Ultrafine particulate matter air pollution, mice and autism

Reading the headline "Study links air pollution to autism, schizophrenia" in a media piece about the study by Joshua Allen and colleagues* (open-access here) made me want to delve a little more into this research. I've talked before about air pollution and autism (see here) on this blog. Although a healthy degree of scepticism is to be expected with any autism correlation, particularly when it comes to something as generalised as air pollution (or pesticide exposure) there is a growing research interest in how this aspect of the environment may have some bearing on autism risk.

Cloudy with a chance of... @ Wikipedia 

A few details about the Allen study might be useful:

• This was a study involving mice. I'll repeat that: this was a study involving mice. It involved exposing a particular strain of mouse, modelled to represent a particular age "during early postnatal development" to "human relevant levels" of air pollution in the form of ultrafine particulates (<100 nm).
• Mouse brains were analysed at different time periods following exposure (24 hours, 40 days and 270 days after) looking at brain morphology, neurotransmitter levels and those all important immune system chemicals involved in processes like inflammation: the cytokines.
• Results: bearing in mind some quite detailed control of the amount of air pollution exposure mimicking ambient doses near roadways, quite a few effects were noted. There was for example, "a persistent dilation of the lateral ventricles" induced by CAPS (concentrated ambient ultrafine particles) "preferentially in male mice". I believe this is called ventriculomegaly.
• "CAPS induces brain region- and sex-dependent alterations in cytokines and neurotransmitters in both males and females". So in male mice, "increased hippocampal glutamate" among other things was observed. In females, "CAPS reduced hippocampal GABA" and more.
• Of the various cytokines included for analysis, an old friend ranked up there when it came to some of the results obtained: IL-6. Again, there seemed to be region and sex specific alterations to this cytokine and some of them were "unanticipated" as per the lower levels of IL-6 and other relations in certain areas. IL-6 shares some features of a pro-inflammatory and anti-inflammatory cytokine [2] although more often than not, it is the pro-inflammatory effects which get the headlines [3]. 
• The word 'microglia' also crops up in the Allen results. "CAPS altered IBA-1 immunostaining in the anterior commissure and hippocampus only in males". IBA-1 is a protein expressed in microglia.
• The authors conclude: "Collectively these data show a dramatic susceptibility of male mice to environmentally relevant levels of early postnatal air pollution exposure, with effects that persist into adulthood and cause permanent neuropathology characterized by ventricular enlargement, a pathology not seen in females".

Reiterating again that this was a study of mice and that mice are mice not humans, these are some intriguing data presented by Allen and colleagues. The focus on male mice slots nicely into the [seemingly] over-representation of autism in boys and men. Elevations in glutamate - hippocampal glutamate [4] in male mice - might also overlap with the growing fascination that autism and schizophrenia research have with this neurotransmitter (see here). Some light reading around the finding of "CAPS-induced ventricular enlargement" observed in males leads down some interesting paths such as a possible relationship with agenesis of the corpus callosum [5] reported to be "a major risk factor for developing autism" according to some authors [6]. In short, there are plenty of correlations seemingly heading back to conditions like autism.

But... there are a few important points to bear in mind before we get too carried away. First and foremost, nothing is reported in the Allen paper around mouse behaviour and how that may or may not have overlapped with other mouse data trying to model autism. One should always be a little cautious when one hears the words 'autistic behaviour' when it comes to a mouse and whether for example, they vocalise or not, or decide to bury their marbles in a particular way as being representative of facets of the condition. It isn't but it's some of the best animal model behaviour that we currently have including the rat models. Allen et al on this occasion reported nothing about behaviour and how it may or may not link to their physiological findings. 

Second is a question already asked by someone in/on the Twittersphere: "Air pollution was so much worse many decades ago yet autism rates staggeringly higher today, not then" (thanks Jill). This is an important point which may have lots of different answers bearing in mind your acceptance that things were worse back in olden times (see here for more news from urban China). Perhaps one of the most relevant issues at the moment was the study by Heather Volk and colleagues [7] discussed in a previous post (see here) talking about gene x environment interactions. If one assumes that genes, gene expression, are being affected by air pollution and that some people might already be more 'at risk' than others, there could be something more to do in this area of investigation.

