Tuesday, 14 August 2018

Autistic traits carrying a 'cognitive cost' into old age?

I don't think anyone should be too alarmed at the findings reported by Gavin Stewart and colleagues [1]. But their observation that "autism traits as measured by the BAPQ [Broad Autism Phenotype Questionnaire] may confer additional risk of cognitive decline in aging" represents something that requires quite a bit of further investigation.

Some twenty 'older' adults who were questioned and deemed to have met criteria for the broader autism phenotype (BAP) were tested on skills related to executive function alongside episodic memory. Their results were compared with twenty 'older' adults who did not reach criteria for the BAP. Authors reported that: "Despite no differences in age, sex ratio, educational history or IQ, the BAP group demonstrated poorer performance on measures of executive function and episodic memory compared to the COA [control older adults] group." They interpret this in the context of that 'additional risk of cognitive decline in aging'.

The numbers of participants in the Stewart study were low and imply that one has to be quite careful about making any sweeping generalisations as a result. Bear also in mind that the BAP does not necessarily equal autism or autism spectrum disorder (ASD) as a function of it describing sub-threshold autistic traits (sub-threshold for a diagnosis). Traits, I might add, that are seemingly not just potentially representative of autism (see here for one example).

But set within a 'gap' in the research base looking at autism in older adults (see here), there is a scheme of work to follow. If for example, the Stewart 'trend' does overlap with the experiences of older adults on the autism spectrum in terms of 'cognitive decline', there is a whole barrage of potentially important implications to consider. More so when one considers that the autism prevalence data continues to head in only one direction (see here) and what this means for societal financial and resource planning.

Just before I go, one more detail was revealed in the Stewart paper: "Older adults who met the BAP criteria also reported higher levels of depression and anxiety." Continuing a theme on this blog that various over-represented issues/diagnoses in relation to autism might not be best described as just being 'comorbid' (see here and see here and see here), I believe that this finding adds further weight to the notion that autistic traits (clinical and sub-clinical) might have some important 'direct' relationships with other psychopathology. Not necessarily a welcome opinion in some quarters, but something that also requires a lot more investigation.

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[1] Stewart GR. et al. Aging with elevated autistic traits: Cognitive functioning among older adults with the broad autism phenotype. Research in Autism Spectrum Disorders. 2018; 54: 27-36.

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Monday, 13 August 2018

Participatory research in autism: some good ideas but who gets to participate?

I was genuinely pleased to read the article published by Sue Fletcher-Watson and colleagues [1] talking about how the incorporation of views and opinions from people with autism / autistic people can hopefully improve the relationship between autism research and clinical practice. Pleased because, as autistic voices become more prominent in many walks of life including important research agencies, so such voices can help both guide research priorities and also aid in the the important translation of research findings from dusty science books/journals to [positively] affecting real lives.

The Fletcher-Watson paper recalls the results of a "shaping autism research seminar series" held here in Blighty. We are told that the "overarching goal was to examine how autism research could become more participatory in nature" where the 'target group' aids in making research "more meaningful – that is, relevant to the community, consistent with their values, and not tokenistic in delivery." 'Nihil de nobis, sine nobis' so the [important] saying goes.

Some key themes emerged from the initiative: "Respect, Authenticity, Assumptions, Infrastructure and Empathy." All of these points serve to enhance autism research and move it away from issues like 'research solely for the benefit of researchers careers' and/or 'research for the benefit of just getting further research grants/money' which probably feature in at least some circumstances. Instead the message is about moving towards a research strategy that has tangible real life impact for those on the autism spectrum, also trying to be sensitive to the numerous wants, needs and desires. All those sweeping psychobbable explanations of autism from yesteryear really haven't served anyone well in terms of enhancing quality of life and so people want something different...

The authors accept that alongside the strengths of such an approach there are also challenges. So for example, we are told that under the category of 'authenticity' where "autism communities can shape a research agenda", one challenge is going to be that "merging perspectives of a diverse group into homogeneous outcomes can result in under-specified priority research topics." Indeed it can, and it has been talked about before in the context of consumers/producers of autism research (see here).

Whilst noble in sentiment, I have some cautions and caveats about this area; not least around the question of exactly how participatory such initiatives truly are and can be when it comes to the very heterogeneous autism spectrum and the multitude of voices to be included (see here). Are voices from the autism spectrum who for example, are critical of the concept of neurodiversity likely to be invited to participate? What about those who don't see their autism or its effects in as positive a light as others? Who are the gatekeepers deciding who is involved in "shaping autism research through meaningful participation" and what is the criteria for participating aside from a diagnosis of autism? What happens also when there are disagreements in research direction between 'professionals' and the communities they serve?

