independent groups. There is also the possibility that certain mitochondrial and interconnected issues, if detected, could be treatable as per again, what has been talked about in CFS circles (see here). Our troops deserve the most thorough and best care we can possibly provide...

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[1] Chen Y. et al. Role of mitochondrial DNA damage and dysfunction in veterans with Gulf War Illness. PLoS ONE. 2017; 12(9): e0184832.

[2] Koslik HJ. et al. Mitochondrial dysfunction in Gulf War illness revealed by 31Phosphorus Magnetic Resonance Spectroscopy: a case-control study. PLoS One. 2014 Mar 27;9(3):e92887.

[3] Zhang S. et al. Mitochondrial alteration in malignantly transformed human small airway epithelial cells induced by a-particles. International Journal of Cancer. 2012; 132: 19-28.

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Managing childhood ADHD with exercise: a systematic review

"Physical activity, in particular moderate-to-intense aerobic exercise, is a beneficial and well-tolerated intervention for children and adolescents with ADHD [attention-deficit hyperactivity disorder]."

Another day, another systematic review and with it, another step closer to determining what intervention(s) might be effective in ameliorating (or at least managing) some of the more 'life-changing' aspects to ADHD.

This time around it was the findings reported by Qin Xiang Ng and colleagues [1] whose analyses seemingly support the use of both short-term and long-term exercise regimes when it comes to managing ADHD. I hasten to add, this is not the first time that this topic has been discussed on this blog (see here) and perhaps links into other non-pharmacological interventions being promulgated with ADHD in mind (see here).

Thirty studies were included in their review and various dimensions of ADHD were found to be [mostly] positively affected by the use of exercise regimes.

Another important detail of the Ng review was the observation that: "No adverse effects arising from physical exercise were reported in any of the studies, suggesting that exercise is a well-tolerated intervention." I guess that might depend on the type of exercise undertaken, but given the startling array of exercise options open to all - including those diagnosed with ADHD - I don't doubt that there is something for everyone. Indeed, if one is to extrapolate from other research, there may be no 'non-responders' to this type of intervention [2] and one might even expect there to be other potential positive effects from regular exercising (see here)...

The take-home message: get (and keep) moving whether diagnosed with ADHD or not.

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[1] Ng QX. et al. Managing childhood and adolescent attention-deficit/hyperactivity disorder (ADHD) with exercise: A systematic review. Complement Ther Med. 2017 Oct;34:123-128.

[2] de Siqueira Mendes Barbalho M. et al. There are no no-responders to low or high resistance training volumes among older women. Exp Gerontol. 2017 Sep 13. pii: S0531-5565(17)30487-4.

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Obesity and overweight in autism meta-analysed

So: "The meta-analysis showed a significant association between obesity and ASD [autism spectrum disorder]. However, no significant association was identified between overweight and ASD."

Those were the conclusions reached by Zhen Zheng and colleagues [1] (open-access) who surveyed the pertinent peer-reviewed science literature up to November 2016 on the topic of the prevalence of overweight and obesity in relation to the autism spectrum (see here).

Including some 15 studies in their meta-analysis mix "encompassing 49,937,078 participants and 1,045,538 individuals with ASD" authors observed a connection between obesity and autism (a body mass index - BMI - between 30 and 39 for obesity and 40 and over for severely obese) but not being overweight. Among the many analyses undertaken by the authors, we are told that "the sensitivity analysis showed that removing any study did not change the final results, suggesting that our findings were robust."

Zheng et al have covered many bases when it comes to the interpretation of their findings. Feeding and eating issues potentially making "healthy dietary interventions less effective"... check (see here). Physical activity levels and 'sedentary activities'... check (see here). Potential side-effects of medication - antipsychotic medication in particular - check (see here). Also: "some individuals with ASD have been reported to have 16p11.2 or 11p14.1 microdeletions, which encompass genes related to obesity susceptibility." Yup, some genetic conditions that manifest autism also place that person at a greater risk for weight issues, either directly or peripherally.

Minus any sweeping generalisations, there are some obvious implications from such results. Obesity places a person at some heightened risk for various adverse health outcomes and potentially, early mortality outside of other, more socially-defined adversities. Prevention and treatment are key. Yes, facets of autism may make intervention slightly more complicated than perhaps noted in not-autism populations but that does not mean that one should not try to impact on the variables that lead someone down a pathway to obesity. And such intervention should be multi-faceted and perhaps also take into account a role for comorbidity that seemingly follows autism (see here)...

Oh, and probably relevant to today's posting, the scientific support for the old "healthy at every size" notion is dwindling...

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[1] Zheng Z. et al. Association among obesity, overweight and autism spectrum disorder: a systematic review and meta-analysis. Sci Rep. 2017 Sep 15;7(1):11697.

