Thursday, 2 October 2014

Volatile organic compounds and autism

As harsh as the phrase volatile organic compounds (VOCs) might appear at first glance, all this refers to is a class of compounds containing carbon which have a tendency to evaporate at room temperature assuming normal air pressure. VOCs have been associated with pollutants as per their inclusion in various literature on the topic of things like indoor air pollution (see here) and the fact that just about everything around us in the modern home or office is likely to release VOCs. Whilst not trying to belittle the potential effects of some of those VOCs (see here) it is important to note however that living things also produce and release VOCs [1] as by-product of metabolism too.

The reason for the chatter about VOCs in today's post relates to a paper by Rosaria Cozzolino and colleagues [2] and their preliminary advances into investigating whether VOCs might have some potential as biomarkers for the autism spectrum disorders (ASDs). In amongst the authorship list on the Cozzolino paper I also note a familiar name - Laura de Magistris - who some people might recognise as being the lead on some of that very interesting leaky gut work (see here).

A few details from the paper first:

  • Regular readers on this blog might already know that I like talking about analytical chemistry, particularly when applied to autism or other potentially related conditions. In the case of the Cozzolino paper it was all about preparing urine samples from 24 children with autism and 21 asymptomatic controls via something called solid-phase extraction, sorry, solid-phase microextraction (SPME) and then applying the solute to analysis via gas chromatography - mass spectrometry (GC-MS) "to obtain metabolomic information patterns". Metabolomics by the way, is basically the collected analysis of small molecules (metabolites) in one or more biofluids.
  • Following some discriminant function analysis (DFA) of results from both groups prepared under both acid and alkaline conditions, authors presented quite a bit of data on what compounds, VOCs, might have some discriminatory function between the autism (A) group and the control (C) group. So: "Among these [compounds], 3-methyl-cyclopentanone, 3-methyl-butanal, 2-methyl-butanal, and hexane under acid conditions, and 2-methyl-pyrazine, 2,3-dimethyl-pyrazine, and isoxazolo under alkaline pH had statistically higher levels in urine samples from autistic children than from the control group".
  • Authors suggested quite a bit more analysis might be needed to look at the "metabolic origins of these variables" and "verify the usefulness... for early-stage [autism] diagnosis".

I know, I know. Mention of the word 'biomarker(s)' when it comes to such a heterogeneous and possibly plural condition like 'the autisms' is still something rather problematic as things currently stand. I'm not saying that there may not be specific types of autism (endophenotypes) which might be amenable to certain biomarkers such as VOCs, but I don't quite think we are there yet in determining the hows and whys. And then there are the very small participant numbers reported on by Cozzolino et al...

But this is not the first times that VOCs have turned up in autism research. The paper by De Angelis and colleagues [3] (open-access) talked about levels of VOCs detected in poop samples being "markedly affected in PDD-NOS [Pervasive Developmental Disorder Not Otherwise Specified ] and, especially, AD [autism] children". Stool analysis and the gut microbiome, as regular readers of this blog might know, is of increasing interest to autism research.

Keeping in mind discussions on VOCs in relation to [some?] autism, I'll also introduce the paper by Kalkbrenner and colleagues [4] which, following a review of the some of the literature on environmental chemical (yes, that word again) exposures and autism, suggested that there may be more to see when it comes to specific environmental factors. So: "some environmental exposures showed associations with autism, especially traffic-related air pollutants, some metals, and several pesticides, with suggestive trends for some volatile organic compounds (e.g., methylene chloride, trichloroethylene, and styrene) and phthalates". This on the back of previous research from this author on this topic [5].

Accepting that VOCs cover a whole slew of different compounds and that not every VOC has been analysed with an autism link (or not) in mind, the various papers hint that we should be a little more wary of this class of compounds and perhaps a little more inquisitive when it comes to a condition like autism.


[1] Shirasu M. & Touhara K. The scent of disease: volatile organic compounds of the human body related to disease and disorder. J Biochem. 2011 Sep;150(3):257-66.

[2] Cozzolino R. et al. Use of solid-phase microextraction coupled to gas chromatography–mass spectrometry for determination of urinary volatile organic compounds in autistic children compared with healthy controls. Analytical & Bioanalytical Chemistry. 2014. 10.1007/s00216-014-7855-z

[3] De Angelis M. et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One. 2013 Oct 9;8(10):e76993.

[4] Kalkbrenner AE. et al. Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence. Curr Probl Pediatr Adolesc Health Care. 2014 Sep 4. pii: S1538-5442(14)00074-1.