The oft-used term 'if you've met one person with autism, you've met one autistic person' always figures in my mind. It denotes that within such a heterogeneous label/diagnosis, there is huge variation in the presentation of autism and the impact that core and related symptoms have on day-to-day living, alongside lots of different views and opinions about autism and what the label means to people. And in this context, terms like 'relevant to the community' and 'consistent with their values' are difficult concepts to entertain in any universal sense because there really is no single 'autistic community' or universally shared values. Remember: if you met one person with autism... Indeed, their meaning may also likely be something slightly different to the 'under-studied' parts of the autism spectrum for example (see here), where voices seem to be currently less well heard in many different scenarios (see here).

I was also a little confused to read the word 'allies' multiple times in the Fletcher-Watson paper, denoting those who are not autistic but share the various views and opinions of those on the spectrum particularly included in the article. 'Allies' is typically a word used in the context of combat and warfare. I appreciate that there are debates/arguments on-going in the autism 'community' that sometimes look and feel like warfare. But the implication from the use of such a 'them-and-us' term, particularly in the context of a research paper, is that if you're 'for' participatory research of the specific type highlighted by the authors, you're an ally. If you're not, or if your opinion differs in terms of possible research priorities (whether you are autistic or not), then by definition, you're not an ally. This is important. Words matter, particularly in the context of 'participatory' research. I say all this also acknowledging that science should really be allegiance-free...

Without wishing to continue too much with the cautions and caveats when such inclusion efforts have noble goals, I have further points. Appreciating that some important research goals have already been published (see here) and with the rapid development of the ICF core sets for autism (see here), there are already plenty of research directions that need to be taken which prioritise people with autism / autistic people and the day-to-day challenges they face; all already including input from people on the autism spectrum. In this respect, participatory research is nothing new to autism.

Insofar as that research 'relevant to the community' (or should that be 'communities') opinion, I'd also advance the idea that 'life-saving' should perhaps represent the first tier of autism research importance to any participatory strategy, as issues such as wandering, suicide risk and early mortality (see here, see here and see here respectively) continue to remain ever-present and significantly impact on many peoples' lives - again, particularly among those who perhaps fall into that 'under-represented' categorisation of autism (see here). The alleviation of pain and suffering, whether physical (see here for one example) or otherwise (see here), should probably form the next tier of research importance. And perhaps another tier of participatory research could be devoted to giving those with autism who seemingly don't have a voice, the means to communicate their wants, needs and desires and thus enable themselves to participate further in such participatory schemes. Just my observations...

A final question I have for such participatory research is an ethical one in the context of some likes and dislikes voiced by some on the autism spectrum: if for example, by tackling such primary issues such as depression and anxiety that plague many people on the autism spectrum and often severely impact on quality of life, it actually means having to intervene on the core presentation of autism (see here and see here for other research in these areas), would such participatory research 'alliances' be brave enough to take on such an option? If for example, it mean't that something like the presence of social-communication issues showed a *connection* to the experience(s) of depression for example (see here), would such participatory research look to evidence-based strategies and possibilities to try and 'change' such core issues and behaviour? Or would the conversations just revert back to something like the tenets of the social model of disability as being the primary reason for such issues as per other examples (see here)?

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[1] Fletcher-Watson S. et al. Making the future together: Shaping autism research through meaningful participation. Autism. 2018 Aug 10:1362361318786721.

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Friday, 10 August 2018

"Risk markers for suicidality" and autism: masking or insight as a feature?

The findings reported by Sarah Cassidy and colleagues [1] continue an important research theme in relation to risk of suicide and autism (see here). The value-added bit to their research on this occasion was the observation that "there are unique factors associated with autism and autistic traits that increase risk of suicidality" and that some of these factors may be potentially modifiable.

Members of this research team have some important research history [2] when it comes to looking at suicidality and autism. This time around they report the results of an on-line survey completed by over 160 adults on the autism spectrum and a similar number of not-autistic controls. Prior to the delivery of this survey we are told that a steering group of autistic adults / adults with autism helped to target the research towards what factors might be relevant, including: "non-suicidal self-injury, mental health problems, unmet support needs, employment, satisfaction with living arrangements, self-reported autistic traits (AQ), delay in ASC [autism spectrum condition] diagnosis, and ‘camouflaging’ ASC."