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Can a 'disturbed gut microbiota' explain a cognitive performance dip in those born by C-section?

In answer to the question posed in the title of this post - Can a 'disturbed gut microbiota' explain a cognitive performance dip in those born by C-section? - I have to say that I don't know. I was however, rather intrigued by the findings reported by Cain Polidano and colleagues [1] (open-access) who observed that "cesarean-born children perform significantly below vaginally-born children, by up to a tenth of a standard deviation in national numeracy test scores at age 8–9" when allowing for "a large range of confounders."

Based on data derived from the Longitudinal Study of Australian Children (LSAC), a sort of Aussie equivalent to ALSPAC here in Blighty, researchers set about examining whether the growth in Caesarean sections might have some long-term implications for child cognitive development. The question of whether those trillions of wee beasties (bacteria and the like) that call our gastrointestinal (GI) tract home might be implicated in the cognitive findings stems from previous research talking about how, theoretically, said bacteria might be doing so much more than just helping us to digest our food or producing the odd nutrient here and there (see here for example). This also bearing in mind that those born by C-section have been suggested to show a different gut bacteria profile from those not. I say all that acknowledging that gut bacteria doing this, that and t'other is going through something of a period of reflection at the moment (see here).

It is the size of the Polidano participant sample (N=3,666) and the "internationally recognized and widely-used longitudinal" nature of the LSAC that interested me in these findings. The authors provide quite a bit of detail on how the initiative works and what measures have been put in place to potentially rule out mediating and/or confounding variables. Even missing data has been discussed and accounted for: "non-random attrition does not appear to be seriously biasing our results."

What is unfortunately missing from the Polidano paper is any measure of 'gut bacteria' to substantiate the possibility of a connection between C-section birth, gut bacteria and academic outcome(s). I say this bearing in mind that whilst there is extensive literature talking about *associations* between C-section birth and a variety of cognitive and developmental outcomes, the details are still a little scarce insofar as whether any association is tied to a specific family of bacteria or indeed, something like overall bacterial diversity. One also has to bear in mind that other factors also affect newborn gut bacterial make-up such as breastfeeding and seemingly specific components of breastfeeding [2]. I note that other authors are also not sold on the ideas generated from the Polidano paper (see here) and caution that C-sections are not somehow demonised as a result (not everyone is 'too posh to push').

"While the magnitude of our estimated difference in outcomes is not large, up to a tenth of a standard deviation in national test scores in numeracy, they are large enough to warrant action." The authors note that their observations might not seem to show a particularly large contribution to cognitive development, they are nonetheless still potentially important. Indeed: "A tenth of a standard deviation in national test scores is comparable in size to differences related to gender, class size and teacher quality that are the focus of policy effort." In other words, don't discount this potentially important area of investigation just yet...

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[1] Polidano C. et al. The relation between cesarean birth and child cognitive development. Scientific Reports. 2017; 7: 11483.

[2] Toscano M. et al. Impact of delivery mode on the colostrum microbiota composition. BMC Microbiology. 2017; 17: 205.

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SHANK3 and intestinal barrier function might have implications for some autism...

According to the Spectrum Wiki, SHANK3 - SH3 and multiple ankyrin repeat domains 3 - is described as "a leading autism candidate gene, with mutations occurring in between 1 and 2 percent of individuals with autism spectrum disorder."

Providing instructions for making the SHANK3 protein, alterations to the structure or function of the SHANK3 gene can have some quite far-reaching consequences, notably including disrupting communication between neurons in the brain.

A recent paper published by Shu-Chen Wei and colleagues [1] provides some further discussion on how issues with SHANK3 may very well extend beyond just 'brain function' and indeed, may overlap with reports of an over-representation of bowel disease in the context of autism (see here). In effect, a *possible* genetic association between autism and inflammatory bowel disease. Possibly...

Wei et al initially relied on a mouse model of SHANK3 disruption, something that has also reached autism research [2]. Said mouse model was artificially exposed to dextran sulfate sodium, a compound that creates experimental colitis mimicking human inflammatory bowel conditions such as ulcerative colitis. Various measures were employed to explore the interaction between colitis in the SHANK3 knockout mice pertinent to the expression of intestinal permeability, hyperpermeability of which is also known as 'leaky gut' in some quarters. Gut permeability issues are 'on the radar' when it comes to at least some autism (see here). Researchers also looked at SHANK3 expression in a cohort of human participants diagnosed with an inflammatory bowel disease called Crohn's disease.

Results: "SHANK3 knockout resulted in a leaky epithelial barrier phenotype, as demonstrated by decreased transepithelial electrical resistance, increased paracellular permeability, and increased Salmonella invasion." Going back to the idea that genetic issues identified as being potentially pertinent to some autism might extend beyond just 'effects on the brain' this is an important finding. Much like in other identified genetic conditions manifesting autism or autistic traits, the indications are that intestinal issues might be part and parcel of some autism where SHANK3 issues have been identified (see here and see here for other examples under other genetic conditions).