[5] Kalkbrenner AE. et al. Perinatal exposure to hazardous air pollutants and autism spectrum disorders at age 8. Epidemiology. 2010 Sep;21(5):631-41.

---------- Cozzolino R, De Magistris L, Saggese P, Stocchero M, Martignetti A, Di Stasio M, Malorni A, Marotta R, Boscaino F, & Malorni L (2014). Use of solid-phase microextraction coupled to gas chromatography-mass spectrometry for determination of urinary volatile organic compounds in autistic children compared with healthy controls. Analytical and bioanalytical chemistry, 406 (19), 4649-62 PMID: 24828982 Kalkbrenner AE, Schmidt RJ, & Penlesky AC (2014). Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence. Current problems in pediatric and adolescent health care PMID: 25199954

Wednesday, 1 October 2014

Maternal complement C1q and offspring psychosis

"In conclusion, exposure to maternal C1q activity during pregnancy may be a risk factor for the development of schizophrenia and psychosis in offspring". That was the primary observation made by Emily Severance and colleagues [1] at Johns Hopkins, extending their scientific interest in immune system involvement being potentially linked to psychiatry [2].
"Serve the public trust, protect the innocent,
uphold the law"

I've already talked about Dr Severance's previous research forays into complement factor C1q and psychiatry on this blog (see here) and how C1q seropositivity was pretty significantly associated with both recent and non-recent onset schizophrenia in their cohort. Said complexing of C1q also turning up food components (gluten and casein) as potentially being involved [3] which has rumbles of Dohan's hypothesis [4] mixed in.

The most recent Severance paper takes things another stage further by trying to "determine if maternal C1q was associated with offspring schizophrenia and psychosis". Archived serum samples provided during pregnancy were therefore analysed for 55 "matched case-control" pairs of mothers - mothers with offspring who went on to develop psychoses as adults and those with offspring who were asymptomatic from such psychiatric issues. "IgG markers of C1q, bovine milk casein, egg ovalbumin, and wheat gluten were measured". Authors reported that: "C1q was significantly elevated in case mothers" and in that case group, where offspring developed psychoses: "C1q was significantly correlated with antibodies to both food and infectious antigens: gluten..., herpes simplex virus type 2..., and adenovirus".

Accepting that the total number of participants included in this latest trial was relatively small, also relying on archived samples collected as part of the US Collaborative Perinatal Project (CPP) [5], these are interesting results. That both food and infectious agent antigens seemed to correlate with C1q adds to other interesting work by Dr Severance and colleagues on, for example, the protozoan Toxoplasma gondii potentially joining forces with food antigens (see here) in some fashion. I don't know enough about the processes potentially involved in any relationship to provide any definitive answers as to the hows and whys but one hazards a guess that something like an effect on gastrointestinal barrier function might play some role [6].

This and other research from people such as the late Paul Patterson [7] continue to drive home the notion that maternal infection, or rather the immune processes and consequence of infection during pregnancy, seem to be able to influence later life outcomes for offspring. We still need to know more about the specific biological processes involved in any relationship including the rising scientific star that is epigenetics [8] (something covered in a recent blog post) and also how subsequent life events (whether biological, social or psychological) contribute to any psychiatric diagnosis. Whether for certain people or groups of people, there may be some merit at looking further at gastrointestinal (GI) functions (see here) or even dietary changes (see here) is perhaps something else worth investing a little more research time and effort into too...

Ben Folds Five to close...


[1] Severance EG. et al. Maternal complement C1q and increased odds for psychosis in adult offspring. Schizophrenia Res. 2014. 4 September.

[2] Severance EG. et al. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res. 2014 Jul 14. pii: S0920-9964(14)00319-3.

[3] Severance EG. et al. Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia. Neurobiol Dis. 2012 Dec;48(3):447-53.

[4] Dohan FC. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophr Bull. 1988;14(4):489-94.

[5] Klebanoff MA. The Collaborative Perinatal Project: a 50-year retrospective. Paediatr Perinat Epidemiol. 2009 Jan;23(1):2-8.

[6] Nouri M. et al. Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells. PLoS One. 2014 Sep 3;9(9):e106335.

[7] Brown AS. & Patterson PH. Maternal infection and schizophrenia: implications for prevention. Schizophr Bull. 2011 Mar;37(2):284-90.

[8] Tang B. et al. Epigenetic changes at gene promoters in response to immune activation in utero. Brain Behav Immun. 2013 May;30:168-75.