Finally, Allen and colleagues seemed to have focused all their attention on the brain of their brave mouse participants. They don't talk about whether other organs or biological systems were affected by air pollution. I know that I'm probably going to get some rolling of the eyes for this but harking back to other mouse models of autism, I note some interest in things like the gastrointestinal (GI) tract to be an upcoming area (see here for example on the VPA mouse model). Assuming that the GI tract will also an important exposure point for air pollution [8], could there be merit in looking at this and other organs too all in the name of the gut-brain axis? Also, not forgetting lungs (see here) and skin as important exposure sites too.

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[1] Allen JL. et al. Early Postnatal Exposure to Ultrafine Particulate Matter Air Pollution: Persistent Ventriculomegaly, Neurochemical Disruption, and Glial Activation Preferentially in Male Mice. Environ Health Perspect. 2014 Jun 5.

[2] Scheller J. et al. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2011; 1813: 878-888.

[3] Rincon M. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends in Immunology. 2012; 33: 571-577.

[4] Kraguljac NV. et al. Increased Hippocampal Glutamate and Volumetric Deficits in Unmedicated Patients With Schizophrenia. JAMA Psychiatry. 2013; 70.

[5] Amato M. et al. Fetal ventriculomegaly, agenesis of the corpus callosum and chromosomal translocation--case report. J Perinat Med. 1986;14(4):271-4.

[6] Paul LK. et al. Agenesis of the corpus callosum and autism: a comprehensive comparison. Brain. 2014; April 25.

[7] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

[8] Kaplan G. Air pollution and the inflammatory bowel diseases. Inflamm Bowel Dis. 2011 May;17(5):1146-8.

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Allen JL, Liu X, Pelkowski S, Palmer B, Conrad K, Oberdörster G, Weston D, Mayer-Pröschel M, & Cory-Slechta DA (2014). Early Postnatal Exposure to Ultrafine Particulate Matter Air Pollution: Persistent Ventriculomegaly, Neurochemical Disruption, and Glial Activation Preferentially in Male Mice. Environmental health perspectives PMID: 24901756

Blood lead levels and childhood behaviour

"Blood lead concentrations, even at a mean concentration of 6.4 µg/dL, were associated with increased risk of behavioral problems in Chinese preschool children, including internalizing and pervasive developmental problems". That was the conclusion of the study by Jianghong Liu and colleagues [1] looking at blood lead levels in preschoolers aged 3-5 years resident in Jiangsu province in China. Some associated media accompanying this study can be viewed here including the text: "This research focused on lower blood lead levels than most other studies and adds more evidence that there is no safe lead level".

You lead... @ Wikipedia 

Lead (Pb) is a metal which has appeared before on this blog - quite a few times in fact (see here and see here for example) - all for the wrong reasons. Outside of it's many and varied industrial uses, including helping many of us get from A to B, lead is pretty dangerous stuff if it manages to find itself into the human and animal body in any amount particularly with its neurotoxic effects [2] in mind.

For quite a few years, much of the guidance on exposure to lead had suggested that blood lead levels above 10 μg/dL "should prompt public health actions" [3] albeit not defining "a threshold for the harmful effects of lead". As per that CDC report [3] there has been an increasing realisation that even blood lead levels below 10 microg/dL may have some undesirable effects particularly on infants and young children. Indeed the revised CDC guidance now lists "5 micrograms per deciliter of lead in blood" as the point where concerns should be raised about blood lead levels and action taken.

Back to the Liu paper...

• Looking at spot blood lead levels (BLLs) or even blood lead concentrations for over 1300 youngsters, researchers administered the "Chinese versions of the Child Behavior Checklist and Caregiver-Teacher Report Form" to parents and teachers of participants when children were aged 6 years old.
• Results: the mean (average) BLL for participants was 6.4 µg/dL, although a range of results were reported. Incremental increases in BLLs correlated with an "increase of teacher-reported behavior scores on emotional reactivity, anxiety problems, and pervasive developmental problems". Also: "mean teacher-reported behavior scores increased with blood lead concentrations, particularly for older girls".
• The authors conclude: "continued monitoring of blood lead concentrations, as well as clinical assessments of mental behavior during regular pediatric visits, may be warranted".

