PCB congeners and 15q11-q13 duplication autism

Contains PCBs @ Wikipedia

The science news is currently awash with talk about results from the Encyclopedia of DNA Elements (ENCODE) project (see here for a good description). The net results have been summarised by quite a few media outlets including the BBC, including the suggestion that junk DNA might not be as junk as first thought (see this post from MJ over at Autism Jabberwocky).

I was interested to see that the words DNA methylation cropped up quite a few times during the course of the various discussions, and how the switching on and off of genes might actually be pretty important to our lives. It all got me thinking back to everyone's favourite gene-environment science, epigenetics (see here).

With all this in mind, a recent paper by Mitchell and colleagues* provides some food for thought. Including a significant authorship contingent from that autism research favourite, the MIND Institute, the paper abstract makes a striking assertion: "These results demonstrate a novel paradigm by which specific POPs [persistent organic pollutants] may predispose to genetic copy number variation of 15q11-q13".

I admit that I did a bit of a double-take when I read this sentence given that it seems to suggest some involvement of POPs in what is a genetic condition.

OK let's just back it up a little and take this one step at a time. 15q11-q13 duplication autism spectrum disorder refers to an issue with chromosome 15 and in particular with something called the PWS/AS critical region; that is a genetic area thought to be linked to the presentation of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) depending on whether inheritance is maternal or paternal. Autism has also been tied into the 15q11-q13 region as per studies like this one from Cook and colleagues**. There is quite a bit of other research on 15q11-q13 and autism in the scientific literature which can be browsed here.

POPs are basically those chemicals/compounds which stick around in the environment and seem not to be easily environmentally degradable. POPs include a range of compounds (see here) some (many?) of which also have the ability to bioaccumulate and potentially cause some quite serious effects on health as per what happened with Yushō disease. I don't want to get too heavily into the nitty-gritty of the health impacts of POPs simply because it is a very complicated area of environmental health sciences.

Certain POPs have been mentioned previously with autism / autistic behaviours in mind as per these archive posts on polybrominated diphenyl ethers (PBDEs) and autism and the flame-proofed mice with a Rett syndrome mutation study. This last study incidentally is also from Prof Janine LaSalle who also heads the current paper.

Mitchell et al report a few things in their study. I'm sorry that I can't post a link to the full-text paper, so you'll have to take my word for it:

• The lipid-rich brain tissue of one hundred and seven human postmortem brain samples were analysed for the presence of 8 polychlorinated biphenyl (PCB) and 7 PBDE congeners via GC-MS among other things. Samples were derived from deceased patients who were diagnosed with various neurodevelopmental disorders of 'known' origin (PWS, AS, Rett syndrome, 15q11-q13 duplication syndromes; n=32), idiopathic autism "of unknown etiology" (n=32) and asymptomatic controls (n=34). Age ranges were wide; between 4 - 61 years old at death across the groups.
• "Unexpectedly, PCB 95 was significantly (p<0.001) higher in the genetic neurodevelopmental group, but not idiopathic autism, as compared to neurotypical controls". Indeed out of 8 PCB congeners analysed, the genetic neurodevelopmental group showed the greatest mean concentration in  5 (although not significantly different levels).
• Furthermore, levels of PCB 95 seemed to be specifically tied to those diagnosed with a maternal15q11-q13 duplication (Dup15q) or deletion in Prader-Willi syndrome.
• Further analysis based on birth date pre- and post- 1976 (used because of the introduction of the 1976 Toxic Substances Control Act which is looking to be replaced by the Safe Chemicals Act of 2011) suggested that levels of PCB 95 were highest in the genetic neurodevelopmental group both pre- and post-1976. 
• A possible connection between PCB 95 and DNA methylation levels in Dup15q samples was undertaken by pyrosequencing for repetitive LINE-1 methylation levels ('similar' to this method). As would probably be expected, significant DNA hypomethylation was recorded compared with control samples (approximately 2% decrease in average methylation). That being said, year of birth was a confounder in that those controls born in the 1980s-1990s tended to show lower methylating functioning than those born in the 1960s-1970s. 
• PBDE levels showed little significant differences across the groups aside that is from one congener, PBDE 153, which showed a greater mean concentration in the control group compared to the other symptomatic groups (p<0.05).