---------- Emily G. Severance, Kristin L. Gressitt, Stephen L. Buka, Tyrone D. Cannon, & Robert H. Yolken (2014). Maternal complement C1q and increased odds for psychosis in adult offspring Schizophrenia Research : 10.1016/j.schres.2014.07.053

Tuesday, 30 September 2014

Autoimmune thyroiditis and depressive disorder

"Our study demonstrates a strong association between anti-TPO levels, which are considered to be of diagnostic value for autoimmune thyroiditis... with uni- or bipolar depression."
"Beware the bad cat bearing a grudge"

So said the study published by Detlef Degner and colleagues [1]. Anti-TPO antibodies by the way, refers to anti-thyroid peroxidase antibodies which, as the name suggests, are antibodies against thyroid peroxidase, an important step in the production of thyroid hormones. Said thyroid hormones have some pretty far-reaching effects on our physiology. Anti-TPO antibodies are also diagnostic for autoimmune related conditions affecting the thyroid such as Hashimoto's thyroiditis.

The Degner paper looked at a small group of participants diagnosed with depression (n=52) and analysed various thyroid related measures compared with a smaller control group made up of 19 participants diagnosed with schizophrenia. Authors reported a "pathologically increased" frequency of anti-TPO antibodies in those with depression compared with those with schizophrenia (32% vs 5% respectively). With something of a rather large confidence interval (CI) and hence the need for quite a bit more investigation, they also reported "the odds ratio of uni- or bipolar patients with depression for an autoimmune thyroiditis was ten times higher...  when compared with schizophrenia patients".

Reiterating again the quite small participant numbers, one needs to be rather careful with this particular study before too many firm conclusions are reached. Added to the fact that there was no asymptomatic control group included for study, I'd like to see quite a bit more done in this area before pinning my colours to any particular mast. That being said, this is certainly not the first time that (a) thyroid function has been correlated with depressive symptoms or depressive disorder [2] and/or (b) elevated levels of anti-TPO antibodies have been linked to depression [3] also crossing different geographies [4]. The paper by Carta and colleagues [5] (open-access) further extends the anti-TPO antibody link to "mood and anxiety disorders". This, complete with some discussion about how a "sub-clinical dysfunction of axis Thyrotropin Releasing Hormone (TRH) – Thyroid Stimulating Hormone (TSH) with consequent alteration of circadian rhythms of TSH" might be involved, linking an "aberrancy in the immuno-endocrine system" as a bridge between autoimmunity and psychiatry.

Autoimmune conditions have been previously discussed on this blog as potentially being a risk factor for mood disorder (see here). Under this banner, I'm minded to bring in another paper by Carta and colleagues [6] discussing how "Anti-TPO prevalence was significantly higher in celiac patients than in the control group" and further: "A higher frequency of PD [panic disorder] and MDD [major depressive disorder] was found in celiac patients with positive anti-TPO when compared to negative anti-TPO patients". This assumes that there may be some elevated risk of autoimmune issues impacting on the thyroid extending into other autoimmune conditions such as celiac (coeliac) disease as per other work. I could start going on about how this research might impact on other peripheral work e.g gluten exposure and feelings of depression but don't want to get too speculative at this point on any correlation with something like gluten or gut permeability.

Suffice to say that outside of just looking at thyroid-stimulating hormone (TSH) levels, the Degner results and other research suggest a whole other ballgame of autoimmune involvement affecting thyroid function and potentially impacting on psychiatry...

Music to close: I Will Wait by Mumford and Sons.


[1] Degner D. et al. Association between autoimmune thyroiditis and depressive disorder in psychiatric outpatients. Eur Arch Psychiatry Clin Neurosci. 2014 Sep 6.

[2] Demartini B. et al. Depressive Symptoms and Major Depressive Disorder in Patients Affected by Subclinical Hypothyroidism: A Cross-sectional Study. J Nerv Ment Dis. 2014 Aug;202(8):603-7.

[3] Pop VJ. et al. Are autoimmune thyroid dysfunction and depression related? J Clin Endocrinol Metab. 1998 Sep;83(9):3194-7.

[4] Muñoz-Cruzado Poce MJ. et al. Prevalence of thyroid disorders in patients diagnosed with depression. Aten Primaria. 2000 Jul-Aug;26(3):176-9.

[5] Carta MG. et al. The link between thyroid autoimmunity (antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the community: a field of interest for public health in the future. BMC Psychiatry. 2004 Aug 18;4:25.

[6] Carta MG. et al. Association between panic disorder, major depressive disorder and celiac disease: a possible role of thyroid autoimmunity. J Psychosom Res. 2002 Sep;53(3):789-93.