Further: "Overexpression of SHANK3 enhanced ZO-1 expression, and knockdown of SHANK3 resulted in decreased expression of ZO-1." ZO-1 refers to zonula occludens-1, something called a tight junction protein which serves an important function in intestinal barrier biochemistry. In effect, ZO-1 and other tight junction proteins seal the space - paracellular space - that is part of the intestinal barrier. The implication being that under expression of SHANK3 seems to have a detrimental effect on metabolites involved in intestinal barrier integrity; something also noted when it came to Wei and colleagues looking at "colonic tissue of patients with Crohn's disease" with ZO-1 in mind.

I used the words 'might have implications for some autism' in the title of this post but hasten to add that much more investigation is still required. Yes, SHANK3 seems to have a place in the aetiology and pathology of 'some autism' but further confirmatory research is required. Not least that, as far as I am aware, no-one has actually looked at intestinal barrier function directly in cases of Phelan-McDermid syndrome a primary outcome of SHANK3 genetic issues, despite some chatter about gastrointestinal issues potentially being no stranger to such a diagnosis [3]. I would also like to see a little more done on the measurement of something like zonulin where SHANK3 is mentioned in the context that zonulin seems to have a connection to intestinal barrier integrity. Whether, similar to other preliminary work looking at autism and zonulin (see here), there may be merit in testing when SHANK3 issues are likewise identified.

And while we're on the topic of mouse models and possible connections to autism, it's worth noting the findings reported by Groves and colleagues [4] talking about what vitamin D deficiency might do to certain mouse behaviours in the context that vitamin D has some autism research history too...

Music to close, and not to make light of SHANK3 but it does conjure up the sound of quite a famous song...

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[1] Wei SC. et al. SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCε-dependent Pathway. Inflamm Bowel Dis. 2017 Oct;23(10):1730-1740.

[2] Yoo J. et al. Shank mutant mice as an animal model of autism. Philosophical Transactions of the Royal Society B: Biological Sciences. 2014;369(1633):20130143.

[3] Kolevzon A. et al. Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring. Journal of Neurodevelopmental Disorders. 2014;6(1):39.

[4] Groves NJ. et al. Adult vitamin D deficiency exacerbates impairments caused by social stress in BALB/c and C57BL/6 mice. Psychoneuroendocrinology. 2017 Sep 6;86:53-63.

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Early autism diagnosis = "more positive outcomes at school age"?

I don't want to dwell too much on the findings reported by Megan Louise Erin Clark and colleagues [1] but I do think they warrant dissemination.

Comparing two groups of children, one who were diagnosed early with an autism spectrum disorder (ASD) (n=48) and another group of children "diagnosed after 3-years" (n=37), authors "investigated the school age outcomes of children." They observed that children diagnosed earlier "demonstrated better verbal and overall cognition at school age, were more likely to attend mainstream school and required less ongoing support than children diagnosed later." They imply that 'earlier diagnosis = more access to intervention' as a potentially important variable in those 'better outcomes' noted for earlier diagnosed children.

Accepting that many factors may influence age of diagnosis when it comes to autism (see here), some of which are outside of the control of parents and professionals (see here), there seemingly is an important message from the Clark findings: early diagnosis counts. Indeed, more than one commentator has talked about the possibility of implementing early intervention even before a diagnosis of autism is received (see here) in the context of meeting potentially 'critical windows' for intervention (see here) that may be 'surpassed' as a consequence of often slow and cumbersome assessment processes. I say this acknowledging however that regression of previously acquired skills is a feature of at least some autism (see here).

Such work has to however be set against what happens in real-life insofar as autism screening and assessment. I've talked about moves here in Blighty to potentially include an autism screener in well-baby visits (see here) - whether engineered or just coincidence - and what that might mean in terms of referrals. The problem however, is that in the continued climate of austerity and financial 'squeezing', the reality of getting an autism assessment is quite consistently one of long waiting lists and seemingly constant obstacles to getting a diagnosis. Precisely the opposite of what is needed for 'more positive outcomes at school age'...

And whilst we're talking about school age outcomes, the debate on inclusive vs. specialised education settings with autism in mind has also received some recent research attention [2]: "Children who remained in general education/inclusion classrooms had higher achievement than those who moved to special education classrooms." Discuss...

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[1] Clark MLE. et al. School Age Outcomes of Children Diagnosed Early and Later with Autism Spectrum Disorder. J Autism Dev Disord. 2017. Sept 14.

[2] Kim SH. et al. Longitudinal follow-up of academic achievement in children with autism from age 2 to 18. J Child Psychology Psychiatry. 2017. Sept 26.

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