I'm intrigued. To quote again from this study: "Our results demonstrated that 3/6 Prader-Willi syndrome and 5/6 Dup15q brain samples showed detectable levels of PCB 95 suggesting that this exposure should be investigated as a potential environmental contributor of the differing copy number variation rates in different regions".

Now I'm not saying that POPs 'cause' 15q11-q13 duplication autism spectrum disorder; the evidence just isn't there to suggest something so direct. As with every study which includes a postmortem element to it, there is always the sensitive issues of why the person died and whether comorbidity (epilepsy, learning disability?) might play an interfering role in any results obtained. It certainly is however an area that needs a lot more investigation.

I've often talked about mutations like SNPs and CNVs in relation to autism and a few other conditions (see here for example); the latest being that stark quote "no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level" from the paper by Richard Anney and colleagues (see post here). Where SNPs and/or CNVs do occur however, particularly when described as de novo as in the recent paper on paternal age and de novo mutations (see here), the question has to be why do such mutations occur outside of just a generic 'randomly based on age' argument? Without tempting too much criticism, I have to admit that 'random' just doesn't wash with me; there has to be a reason. One candidate outside of just maturation has to be environment.

A few final points to make and then I'm done. This is not the first time that PCB 95 has cropped up and interestingly has been previously tied into autism and calcium signalling as per this study by Wayman and colleagues*** (full-text). The issue of DNA hypomethylation and autism has also been covered on this blog previously so I'm not going to get too involved in that at this time.

And relax.

Despite the small participant numbers included in the study, I will say once again that I am intrigued by the results presented by Mitchell and colleagues and very much look forward to hearing more from this research group and others on our seemingly very delicate relationship with the modern environment around us.

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* Mitchell MM. et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environmental & Molecular Mutagenesis. August 2012.

** Cook EH Jr. et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. American Journal of Human Genetics. 1997; 60: 928-934.

*** Wayman GA. et al. PCB-95 Modulates the Calcium-Dependent Signaling Pathway Responsible for Activity-Dependent Dendritic Growth. Environmental Health Perspectives. 2012; 120: 1003-1009.

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Mitchell MM, Woods R, Chi LH, Schmidt RJ, Pessah IN, Kostyniak PJ, & Lasalle JM (2012). Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environmental and molecular mutagenesis PMID: 22930557

Dried blood spots, cytokines and autism

Thank you Robert Guthrie @ Wikipedia

The Nature website recently carried an interesting headline: "Archived blood spots could be epigenetic jackpot" based on a recent study by Huriya Beyan and colleagues* on the application of DNA methylomics to stored Guthrie cards to study early infant epigenetics.

Just in case this makes no sense to you, the basic suggestion is that all those dried blood spots taken from days old infants to test for various inborn errors of metabolism like PKU, could be used to examine the switching on or off of genes well before most diseases or conditions become apparent. At the very least it would compare what's there at birth with what might be there at later stages in life and focus attention on factors in that intervening period.

I'm interested in this area for lots of different reasons. Not least that infant dried blood spots - whilst a little traumatic to see when blood is taken from this tiny little baby - are indeed a treasure trove of information waiting to be discovered. With regards to a condition like autism(s) which only really manifest in early childhood, there could be several markers, endophenotypic biomarkers, waiting on those little pieces of card and possibly not just all epigentic ones.

Indeed I'm very happy to report that autism research has already taken advantage of the infant dried blood spots available as evidenced by this study by Abdallah and colleagues** on neonatal levels of cytokines in cases of autism. Regular readers will know that I've done cytokines and autism on the blog quite a few times (see here for example). Cytokines, those chemical messengers, linked to interesting things like inflammation are finding a real home in autism research and other areas of investigation but still some questions need to be answered (why? who? what to do about it?).

Abdallah et al looked at several hundred neonatal blood spot samples (n=359) where autism was eventually confirmed compared with a sizable control population (n=741). They found quite a bit of evidence to suggest that children with autism were more likely to present with 'hypoactive immune cell activity' as youngsters than controls including lower levels of everyone's favourite interferon, interferon gamma.