"Results are consistent with previous findings that autistic adults are at significantly increased risk of suicidality compared to the general population." As worrying as that finding is, the observation that suicidality is elevated in relation to autism is nothing new. Indeed, as far back as the late 1990s, there were rumblings of 'under-reporting' of suicidality in relation to autism and related developmental disorders.

Continuing: Various psychiatric labels/conditions were identified as being present in those with autism at a greater frequency than controls. This included various 'comorbidities' previously discussed with autism in mind (see here and see here). Several of those conditions have also been identified as key risk variables when it comes to suicidality. I was also particularly drawn to the rate of personality disorder (PD) identified in this sample: 18% in females with autism compared with 3-4% in control females for example. This is interesting in light of other research explored on this blog (see here) and again, some evidence of an enhanced risk for suicide alongside such a condition. And mention of 'Myalgic encephalopathy' I assume akin to Myalgic Encephalomyelitis (ME), another mainstay topic of this blog, perhaps taps into an area that requires lots more study on the possible overlap between autism and ME/CFS (chronic fatigue syndrome) (see here). Indeed, in future posts I'll be [again] covering research on the issue of suicide in relation to ME/CFS [3] that could also be relevant to autism and ME/CFS when co-occurring, reiterating that ME/CFS is not a psychiatric or mental health diagnosis...

Onward: "These results suggest that autism diagnosis and autistic traits explain significant additional variance in suicidality beyond a range of known risk factors, and are therefore independent risk markers for suicidality." So 'autistic traits as being independent risk markers for suicidality'. This is not the first time that such peer-reviewed sentiments have been reported (see here) and probably won't be the last. The logical implications from such a finding is that a reduction in autistic traits may well impact on suicidality. This is not a sentiment that some people will find palatable, but that's the logical implication stemming from such a finding.

Finally, quite a lot has been made (on social media at least) about the issue of camouflaging (masking) and a possible connection to suicidality in relation to autism. Masking reflects the idea that some on the autism spectrum actively camouflage signs and symptoms "in order to cope in social situations." The authors report that: "Camouflaging and unmet support needs appear to be risk markers for suicidality unique to ASC [autism spectrum conditions]." I'm however slightly cautious of this at the moment when wearing my objective science hat. One has to remember that, at present, there aren't many (any?) well validated tools for objectively assessing masking in relation to autism. In this study, Cassidy and colleagues mention how: "A brief set of four questions were designed to quantify tendency to camouflage." The answers to such a small set of open questions are subject to considerable bias (particularly if the individual is active on social media and perhaps privy to all the discussions around masking on there). One also cannot discount the idea that having the fundamental ability of 'insight' to be able to mask/camouflage may itself be a risk factor for suicidality. I say this on the basis of other research talking about how a higher cognitive capacity in relation to autism seems to increase the risk of vulnerability to depression (see here) as a function of the link between depression and suicidality. Simple answers to complex questions are likely to be few and far between.

So, where next? Well, being careful not to fall into any sweeping generalisations or psychobabble explanations of suicide risk in relation to autism, it strikes me that there are a few things to think about in terms of harm reduction. Screening for something like depression and/or non-suicidal self-injury (NSSI) should be much more widespread in the context of autism. Obviously, such behaviours / diagnoses are not just 'locked in' over a lifetime, so such screening needs to be done quite regularly. I would also mention that other comorbidity seemingly over-represented when it comes to autism might also exert an important effect too (see here). Tackling 'unmet support needs' also looks to be important. I'm slightly less sure of how to go about affecting this, given that the availability of many services are seemingly at the whim of finances and resources, which continue to be in short supply in these austere times (see here). But where there's a will, there's a way. I'll also reiterate that if certain autistic traits are themselves independent risk factors for suicidality, it surely follows that moves to reduce such behaviours would impact on suicidality. Indeed, in this context, the active process of masking could be seen as a double-edged sword when it comes to suicidality and autism.

And I'm also minded to bring in some important literature where autism is talked about in the context of euthanasia and assisted suicide (see here) and what lessons could be learned from some of the accounts detailed there. It's another difficult topic to discuss but something that is becoming increasingly relevant (see here).

As always, if you need someone to talk to (or text), there are organisations available. Please use them.

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[1] Cassidy S. et al. Risk markers for suicidality in autistic adults. Mol Autism. 2018 Jul 31;9:42.

[2] Cassidy S. et al. Suicidal ideation and suicide plans or attempts in adults with Asperger's syndrome attending a specialist diagnostic clinic: a clinical cohort study. Lancet Psychiatry. 2014 Jul;1(2):142-7.

