A very brief post this one to direct your attention to the on-line publication of the program book for the 2012 IMFAR conference being held in Toronto.
IMFAR, the International Meeting For Autism Research, is an annual event which is probably one of the biggest autism research get-togethers currently in place. I do like to keep track of the various posters and presentations which form part of the conference, which sometimes give you a hint as to what research is likely to appear soon in the peer-reviewed domain.
A quick glance through the program book reveals some interesting work. So starting from back to front of the book (cos that's the kind of guy I am)
Page 96. 157.027 Gene Expression Profiles of Inflamed Bowel Biopsy Tissue in ASD Children Are Consistent with Inflammatory Bowel Disease (abstract here). Drs Stephen Walker and Arthur Krigsman are the names attached to this one.
Page 69. 133.212 The Role of a Biomarker in the Double Blind Placebo – Controlled Study of CM-AT in Children with Autistic Disorder Ages 3-8 (abstract here). Dr Joan Fallon and her very interesting studies of CM-AT.
Page 66. 133.212 Double-Blind Placebo-Controlled Trial of Methyl B12 Injections for Children with Autism (abstract here). (Dr Jill James)
Page 42. 118.078 Genome-Wide DNA Methylation in Pregnancy – Preliminary Results From the EARLI Study (abstract here). A link to my epigenetics 101 post is here.
Page 41. 118.067 Intrauterine and Neonatal Levels of Neurotrophic Factors and Matrix Metalloproteinases-9 and Risk of Autism Spectrum Disorders (abstract here).
Page 34. 112.212 Low Iron Status and Sleep Disturbance in Children with Autism (abstract here). My post from a while back on iron deficiency and autism is here.
Page 33. 112.197 Ambient Prism Lenses Modulate Spatial Attention in Autism: An Event-Related Potential Study (abstract here). A previous posts on visual perception and autism is here.
Page 29. 109.151 Global DNA Methylation Changes in Brain Tissues From Individuals with Autism (abstract here).
Page 26. 107.107 Glutamate / Glutamine in the Basal Ganglia Is Associated with Executive Function and Communication Impairments in Autism: A [1H]MRS Study (abstract here). I'm fast becoming a bit of a fan of amino acids chemistry and autism as per this post.
There is a lot more research which, quite frankly, I could see myself getting quite lost in for a few days had I been attending to the conference. I would be really interested if anyone attending IMFAR 2012 could have a look at these papers/posters and provide some comment.
News and views on autism research and other musings. Sometimes uncomfortable but rooted in peer-reviewed scientific research.
Monday, 30 April 2012
Sunday, 29 April 2012
Sulphate and the autism mouse model
I have to say that I was losing hope. I was convinced that sulphate (or sulfate if you prefer) was destined to end up as that dusty, forgotten toy under the autism research bed. Indeed a post last year all but convinced me that despite all the extremely compelling science on sulphation and autism a few years back, principally attached to Dr Rosemary Waring, sulphate was not generating the current interest that it should be.
Sulphate has however prevailed. Featuring in recent papers like this one and this one. Now further evidence that sulphate is becoming interesting again to autism research in this paper by Corley and colleagues* from the University of Hawaii and their findings based on the BTBR T+tf/J mouse model of autism.
I'm sorry that I am not able to post a link to the full-text paper, but will try and summarise the findings from this brief paper for you:
Accepting that mice and rodent models of autism, of any condition, are still open to some interpretation, these are impressive findings. I recently had an interesting discussion with a Facebook friend, Carole, about another paper using a rat model of schizophrenia (this paper) which indeed questions about whether rodent models are capable of accurately portraying autistic or schizophrenic behaviours. The answer is probably yes, at least to a degree, bearing in mind that autism in people is a mighty complex thing (and often not present in isolation).
I also hark back to the special edition of the journal Autism Research which extolled the virtues of using a mouse model for autism and defended its use as 'a' tool on the road towards examining the underlying genetic and biological processes potentially accompanying a diagnosis of autism.
I'd like to think that now that the sulphate findings have been replicated in the mouse model, a whole new chapter of sulphate chemistry with autism in mind might begin. So looking at the effects of depleted plasma sulphate on things like neurotransmitters and also the very important function of sulphate in the gastrointestinal tract (gut). I wonder also if the sulphate findings in urine might be a next step in the mouse model studies alongside what happens when sulphate is 'added' by Epsom Salt baths perhaps?
I'm sorry that I am not able to post a link to the full-text paper, but will try and summarise the findings from this brief paper for you:
- The BTBR T+tf/J mouse model of autism has been suggested to be one of the more 'accurate' ways of modelling certain autistic behaviours in mice in that behaviours cover the current triad of behavioural domains. This overview by McFarlane and colleagues** (full-text) provides a little more information on the model.
- The current study simply looked at plasma sulphate levels in the BTBR T+tf/J mice compared initially with in-bred (B6) and outbred (CD-1) comparison mice. Indeed there were two experiments to this paper; the second involving a further analysis of a separate group of BTBR T+tf/J and B6 mice.
- Age, food, water, light and other variables were constant across the groups. Gender and site and timing of blood draw were also controlled for.
- Plasma sulphate levels were determined via a turbidimetric (cloudiness) method specifically for sulphate.
- Significantly lower levels of plasma sulphate were observed in the BTBR T+tf/J mice compared to other strains in both experiments (p<0.05). Indeed the levels of sulphate were reduced by about 50% in the BTBR T+tf/J mice model. This was no fluke finding.
I also hark back to the special edition of the journal Autism Research which extolled the virtues of using a mouse model for autism and defended its use as 'a' tool on the road towards examining the underlying genetic and biological processes potentially accompanying a diagnosis of autism.
I'd like to think that now that the sulphate findings have been replicated in the mouse model, a whole new chapter of sulphate chemistry with autism in mind might begin. So looking at the effects of depleted plasma sulphate on things like neurotransmitters and also the very important function of sulphate in the gastrointestinal tract (gut). I wonder also if the sulphate findings in urine might be a next step in the mouse model studies alongside what happens when sulphate is 'added' by Epsom Salt baths perhaps?
* Corley MJ. et al. Reduced sulfate plasma concentrations in the BTBR T+tf/J mouse model of autism. Physiology & Behaviour. April 2012.
DOI: 10.1016/j.physbe.2012.04.010
** McFarlane HG. et al. Autism-like behavioral phenotypes in BTBR T1tf/J mice. Genes, Brain & Behaviour. 2008; 7: 152-163
** McFarlane HG. et al. Autism-like behavioral phenotypes in BTBR T1tf/J mice. Genes, Brain & Behaviour. 2008; 7: 152-163
Friday, 27 April 2012
Short chain fatty acids and ammonia in autism
It is perhaps apt that Jon Brock over at Cracking the Enigma recently posted about the Australasian Society for Autism Research highlighting the various links being forged regarding autism research in that part of the world. Apt because there are several very good autism research groups producing findings which have some potential real-world application to autism, in that part of the World. I speak in particular of the team based at the Sansom Institute for Health Research based at the University of South Australia. Members of UNISA recently publishing a fine review of how glutathione and relations show quite a consistent relationship to cases of autism. Autism research movers and shakers please take note.
Indeed another paper published by Wang and colleagues* adds to the repertoire, suggesting that levels of fecal short chain fatty acids (SCFAs) and ammonia were higher in their cohort of children with autism compared to asymptomatic controls and hence showing alteration in the fermentation process.
As a sort of introduction to SCFAs and fermentation, readers might find this article by Topping & Clifton** (full-text) and this article by Macfarlane & Macfarlane*** (full-text) to be of interest. Basically, think carbohydrates and gut bacteria and eventually you head the direction of SCFAs. If you happen to brew your own beer, fermentation might not necessarily be a strange concept alongside memories of 'auto-brewery syndrome' (not personal memories I might add).
Unfortunately I can't post a link to the full-text but here are a few details:
There are some obvious caveats to accompany this latest study. Aside from participant numbers being relatively small and covering quite a lot of chronological age in childhood, and the slight discrepancy in controlling for gender, there was quite a bit of 'overlap' when it came to individual results from the autism and control groups. Indeed if I were to criticise at all, I perhaps would have like to have seen some plotted information on the dispersion of values obtained from individuals just to visualise and ensure that results were not skewed by a few outlier results. As has however been discussed recently, outliers in a heterogeneous condition like autism are very often a source of great interest.
This is not the first time that the words 'autism' and 'fermentation' have come to my attention. Quite a few years back I remember some interesting work being done at Cranfield University by Maria Pilar Bilbao Montoya as part of her higher studies. Working with gastroenterologist, John Hunter, Maria presented some initial work suggesting similar things in their cohort I believe. I might be wrong but I also remember that Dr Sophie Rosseneu might have had some unpublished work in this area also as a tie up with her findings on yeasts and autism?
Memories aside, there are some interesting points to take from this research. SCFAs such as propionic acid (PA) have recently been seen in the autism research arena as per this paper (full-text) by El-Ansary and colleagues looking at what happens when you inject rats with PA in sizeable quantities. For those of you who are unimpressed with the proposed PA-gut-brain link, maybe a few other choice papers might be useful, here and here. And perhaps some evidence for the presence of PA in other biological fluids from cases of autism?
I've talked ammonia before on this blog with reference to some mitochondrial findings. Wang and colleagues look more to the GI effects of ammonia given that it was detected in stool samples and how this might tie into issues with gut permeability so commonly discussed. Indeed ammonia - the whole nitrogen balance - takes us back to some old friends, glutamine and glutamate, one of which has been making quite a bit of news lately (here's the paper abstract).
The big question has to be why the reported differences in this latest study? I can't give a specific answer to this question but given the interest in carbohydrate metabolism and autism, the suggestion of things like lactose intolerance, added to the growing research base on gut bacteria and autism, one has to suspect that the answer might lie, partially at least, somewhere in these regions.