I've talked before about the often conflicting results on immune function in cases of autism and how researchers such as Harumi Jyonouchi have presented similarly 'depressed' immune function related to cases of autism whilst others report immune over-activity or the presence of autoantibodies. I will at this point press a few words home to you: heterogeneity, endophenotypes, comorbidity and gene-environment interactions.

Indeed this recent study by Goines and Ashwood*** (Paul Ashwood that is) kinda summarises how complicated cytokine dysregulation seems to be with autism in mind and how environment combined with genetics may very well play an important role in the presentation of immune function in cases of autism.

Neonatal blood spots offer a fascinating opportunity to explore lots and lots of features potentially related to autism and beyond. Neonatal vitamin D status as per this study by McGrath and colleagues**** using the same Danish neonatal database following on from the recent interest in vitamin D and autism is just one example of where this could go. Indeed given the millions of people around the world who undergo neonatal blood spot screening every year, the possibilities of comparisons by diagnosis, geography, ethnicity, etc. and across different times, are seemingly endless.

To finish a song by another Robert (Smith not Guthrie) about it being Friday and someone being in love? (even though at the time of publication of this post, it is actually still Tuesday where I am).

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* Beyan H. et al. Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans. Genome Research. August 2012.

** Abdallah MW. et al. Neonatal levels of cytokines and risk of autism spectrum disorders: An exploratory register-based historic birth cohort study utilizing the Danish Newborn Screening Biobank. Journal of Neuroimmunology. August 2012.

*** Goines PE. & Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment. Neurotoxicology & Teratology. August 2012.

**** McGrath JJ. et al. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Archives of General Psychiatry. 2010; 67: 889-894.

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Abdallah MW, Larsen N, Mortensen EL, Atladóttir HO, Nørgaard-Pedersen B, Bonefeld-Jørgensen EC, Grove J, & Hougaard DM (2012). Neonatal levels of cytokines and risk of autism spectrum disorders: An exploratory register-based historic birth cohort study utilizing the Danish Newborn Screening Biobank. Journal of neuroimmunology PMID: 22917523

C1q activation and schizophrenia

The Doorman @ Wikipedia

I'm back to schizophrenia with this post based on another very interesting paper by Dr Emily Severance and colleagues* describing some of the potential ins and outs of C1q activation, diet and immune function.

Regular readers of this blog might remember the last offering from Dr Severence et al on gastrointestinal (GI) inflammation and immune activation in cases of schizophrenia (see here**). The net finding suggesting that inflammation might tie into permeability of the GI membrane and onwards to the appearance of antibodies to various foodstuffs. Not a million miles away from the suggestions of the late Curt Dohan and his ideas about schizophrenia and food*** it has to be said.

Perhaps a brief description first?

The complement system is something that has also cropped up on this blog previously with reference to the C4b null allele work carried out by the late Reed Warren and colleagues (here). Basically this is a system charged with aiding in the clearance of pathogens. The complement protein C1q alongside its siblings (C1r and C1s) is a sort of first line in the classical complement pathway, functioning as a recognition unit as it binds to already antigen bound immunoglobulin complexes such as IgG or IgM. I suppose its a sort of nightclub bouncer of the immune system which gets rid of immunoglobulins which have already found an antigenic friend - "you and your friend, out of here".

C1q is a pretty important molecule given that a lack of it has been linked to issues of autoimmunity such as systemic lupus erythematosus (SLE)**** suggested as a result of the reduced clearance of apoptotic cells (which brings us back to those very interesting executioner molecules, the caspases). It is also noteworthy that C1q might have another disposal function with regards to synaptic pruning***** (full-text).

All very important I'm sure you'll agree. So what about the latest paper?