[3] Devendorf AR. et al. Suicidal ideation in non-depressed individuals: The effects of a chronic, misunderstood illness. J Health Psychol. 2018 Jul 1:1359105318785450.

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Thursday, 9 August 2018

On postpartum paracetamol metabolites and risk of offspring ADHD: details matter

The findings reported by Yuelong Ji and colleagues [1] provide the blogging fodder today, as once again the topic of acetaminophen (a.k.a paracetamol) use during pregnancy and offspring risk of attention deficit hyperactivity disorder (ADHD) is in the spotlight. I say 'once again' because this topic has cropped up time and time again on this blog (see here for example).

On this research occasion, the starting point was the Boston Birth Cohort (a cohort that has been mentioned before) and specifically, an analysis of "maternal plasma acetaminophen metabolites levels measured within a few days after delivery and ADHD diagnosis in the offspring" as a measure of paracetamol exposure. The metabolites in question were "unchanged acetaminophen, acetaminophen glucuronide, and 3-(N-Acetyl-l-cystein-S-yl) acetaminophen." All were measured in blood plasma using one of the gold-standard chemical analytical techniques: mass spectrometry. A diagnosis of ADHD was extracted from medical records on the basis of ICD-9 and/or ICD-10 definitions.

Results: taking into account other potential confounding variables, authors reported finding "a significant positive association between maternal blood acetaminophen metabolite levels measured within 1–3 days postpartum and ADHD diagnosis in offspring." It's perhaps however important to understand how such a finding was arrived at, bearing in mind that ADHD was not the only diagnostic fruit examined in the Ji study. So: "The main exposures analyzed in this study were maternal acetaminophen metabolite levels, which were inverse normal transformed to approximate the normal distribution." What this means is that rather than reporting the specific levels of each paracetamol metabolites across different diagnoses and a 'neurotypical group' ("Children without any diagnosis of ASD [autism spectrum disorder], ADHD, developmental delays, or intellectual disabilities were classified as neurotypical (NT)"), authors chose to covert the raw values into groupings. Groupings were based around "no detection, below median, above median of detected values." I'm not altogether sure that this is the best way to report results; certainly I would have liked to have seen the raw values for each metabolite according to group as a comparator; but that's just my research preference. Researchers mention that they did not see any association between paracetamol metabolites and any other diagnostic label, and also stressed how the association remained when other potentially confounding variables were taken into account. And when it comes to ADHD, there are a few (see here for example).

How much weight can we give these results? Well, this is probably the first time that someone has looked at actual paracetamol metabolites in mums rather than just relying on maternal or doctor records of paracetamol usage during pregnancy, and that's a good thing. Authors also mention that their study was "further strengthened by the diagnosis of ADHD by both general pediatricians and developmental specialists." Add in the prospective design of the study, and you have some potentially important evidence for a *relationship* between paracetamol use and subsequent offspring development.

But... "this study only included a one-time measurement of maternal acetaminophen metabolite levels within 1–3 days postpartum." The authors rightly acknowledge that paracetamol is pretty quickly metabolised in the body so, at best, their study really only looked at recent paracetamol use immediately during or after birth. Maybe further study of archived samples during pregnancy (at multiple points during pregnancy) would provide some further information? And comments from the authors like "women with detectable levels of acetaminophen biomarkers are likely to be more regular users" really don't have any place in a scientific paper without supporting evidence. Particularly when pain relief is going to be pretty important when it comes to the process of childbirth.

Also: "our metabolite measurement method did not include acetaminophen sulfate, which accounts for 30–44% of the total metabolites of acetaminophen under the normal dosage." I don't want to go into the nitty-gritty of paracetamol metabolism, but just going back to the research looking at sulphation (sulfation) in the context of autism (see here), it would have been useful to examine both paracetamol sulphate and paracetamol glucuronide at the same time. Certainly it would have provided a more complete picture of typical paracetamol metabolism.

Don't get me wrong, I am interested in the Ji findings and their addition to the literature on paracetamol use and offspring outcomes. This still remains an important area of investigation. I'm not however completely convinced that the evidence presented by Ji and colleagues counts as particularly strong evidence despite the important measurement of paracetamol metabolites in this context...

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[1] Ji Y. et al. Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder. Brain Sci. 2018 Jul 3;8(7). pii: E127.