Bearing in mind this was a study looking at parent and teacher scoring of Chinese children and not more formal assessment of behavioural (or cognitive) issues, also focused on spot samples rather than multiple samples to assess BLLs, there are some important lessons to be learned from these results. Not least is the continued undesirability of contact with lead and it's potential effects on behaviour. I think back to some of the chatter on lead exposure and crime (see here) taking into account the old 'correlation is not the same as causation' mantra as one potential societal effect.

Reading through some of the other literature in this area, it's not difficult to find supporting information about the detrimental effects of lead exposure particularly in children. The paper by Hou and colleagues [4] (open-access here) pretty much sums it up: "Compared with healthy children, more children with lead poisoning had abnormal behaviors, especially social withdrawal, depression, and atypical body movements, aggressions and destruction". They conclude: "Lead is a neurotoxin with no physiological functions in the human body, the ideal concentration of which in the blood is zero".

Whilst exposure to lead through older formulations of petrol or house paint or plumbing is a declining issue in many areas of the world, I don't think we can be complacent about our situation. Roberts and colleagues [5] commented on this issue in their study (bearing in mind their use of the 10 microg/dL cutoff level). They noted: "Despite a low prevalence of children with EBLL [elevated blood lead levels], parental report suggested that approximately 29% of children had lead-based paint in their home environment". Similar analyses of other areas of lead exposure risk such as dust, soil and water suggest continued monitoring is required as per the study results from Oulhote and colleagues [6].

If there is a take-home message from this post and the Liu results it is that lead exposure can have often pronounced developmental effects on behaviour (and cognition) in infants and children and that even markers of low levels of exposure should be examined with much greater assiduity. Without trying to brush everyone with autism as lead poisoned, such results might also direct much greater research attention when findings of EBLL are noted in cases of autism (see here). Indeed, papers like the one from El-Ansary and colleagues [7] might offer much more information than they have hitherto been given credit for...

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[1] Liu J. et al. Blood Lead Concentrations and Children’s Behavioral and Emotional Problems. JAMA Pediatrics. 2014. June 30.

[2] Lidsky TI. & Schneider JS. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain. 2003; 126: 5-19.

[3] CDC. nterpreting and managing blood lead levels < 10 microg/dL in children and reducing childhood exposures to lead: recommendations of CDC's Advisory Committee on Childhood Lead Poisoning Prevention. MMWR Recomm Rep. 2007 Nov 2;56(RR-8):1-16.

[4] Hou S. et al. A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Theor Biol Med Model. 2013 Feb 18;10:13.

[5] Roberts JR. et al. Are children still at risk for lead poisoning? Clin Pediatr (Phila). 2013 Feb;52(2):125-30.

[6] Oulhote Y. et al. mplications of different residential lead standards on children's blood lead levels in France: predictions based on a national cross-sectional survey. Int J Hyg Environ Health. 2013 Nov;216(6):743-50.

[7] El-Ansary AK. et al. Relationship between chronic lead toxicity and plasma neurotransmitters in autistic patients from Saudi Arabia. Clin Biochem. 2011 Sep;44(13):1116-20.

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Liu, J., Liu, X., Wang, W., McCauley, L., Pinto-Martin, J., Wang, Y., Li, L., Yan, C., & Rogan, W. (2014). Blood Lead Concentrations and Children’s Behavioral and Emotional Problems JAMA Pediatrics DOI: 10.1001/jamapediatrics.2014.332

Organic acids as biomarkers of autism?

Whilst I am always a little cautious about the use of the word 'biomarker' when applied to a heterogeneous condition like autism, even the autisms, I am nevertheless always intrigued at any reasonable prospect reported in the scientific literature. So it was when I read the paper by Joanna Kałużna-Czaplińska and colleagues [1] and their assertion that "there is a significant metabolic difference between autistic and non-autistic children" and onwards that "21 metabolites were identified as potential biomarkers".