• Blood samples were drawn from various groups of participants: n=61 non-recent onset schizophrenia (SZ), n=38 recent onset schizophrenia (ROSZ) and n=63 controls. Mean ages and gender splits were quite literally all over the place alongside other demographic information like the percentages of smokers/non-smokers across the groups.
• Analysis of serum was undertaken for: (a) total IgG antibody binding to C1q, (b) C1q seropositivity and (c) C1q immune complexes containing food antigens.
• Results: C1q antibody levels were highest in the ROSZ group and moderately elevated in the SZ group compared with controls.
• Based on cut-off values, C1q seropositivity was associated with both ROSZ and SZ groups with corrected odds ratios (ORs) of 8.02 and 3.15 respectively alongside some quite wide-ranging confidence intervals.
• Looking at milk casein and wheat gluten as being potential sources of C1q immune complexes, there was indeed a sizable presence of C1q milk casein or wheat gluten antigen complexing to be had. Indeed, particularly for the SZ group - the chronically affected group - "the presence of an immune complex containing C1q and a casein or gluten food antigen yielded a significant odds ratio for disease association".
• There was no significant positive association between C1q and other antigens including an old friend, T.gondii (well, not so much of a friend).
• Although not formally part of this experiment, the authors also report that in the SZ group at least "C1q was associated with a marker of GI inflammation, ASCA" with reference to the anti-Saccharomyces cerevisiae IgG antibodies (ASCA) that formed part of their last paper.

So, in their cohort at least, the authors found quite a strong presence of C1q activation in cases of schizophrenia meaning that this was a system hard at work trying to get rid of those immunoglobulin-antigen complexes. Added to the fact that milk and wheat were quite significantly a part of those immunoglobulin-antigen C1q complexes.

Another detail from this paper interests me. Mention is made of the possibility of C1q autoantibodies as an explanation for the strong C1q immunoreactivity noted in both schizophrenia groups particularly the ROSZ group. I'm very intrigued by this prospect given the emerging evidence on a possible role for autoimmunity in cases of other conditions like autism and indeed some direction in the current paper towards the work of Ari Vojdani and colleagues and their anti-gluten and anti-casein peptide antibodies******. 

For quite a few years now, its often been at the back of quite a few people's minds that the whole gluten and casein peptide theory of autism might actually result not just in a direct pharmacological 'opioid' effect from such peptides as per the speculations of Sun and Cade*******, but also an immune system effect as the body starts to recognise such peptides outside of places like the GI tract (as a result of enhanced gut permeability). It is speculative but we've already kinda seen hints of this in other areas with for example, the Sutterella IgG findings in cases of autism (see here) and so-called bacterial translocation. So how about peptide translocation similar to that speculated in coeliac disease?

All in all I am once again mightily impressed with the work coming out of Johns Hopkins in this area and yet again dream about how this platform and methodology could so readily be tested in cases of autism and lots of other related conditions too.

To finish, I'm in the mood for something a bit different, so how about The Cincy Brass covering a Gaga classic?

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* Severance EG. et al. Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia. Neurobiology of Disease. 2012. July 2012.
DOI: 10.1016/j.nbd.2012.07.005

** Severance EG. et al. Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophrenia Research. 2012; 138: 48-53.
DOI: 10.1016/j.schres.2012.02.025

*** Dohan FC. Genetic hypothesis of idiopathic schizophrenia: its exorphin connection. Schizophrenia Bulletin. 1988; 14: 489-494.

**** Horák P. et al. C1q complement component and -antibodies reflect SLE activity and kidney involvement. Clinical Rheumatology. 2006; 25: 532-536.

***** Stevens B. et al. The classical complement cascase medicates CNS synapse elimination. Cell. 2007; 131: 1164-1178.

****** Vojdani A. et al. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. International Journal of Immunopathology & Pharmacology. 2003; 16: 189-199.

******* Sun Z. & Cade JR. A peptide found in schizophrenia and autism causes behavioural changes in rats. Autism. 1999; 3: 85-89.

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Severance EG, Gressitt K, Halling M, Stallings CR, Origoni AE, Vaughan C, Khushalani S, Alaedini A, Dupont D, Dickerson FB, & Yolken RH (2012). Complement C1q formation of immune complexes with milk caseins and wheat glutens in schizophrenia. Neurobiology of disease PMID: 22801085

What are the early behavioural signs of autism?

Baby stare @ Paul Whiteley

"Autism is a developmental disorder presenting in early infancy". I think most people would agree with this statement; even those who know very little about autism and its intricacies. I can remember years ago using various videos (yes before DVDs et al there were videos) to demonstrate to groups of students how autism might manifest itself in young children and how presentation can differ from child to child depending on lots of different factors.