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Wednesday, 8 August 2018

Autism prevalence in California: 1931 to 2014

Credit: Nevison et al, 2018
'Autism prevalence' is a topic of real discussion both inside and outside of autism research circles. It's not so much a debate about whether there has been an increase in the numbers of people being diagnosed with autism or autism spectrum disorder (ASD) - there has and continues to be (see here and see here) - but rather the extent of the increase and the possible reason(s) behind such an increase.

The paper published by Cynthia Nevison and colleagues [1] adds something further to the autism prevalence discussions. They focused on how much of an increase in cases of autism has been noted in one part of the United States (US) and how some notable birth years have been seemingly driving the increase.

OK, first things first, Nevison et al are no strangers to the [peer-reviewed] debates around the autism numbers (see here and see here). Their previous analyses have concluded that the increase in cases of autism in the US is NOT solely driven by changing diagnostic criteria or diagnostic switching/substitution, although these factors have probably played some role. Yes folks, there might have been a very real increase in the numbers of people being diagnosed with autism (see here).

On this most recent research occasion, Nevison and co-author Mark Blaxill are joined by a noteworthy figure in the field of autism prevalence tracking, Walter Zahorodny. Zahorodny is intricately involved in tracking autism prevalence in New Jersey (see here) and was also listed as an author on the most recent CDC stats regarding estimated autism prevalence that were quite quietly published a few months back [2]. In short, he's an expert in such matters.

Authors started with the California Department of Developmental Services (CDDS) data on autism which "provides services to eligible individuals living in California who meet the DSM diagnostic criteria for autism." In the age of the (very) wide autism spectrum, the CDDS has been pretty reserved in terms of who gets the services it offers. The term 'code 1 autism' has been used to refer to CDDS recipients eligibility, where autism or autistic disorder was typically the diagnosis listed and importantly: "individuals applying for CDDS services must demonstrate significant functional disability in 3 out of 7 life challenges, which include self-care, language, learning, mobility, self-direction, capacity for independent living and economic self-sufficiency." We are told that: "Milder subtypes such as Asperger’s syndrome and PDD-NOS [pervasive developmental disorder - not otherwise specified] have not been eligible for services unless they have another qualifying disability" (authors words not mine). With the onset of the DSM-5 description of autism, where individual diagnoses like PDD-NOS and Asperger syndrome have been 'rolled' into one definition (autism spectrum disorder), the CDDS has had to adapt and change. The years 2016 and 2017 have been particularly important for the DSM-5 change to the CDDS.

Added to their examination of the CDDS data, authors also looked at a couple of other initiatives with autism prevalence data: The Individuals with Disabilities Education Act (IDEA) and the Autism and Developmental Disabilities Monitoring (ADDM) Network. As I've already mentioned, Zahorodny has been quite 'active' in ADDM research circles for some time.

From all this [estimated] prevalence of autism data, authors set about to 'visualise' autism prevalence data extracted from the CDDS and other information sources and further examine whether "ASD is truly a constant prevalence condition" taking into account the various methods for collecting data on autism prevalence.

Credit: Nevison et al. 2018
Results: "The data are consistent across methods in showing a strong upward trend over time." The long-term trend of autism prevalence based on the CDDS data show "an apparent ~ 1000-fold increase in CDDS autism prevalence between birth year 1931, when prevalence was only ~ 0.001%, and birth year 2012, when prevalence had increased to 1.18% among 5 year-olds born in that year." Nevison et al talk about "age-resolved snapshot and constant-age tracking method[s]" as tools in their research, but the long-and-short of it is that the only way was up when it came to autism prevalence across the years. They further note: "The increase from ~ 0.001 to 1.18% in the 2012 birth cohort has occurred gradually, with a slow upward creep starting as far back as the 1940s, but with several change points along the way, around ~ 1980, ~ 1990, and ~ 2007, when the rate of growth accelerated."

I don't think there is too much more to say about the Nevison findings aside from reiterating that autism prevalence seems to have quite dramatically changed over the last 80 years or so. Insofar as those upticks in diagnoses around birth years 1980, 1990 and 2007, I'd be interested to know a little more about what factors might have been contributory to those particular years' growth or whether they are just statistical blips.

And before you say it, no, it's probably not just better awareness and the like...

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[1] Nevison C. et al. California Autism Prevalence Trends from 1931 to 2014 and Comparison to National ASD Data from IDEA and ADDM. J Autism Dev Disord. 2018. July 5.

[2] Baio J. et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. Morbidity and Mortality Weekly Report (MMWR). 2018; 67(6): 1-23.