* Wang L. et al. Elevated fecal short chain fatty acids and ammonia concentrations in children with autism spectrum disorder. Digestive Diseases and Sciences. April 2012
DOI: 10.1007/s10620-01202167-7
** Topping DL. & Clifton PM. Short-Chain Fatty Acids and Human Colonic Function: Roles of Resistant Starch and Nonstarch Polysaccharides. Physiological Reviews. 2001; 81: 1031-1064
*** Macfarlane S. & Macfarlane GT. Regulation of short chain fatty acid production. Proceedings of the Nutrition Society. 2003; 62: 67-72
Indeed another paper published by Wang and colleagues* adds to the repertoire, suggesting that levels of fecal short chain fatty acids (SCFAs) and ammonia were higher in their cohort of children with autism compared to asymptomatic controls and hence showing alteration in the fermentation process.
As a sort of introduction to SCFAs and fermentation, readers might find this article by Topping & Clifton** (full-text) and this article by Macfarlane & Macfarlane*** (full-text) to be of interest. Basically, think carbohydrates and gut bacteria and eventually you head the direction of SCFAs. If you happen to brew your own beer, fermentation might not necessarily be a strange concept alongside memories of 'auto-brewery syndrome' (not personal memories I might add).
Unfortunately I can't post a link to the full-text but here are a few details:
- Based on the collective studies of Dr Wang's PhD (scroll down to see her thesis details), this study looked at fecal specimens from a relatively small group: 23 children (mean age ~ 10 years) diagnosed with ASD compared with 31 age-matched controls.
- Although not everyone's choice of biological medium to work with, fecal samples - as in poo samples - were analysed via various methods including colorimetry (ammonia) and gas chromatography (SCFAs). Other compounds such as p-cresol were analysed via liquid chromatography.
- Results: fecal concentrations of total SCFAs were elevated in autism samples (p=0.012) as were levels of ammonia (p=0.007). Interestingly no elevation was observed in levels of p-cresol in autism samples as has previously been described.
- More specifically with individual SCFAs, some interesting compounds cropped up as being elevated in autism samples including: propionic acid, butyric and isobutyric acids and valeric and isovaleric acids. Indeed out of the battery of SCFAs analysed, only caproic acid showed no significant difference between the groups.
- The authors conclude that fecal levels of these large bowel fermentation products might tie into the accompanying gastrointestinal (GI) findings observed in some children with autism and differences in the bacteria inhabiting the darkest recesses.
There are some obvious caveats to accompany this latest study. Aside from participant numbers being relatively small and covering quite a lot of chronological age in childhood, and the slight discrepancy in controlling for gender, there was quite a bit of 'overlap' when it came to individual results from the autism and control groups. Indeed if I were to criticise at all, I perhaps would have like to have seen some plotted information on the dispersion of values obtained from individuals just to visualise and ensure that results were not skewed by a few outlier results. As has however been discussed recently, outliers in a heterogeneous condition like autism are very often a source of great interest.
This is not the first time that the words 'autism' and 'fermentation' have come to my attention. Quite a few years back I remember some interesting work being done at Cranfield University by Maria Pilar Bilbao Montoya as part of her higher studies. Working with gastroenterologist, John Hunter, Maria presented some initial work suggesting similar things in their cohort I believe. I might be wrong but I also remember that Dr Sophie Rosseneu might have had some unpublished work in this area also as a tie up with her findings on yeasts and autism?
Memories aside, there are some interesting points to take from this research. SCFAs such as propionic acid (PA) have recently been seen in the autism research arena as per this paper (full-text) by El-Ansary and colleagues looking at what happens when you inject rats with PA in sizeable quantities. For those of you who are unimpressed with the proposed PA-gut-brain link, maybe a few other choice papers might be useful, here and here. And perhaps some evidence for the presence of PA in other biological fluids from cases of autism?
I've talked ammonia before on this blog with reference to some mitochondrial findings. Wang and colleagues look more to the GI effects of ammonia given that it was detected in stool samples and how this might tie into issues with gut permeability so commonly discussed. Indeed ammonia - the whole nitrogen balance - takes us back to some old friends, glutamine and glutamate, one of which has been making quite a bit of news lately (here's the paper abstract).
The big question has to be why the reported differences in this latest study? I can't give a specific answer to this question but given the interest in carbohydrate metabolism and autism, the suggestion of things like lactose intolerance, added to the growing research base on gut bacteria and autism, one has to suspect that the answer might lie, partially at least, somewhere in these regions.
* Wang L. et al. Elevated fecal short chain fatty acids and ammonia concentrations in children with autism spectrum disorder. Digestive Diseases and Sciences. April 2012
DOI: 10.1007/s10620-01202167-7
** Topping DL. & Clifton PM. Short-Chain Fatty Acids and Human Colonic Function: Roles of Resistant Starch and Nonstarch Polysaccharides. Physiological Reviews. 2001; 81: 1031-1064
*** Macfarlane S. & Macfarlane GT. Regulation of short chain fatty acid production. Proceedings of the Nutrition Society. 2003; 62: 67-72
Thursday, 26 April 2012
Top 10 environmental pollutants and autism
I did promise in a recent post on rich/poor kids, older mums/dads and autism, that I would pass comment on the editorial by Landrigan and colleagues* (full-text) published in the journal Environmental Health Perspectives. I couldn't let this paper go by without some reference given that it provides quite a bit of background as to where autism research should be looking if we are to assume that certain aspects of the environment might play a role in symptom onset in at least some cases of autism and perhaps other related conditions.
Indeed there are several other papers in the same journal which might also be relevant to this post, including:
I have to say that I don't have the time, energy or expertise to go through each and every one of these papers but would instead refer to quite a nice summary here on two of the papers and invite any comments from those that did read them. Please also consider this entry as a sort of continuation of my interest in pesticide exposure and health as per this and this post.
There are a few things to note about the Landrigan commentary including:
I'm sure you will agree that there are quite a few very bold statements included in this editorial not least the top 10 chemical targets for further research. I imagine that there will be some discussions on the rights and wrongs of naming and shaming the potential chemical offenders as time goes on.
The good news about these chemicals / compounds is that with the technology available these days, all are perfectly testable, and can be analysed in various biological fluids. One would therefore imagine that designing a large enough study covering people with autism, their parents, even siblings and appropriate comparators, controlling for comorbidity, even incorporating some degree of 'endophenotype' research and genetic / epigenetic elements is a perfectly feasible way of testing one or more of the '10 chemical hypotheses'.
Assuming some connection is confirmed and bearing in mind the complexity of cause-and-effect, the next question might be 'what can we do about it'? Minimising contact with these agents, particularly during conception and pregnancy and into early childhood, utilising the various ways and means available to remove these chemicals from the body - yes, even using that dreaded biomedical 'mumbo-jumbo' word detox - and assessing outcome both behavioural and biochemical (see here). Who knows perhaps even looking at the various detoxification mechanisms such as glutathione and its relations which have ascended up the evidence ranks quite recently to note any possible association.
Stop already with the speculation, I hear you cry. And I will.
To finish, do you feel compelled to walk like an Egyptian?
* Landrigan P. et al. A research strategy to discover the environmental causes of autism and neurodevelopmental disabilities. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104285
** Sheldon JF. et al. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104553
*** Kalkbrenner AE. et al. Maternal smoking during pregnancy and the prevalence of autism spectrum disorders using data from the Autism and Developmental Disabilities Monitoring Network. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104556
**** Wayman GA. et al. PCB 95 promotes dendritic growth via ryanodine receptor-dependent mechanisms. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104832
***** Wayman GA. et al. PCB 95 modulates calcium-dependent signaling pathway responsible for activity-dependent dendritic growth. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104833
Indeed there are several other papers in the same journal which might also be relevant to this post, including:
- This one by Sheldon and colleagues** (open-access) looking at pesticide exposure and autism,
- This paper by Kalkbrenner and colleagues*** (open-access) looking at maternal smoking during pregnancy,
- This paper by Wayman and colleagues**** (open-access) looking at non-dioxin like polychlorinated biphenyls (PCBs) and dendritic growth,
- and another paper by Wayman and colleagues***** (open-access) on ryanodine receptor dysregulation following PCB exposure.
I have to say that I don't have the time, energy or expertise to go through each and every one of these papers but would instead refer to quite a nice summary here on two of the papers and invite any comments from those that did read them. Please also consider this entry as a sort of continuation of my interest in pesticide exposure and health as per this and this post.
There are a few things to note about the Landrigan commentary including:
- Acceptance that autism is a family of conditions of which the authors suggest that about 30-40% of cases might be attributable to genetic inheritance.
- An estimated 3% of all neurobehavioural conditions are "caused directly by toxic environmental exposures" and some 25% caused by interactions between environmental factors and inherited susceptibilities.
- There is accumulating 'proof of principle' evidence for some role for environmental factors in cases of autism.
- Added to what is already known about the neurological and developmental effects of some of these environmental agents combined with the growth and growth in areas such as epigenetics, there are some pieces of the research puzzle which seem to overlap with evidence from autism research.
- A workshop titled 'Exploring the Environmental Causes of Autism and Learning Disabilities' generated a list of 10 chemicals widely persistent in the environment which might cause developmental neurotoxicity. These were: Lead, Methylmercury, Polychlorinated biphenyls (PCBs), Organophosphate (OP) pesticides, Organochlorine (OC) pesticides, Endocrine disruptors, Automotive exhaust, Polycyclic aromatic hydrocarbons (PAHs), Brominated flame retardants, Perfluorinated compounds. The chemicals with links will take you to previous posts on this blog which have covered the compound in question; some with autism in mind, others with a more peripheral connection.
I'm sure you will agree that there are quite a few very bold statements included in this editorial not least the top 10 chemical targets for further research. I imagine that there will be some discussions on the rights and wrongs of naming and shaming the potential chemical offenders as time goes on.
The good news about these chemicals / compounds is that with the technology available these days, all are perfectly testable, and can be analysed in various biological fluids. One would therefore imagine that designing a large enough study covering people with autism, their parents, even siblings and appropriate comparators, controlling for comorbidity, even incorporating some degree of 'endophenotype' research and genetic / epigenetic elements is a perfectly feasible way of testing one or more of the '10 chemical hypotheses'.