I struggle to remember the name of the particular program, but one video in particular gave a very personal, very moving account of a young girl with autism, showing home videos of the child growing up accompanied by a mum's description of her and the presentation of her autism. In one scene, the child is shown in her cot aged somewhere between 3 and 6 months old. It was always striking to me how 'detached' the child seemed even at that early age and based on just a few short minutes of commentary and pictures. The lack of eye contact pinpointing the potential for something in her future development.

Fast forward back to modern times (yes with DVDs and Blue-Ray and portable media) and an interesting paper by Barbaro & Dissanayake* brings me to this post looking at some of the various research done on potential early behavioural markers of autism spectrum conditions. I hasten to add that I have sort of touched upon this topic in a very early post on this blog (here) but consider this a bit of a more detailed update.

The Barbaro paper indeed highlights the lack of eye contact in their analysis of potential early markers of autism, alongside another important skill again already discussed on this blog, pointing. 

But what of the other research done in this area?

• As one might imagine, there is a considerable body of research examining potential early markers of autism. Some names pop up more consistently than others in this area of investigation, one of them being Dr Robyn Young. Dr Young's papers seem to confirm quite a few things that people have suspected for a while. So for example, parents of children with autism are pretty good at spotting when development is not quite as it should be**. Other papers have also said as much, bearing in mind that the experiences when communicating those concerns to certain healthcare professionals might not exactly be 'optimal' in some cases (see this post). 
• Using home videos as potential screening tools is another area where some important data have been collected. This paper by Dr Young and colleagues*** describes how even with a relatively small participant group, several discriminating features were apparent in pre-verbal children who went on to receive a diagnosis of autism including gaze aversion and issues with 'proto-declarative showing'. Notice again the emphasis on social communicative functions (as per the ADTree classifier work), bearing in mind that pointing generally comes a little later than eye contact in child development terms. Similar joint attention findings were also reported in this study by Watson and colleagues****.
• Another quite famous name in this area of research is that of Dr Sally Ozonoff (yes, she of the MIND Institute) and her observations down the years. In particular, her paper reviewing the potential usefulness of family home movies and the early development of autism***** deserves mention. 
• It is however when it comes to examining onset patterns in autism that Dr Ozonoff really comes into her own as per this paper****** (full-text) describing the dimensionality of onset patterns over dichotomous categories.  Again, parents are seen as key partners in 'predicting' autism (see this paper******* full-text). Interestingly, Dr Ozonoff in quite a few of her papers makes mention of the fact that her data does not seem to suggest that symptoms are present at birth as was suggested by Kanner, but rather emerge over time and show a regressive or diminishing factor. A good example is in this study******** (full-text) which prospectively looked at the early signs of autism and suggested that the period between 6 and 12 months seems to be an important one; again re-emphasising the social-communicative features to be paramount. 
• I should also make reference to this paper by Turner-Brown and colleagues********* which has received some publicity on the First Year Inventory for screening at 12 months of age, just to keep up to date.

I admit that I've only really scratched the surface with this post and indeed only paid lip-service to important concepts like regression; aspects of which have been covered in other posts (see here). I would perhaps refer to an additional reference on the topic of regression and onset patterns with a link to this paper by Cohen-Ophir and colleagues********** (full-text). They reported on three case studies charting a slightly different progression into autism outside of the categorisations of (a) slow / subtle regression and/or (b) rapid regression (or indeed (c) the delays + regression phenotype) suggestive of initial developmental delay, a period of rescuing skills falling into typical development, followed by regression into classic autism. 

There are also a few other areas of potential interest to the issue of early behavioural presentation neatly summed in this paper by Clifford and colleagues************ on temperament in high risk infants and this paper by Flanagan and colleagues************ on head lag (I know this is more presentation rather than behavioural).

So to answer the question to the title of this post, what are the early behavioural signs of autism? It seems that social-communicative factors such as issues with eye contact and later pointing might be possible red flags, but also realising that the heterogeneity noted in the presentation of autism to some degree also mirrors onset patterns and the presentation of early behaviours. 

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* Barbaro J. & Dissanayake C. Early markers of autism spectrum disorders in infants and toddlers prospectively identified in the Social Attention and Communication Study. Autism. June 2012.