---------- Degner D, Haust M, Meller J, Rüther E, & Reulbach U (2014). Association between autoimmune thyroiditis and depressive disorder in psychiatric outpatients. European archives of psychiatry and clinical neuroscience PMID: 25193677

Monday, 29 September 2014

Term vs. preterm birth and the presentation of autism

The paper by Katherine Bowers and colleagues [1] continues the interest in the concept of 'the autisms' with their observations on the presentation of autism (and its comorbidities) when looking at those "born preterm versus those born at term".

We'd better get back, 'cause it'll be dark soon,
and they mostly come at night... mostly
Based on an analysis of quite a healthy participant number heading up to 900 "males and females with autism spectrum disorder", authors reported on several phenotypic differences between the 13% born preterm compared to the majority born following a full-term pregnancy. These differences, also influenced by gender, were in core areas such as language skills and the presence of comorbidities such as sleep apnea and attention-deficit hyperactivity disorder (ADHD). The authors conclude that their results "may have implications for understanding the underpinnings of a subset of individuals with autism spectrum disorder and contribute to the development of focused treatments for autism spectrum disorder among children born preterm".

Whilst one should always be a little cautious about making too much of any specific link with something like preterm birth (see here to illustrate the many and varied outcomes following this variable) I was interested in the Bowers' results. I think back to similar research into autism subgroups from Unwin and colleagues [2] (talked about in a previous post) describing how low birth weight was "associated with greater sleep disturbances".

Although many variables can affect foetal growth measures, preterm birth can adversely impact on birth weight and with that, one might see a possible common feature appearing in relation to issues at birth. That being said, the strength of any association between preterm birth and something like the comorbid presence of ADHD in cases of autism is likely to be a complex issue as per the findings from Harris and colleagues [3] who concluded that in the general population: "former late preterm infants have similar rates of LD [learning disabilities] and ADHD as term infants".

Bowers et al also took into account a role for gender in their results, reporting that there may be more to see here. Although quite an obvious variable to look at when it comes to autism (see here), there is perhaps not as much appreciation of how sex might link into autism phenotypes as one might imagine. Recently, Reinhardt and colleagues [4] did venture into this area, concluding that whilst they did not see any "significant effects of sex or a diagnostic group by sex interaction" when it came to autism presentation, further research is indicated in this area. I might add that such investigations might also wish to look further at comorbidity too, or autism plus [5] if you like.

Music to close and Bulletproof by La Roux.


[1] Bowers K. et al. Phenotypic differences in individuals with autism spectrum disorder born preterm and at term gestation. Autism. 2014 Sep 5. pii: 1362361314547366.

[2] Unwin LM. et al. A "bottom-up" approach to aetiological research in autism spectrum disorders. Front Hum Neurosci. 2013 Sep 19;7:606.

[3] Harris MN. et al. ADHD and learning disabilities in former late preterm infants: a population-based birth cohort. Pediatrics. 2013 Sep;132(3):e630-6.

[4] Reinhardt VP. et al. Examination of Sex Differences in a Large Sample of Young Children with Autism Spectrum Disorder and Typical Development. J Autism Dev Disord. 2014 Sep 5.

[5] Gillberg C. & Fernell E. Autism Plus Versus Autism Pure. J Autism Dev Disord. 2014 Jun 24.

---------- Bowers K, Wink LK, Pottenger A, McDougle CJ, & Erickson C (2014). Phenotypic differences in individuals with autism spectrum disorder born preterm and at term gestation. Autism : the international journal of research and practice PMID: 25192860

Sunday, 28 September 2014

Autism across DSM-IV and DSM-5 descriptions

The paper/poster(?) by Harker & Stone [1] kinda says it all when it comes to the question: what changed in the description of autism between the DSM-IV-TR and DSM-5? The added bonus of comparing the US IDEA (Individuals with Disabilities Education Act) description of autism with DSM-5 will, I assume, also be important to quite a few people not least when it comes to any further research which uses the datasets on numbers of cases for example (see here).

I have little more to say aside from reiterating what already appears to be happening when it comes to the use of the revised descriptions of autism - autism spectrum disorder - in DSM-5 on numbers being diagnosed (see here). That and the requirement for quite a bit more investigation on the social communication disorder (SCD) category [2] including what a diagnosis of SCD actually translates into in terms of services and provisions offered compared to a DSM-5 diagnosis of ASD...


[1] Harker CM. & Stone WL. Comparison of the Diagnostic Criteria for Autism Spectrum Disorder Across DSM-5, DSM-IV-TR, and the Individuals with Disabilities Act (IDEA)3 Definition of Autism.

[2] Norbury CF. Practitioner review: Social (pragmatic) communication disorder conceptualization, evidence and clinical implications. J Child Psychol Psychiatry. 2014 Mar;55(3):204-16.