Assuming some connection is confirmed and bearing in mind the complexity of cause-and-effect, the next question might be 'what can we do about it'? Minimising contact with these agents, particularly during conception and pregnancy and into early childhood, utilising the various ways and means available to remove these chemicals from the body - yes, even using that dreaded biomedical 'mumbo-jumbo' word detox - and assessing outcome both behavioural and biochemical (see here). Who knows perhaps even looking at the various detoxification mechanisms such as glutathione and its relations which have ascended up the evidence ranks quite recently to note any possible association.
Stop already with the speculation, I hear you cry. And I will.
To finish, do you feel compelled to walk like an Egyptian?
* Landrigan P. et al. A research strategy to discover the environmental causes of autism and neurodevelopmental disabilities. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104285
** Sheldon JF. et al. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104553
*** Kalkbrenner AE. et al. Maternal smoking during pregnancy and the prevalence of autism spectrum disorders using data from the Autism and Developmental Disabilities Monitoring Network. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104556
**** Wayman GA. et al. PCB 95 promotes dendritic growth via ryanodine receptor-dependent mechanisms. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104832
***** Wayman GA. et al. PCB 95 modulates calcium-dependent signaling pathway responsible for activity-dependent dendritic growth. Environmental Health Perspectives. April 2012
DOI: 10.1289/ehp.1104833
Wednesday, 25 April 2012
Rich kids, older dads and autism? Or poor kids, older mums and autism?
I'm confused.
I must admit that it is fairly easy to confuse me as family members and work colleagues will readily attest. Not to dwell too much on the point but I'm the sort of chap who easily gets lost even with a map and car GPS, to the cries of "we've been past that building already" and "just ask someone". Given that I am a man, asking someone for directions is just not in my vocabulary.
The source of my current confusion is contained in one edition of the Journal of the American Academy of Child & Adolescent Psychiatry (JAACAP) containing two papers published fairly recently. The first by Rai and colleagues* reports on parental socio-economic status (SES) and risk of offspring autism in Sweden. The second is by Sandin and colleagues** looking at advancing maternal age and risk of offspring autism. The results: kids with a lower SES in Sweden have a greater risk of autism and older mums conceiving later might increase the risk of their children being diagnosed with autism.
A short summary of the Rai paper first:
And for the Sandin paper:
Why then my confusion?
Well as has been pointed out by a few people in the Twitter-sphere, quite a lot of data has already been produced and published suggesting that SES might have a link to autism risk; the findings generally reporting that kids from families with a higher SES (rich kids) might be at greater risk than their poorer counterparts. Added to the fact that quite a lot of attention has also been directed to older dads, older sperm and more possibility of some kind of genetic-environmental effect being linked to an increased risk of autism in offspring - remembering the Nature papers on de novo mutation and dads recently - you can perhaps see why I might be a little confused with these results which seem to suggest something slightly different.
I hasten to add that I am not questioning the studies, current or previous, how they were carried out or anything like that, it's just that with all the fuss being made about factors like higher SES and paternal age, one can't help but wonder if such issues are as definitive as they are often portrayed. Of course there are caveats to such generalisations. Who was looked at and where do they live alongside the myriad of interfering variables which might not be controlled for. Autism being an extremely heterogeneous condition with aetiology most likely linked to lots and lots of different factors variably depending on genes and environment should also not be forgotten. I hark back to other studies on SES and autism which to some degree substantiate the current findings from Rai and colleagues; to quote from King & Bearman*** (full-text) "We find that the socioeconomic gradient for autism has begun to reverse".
Still, what these latest figures serve to show is that autism is still very much of an enigma and one should always be wary of sweeping generalisations when it comes to risk. The added assumption also when asking questions like "what causes autism" or rather "what factors are associated with the increase in cases of autism", as well as being mindful of heterogeneity and comorbidity, we should also be responsive to the fact that the causes may be fluidic and fluctuating. What might drive increase in one cohort at one time period, may not necessarily carry the same weight in others at other times. I will talk more about this in subsequent posts on the back of some interesting suggestions regarding environmental pollutants (see here for a sneak preview of the research).
To finish, I'm minded to suggest something a little bit lively to relieve me of my confusion. How about a spot of B52s?
* Rai D. et al. Parental socioeconomic status and risk of offspring autism spectrum disorders in a Swedish population-based study. JAACAP. 2012; 51: 467-476.
** Sandin S. et al. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. JAACAP. 2012; 51: 477-486
*** King MD. & Bearman PS. Socioeconomic status and the increased prevalence of autism in California. American Sociological Review. 2011; 76: 320-346.
I must admit that it is fairly easy to confuse me as family members and work colleagues will readily attest. Not to dwell too much on the point but I'm the sort of chap who easily gets lost even with a map and car GPS, to the cries of "we've been past that building already" and "just ask someone". Given that I am a man, asking someone for directions is just not in my vocabulary.
The source of my current confusion is contained in one edition of the Journal of the American Academy of Child & Adolescent Psychiatry (JAACAP) containing two papers published fairly recently. The first by Rai and colleagues* reports on parental socio-economic status (SES) and risk of offspring autism in Sweden. The second is by Sandin and colleagues** looking at advancing maternal age and risk of offspring autism. The results: kids with a lower SES in Sweden have a greater risk of autism and older mums conceiving later might increase the risk of their children being diagnosed with autism.
A short summary of the Rai paper first:
- Rai et al were intrigued about how the data on SES and autism (high family SES = increased risk of offspring autism) seemed to fly in the face of many other conditions where lower SES increased risk.
- Based on a total population of just over half a million children aged 0-17 years living in Stockholm county between 2001-2007, they wanted to look at the 5000 or so cases of autism included in the population, matched 10-1 with age and gender controlled asymptomatic children, to see if SES factors were relevant.
- Importantly, they controlled for various potential sources of bias including things like parental age, migration status and various birth characteristics.
- Results: lower SES seemed to be associated with a risk of autism in offspring.
And for the Sandin paper:
- A slightly different approach based on a meta-analysis of epidemiological studies reporting on autism up to January 2012.
- Sixteen publications met their criteria for study inclusion resulting in a total sample population of just over 25,000 people with autism - autism spectrum conditions - compared with 8.5 million controls.
- Results: based on various analyses of age and age-brackets, a dose response effect of maternal age on risk of offspring autism was apparent in most studies. So older mums with a greater 'age dose' were at greater risk of having a child with autism. Mums who were 35 years old or older at conception/birth were about 1.5 times more likely to have a child with autism compared to those mums falling into the 25-29 years age bracket. Interestingly, young mums (below 20 years of age) showed a significant decrease in risk of offspring autism.
Why then my confusion?
Well as has been pointed out by a few people in the Twitter-sphere, quite a lot of data has already been produced and published suggesting that SES might have a link to autism risk; the findings generally reporting that kids from families with a higher SES (rich kids) might be at greater risk than their poorer counterparts. Added to the fact that quite a lot of attention has also been directed to older dads, older sperm and more possibility of some kind of genetic-environmental effect being linked to an increased risk of autism in offspring - remembering the Nature papers on de novo mutation and dads recently - you can perhaps see why I might be a little confused with these results which seem to suggest something slightly different.
I hasten to add that I am not questioning the studies, current or previous, how they were carried out or anything like that, it's just that with all the fuss being made about factors like higher SES and paternal age, one can't help but wonder if such issues are as definitive as they are often portrayed. Of course there are caveats to such generalisations. Who was looked at and where do they live alongside the myriad of interfering variables which might not be controlled for. Autism being an extremely heterogeneous condition with aetiology most likely linked to lots and lots of different factors variably depending on genes and environment should also not be forgotten. I hark back to other studies on SES and autism which to some degree substantiate the current findings from Rai and colleagues; to quote from King & Bearman*** (full-text) "We find that the socioeconomic gradient for autism has begun to reverse".
Still, what these latest figures serve to show is that autism is still very much of an enigma and one should always be wary of sweeping generalisations when it comes to risk. The added assumption also when asking questions like "what causes autism" or rather "what factors are associated with the increase in cases of autism", as well as being mindful of heterogeneity and comorbidity, we should also be responsive to the fact that the causes may be fluidic and fluctuating. What might drive increase in one cohort at one time period, may not necessarily carry the same weight in others at other times. I will talk more about this in subsequent posts on the back of some interesting suggestions regarding environmental pollutants (see here for a sneak preview of the research).
To finish, I'm minded to suggest something a little bit lively to relieve me of my confusion. How about a spot of B52s?
* Rai D. et al. Parental socioeconomic status and risk of offspring autism spectrum disorders in a Swedish population-based study. JAACAP. 2012; 51: 467-476.
** Sandin S. et al. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. JAACAP. 2012; 51: 477-486
*** King MD. & Bearman PS. Socioeconomic status and the increased prevalence of autism in California. American Sociological Review. 2011; 76: 320-346.
Tuesday, 24 April 2012
Glutathione and autism reloaded
I hope that I don't seem to be treading on old ground with this post on glutathione (GSH) and autism. I have covered some research on a possible link between glutathione and autism spectrum conditions previously (see here) following some interesting suggestions on the potential value of measuring GSH levels as a kind of biomarker for autism. The caveat being that despite an initial AUC=1 much more investigation is required.
This post is slightly different in that I wish to bring to your attention a review paper by Main and colleagues* (full-text) which highlights pretty much what we know, or think we know, about GSH and autism so far. Before progressing I think I should reiterate my caveat of not providing medical or other advice and strongly recommending that a medical physician be involved in all decision making aspects impacting health.
Aside from the content of the paper which I will run through shortly, a familiar name on the authorship list pulled me into this post. Dr Manya Angley, a Pharmacist from the University of South Australia, who has been involved in some really interesting work in autism research (here and here) was part of the team. Avid readers of this blog (if there are any!) might remember my first ever blog post on a paper with some pretty nifty techniques and results based on gut bacterial metabolites turning up in the urine of a group of children with autism. Well, Dr Angley was part of that authorship team also with some impressive company.