** Young RL. et al. Parental identification of early behavioural abnormalities in children with autistic disorder. Autism. 2003; 7: 125-143.

*** Clifford S. et al. Assessing the early characteristics of autistic disorder using video analysis. JADD. 2007; 37: 301-313.

**** Watson LR. et al. Communicative gesture use in infants with and without autism: a retrospective home video study. American Journal of Speech-Language Pathology. July 2012.

***** Palomo R. et al. Autism and family home movies: a comprehensive review. Journal of Developmental & Behavioral Pediatrics. 2006; 27: S50-S68.

****** Ozonoff S. et al. The onset of autism: patterns of symptom emergence in the first years of life. Autism Research. 2008; 1: 320-328.

******* Ozonoff S. et al. How early do parent concerns predict later autism diagnosis? Journal of Developmental & Behavioral Pediatrics. 2009; 30: 367-375.

******** Ozonoff S. et al. A prospective study of the emergence of early behavioral signs of autism. Journal of the American Academy of Child & Adolescent Psychiatry. 2010; 49: 256-266.

********* Turner-Brown LM. et al. The First Year Inventory: a longitudinal follow-up of 12-month-old to 3-year-old children. Autism. July 2012.

********** Cohen-Ophir M. et al. Autism in early childhood: an unusual developmental course - three case reports. Case Reports in Psychiatry. 2012.
DOI: 10.1155/2012/946109

*********** Clifford SM. et al. Temperament in the first 2 years of life in infants at high-risk for autism spectrum disorders. JADD. August 2012.

************ Flanagan JE. et al. Head lag in infants at risk for autism: a preliminary study. American Journal of Occupational Therapy. 2012; 66: 577-585.

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Barbaro J, & Dissanayake C (2012). Early markers of autism spectrum disorders in infants and toddlers prospectively identified in the Social Attention and Communication Study. Autism : the international journal of research and practice PMID: 22735682

ADTree reloaded: classifying autism based on 7 ADI-R items?

A lengthy quote to begin this post:

"Deploying a variety of machine learning algorithms, we found one, the Alternating Decision Tree (ADTree), to have high sensitivity and specificity in the classification of individuals with autism from controls. The ADTree classifier consisted of only 7 questions, 93% fewer than the full ADI-R, and performed with greater than 99% accuracy when applied to independent populations of individuals with autism, misclassifying only one out of the 1962 cases used for validation".

Interested? The quote comes from this recent paper by Dennis Wall and colleagues* (full-text) following up some related research from this group based on another gold standard autism assessment schedule, the ADOS (see here).

I'm not going to dwell too much on the study details aside from saying:

• The ADI-R (Autism Diagnostic Interview - Revised) is probably one of the more time and resource-intensive interview questionnaires used for the assessment of autism, coming in at 93 questions long and asking about current behaviour and 'most abnormal' (aged 4-5 years) if appropriate.
• An abbreviated ADI-R would therefore be quite a useful measure in these austere times; particularly one which could maintain the same level of accuracy as completion of the full schedule.
• Similar to their previous study, Wall and colleagues applied various machine learning algorithms (n=15) to ascertain whether any might be able to determine which ADI-R items are most relevant to diagnosis based on the AGRE dataset.
• Once again, the Alternating Decision Tree (ADTree) model performed best: perfect sensitivity (1.0), a low false-positive rate (0.013) and "overall accuracy of 99.9%".
• Seven items of the ADI-R comprised the ADTree model: (i) comprehension of simple language at most abnormal (4-5 years), (ii) reciprocal conversation (regarding the ability to facilitate the flow of conversation), (iii) use of imaginative / pretend play at most abnormal (I have post about pretend play coming up fairly soon), (iv) social imaginative play with peers at most abnormal, (v) direct gaze at most abnormal, (vi) group play with peers at most abnormal (spontaneous games or activities) and (vii) age when abnormality was first evident.
• Testing accuracy was again carried out on participant data from the Boston Autism Consortium (AC) and the Simons Simplex Collection (SSC) from where the quite compelling data for the success of the ADTree model was derived.