Let me expand on this a little...

• This was a small study looking at potential biomarker identification on the basis of the analysis of urine samples via gas chromatography-mass spectrometry (GC-MS). If you want some further background on this technique applied to autism research, have a look at a previous post (see here) where it has been utilised. Overnight urine samples from 14 children (aged 4-10 years) diagnosed with an autism spectrum disorder (ASD) undergoing "rehabilition" (whatever that means) were analysed in comparison to samples from 10 asymptomatic controls.
• Quite a bit of information is included about sample treatment and the analytical method. Each sample result was represented as a TIC (total ion count) and, as is often the case with such methods, data processing was an important part of the analysis. Most compounds were identified by cross-referencing with the NIST mass spectra library and via fragmentation patterns. Principal component analysis (PCA) was "applied to check the dataset structure and assess the variability of the profiles belonging to groups of autistic vs. non-autistic children". 
• Results: as indicated, 21 metabolites were deemed as "potential marker metabolites" some detected in higher quantities in the autism samples, and some lower. Fourteen of these compounds were described as organic acids. Without hopefully breaking any copyright, I've attached a copy of the table included in the paper with all the compounds differing between autism and control samples. The eagle-eyed will also note the big 'H' - homocysteine - to be a part of that list, and as expected, elevations in urinary homocysteine for the autism group as per other work in this area (see here).
• Given the title of this post I'll point out a few organic acids which seemed to be important differentiators between autism and control samples: (i) levels of beta hydroxybutyric acid were elevated in autism sample. This compounds has been talked about previously on this blog with regards to inborn errors of metabolism and autism (see here). (ii) Hydroxybenzoic acid was again elevated and perhaps ties into other findings from this group [2] potentially indicative of intestinal dysbiosis. (iii) Succinic acid levels were also generally elevated, and as the authors point out: "is considered a potential marker for deficiency of CoQ10 and riboflavin in children with autism". Co-enzyme Q10 y'say? I could go on, but won't.
• Various statistical models (PCA) were applied to the datasets which led authors to find: "The group of samples from non-autistic control children [were] more homogeneous than the group from autistic children". Further: "There is a clear distinction between those two groups of samples". ROC analysis looking at the performance of the PCA models was also applied leading authors to conclude that there may be something in their results from a diagnostic point of view.

Obviously the Kałużna-Czaplińska results are preliminary and in need of further independent replication. I note that quite a bit of the other literature in this area of biomarkers tend to use both training and test sets, where training samples provide your initial compounds of interest and test sets do just that, test your biomarker assumptions (see here). This wasn't the case in the current study but still leaves the door open to independent verification. That also the word 'comorbidity' does not seem to be mentioned as part and parcel of the autism group means the questions of how widespread comorbidity was in the autism participant group and whether this might have exerted an effect on the results obtained are unanswered. I might also quibble about the way that peaks in the TIC were assigned a compound name: "Peaks with the similarity index more than 80% were assigned compound names..." but now I'm just nit-picking.

That all being said, I do see some promise in the results obtained by Kałużna-Czaplińska et al. I note in another paper by some of the authors [3] they talk about how probiotic therapy might impact on both some of the behavioural measures of autism and also levels of one of the compounds picked up in their latest analysis, D-arabinitol. Again, I'd like to see more research done on this, alongside their other suggestion on the use of B vitamins (and magnesium) potentially affecting organic acids in cases of paediatric autism [4] talked about in a previous post (see here). The focus on the inner working of the gut, and particularly the trillions of gut bacteria which call us home, potentially being connected to some of these biomarkers, ties in well with an emerging autism research area (see here).

Music to close, and yet again my brood provide the inspiration as Bob Marley is fast becoming a YouTube favourite in our home with the classic One Love. You know you're getting old when your kids start listening to cooler music than you do...

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[1] Kałużna-Czaplińska J. et al. Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. Journal of Chromatography B. 2014. Feb 2.