The current review carries a few interesting details:
There is quite a lot of other information included in this review which should keep any interested parties content for a few hours. I would hasten to add that in this post I am not uniformly suggesting that everyone with autism has issues with glutathione, cysteine or homocysteine as per my mantra of heterogeneity and comorbidity.
One would however hope that with the continuing development of the third and final NICE guidance for autism in children and young people here in the UK, reviews like this one will figure strongly in informing the panel about potential areas of importance. If anything else this paper should invigorate some real interest into how amino acid and antioxidant chemistry in autism is not just alternative "biomedical" mumbo-jumbo.
To finish, the Carpenters and 'Top of the world'. Have a great day!
* Main PAE. et al. The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutrition & Metabolism. April 2012.
DOI: 10.1186/1743-7075-9-35
This post is slightly different in that I wish to bring to your attention a review paper by Main and colleagues* (full-text) which highlights pretty much what we know, or think we know, about GSH and autism so far. Before progressing I think I should reiterate my caveat of not providing medical or other advice and strongly recommending that a medical physician be involved in all decision making aspects impacting health.
Aside from the content of the paper which I will run through shortly, a familiar name on the authorship list pulled me into this post. Dr Manya Angley, a Pharmacist from the University of South Australia, who has been involved in some really interesting work in autism research (here and here) was part of the team. Avid readers of this blog (if there are any!) might remember my first ever blog post on a paper with some pretty nifty techniques and results based on gut bacterial metabolites turning up in the urine of a group of children with autism. Well, Dr Angley was part of that authorship team also with some impressive company.
The current review carries a few interesting details:
- It pretty much highlights all the work that has been done on measuring glutathione levels in autism up to November 2011. As anyone who has done a systematic review will tell you, this is no mean feat and perfect for answering an undergraduate exam paper such as 'Glutathione and autism: describe and critically discuss'.
- Lower levels of GSH and alterations to chemical relations in cases of autism are a pretty consistent feature of the research carried out so far.
- Serum cysteine levels also seem to be reduced and potentially associated with the severity of presented autistic symptoms. One has to wonder how this might fit into the sulphation issues previously highlighted in cases of autism and whether indeed as in some cases of schizophrenia also, cysteine in the form of NAC might be an area requiring much more serious investigation.
- Serum homocysteine levels in cases of autism don't seem to show significant differences with control values. I was slightly shocked by this finding given previous research. Indeed a more recent paper not included in the current review suggested that hyperhomocysteinemia might be a useful biomarker for autism itself.
- A significant increase in plasma vitamin B6 - pyridoxal-5′-phosphate - was noted in several studies potentially relating to issues with the bioavailability of the vitamin. Perhaps one reason why B6 never lived up to its potential?
There is quite a lot of other information included in this review which should keep any interested parties content for a few hours. I would hasten to add that in this post I am not uniformly suggesting that everyone with autism has issues with glutathione, cysteine or homocysteine as per my mantra of heterogeneity and comorbidity.
One would however hope that with the continuing development of the third and final NICE guidance for autism in children and young people here in the UK, reviews like this one will figure strongly in informing the panel about potential areas of importance. If anything else this paper should invigorate some real interest into how amino acid and antioxidant chemistry in autism is not just alternative "biomedical" mumbo-jumbo.
To finish, the Carpenters and 'Top of the world'. Have a great day!
* Main PAE. et al. The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutrition & Metabolism. April 2012.
DOI: 10.1186/1743-7075-9-35
Sunday, 22 April 2012
S100B protein and autism
I am a little late getting to this paper given that other bloggers have discussed some of the ins and outs of its content and potential implications for autism spectrum conditions. Hopefully I can add some additional value to this area of endeavour with this post.
I freely admit that until the paper by Al-Ayadhi and Mostafa* was published I had never come across the S100B protein ever. Indeed had someone asked me 'what is the S100B protein' I might have been tempted to say either some kind of experimental protein shake or perhaps some elaborate lab-grown meat alternative as per this story.
As it happens S100B protein is a member of the S100 proteins, so named because the protein is 100% soluble in ammonium sulphate at neutral pH. S100B protein is synthesised in quite considerable amounts by astrocytes and has been tied into various functions including long-term neuronal synaptic plasticity. At elevated levels however, S100B protein has been associated with neuronal death among other things as per this study looking at levels in Olympic boxers.
With this in mind together with some speculation on a link with autoimmunity, or more specifically autoantibodies tied into neurological damage, the authors set about looking at S100B as a marker of potential neurological damage combined with antiribosomal P protein antibodies. For those avid viewers, antiribosomal P protein antibodies have already been looked at by this Saudi autism research group before, specifically with plasma neurokinin A levels in mind.
A summary of the current paper:
These results are interesting insofar as the main findings suggestive of increased serum levels of S100B in autism and a kind of sliding scale involvement when taking severity of presented symptoms into account. I would hasten to add that S100B protein has also cropped up in other conditions including schizophrenia and bipolar disorder although questions about whether this is a central finding or perhaps related to issues with glucose metabolism for example, remain unanswered. I note for example, markers of body weight and body mass were not recorded in the recent study thus remaining a potential confounding variable.
Alongside the other research being undertaken by this group with autism as a specific focus, a fuzzy picture is starting to be built up of quite a complex relationship between the immune system, various neurological functions and autism, at least in the small numbers of cases included in their studies.
To finish, I was torn between 2 songs for this post. Instead of deciding I offer a choice: The Pixies and Monkey gone to heaven or The Descendents and I'm the one. It's your choice.
* Al-Ayadhi L. & Mostafa GA. A lack of association between elevated serum levels of S100B protein and autoimmunity in autistic children. Journal of Neuroinflammation. March 2012.
DOI: 10.1186/1742-2094-9-54
I freely admit that until the paper by Al-Ayadhi and Mostafa* was published I had never come across the S100B protein ever. Indeed had someone asked me 'what is the S100B protein' I might have been tempted to say either some kind of experimental protein shake or perhaps some elaborate lab-grown meat alternative as per this story.
As it happens S100B protein is a member of the S100 proteins, so named because the protein is 100% soluble in ammonium sulphate at neutral pH. S100B protein is synthesised in quite considerable amounts by astrocytes and has been tied into various functions including long-term neuronal synaptic plasticity. At elevated levels however, S100B protein has been associated with neuronal death among other things as per this study looking at levels in Olympic boxers.
With this in mind together with some speculation on a link with autoimmunity, or more specifically autoantibodies tied into neurological damage, the authors set about looking at S100B as a marker of potential neurological damage combined with antiribosomal P protein antibodies. For those avid viewers, antiribosomal P protein antibodies have already been looked at by this Saudi autism research group before, specifically with plasma neurokinin A levels in mind.
A summary of the current paper:
- Sixty-four children diagnosed with DSM-IV autism, mean age 8.4 years were included for study and compared against 46 age- and sex-matched asymptomatic controls.
- Serum levels of S100B protein were measured by ELISA. Actually, samples were all analysed twice just to make sure there was some degree of consistency in the findings. At the same time, serum IgG and IgM antiribosomal P protein antibodies were also measured. ELISA relies on the principle of antibody-antigen interaction which can sometimes be affected by cross-reactivity. In this study, such confounders were not observed in any significant measure.
- The results: serum levels of S100B protein were elevated in the autism group compared to controls (p<0.001). There was quite a bit of overlap between the groups so no AUC=1 for this study group this time around. Based on CARS scores, severity of autism also seemed to be a factor: more severe cases seemed to show elevated levels compared with milder or moderate cases (according to CARS).
- Increased serum levels of antiribosomal P protein antibodies were also reported in the autism group compared with controls and again severity of CARS autism was also a factor.
- When it came to plotting any correlation between the two variables, S100B and antiribosomal P protein antibodies, it was a case of close but no statistical cigar.
These results are interesting insofar as the main findings suggestive of increased serum levels of S100B in autism and a kind of sliding scale involvement when taking severity of presented symptoms into account. I would hasten to add that S100B protein has also cropped up in other conditions including schizophrenia and bipolar disorder although questions about whether this is a central finding or perhaps related to issues with glucose metabolism for example, remain unanswered. I note for example, markers of body weight and body mass were not recorded in the recent study thus remaining a potential confounding variable.
Alongside the other research being undertaken by this group with autism as a specific focus, a fuzzy picture is starting to be built up of quite a complex relationship between the immune system, various neurological functions and autism, at least in the small numbers of cases included in their studies.
To finish, I was torn between 2 songs for this post. Instead of deciding I offer a choice: The Pixies and Monkey gone to heaven or The Descendents and I'm the one. It's your choice.
* Al-Ayadhi L. & Mostafa GA. A lack of association between elevated serum levels of S100B protein and autoimmunity in autistic children. Journal of Neuroinflammation. March 2012.
DOI: 10.1186/1742-2094-9-54
Thursday, 19 April 2012
Porphyrins and autism
Excluding pretty boy vampire consumers, it is well known that human blood is a fantastic source of nutrients for lots of different pathogens. A recent article by Pishchany and Skarr* (full-text) said as much, with particular focus on the iron and amino acid content of hemoglobin - the oxygen-carrying protein which makes blood red - as a target for some invading critters. I don't want to dwell too much on blood-borne pathogens and their dietary habits (burp, excuse me) but this paper does provide quite a nice introduction into something which has cropped up over the years in relation to autism spectrum conditions, the porphyrins.
I'll readily admit that porphyrins are not generally part of my 'knows what he is talking about' repertoire, a very limited repertoire by all accounts, and so once again the caveat is not to take my word as gospel. Porphyrins are an interesting class of compounds notably involved with hemoglobin by way of heme, a co-factor of hemoglobin. Porphyrins and porphyria - a group of genetic disorders involving various 'faulty' enzymes needed to make heme - have been banded around autism research circles for quite a few years now. That, alongside some recent interest in porphyrins on social media brought me to this post and a review of some of the evidence suggesting involvement with autism.