So the ADI-R has been boiled down to 7 pertinent items. The ADOS boiled down to 8 distinguishing module 1 items. I think most people would stand up and take note of these findings even if further replication is still required (based on different geographical groups for example). Don't get me wrong, there is still a large degree of skill required to deliver the ADI-R and ADOS and maintain your reproducibility and diagnostic prowess so I don't think this combined data will be putting people out of work just yet; certainly not with the number of people estimated to be coming through the diagnostic process. That and the fact that these are assessment instruments and so are subservient to a final clinical opinion for an autism diagnosis or not.

Aside from the grand findings I am interested in the types of behaviours which are noted to be important for diagnosis. All very 'social-communicative' (sounds familiar) and not at all heavy on the 'restricted and repetitive behaviour' side of things. Indeed, looking back at the ADOS ADTree paper, I might be wrong but only one element, 'functional play with objects' seems to have any strong relation to issues with repetitive behaviours. This could be that we aren't asking the right questions about this area of behaviour, but I would hedge my bets that more likely is the stress on the social-communicative side of presentation as being key to diagnosis. I think I might have to look at this further in future posts.

Finally, I have previously talked about the lack of instruments to appropriately and accurately assess 'change' in autism (as a function of maturation or intervention or anything else). Y'know with these combined data, I think we might have the outline of something really quite useful...

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* Wall DP. et al. Use of artificial intelligence to shorten the behavioral diagnosis of autism. PLoS ONE. 2012; 7: e43855.

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Dennis P. Wall, Rebecca Dally, Rhiannon Luyster, Jae-Yoon Jung, & Todd F. DeLuca (2012). Use of artificial intelligence to shorten the behavioral diagnosis of autism PLoS ONE : 10.1371/journal.pone.0043855

The kynurenic acid hypothesis of schizophrenia

I'm back to tryptophan again in this post. No matter how hard I try, I just can't seem to get away from this interesting aromatic amino acid and its seemingly far-reaching effects on many aspects of human health.

Kynurenic acid @ Wikipedia

Today I'm exploring an interesting hypothesis looking at how a metabolite of tryptophan, kynuernic acid, might hold some connection to cases of schizophrenia in the so-called kynurenic acid hypothesis of schizophrenia*.

OK, probably best to start with a few caveats. Me = not an expert on schizophrenia, is probably the biggest caveat and so apologies in advance for any errors or important omissions you might find in this post. Schizophrenia, from a conceptual point of view, probably shares some similarity with quite a few other behaviourally defined conditions like autism, insofar as being defined as a spectrum condition. This, together with the risk/effect of certain comorbidity, almost certainly implies that finding 'specifics' in terms of universal theories of causation or effect, are probably going to be difficult at best. Many roads might lead to Rome.

Schizophrenia unlike autism however, does not seem to be a developmental condition present from early infancy (despite the history linking the two conditions). This is not to say however that there may not be a strong genetic component to schizophrenia if you like 'waiting in the wings' to express itself as maturation and environment play their hands. Instead schizophrenia has been associated with different stages of symptom presentation: a prodromal period, an acute phase and a relapse phase (see here) with some marked inter-individual variation on the timing of these phases. One therefore has to be quite careful when ascribing markers or generic theories to schizophrenia based on all these factors.

Back to the kynurenic acid theory, and the finding of elevated kynurenic acid (kynurenate) in post-mortem brain samples from people with schizophrenia** represents one of the first discoveries of some possible connection. The connection between elevated levels of kynurenate in certain brain areas is matched by a suggestion of reduced glutamate receptor function. Reports of elevations of kynurenic acid in cerebrospinal fluid in cases of schizophrenia followed*** and not just once (here and here). 

Then things start to get a little more speculative as questions start being asked as to why elevated kynurenic acid is there in the first place. The enzymes (and their cofactors) along the pathway to the formation of kynurenic acid have come under scrutiny as for example, per this preliminary report from Holtze and colleagues**** (full-text) on SNPs in the kynurenine 3-monooxygenase (KMO) enzyme. That and reduced levels of mRNA and lower enzyme activity have been found*****. Another enzyme suggested to show some involvement in this tangled hypothesis is that of indoleamine 2,3-dioxygenase (IDO). The suggestion is that the immune system may be able to affect the functioning of IDO in cases of schizophrenia (here) and hence increase production of kynurenic acid with some interesting knock-on effects based on the antagonistic effects on things like N-methyl-D-aspartate (NMDA) and its receptor.