[2] Kałużna-Czaplińska J. Noninvasive urinary organic acids test to assess biochemical and nutritional individuality in autistic children. Clin Biochem. 2011 Jun;44(8-9):686-91.

[3] Kałużna-Czaplińska J. & Błaszczyk S. The level of arabinitol in autistic children after probiotic therapy. Nutrition. 2012 Feb;28(2):124-6.

[4] Kałużna-Czaplińska J. et al. B vitamin supplementation reduces excretion of urinary dicarboxylic acids in autistic children. Nutr Res. 2011 Jul;31(7):497-502.

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Kałużna-Czaplińska J, Zurawicz E, Struck W, & Markuszewski M (2014). Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences PMID: 24565890

Joint hypermobility, gait and autism

I have already made mention of the paper by Maya Shetreat-Klein and colleagues [1] on this blog as part of a post on the potential usefulness of kata training for at least some people on the autism spectrum (see here). Based on an analysis of 38 children diagnosed with autism spectrum disorder (ASD) and a similar number of asymptomatic controls (all medication free), researchers set about recording "the characteristics of gait and prevalence of toe walking, the range of passive joint mobility, and age at walking" for their groups. They concluded that: "Children with ASDs had significantly greater joint mobility... more gait abnormalities... and on average walked 1.6 months later than their non-autistic peers". Ergo, much greater research focus should be directed to motor issues in cases of autism.

The cliff walk @ Wikipedia 

A few further details from the study might be useful:

• The analysis of movement such as gait and mobility is a science which I won't even pretend to understand. You get terms like goniometer fulcrum which probably makes a lot of sense to those in the know, but to me just sounds like a character from Game of Thrones. Suffice to say however that various measures were used to ascertain passive joint mobility - that is suppleness - across fingers, wrist, elbow and ankle. Gait was also analysed based on participants being "videotaped while walking and running barefoot up and down a hallway in the physician's office for 1-2 min".
• Results: as a group, participants with autism showed significantly greater values for maximum passive joint mobility angles across nearly all measured joints than controls. Taking one example, finger extension (or should that be 'finger metacarpo-phalangeal joint extension angle'), the authors present the very stark differences in angles obtained in histogram form between ASD and control participants. The majority of those with autism able to extend 110 degrees or over; such a feat only noted in 1 of the control participants. I might direct you to a post I wrote a while back on joint hypermobility (see here) which I'll talk about it moment.
• When it came to gait, the authors observed: "toe-walking was significantly more prevalent in children with autism" than controls (33% vs 3% observed on video only). I've talked about toe walking and autism in a previous post (see here) and what it may or may not mean for autism when present. Several other features of gait were also observed; 33% of children with autism were described as apraxic (an inability to execute learned purposeful movements) and 20% were described as clumsy. Both of these issues were not noted in any of the control group participants.

I found the Shetreat-Klein paper to be quite an intriguing read. Not only for the results obtained but because nestled in the paper introduction was reference to some of the original descriptions of autism by Leo Kanner, and how he "commented on the motor deficits in many of his patients". I've talked previously on this blog about how the seminal 1943 paper from Kanner [2] contained so much more than just descriptions of the triad (now dyad) of behaviours which make up the clinical diagnosis of the condition (see here). Aspects which we have perhaps ignored for too long...

The word 'hypotonia' - roughly translated as decreased or low muscle tone - is also a discussion point in the paper: "Our findings that passive joint mobility is on average increased in autism corroborates other studies that report a significantly increased proportion of clinically hypotonic children among those with ASD". Once again, I can't profess to be able to offer any great insight into this issue aside from some light reading around this concept and other uses in the research texts with autism in mind. Hypotonia seems to crop up quite a bit in various case reports detailing often rare genetic conditions with autism as part of presentation. Take for example the paper by Belengeanu and colleagues [3] reporting on a young child presenting with developmental delay and among other things, hypotonia. The paper by Shuvarikov and colleagues [4] talking about a potential HERV (human endogenous retrovirus) mediated genetic deletion with hypotonic features is another example; HERVs are another favourite talking point on this blog (see here).