One of the earliest papers that I've been able to find on porphyria in general medicine is this one** (full-text) by Dobriner and colleagues (1938). It makes for an interesting read because not only does it introduce some of the porphyrins looked at in later publications but it also talks about the effects of daily injections of liver extract on both symptoms and the presentation of porphyrins. Of course I am not advocating liver extract injections for anything (please file under 'words that I thought I would never utter in a sentence') but it provides a good historical record.
The paper by James Woods and colleagues*** (full-text) is as good as any to start with when looking at porphyrins and autism spectrum conditions. I am reliably informed that Dr Woods is a bit of an expert when it comes to all things porphyrin as per some of his other publications (here and here). Indeed this paper**** (full-text) has quite a nice graphical aid as to the different type of porphyrins and their biosynthesis which are subsequently discussed in this post.
Back to the 2010 paper, aside from finding little difference in levels of confounding compounds like mercury across their groups (see recent post here), they did report "... the mean concentrations of hexacarboxyl- (p < 0.01), pentacarboxyl- (p < 0.001), and copro- (p < 0.009) porphyrins were significantly higher among AU [autism] compared with NT [neurotypical] groups". What this translates as is the suggestion that whilst young children seem to have naturally high levels of porphyrins excreted in urine, the levels detected at a group level in autism were elevated beyond those normally expected.
Woods and colleagues go on to speculate that either genetic or mitochondrial (or both) issues might be areas worth pursuing to account for their findings; both areas which also have more than a passing relationship to at least some cases of autism. Indeed a sort of add-on paper from the Woods group***** (full-text) even more recently published by this group talks about issues with porphyrin metabolism as being "... strong predictors of both AUT and PDD-NOS". There are also some interesting urinary creatinine findings in this paper also (see here for previous discussions).
Other authors have also reported similar findings to Woods and colleagues. I say similar but Kern and colleagues****** suggested that alongside elevated levels of urinary pentacarboxy- and copro-porphyrins, elevated levels of precoproporphyrins were also found. The caveat being that this studied relied on a much smaller participant group. There are other studies noting similar findings quite consistently and across different countries including Korea (Youn et al, 2010) and Australia (Austin & Shandley, 2008).
All in all, I would be tempted to say that irrespective of a link between heavy metals or not, elevated levels of porphyrins quite consistently appearing in cases of autism should be the topic of a lot more research. At the moment, no-one really knows how issues with porphyrins fits into autism and its presentation. There are some discussions linking such issues to the role of heme in neuronal glutaminergic chemistry and tryptophan-serotonin chemistry, both of which have been connected to autism.
I'd better add porphyrins to the autism research wish list.
* Pishchany G. & Skaar EP. Taste for blood: hemoglobin as a nutrient source for pathogens. PLoS Pathogens. March 2012
DOI: 10.1371/journal.ppat.1002535
** Dobriner K. et al. The excretion of porphyrins in congenital porphyria. Journal of Clinical Investigation. 1938; 17: 761-764.
*** Woods JS. et al. Urinary porphyrin excretion in neurotypical and autistic children. Environmental Health Perspectives. 2010; 118: 1450-1457
DOI: 10.1289/ehp.0901713
**** Daniell WE. et al. Environmental chemical exposures and disturbances of heme synthesis. Environmental Health Perspectives. 1997; 105: 37-53
***** Heyer NJ. et al. Disordered porphyrin metabolism: a potential biological marker for autism risk assessment. Autism Research. February 2012.
DOI: 10.1002/aur.236
****** Kern JK. et al. Toxicity biomarkers in autism spectrum disorder: a blinded study of urinary porphyrins. Pediatrics International. 2011; 53: 147-153
DOI: 10.1111/j.1442-200X.2010.03196.x
I'll readily admit that porphyrins are not generally part of my 'knows what he is talking about' repertoire, a very limited repertoire by all accounts, and so once again the caveat is not to take my word as gospel. Porphyrins are an interesting class of compounds notably involved with hemoglobin by way of heme, a co-factor of hemoglobin. Porphyrins and porphyria - a group of genetic disorders involving various 'faulty' enzymes needed to make heme - have been banded around autism research circles for quite a few years now. That, alongside some recent interest in porphyrins on social media brought me to this post and a review of some of the evidence suggesting involvement with autism.
One of the earliest papers that I've been able to find on porphyria in general medicine is this one** (full-text) by Dobriner and colleagues (1938). It makes for an interesting read because not only does it introduce some of the porphyrins looked at in later publications but it also talks about the effects of daily injections of liver extract on both symptoms and the presentation of porphyrins. Of course I am not advocating liver extract injections for anything (please file under 'words that I thought I would never utter in a sentence') but it provides a good historical record.
The paper by James Woods and colleagues*** (full-text) is as good as any to start with when looking at porphyrins and autism spectrum conditions. I am reliably informed that Dr Woods is a bit of an expert when it comes to all things porphyrin as per some of his other publications (here and here). Indeed this paper**** (full-text) has quite a nice graphical aid as to the different type of porphyrins and their biosynthesis which are subsequently discussed in this post.
Back to the 2010 paper, aside from finding little difference in levels of confounding compounds like mercury across their groups (see recent post here), they did report "... the mean concentrations of hexacarboxyl- (p < 0.01), pentacarboxyl- (p < 0.001), and copro- (p < 0.009) porphyrins were significantly higher among AU [autism] compared with NT [neurotypical] groups". What this translates as is the suggestion that whilst young children seem to have naturally high levels of porphyrins excreted in urine, the levels detected at a group level in autism were elevated beyond those normally expected.
Woods and colleagues go on to speculate that either genetic or mitochondrial (or both) issues might be areas worth pursuing to account for their findings; both areas which also have more than a passing relationship to at least some cases of autism. Indeed a sort of add-on paper from the Woods group***** (full-text) even more recently published by this group talks about issues with porphyrin metabolism as being "... strong predictors of both AUT and PDD-NOS". There are also some interesting urinary creatinine findings in this paper also (see here for previous discussions).
Other authors have also reported similar findings to Woods and colleagues. I say similar but Kern and colleagues****** suggested that alongside elevated levels of urinary pentacarboxy- and copro-porphyrins, elevated levels of precoproporphyrins were also found. The caveat being that this studied relied on a much smaller participant group. There are other studies noting similar findings quite consistently and across different countries including Korea (Youn et al, 2010) and Australia (Austin & Shandley, 2008).
All in all, I would be tempted to say that irrespective of a link between heavy metals or not, elevated levels of porphyrins quite consistently appearing in cases of autism should be the topic of a lot more research. At the moment, no-one really knows how issues with porphyrins fits into autism and its presentation. There are some discussions linking such issues to the role of heme in neuronal glutaminergic chemistry and tryptophan-serotonin chemistry, both of which have been connected to autism.
I'd better add porphyrins to the autism research wish list.
* Pishchany G. & Skaar EP. Taste for blood: hemoglobin as a nutrient source for pathogens. PLoS Pathogens. March 2012
DOI: 10.1371/journal.ppat.1002535
** Dobriner K. et al. The excretion of porphyrins in congenital porphyria. Journal of Clinical Investigation. 1938; 17: 761-764.
*** Woods JS. et al. Urinary porphyrin excretion in neurotypical and autistic children. Environmental Health Perspectives. 2010; 118: 1450-1457
DOI: 10.1289/ehp.0901713
**** Daniell WE. et al. Environmental chemical exposures and disturbances of heme synthesis. Environmental Health Perspectives. 1997; 105: 37-53
***** Heyer NJ. et al. Disordered porphyrin metabolism: a potential biological marker for autism risk assessment. Autism Research. February 2012.
DOI: 10.1002/aur.236
****** Kern JK. et al. Toxicity biomarkers in autism spectrum disorder: a blinded study of urinary porphyrins. Pediatrics International. 2011; 53: 147-153
DOI: 10.1111/j.1442-200X.2010.03196.x
Tuesday, 17 April 2012
Functional connectivity, NAC & schizophrenia
I promise that I am not getting obsessed with N-acetyl-cysteine (NAC) nor am I moving my focus from autism research to schizophrenia research despite recent posts. It just so happened that I stumbled upon this paper by Carmeli and colleagues* (full-text) recently and the needle on my interest-o-meter started to register something potentially important.
Indeed, there were several things about this paper which just made it seem right to comment on it: the use of that dark art, EEGs, the small participant group with schizophrenia, the NAC thing and the tie-up with glutathione. My previous posts on the potential for overlap between schizophrenia and autism and the significantly over-represented paper discussion serve as reminders that although discrete conditions, the words 'cut from the same cloth' in a biochemical sense might not necessarily be an inappropriate saying.
The paper is available to all but a summary:
Despite the small sample size, these are interesting findings. Interesting because of the implications for schizophrenia and brain function which kinda follows on from the recently discussed study on schizophrenia and dietary intervention from a few years back. I know synchronisation is not the same as cerebral blood flow, but the link is the suggestion that at least some of the brain findings in schizophrenia might, just might, be functional rather than just structural and hence partially reversible in the same way that pharmacotherapy such as neuroleptics are used. A similar thing also to what Dr Michael Merzenich discussed in this recent piece in Nature on neuroplasticity and brain training. I would hasten to add that I am reserving judgement on the schizophrenia - brain training link until more substantial evidence is forthcoming.
As to the involvement of NAC and glutathione in schizophrenia, well this paper by Olivia Dean and colleagues** (full-text) seems to sum it up quite well. That and a post by Dr Deans with a rather appropriate title (I have a NAC for that). I also think back to the study looking at possible biomarkers for schizophrenia and their finding of issues with cystine (the dimer of cysteine) and can't help but think that there might be something crucial there which really should be looked at with greater assiduity.
* Carmeli C. et al. Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial. PLoS ONE. February 2012.
DOI: 10.1371/journal.pone.0029341
** Dean O. et al. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. Journal of Psychiatry & Neuroscience. 2011; 36: 78-86.