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Thursday, 2 August 2018

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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Friday, 27 July 2018

'Comprehensive metabolomics' and ME/CFS: lipid and energy production turn up again

The findings reported by Dorottya Nagy-Szakal and colleagues [1] describing the results of "biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS [myalgic encephalomyelitis/chronic fatigue syndromepatients and 50 healthy controls" provide the rather long blogging fodder today.

Just in case that opening quote sounds like gibberish, this was a study that in effect examined two quite prominent biological 'systems' alongside looking at symptom profiles of participants diagnosed with ME/CFS compared with controls. Metabolomics is a discipline that is no stranger to this blog, and is focused on the analysis of small molecule metabolities in a range of biological fluids (see here). The interface between the technology used to separate out and analyse said metabolites and the statistical analysis of the huge amounts of data generated as a result, are what make metabolomics the science that it is. 'Fecal bacterial metagenomics' also known as microbiomics (see here) refers to the science of cataloguing what bacterial species are present in poo(p) samples. Yes, bacteria have their own genomes too, and stool samples can therefore be a rather informative medium.

It's important to realise that this isn't the first time that metabolomics has been spoken in the same breath as CFS/ME (see here and see here for examples); something alluded to in the Nagy-Szakal paper. Indeed, this most recent paper adds to the authors other work in this area [2] (see here for my take) where the focus was on immune-related parameters and their *association* with CFS/ME in the context of the gut and its bacterial inhabitants. And once again, there are some eminent research names included on the authorship list as last time...

So, fifty participants diagnosed with CFS/ME were compared with 50 asymptomatic (I hate the words 'healthy control') participants, and their blood (plasma) and stool were analysed. Mass spectrometry played an important role in their metabolomic work, as over 550 compounds were initially separated out from the samples provided and identified.

Results: "Among the top plasma biomarkers differentiating ME/CFS patients from controls were decreased levels of betaine, complex lipids (lysophosphatidylcholine [LPC], phosphatidylcholine [PC]) and sphingomyelin (SM), and increased levels of triglycerides (TG), α-N-phenylacetyl-glutamine, ε-caprolactam and urobilin." I'm not going to go through all of those compounds individually as to their possible relevance but there are some important classes of compound being mentioned (i.e. lipids and triglycerides).

Authors also mention another group of compounds as also potentially being important: ceramides. You may have heard the word 'ceramide' before if you are/were a user of certain brands of shampoo in recent times (see here). Outside of any hair care role, ceramide "is a waxy lipid implicated in suppression of electron transport, insulin and leptin resistance and apoptosis." Among the many roles they play 'in' the body, there is some research literature to suggest that ceramides "may play a role in gut barrier dysfunction and increased gut permeability." Interesting (see here). And going back to the Nagy-Szakal results we are told that "patients with ME/CFS and IBS [irritable bowel syndromehave increased plasma levels of ceramide." Even more interesting.

Having mentioned the gut and gut issues in the form of IBS, it's also important to note that the authors made allowances for the presence of such gut dysfunction in their participant groups. And yes, one needs to remember that it was "based on self-reported diagnosis of IBS on the medical history form". As probably expected, the introduction of IBS (self-reported) did seem to affect the metagenomic (microbiomic) data obtained (something authors talked about in their last paper). More than that: "Chemical enrichment analysis of plasma metabolites revealed that metabolomic profiles of ME/CFS patients with IBS were distinguished from controls by levels of TG, ceramides, phosphatidylethanolmines (PE) and metabolites in the carnitine-choline pathway." Indeed also, take away the IBS bit from the ME/CFS findings and: "ME/CFS patients without IBS co-morbidity showed disturbances in PCs and carnitine-choline pathways, similar to the disturbances found in the overall ME/CFS cohort." Again, interesting.

Authors conclude that their results draw attention to a few areas already pertinent to CFS/ME, in particular, "lipid and energy metabolism." The word 'mitochondria' figures a few times in their results write-up and specifically how: "compounds in the choline-carnitine pathway were decreased in ME/CFS patients regardless of their IBS status." I've written about quite a bit of research on mitochondria and CFS/ME (see here and see here for examples) and how even if there aren't genetic reasons for mitochondrial issues (see here), this does not mean that there may not be more other issues with this system (see here).

We really need much more research in the area of metabolomics and ME/CFS. And patients really need it now, not some time later in the future...

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[1] Nagy-Szakal D. et al. Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. Sci Rep. 2018 Jul 3;8(1):10056.

[2] Nagy-Szakal D. et al. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2017; 5: 44.

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