That all being said, I'd also like to go back to the previous mention of joint hypermobility. Shetreat-Klein et al do talk about whether the descriptions of hyptonia in cases of ASD, or at least "joints with ligamentous laxity", might suggest "a disorder of elastin or collagen". Collagen issues immediately brought my mind back to the condition called Ehlers-Danlos syndrome (EDS), a heritable disorder of connective tissue. One of the primary features of EDS - accepting that there are various different presentations - is hyper-flexible joints. The literature looking at any overlap between autism and EDS is currently sparse, very sparse. I did happen upon the paper by Takei and colleagues [5] (open-access here) detailing a single case where "autistic disorder and EDS were diagnosed" concurrently. Takei et al describe a family history of EDS and as they note: "We speculate that associations exist between connective tissue diseases and autistic disorders, and that connective tissue abnormalities may contribute to autistic symptoms". I do wonder whether this might be an area requiring a little more scientific inspection.

The take home message from this post is that joint mobility and gait issues do seem to be quite apparent across the autism spectrum. Alongside other research in this area, one might start asking further questions about the hows and whys of such findings and whether it may offer further insight into some of the underlying issues potentially associated with at least some of the autisms?

To close, football (soccer). Now knowing that Germany are the 2014 World Cup Champions and this is the first lifting of the Jules Rimet trophy in a reunified Germany, I'm sure David Hasselhoff might have something to say...

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[1] Shetreat-Klein M. et al. Abnormalities of joint mobility and gait in children with autism spectrum disorders. Brain Dev. 2014 Feb;36(2):91-6.

[2] Kanner L. Autistic disturbances of affective contact. Nervous Child. 1943; 2: 217-250.

[3] Belengeanu V. et al. A de novo 2.3 Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl. Gene. 2014 Apr 10;539(1):168-72.

[4] Shuvarikov A. et al. Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays. Hum Mutat. 2013 Oct;34(10):1415-23.

[5] Takei A. et al. High-functioning autistic disorder with Ehlers-Danlos syndrome. Psychiatry Clin Neurosci. 2011 Oct;65(6):605-6.

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Shetreat-Klein M, Shinnar S, & Rapin I (2014). Abnormalities of joint mobility and gait in children with autism spectrum disorders. Brain & development, 36 (2), 91-6 PMID: 22401670

Organic food: meta-analysed

A very quick post to direct you to the paper by Barański and colleagues [1] which is currently making a few headlines and sparking some debate (see here and see here) with their assertions: "the concentrations of a range of antioxidants such as polyphenolics were found to be substantially higher in organic crops/crop-based foods" and "the frequency of occurrence of pesticide residues was found to be four times higher in conventional crops, which also contained significantly higher concentrations of the toxic metal Cd [cadmium]".

Lead by researchers based at Nafferton Farm affiliated to Newcastle University, the literature review and meta-analysis looked at over 300 studies looking at "the composition of crops and foods". According to the BBC website, Carlo Leifert who headed the review said: "This study demonstrates that choosing food produced according to organic standards can lead to increased intake of nutritionally desirable antioxidants and reduced exposure to toxic heavy metals".

I've had the pleasure of visiting Nafferton Farm once or twice and chatting to Carlo and his team about some of the work going on. It is a lovely part of the world and some great science is being done and reported in the peer-reviewed press [2]. Appreciating that there are still some significant gaps in the science about organic vs. conventional farming methods and their impact on food in terms of yields and nutritional quality, I do think that this latest (and largest) review is something which should not be ignored...

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[1] Barański M. et al. Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: a systematic literature review and meta-analyses. Br J Nutr. 2014 Jun 26:1-18.

[2] Stergiadis S. et al. Improving the fatty acid profile of winter milk from housed cows with contrasting feeding regimes by oilseed supplementation. Food Chem. 2014 Dec 1;164:293-300.