Saturday, 27 September 2014

Yes, people with autism do have headaches

I don't mean to be haughty but a sentence included in the paper by Victorio [1] led to the title of today's very quick post. Based on a chart review of patients diagnosed with an autism spectrum disorder (ASD) attending a neurology clinic, the author concluded that "ASD patients, despite being known to have indifference to pain, can experience headaches".

Pain is something which has cropped up quite a bit in the autism research arena and has appeared more than once on this blog (see here and see here). The suggestion of an 'indifference' to pain being potentially over-represented in relation to autism I think stretches back to some older work which I have to say, has been pretty widely disputed in more recent years [2].

The focus on migraine as "the most frequent headache type" reported by Victorio might also be quite interesting in light of other research linking migraine headaches to some of the sensory issues reported in cases of autism [3]. Moving migraine away from just the head was also a suggestion put forward by another author [4] which opens up a whole new world of possibilities...


[1] Victorio M. Headaches in patients with autism spectrum disorder. The Journal of Headache and Pain 2014, 15(Suppl 1):B37.

[2] Nader R. et al. Expression of pain in children with autism. Clin J Pain. 2004 Mar-Apr;20(2):88-97.

[3] Sullivan JC. et al. The presence of migraines and its association with sensory hyperreactivity and anxiety symptomatology in children with autism spectrum disorder. Autism. 2013 Sep 26;18(6):743-747.

[4] Casanova MF. The minicolumnopathy of autism: A link between migraine and gastrointestinal symptoms. Med Hypotheses. 2008;70(1):73-80.

---------- Victorio, M. (2014). EHMTI-0290. Headaches in patients with autism spectrum disorder The Journal of Headache and Pain, 15 (Suppl 1) DOI: 10.1186/1129-2377-15-S1-B37

Friday, 26 September 2014

Schizophrenia after child and adolescent psychiatric disorders

More of a 'bring to your attention' post today, as I bring to your attention(!) the paper by Cecilie Frejstrup Maibing and colleagues [1] who concluded: "The risk of being diagnosed with schizophrenia spectrum disorders [SSD] after a child and adolescent psychiatric disorder was significantly increased particularly in the short term but also in the long-term period".
"I coulda been a contender"

The findings were based on an analysis of one of those very informative Scandinavian registries - based in Denmark - which initially identified over 25,000 people born between 1990-2000 diagnosed "with child and adolescent psychiatric disorders". Some 1200 of these people were subsequently diagnosed with schizophrenia spectrum disorders leading to the various conclusions and statistics being produced including: "The risk of schizophrenia spectrum disorders was highly elevated, particularly within the first year after onset of the child and adolescent psychiatric disorder, and remained significantly elevated >5 years with an incidence rate ratio of 4.93". Further: "among persons diagnosed with a child and adolescent psychiatric disorder between the ages 0-13 years and 14-17 years, 1.68% and 8.74 %, respectively, will be diagnosed with a schizophrenia spectrum disorder <8 years after onset of the child and adolescent psychiatric disorder".

With my autism research blogging hat on, and without hopefully making too many sweeping generalisations, I found the Maibing research to be rather interesting. I've previously talked about spectrums colliding on this blog (see here) with specific reference to the work of Kenneth Gadow [2] for example, on "an interrelation between ASD [autism spectrum disorder] and SSD symptoms". That and a post on 'labels and lumping' (see here) affirms that there may indeed be common ground between some of the spectrums, which I might add, are probably plural spectrums [3] (see my take here). As per other research on the possibility of Asperger syndrome in first-episode psychosis (see here), diagnostic vigilance seems to be a key point to take from the Maibing work, and that appears to extend well beyond just what happens after a diagnosis of autism is received...

So, Golden Touch by Razorlight.


[1] Maibing CF. et al. Risk of Schizophrenia Increases After All Child and Adolescent Psychiatric Disorders: A Nationwide Study. Schizophr Bull. 2014 Sep 5. pii: sbu119.

[2] Gadow KD. Schizophrenia spectrum and attention-deficit/hyperactivity disorder symptoms in autism spectrum disorder and controls. J Am Acad Child Adolesc Psychiatry. 2012 Oct;51(10):1076-84.

[3] Arnedo J. et al. Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies. Am J Psychiatry. 2014. September 15.

---------- Maibing CF, Pedersen CB, Benros ME, Mortensen PB, Dalsgaard S, & Nordentoft M (2014). Risk of Schizophrenia Increases After All Child and Adolescent Psychiatric Disorders: A Nationwide Study. Schizophrenia bulletin PMID: 25193974