DOI: 10.1503/jpn.100057
Indeed, there were several things about this paper which just made it seem right to comment on it: the use of that dark art, EEGs, the small participant group with schizophrenia, the NAC thing and the tie-up with glutathione. My previous posts on the potential for overlap between schizophrenia and autism and the significantly over-represented paper discussion serve as reminders that although discrete conditions, the words 'cut from the same cloth' in a biochemical sense might not necessarily be an inappropriate saying.
The paper is available to all but a summary:
- N-acetyl-cysteine (NAC) was given to participants diagnosed with DSM-IV schizophrenia (N=11) in a randomised, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). Yes, you saw right, the trial only included 11 participants which dropped to 8 participants when all was said and done. Having said that, this group (I think) were involved in a larger trial of NAC and schizophrenia undertaken by some of the authors.
- Resting EEGs were carried out at baseline, 2 months (treatment cross-over point) and 4 months (study end). I am not an EEG Jedi Master so an easy description I cannot give [said in best Yoda voice] of what was done aside from pasting from the article: "..whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs". I think this means that neural synchrony was a big part of the analysis but don't quote me on that.
- After some statistical wizardry, the results suggested that NAC supplementation seemed to affect EEG synchronisation in a couple of brain areas and despite the small participant numbers, the results seemed to be fairly similar across individual participants at least in relation to a few of those brain areas. From a behavioural perspective, the results also seemed to tie into other findings of issues with executive functions and attention noted in people with schizophrenia.
Despite the small sample size, these are interesting findings. Interesting because of the implications for schizophrenia and brain function which kinda follows on from the recently discussed study on schizophrenia and dietary intervention from a few years back. I know synchronisation is not the same as cerebral blood flow, but the link is the suggestion that at least some of the brain findings in schizophrenia might, just might, be functional rather than just structural and hence partially reversible in the same way that pharmacotherapy such as neuroleptics are used. A similar thing also to what Dr Michael Merzenich discussed in this recent piece in Nature on neuroplasticity and brain training. I would hasten to add that I am reserving judgement on the schizophrenia - brain training link until more substantial evidence is forthcoming.
As to the involvement of NAC and glutathione in schizophrenia, well this paper by Olivia Dean and colleagues** (full-text) seems to sum it up quite well. That and a post by Dr Deans with a rather appropriate title (I have a NAC for that). I also think back to the study looking at possible biomarkers for schizophrenia and their finding of issues with cystine (the dimer of cysteine) and can't help but think that there might be something crucial there which really should be looked at with greater assiduity.
* Carmeli C. et al. Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial. PLoS ONE. February 2012.
DOI: 10.1371/journal.pone.0029341
** Dean O. et al. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. Journal of Psychiatry & Neuroscience. 2011; 36: 78-86.
DOI: 10.1503/jpn.100057
Saturday, 14 April 2012
Significantly over-represented in autism
Comorbidity in autism spectrum conditions is of great interest to this blog. Not only because of the possible impact that certain comorbidities might have on the presentation of some cases of autism but also because, for one reason or another, certain types of comorbidity just don't seem to get either the acknowledgement or necessary resources for potential remediation that they require. As I have said many, many times, having an autism spectrum condition is not seemingly protective of having any other condition.
It was with comorbidity in mind that I was particularly interested in this study by Kohane and colleagues* (full-text) highlighting several important conditions to be noted alongside a diagnosis of autism.
The paper is open-access - everyone's favourite kind of paper - but if you want a short summary...
I'm not going to say too much more about these findings than has already been discussed on this blog. Epilepsy and seizure-type disorders are important comorbidities. Schizophrenia - well, that has also been covered quite recently from a diagnostic and potential biochemical point of view. Inflammatory bowel disease and autism, see here and here.
Other bowel disorders. There are some interesting comparisons with other datasets, including that of quite a widely discussed study on gastrointestinal (GI) issues related to autism by Black and colleagues** (full-text). They suggested that based on similar UK data, bowel problems were no more likely to occur in autism than in not-autism. Allowing for methodological caveats, it seems participant numbers might have been a factor in their findings. Certainly other studies, using different, more direct 'look-and-see' methodologies have arrived at different conclusions. Interesting also that the paper by Horvath and colleagues picked up the suggestion of issues with carbohydrate metabolism in cases of autism over 10 years before the recent Kushak paper. Who'd have thought it?
What the current study from Kohane and colleagues does reinforce is the notion that autism can and does carry comorbidity; and whilst arguments about the how and why of those comorbidities still rage in some quarters, there is a need for parents and professionals alike to be vigilant for them. Indeed, type 1 diabetes carries some pretty critical outcome if not treated.
Tracking back to the opening paragraph of this post, one has also to question what effect such comorbidities if present, might have on the presentation of autism and whether tackling some of the comorbidity might just have some surprising knock-on effects to the presentation of core symptoms and overall quality of life.
* Kohane IS. et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS ONE. April 2012.
DOI: 10.1371/journal.pone.0033224
** Black C. et al. Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database. BMJ. 2002; 325: 419-421
It was with comorbidity in mind that I was particularly interested in this study by Kohane and colleagues* (full-text) highlighting several important conditions to be noted alongside a diagnosis of autism.
The paper is open-access - everyone's favourite kind of paper - but if you want a short summary...
- Based on an analysis of electronic health records from 2001 - 2010, data from the US Shared Health Research Informatics Network (SHRINE) system developed by some of the same authors was analysed. With a total sample size of over 2.3 million patients, data for ICD-9 diagnosed participants with an autistic disorder, Asperger syndrome or other pervasive developmental disorder under 35 years of age (N=14,381) were retrospectively mined to assess the prevalence of various comorbidity. The final total of participants is likely to be an over-estimation given that patients were not individually indexed, so if they travelled to more than one hospital included in the dataset they would be counted twice.
- The results: based on diagnoses made via ICD-9 classification, several conditions seemed to be pretty prevalent comorbid to a diagnosis of autism. In ascending order across the total autism participant groups these included: epilepsy (19.4%), CNS/head anomalies (12.4%), bowel disorders (not including inflammatory bowel disorders) (11.7%) and schizophrenia (2.4%).
- Comparisons with non-autism controls showed that these and most of the other comorbidities identified were significantly more frequently reported in cases of autism. Indeed, even some quite rare associations with autism such as muscular dystrophy were nonetheless still more prevalent in autism than in not-autism.
- When looking at age, and in particular changes to prevalence of comorbidity across age, there were a few interesting details to emerge. So, bearing in mind the p-value used, epilepsy, sleep disorders and bowel problems were statistically just as prevalent in the 18-34 years group as they were in the 0-17 years group. That being said, the older group with autism (18-34 years) showed significantly more frequent presentation with type-1 diabetes, inflammatory bowel disease and schizophrenia than the younger group.
I'm not going to say too much more about these findings than has already been discussed on this blog. Epilepsy and seizure-type disorders are important comorbidities. Schizophrenia - well, that has also been covered quite recently from a diagnostic and potential biochemical point of view. Inflammatory bowel disease and autism, see here and here.
Other bowel disorders. There are some interesting comparisons with other datasets, including that of quite a widely discussed study on gastrointestinal (GI) issues related to autism by Black and colleagues** (full-text). They suggested that based on similar UK data, bowel problems were no more likely to occur in autism than in not-autism. Allowing for methodological caveats, it seems participant numbers might have been a factor in their findings. Certainly other studies, using different, more direct 'look-and-see' methodologies have arrived at different conclusions. Interesting also that the paper by Horvath and colleagues picked up the suggestion of issues with carbohydrate metabolism in cases of autism over 10 years before the recent Kushak paper. Who'd have thought it?
What the current study from Kohane and colleagues does reinforce is the notion that autism can and does carry comorbidity; and whilst arguments about the how and why of those comorbidities still rage in some quarters, there is a need for parents and professionals alike to be vigilant for them. Indeed, type 1 diabetes carries some pretty critical outcome if not treated.
Tracking back to the opening paragraph of this post, one has also to question what effect such comorbidities if present, might have on the presentation of autism and whether tackling some of the comorbidity might just have some surprising knock-on effects to the presentation of core symptoms and overall quality of life.
* Kohane IS. et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS ONE. April 2012.
DOI: 10.1371/journal.pone.0033224
** Black C. et al. Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database. BMJ. 2002; 325: 419-421
Thursday, 12 April 2012
A macroepigenetic approach to autism?
Summary and review papers are always excellent fodder for a blog post because of the ideas and hypotheses they can generate based on a synthesis of lots of different research across different areas. Everyone strives to be 'lateral thinkers' during such papers in an attempt to fit together evidence pertinent to their viewpoint. As to how many actually succeed in making that magical connection is a slightly different story.
One recent review paper which caught my eye was this one by Dufault and colleagues* (full-text) which looked at some of the evidence for the role of diet and toxic substances in the environment as being involved in the increasing numbers of cases of autism in the United States (see the 2012 CDC figures here). I tread carefully with this line of thinking bearing in mind the headline which was covered as part of my post on obese mums and risk of autism - "Obesity in pregnancy causing rise in autism cases" - er, not exactly that simple.
I was drawn to the Dufault paper on several levels. Mention of the word 'epigenetics' (I'm sure you've grown tired of me describing this as changes to gene function over changes to the genome) was a pretty big attraction. As a sidelines, epigenetics is something which the ALSPAC are also working up to now some of their cohort has hit the magical age of 21 years old (see here) alongside some interest from people like David Barker, he of the Barker hypothesis.
I digress.
Reference also to the possible effects of diet and environment on cases of autism was also a big pull from the Dufault paper. Richard Deth (pronounced Deeth) on the authorship list was also a draw given some of his past research on methylation and autism (including reference to the D4 dopamine receptor) and the hyperhomocysteinemia findings which have frequented this blog from time to time.
The latest paper is full-text but a few pointers:
I hope you are still here after reading all that. It's taken me a few reads of the paper to start to come to grips with all the various strands of evidence incorporated and the overview presented here is not intended to be a definitive one. I suppose the main conclusion is that various factors might be implicated in producing an epigenetic response in autism including pesticide exposures, heavy metals and dietary components like HFCS. The sum of these factors being greater than the individual factors acting alone.