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Barański M, Srednicka-Tober D, Volakakis N, Seal C, Sanderson R, Stewart GB, Benbrook C, Biavati B, Markellou E, Giotis C, Gromadzka-Ostrowska J, Rembiałkowska E, Skwarło-Sońta K, Tahvonen R, Janovská D, Niggli U, Nicot P, & Leifert C (2014). Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: a systematic literature review and meta-analyses. The British journal of nutrition, 1-18 PMID: 24968103

Maternal C-Reactive Protein (CRP) and offspring schizophrenia

A big quote to start this post: "This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implications for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders".

Ophelia @ Wikipedia 

The source for this quote was the paper by Sarah Canetta and colleagues [1] based on an analysis of serum samples from mums for C-reactive protein (CRP) as part of the Finnish Prenatal Study of Schizophrenia cohort under the leadership (well, grant holding) of Prof. Alan Brown. Some media interest in this paper can be seen here.

Regular readers of this blog might have heard me talk about some of Prof. Brown's previous research, again with CRP in mind but with an autism research slant (see here). I'll come back to some of that work shortly alongside some more recent research [2] in that area.

In this latest paper, archived maternal serum samples related to nearly 800 people (offspring) diagnosed with schizophrenia or schizo-affective disorder were assayed for CRP and results compared with maternal CRP levels related to a similarly sized asymptomatic control group. "Increasing maternal C-reactive protein levels, classified as a continuous variable, were significantly associated with schizophrenia in offspring (adjusted odds ratio=1.31, 95% confidence interval=1.10-1.56)". Even after controlling for confounders including a parental "history of psychiatric disorders" results remained significant. Ergo, one marker of inflammation present and elevated in spot sera samples of mums may have some implications for subsequent development of offspring.

Having recently heard the sad news about the death of Paul Patterson (see his obituary here) my first thoughts turned to his valuable contributions to this area and the proposed maternal immune activation hypothesis of schizophrenia and autism [3] (open-access here). You'll note that Prof. Brown was the co-author on that last citation with Prof. Patterson, giving you a feel for how such research connections might fit together.

My second thought was slightly more of a critical one with the realisation that CRP whilst a good marker of the acute-phase response linked to inflammation [4] may not necessarily present the whole picture when measured in a spot sample fashion or without reference to the multitude of other compounds reactive to an inflammatory status. Think cytokines for example (see here). I note also in the latest paper that maternal levels of CRP were the focus, and not specifically CRP levels in offspring with and without a diagnosis of schizophrenia. It would be interesting to see how the two measurements might correlate (or not). That being said, and as I've reported before, there is quite a body of evidence suggestive of on-going issues with CRP in at least a proportion of people on the schizophrenia spectrum. Inflammation and psychiatry seem to have some common ground (see here).

Going back to the CRP work with autism in mind, I do think there is a pattern emerging from the available peer-reviewed evidence suggestive that inflammation (excess inflammation or elevated markers of inflammation?) during critical periods of pregnancy might have some connection with later offspring outcomes. The processes potentially relevant to any association are still the source of some speculation, as are the various ways that inflammation might come about: air pollution (see here), maternal obesity (see here), etc. Take yer pick, accepting that genetics and/or epigenetics are probably also going to play a role. What remains to be seen is how the idea of mitigating inflammation - however one goes about doing this - during those critical periods of pregnancy may impact on offspring risk of developmental or psychiatric outcomes. Indeed, as the paper from Patterson and Brown [3] concluded: "It has been suggested that the overall decline in bacterial illnesses due to antibiotic therapy and the initiation of immunization programs may be at least partially responsible for the reduction in the incidence of schizophrenia in certain countries in the last several decades". Does this mean such strategies have already impacted on some of the prevalence figures?

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[1] Canetta S. et al. Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort. Am J Psychiatry. 2014 Jun 27. doi: 10.1176/appi.ajp.2014.13121579.

[2] Brown AS. et al. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014 Feb;19(2):259-64.

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

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Canetta, S., Sourander, A., Surcel, H., Hinkka-Yli-Salomäki, S., Leiviskä, J., Kellendonk, C., McKeague, I., & Brown, A. (2014). Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort American Journal of Psychiatry DOI: 10.1176/appi.ajp.2014.13121579