Fair enough. But are the findings actually related to schizophrenia or purely epiphenomenal? There have been a few clues suggesting specific effects from elevated kynurenic acid as per this paper****** on various cognitive functions related to schizophrenia. Indeed extrapolating from rodent studies seems to have been quite a popular thing to do with kynurenic acid in mind as per other papers (here, here and here). There are some interesting themes to this work focused on things like the timing of kynurenic acid exposure; so, adolescence seems to be quite a sensitive period. I assume this makes such work all the more 'attractive' given the timing of symptom onset (see here) in many cases of schizophrenia.

On balance, the collected evidence does seem to be at least pointing the way to kynurenic acid elevations as being related to cases of schizophrenia. But it doesn't just stop there. I've already mentioned a possible role for immune function in accounting for kynurenic acid levels in schizophrenia. Various infectious agents have been suggested to show some 'connection' to activation of the kynurenine pathway including influenza A (here) and an old friend, Toxoplasma gondii (here). Of course one has to be quite careful not to put all your inflammatory eggs in one basket when it comes to immune function and inflammation.

Accepting all this collected data, the question then turns to what can be done about kynurenic acid and any excessive production and what implications that might have for the presentation of schizophrenia. I think I've probably said it before but I will repeat myself: when we talk about medication to treat/manage this condition or that condition or any condition, interventions don't just generally affect one system and one system alone, they most likely with affect lots of different systems and exert quite a few effects. Antipsychotics for example, have been suggested to be quite good antiparasitics also (see here) bearing in mind the T.gondii link suggested with cases of schizophrenia. So it is with kynurenic acid in mind, as Myint and colleagues******* demonstrated in their study looking at the effects of antipsychotics on the kynurenine pathway among other things.

Perhaps even more surprising is the suggestion that medications which target some of the processes involved with inflammation such as the COX-2 inhibitors might also show some potential with kynurenic acid and schizophrenia in mind (here) together with a growing evidence base on the use of non-steroidal anti-inflammtory drugs (NSAIDs) for cases of schizophrenia (here). At this point I will stress that I am not providing or intending to provide medical advice nor endorsement about these strategies.

I've focused on schizophrenia and kynurenic acid in this post but recognise that this might not be an exclusive relationship bearing in mind all the issues previously cited on diagnosis and symptom presentation. Indeed I was particularly drawn to this paper******** by McFarlane and colleagues looking at the Dangermouse that is the BTBR mouse (see this post), and how hidden away in all the findings of this mouse model, issues with KMO might just have some function in cases of autism. Perhaps an area ripe for further investigation and in particular, when overlap exists in the dual presentation of autism and schizophrenia?

This post has been quite a brief overview of the potential role of kynurenic acid in cases of schizophrenia and as such I've only scratched the surface of the potential meaning of this work and tie-ups with other areas and other theories. What I hope I've demonstrated is that once again, looking at amino acid chemistry might hold some valuable clues about behaviourally-defined conditions, and in particular how the aromatic amino acids seem to be potentially big players in such conditions.

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* Erhardt S. et al. The kynurenic acid hypothesis of schizophrenia. Physiology & Behaviour. 2007; 92: 203-209.

** Schwarz R. et al. Increased cortical kynurenate content in schizophrenia. Biological Psychiatry. 2001; 50: 521-530.

*** Erhardt S. et al. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neuroscience Letters. 2001; 313: 96-98.

**** Holtze M. et al. Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls. Journal of Psychiatry & Neuroscience. 2012: 37: 53-57.

***** Wonodi I. et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Archives of General Psychiatry. 2011; 68: 665-674.

****** Akagbosu CO. et al. Exposure to kynurenic acid during adolescence produces memory deficits in adulthood. Schizophrena Bulletin. December 2010.

******* Myint AM. et al. Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients. Brain, Behavior & Immunity. 2011; 25: 1576-1581.

******** McFarlane HG. et al. Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes, Brain & Behavior. 2008; 7: 152-163.