To finish, I have been getting a little too carried away with the Beautiful South lately and so to conclude, a Song for Whoever (the video is not the real song video but the sound was the best quality).
* Dufault R. et al. A macroepigenetic approach to identify factors responsible for the autism epidemic in the United States. Clinical Epigenetics. April 2012.
DOI: 10.1186/1868-7083-4-6
** Dufault R. et al. Mercury exposure, nutritional deficiencies and metabolic disruptions may affect learning in children. Behavioral & Brain Functions. 2009; 5: 44.
DOI: 10.1186/1744-9081-5-44
** D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Molecular Psychiatry. 2005; 10: 1006-1016
DOI: 10.1038/sj.mp.4001714
One recent review paper which caught my eye was this one by Dufault and colleagues* (full-text) which looked at some of the evidence for the role of diet and toxic substances in the environment as being involved in the increasing numbers of cases of autism in the United States (see the 2012 CDC figures here). I tread carefully with this line of thinking bearing in mind the headline which was covered as part of my post on obese mums and risk of autism - "Obesity in pregnancy causing rise in autism cases" - er, not exactly that simple.
I was drawn to the Dufault paper on several levels. Mention of the word 'epigenetics' (I'm sure you've grown tired of me describing this as changes to gene function over changes to the genome) was a pretty big attraction. As a sidelines, epigenetics is something which the ALSPAC are also working up to now some of their cohort has hit the magical age of 21 years old (see here) alongside some interest from people like David Barker, he of the Barker hypothesis.
I digress.
Reference also to the possible effects of diet and environment on cases of autism was also a big pull from the Dufault paper. Richard Deth (pronounced Deeth) on the authorship list was also a draw given some of his past research on methylation and autism (including reference to the D4 dopamine receptor) and the hyperhomocysteinemia findings which have frequented this blog from time to time.
The latest paper is full-text but a few pointers:
- 'Macroepigenetics' is a term introduced by this paper which refers to "... the process of examining food supplies and their impact on body metabolism and gene function along with what is known about environmental exposures across populations".
- Mercury features quite heavily in this paper and in particular, the mercury toxicity model, detailing the link between dietary elements, deficiencies in certain essential metals like zinc and environmental exposures to heavy metals. I know there is still some heated debate about things like mercury and whether or not exposures to different types of mercury might be implicated in at least some cases of autism. I'm not going to say anything else about this particular discussion for now.
- Consumption of high fructose corn syrup (HFCS) also gets a mention in the paper. To my mind, this is one of the first times HFCS has been linked to autism outside of a past paper from some of the same authors** (full-text). The theory goes that among other things, HFCS has the propensity to affect levels of calcium and zinc; low levels of zinc imply that certain metal binding proteins such as metallothionein might not function optimally to remove heavy metals such as mercury. At this point I would link to an interesting post by Dr Emily Deans on fructose malabsorption in relation to depression highlighting how, alongside other issues with carbohydrate metabolism, problems with fructose can potentially link to problems with zinc. I hasten to add that Dr Deans' discussions are strictly limited to the suggestion of a link between fructose malabsorption and depression and nothing else.
- Paraoxonase-1 (PON-1), everyone's favourite organo-phosphate (OP) pesticide detoxifier, also gets a mention. Accepting that most people are exposed to some degree of OP residues, the authors present data on the amount of residue present in food and how crops such as wheat and corn seem to be top of the pops in terms of residue amount. Corn obviously being a required raw material in the process of making HFCS and indeed mercury has also been found in samples of HFCS. The implication being that fructose and/or mercury can affect the expression of PON1 and this might be dose-dependent, which when coupled to data from this study by D'Amelio and colleagues*** (full-text) on the expression of PON1 in US and Italian cohorts, suggests a reduced ability in the US group to metabolise some OPs.
- Methionine, homocysteine and various compounds in-between are also discussed in the paper with particular reference to oxidative stress and DNA / histone methylation. Some interesting facts: PON1 turns out to be pretty essential for reducing homocysteine levels and high homocysteine levels are associated with the under-methylation - hypomethylation - of DNA. This might, just might, tie into these findings suggestive of an inverse relationship between homocysteine levels and PON1 arylesterase activity in a group of children with autism.
I hope you are still here after reading all that. It's taken me a few reads of the paper to start to come to grips with all the various strands of evidence incorporated and the overview presented here is not intended to be a definitive one. I suppose the main conclusion is that various factors might be implicated in producing an epigenetic response in autism including pesticide exposures, heavy metals and dietary components like HFCS. The sum of these factors being greater than the individual factors acting alone.
I admit that I'm not totally convinced by all the issues discussed in this paper as being universally applicable to all cases of autism. Here in the UK, as in Italy and other parts of Europe, HFCS is still only tentatively findings its way into the shopping baskets of this nation of shopkeepers. Having said that, I have seen nothing that suggests autism has the same aetiological roots across all nations as indeed this paper asserts differences. Added to the fact there is some pretty convincing evidence that for example, zinc deficiency can be comorbid to cases of autism as per a post from a few months back, I have an open mind to the concepts detailed in the paper.
The authors suggest that their review of gene-environment interactions with a particular slant on autism in the United States might offer a kind of template for other individuals or groups to conduct and report similar papers for other potential factors and in other parts of the world. I would champion this notion that we do need to start looking at more complicated patterns of potential risk factors for autism, whether based on endophenotypes, geography or other factors, with a focus on how environment and genes might be working variably, but synergistically.
The authors suggest that their review of gene-environment interactions with a particular slant on autism in the United States might offer a kind of template for other individuals or groups to conduct and report similar papers for other potential factors and in other parts of the world. I would champion this notion that we do need to start looking at more complicated patterns of potential risk factors for autism, whether based on endophenotypes, geography or other factors, with a focus on how environment and genes might be working variably, but synergistically.
To finish, I have been getting a little too carried away with the Beautiful South lately and so to conclude, a Song for Whoever (the video is not the real song video but the sound was the best quality).
* Dufault R. et al. A macroepigenetic approach to identify factors responsible for the autism epidemic in the United States. Clinical Epigenetics. April 2012.
DOI: 10.1186/1868-7083-4-6
** Dufault R. et al. Mercury exposure, nutritional deficiencies and metabolic disruptions may affect learning in children. Behavioral & Brain Functions. 2009; 5: 44.
DOI: 10.1186/1744-9081-5-44
** D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Molecular Psychiatry. 2005; 10: 1006-1016
DOI: 10.1038/sj.mp.4001714
Wednesday, 11 April 2012
Assessing autism the ADTree classifier way
The Autism Diagnostic Observation Schedule (ADOS) has a hallowed place in autism research and practice. At 23 years of age, ADOS and its counterpart, the Autism Diagnostic Interview (ADI), have pretty much cornered the gold-standard autism assessment market over the years. ADOS in particular with its sliding scale of modules covering the spectrum of language and developmental ability and generous assortment of 'props', resides in quite a few cupboards of child development centres and research institutes worldwide.
One of the nice things about ADOS aside from the hands-on, interactive tasks particularly in the more 'early-years' modules, is the way that it valiantly attempts to standardise behaviour and codes autism, autism spectrum or not via the use of an algorithm. This paper headed by one of the primary architects of ADOS, Cathy Lord, summarises the development of that algorithm based on the ADOS-G (generic). Said algorithm having fairly recently been revised by Katherine Gotham and colleagues to amalgamate some features (communication + social interaction = social affect) potentially tied into the proposed revisions for autism diagnosis in DSM-V.
Perfect you might say, so if it ain't broken why fix it? Well, gold standard or not, ADOS can be quite time-consuming to deliver (but not as time-consuming as the ADI I might add). Assessors also need to be properly trained and kept up-to-date with their ADOS training, and despite all its standardised prowess, people are people and sometimes mistakes are made - which is partly why ADOS is an assessment tool and not an all-encompassing diagnostic tool. Of course there are other 'issues' that have been raised with ADOS in mind (e.g. comorbid ADHD interfering, assessing Asperger syndrome) but I'm not here to start that critique.
Enter then a study by Dennis Wall and colleagues* (full-text) and their suggestion that based on some clever machine-learning algorithms, 8 out of the 29 items normally used in the delivery of a module 1 ADOS (no speech present) might just have the ability 'to classify autism' with complete or near 100% accuracy.
Despite the obvious issues concerning a reliance on pre-ADOSed children and the use of only a handful of non spectrum controls, I find myself very interested in these results and the performance of the ADTree classifier. As per the study conclusions "The ADTree classifier consisted of eight questions, 72.4% less
* Wall DP. et al. Use of machine learning to shorten observation-based screening and diagnosis of autism. Translational Psychiatry. April 2012.
DOI: 10.1038/tp.2012.10
One of the nice things about ADOS aside from the hands-on, interactive tasks particularly in the more 'early-years' modules, is the way that it valiantly attempts to standardise behaviour and codes autism, autism spectrum or not via the use of an algorithm. This paper headed by one of the primary architects of ADOS, Cathy Lord, summarises the development of that algorithm based on the ADOS-G (generic). Said algorithm having fairly recently been revised by Katherine Gotham and colleagues to amalgamate some features (communication + social interaction = social affect) potentially tied into the proposed revisions for autism diagnosis in DSM-V.
Perfect you might say, so if it ain't broken why fix it? Well, gold standard or not, ADOS can be quite time-consuming to deliver (but not as time-consuming as the ADI I might add). Assessors also need to be properly trained and kept up-to-date with their ADOS training, and despite all its standardised prowess, people are people and sometimes mistakes are made - which is partly why ADOS is an assessment tool and not an all-encompassing diagnostic tool. Of course there are other 'issues' that have been raised with ADOS in mind (e.g. comorbid ADHD interfering, assessing Asperger syndrome) but I'm not here to start that critique.
Enter then a study by Dennis Wall and colleagues* (full-text) and their suggestion that based on some clever machine-learning algorithms, 8 out of the 29 items normally used in the delivery of a module 1 ADOS (no speech present) might just have the ability 'to classify autism' with complete or near 100% accuracy.
- Wall and colleagues constructed 16 possible machine-learning algorithms based on the 29 coding items of the ADOS module 1. For anyone really interested, these 29 items are spread across several domains including: (a) language and communication (9 items including vocalisations, response to name, pointing and use of gestures), (b) reciprocal social interaction (11 items including eye contact, giving, requesting, showing and response to joint attention), (c) play (2 items - functional object play and imagination), (d) restricted, repetitive behaviours and interests (4 items including unusual sensory interests and hand / finger mannerisms) and (e) 'other abnormal behaviours' (3 items including overactivity and anxiety). I should point out that when it comes to the final algorithm, only 17 of these 29 items are actually used (at least according to the original pre-Gotham algorithm - the revised algorithm uses 14 items I think??) and even then, only 12 items contribute to the autism / autism spectrum cut-off scores used based on items in the communication and social domains.
- Based on the use of data from a group of children with autism with module 1 ADOS scores from the AGRE dataset (autism: n=612; non spectrum: n=11), 90% of participants were used as part of a training set and the remaining 10% as a tester set as part of the proposed algorithms (much the same way that other studies have used).
- Further validation of the best classifiers was undertaken based on other independent samples who reached cut-offs from module 1 ADOS to include data from the Boston Autism Consortium (autism: n=110; non spectrum: n=4) and the Simons Simplex Collection (autism: n=336; non spectrum: n=0).
- Although 2 out of the 16 algorithms "operated with perfect sensitivity, specificity and accuracy", one of them, the ADTree classifier, was selected as the best option because it relied on only 8 items of the module 1 ADOS to produce such results (the alternative used a whopping 9 items). Validation using the Autism Consortium and Simons Simplex Collection data correctly classifying all but 2 participants (from the Simons collection) who exhibited "... the potential presence of non spectrum behaviours".
- Drum-roll for the 8 distinguishing module 1 items isolated: (i) frequency of vocalisation directed to others, (ii) unusual eye contact, (iii) responsive social smile, (iv) shared enjoyment in interaction, (v) showing, (vi) spontaneous initiation of joint attention, (vii) functional play with objects and (viii) imagination/creativity. Use of these 8 items would also reduce the number of activities needed to elicit behaviours; so goodbye 'response to name' and 'response to joint attention'. I'm glad to say that the 'birthday party' activity remained!
Despite the obvious issues concerning a reliance on pre-ADOSed children and the use of only a handful of non spectrum controls, I find myself very interested in these results and the performance of the ADTree classifier. As per the study conclusions "The ADTree classifier consisted of eight questions, 72.4% less
than the complete ADOS Module 1". Purely from a practical point of view and the quite significant levels of concentration needed to manage tasks and elicit scores from the original module 1 ADOS, there is an obvious advantage to focusing on 8 items as opposed to 29 items. I do wonder exactly how much time will be shaved off an assessment bearing in mind that the majority of module 1 activities still need to be covered in order to elicit proper responses to items. So activities like 'free play', 'functional and symbolic imitation' and 'birthday party' are still required and can often take up the lion's share of assessment time.
Whilst the 8 selected items are interesting, there are some notable absences from the classifiers based on things like issues with pointing, the use of gestures and the use of facial expressions directed to others. I was always under the impression that these were important facets of autism, or at least autism in the early years but this study suggests not so in terms of classification. What exactly this might say for other results linking pointing, proto-declarative pointing for example, to autism is source for speculation.
Whilst the 8 selected items are interesting, there are some notable absences from the classifiers based on things like issues with pointing, the use of gestures and the use of facial expressions directed to others. I was always under the impression that these were important facets of autism, or at least autism in the early years but this study suggests not so in terms of classification. What exactly this might say for other results linking pointing, proto-declarative pointing for example, to autism is source for speculation.
Homing in on those classifier items also opens a number of doors to things like quick and early screening and even where attention perhaps needs to be focused with regards to measuring outcome - that is how maturation and/or intervention may impact on core symptoms (at least for young and/or non-verbal people on the autism spectrum). Whether also this type of machine-analysis is applicable to other schedules related to autism screening and assessment is another question.
* Wall DP. et al. Use of machine learning to shorten observation-based screening and diagnosis of autism. Translational Psychiatry. April 2012.
DOI: 10.1038/tp.2012.10
Tuesday, 10 April 2012
Maternal obesity and risk of autism
There have been more than a few studies of association done with autism spectrum conditions in mind. I'm thinking about factors such as adverse conditions at birth, various environmental factors and even season of birth / conception being linked to a heightened risk of autism. Enter a new risk factor, and perhaps one of the most contentious yet, mum's weight before and during pregnancy and in particular the 'association' between overweight or obese mums and autism risk as per this study by Paula Krakowiak and colleagues (full-text)*.
I say contentious because obesity is, pardon the pun, big news in health circles as we are all bombarded with news about how rates are rising and how obesity increases risk for lots of other conditions including an early exit from this mortal coil. Whilst not wishing to belittle the 'obesity crisis', I hark back to a previous post last year on how the projections about obesity rates are still a little fuzzy; to quote Physicist Niels Bohr: "prediction is very difficult, especially about the future".
The Krakowiak study has generated quite a few headlines. Probably the most direct, and at the same time inaccurate, is this one 'Obesity in pregnancy causing rise in autism cases' which makes so many assumptions that I really don't know where to begin. The latest CDC figures on autism, 1 in 88, have the potential to be contorted to fit lots of arguments about autism causation it seems.
What did the study actually say:
Where do we go with this I thought I heard you ask? Well, I'm pretty sure that if you are what might be described as a slim-figured mother with a child with autism, you probably aren't all that impressed with this latest contribution. Indeed this is a consistent feature when reporting studies of association in that association and heightened risk is not an absolute measure, so not every mum of a child with autism is obese and neither is every obese mum going to have a child with autism.
The authors do speculate on one or two ideas as to why they found an association between mum's metabolic health and risk of autism, mainly centred on insulin and the regulation of maternal glucose levels in relation to effects on offspring. The theory goes that foetal exposure to high levels of glucose results in an sustained overproduction of insulin which increase the requirement for oxygen inducing chronic intrauterine tissue hypoxia. Glucose has previously been mentioned on this blog (here).
Interestingly a similar process has also been suggested for schizophrenia** (which again has also been linked to maternal diabetes). Indeed the paper by Van Lieshout & Voruganti** (full-text) offers a couple of other possible explanations which might also be relevant to cases of autism including a role for those dastardly proinflammatory cytokines and/or oxidative stress. Similar findings also go for ADHD.
For the moment however there is nothing further than speculation to be had as to the 'relationship' between mum's metabolic health and offspring outcome with autism in mind. Yes, we need to look at maternal health both pre- and during pregnancy as potentially a moderating factor in risk of autism in offspring, but we are quite a way off from suggesting that maternal obesity 'causes' autism at the present time.
* Krakowiak P. et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. April 2012
DOI: 10.1542/peds.2011-2583
** Van Lieshout RJ. & Voruganti LP. Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms. Journal of Psychiatry & Neuroscience. 2008; 33: 395-404.
I say contentious because obesity is, pardon the pun, big news in health circles as we are all bombarded with news about how rates are rising and how obesity increases risk for lots of other conditions including an early exit from this mortal coil. Whilst not wishing to belittle the 'obesity crisis', I hark back to a previous post last year on how the projections about obesity rates are still a little fuzzy; to quote Physicist Niels Bohr: "prediction is very difficult, especially about the future".
The Krakowiak study has generated quite a few headlines. Probably the most direct, and at the same time inaccurate, is this one 'Obesity in pregnancy causing rise in autism cases' which makes so many assumptions that I really don't know where to begin. The latest CDC figures on autism, 1 in 88, have the potential to be contorted to fit lots of arguments about autism causation it seems.
What did the study actually say:
- It was another side to the CHARGE initiative which included over 500 children diagnosed with an autism spectrum condition, an additional 170 or so children with a developmental delay/disorder and 315 asymptomatic controls. The aim was to ascertain whether various metabolic conditions (obesity, diabetes, hypertension) forming part of the so-called metabolic syndrome might show association with either autism or elements related to offspring development. Children were all diagnosed with autism and importantly the diagnosis was independently confirmed as part of the initiative. Additional data on things like maternal health and weight were derived from either medical records or structured interview with mums.
- Based on the collected data, all metabolic conditions were more prevalent in mums of children with autism compared with controls; for example, cases of type-2 diabetes or gestational diabetes were present in 9.3% and 11.6% of autism and developmental delay groups respectively compared with only 6.4% of controls. The elevated odds ratio (OR) reflected this greater frequency both for autism and developmental disorders compared with controls. Interestingly, the OR was actually greater for cases where developmental disorders were present (2.35) over autism cases (1.61). Mums with maternal obesity (body mass index, BMI over 30) had a 60% increased risk of having a child with autism compared with non-obese mothers and risk increased further if diabetes or hypertension were present before or during pregnancy.
- Based on measures of cognitive and adaptive development, the Mullen Scales of Early Learning (MSEL) and an old favourite, the Vineland Adaptive Behaviour Scales (VABS), the presence of maternal diabetes in the autism group correlated with more significant 'deficits' in expressive language. Having said that, excluding children with autism from the analysis also showed that metabolic conditions collectively were associated with poorer functioning in areas of motor skills and receptive and expressive language.
Where do we go with this I thought I heard you ask? Well, I'm pretty sure that if you are what might be described as a slim-figured mother with a child with autism, you probably aren't all that impressed with this latest contribution. Indeed this is a consistent feature when reporting studies of association in that association and heightened risk is not an absolute measure, so not every mum of a child with autism is obese and neither is every obese mum going to have a child with autism.
The authors do speculate on one or two ideas as to why they found an association between mum's metabolic health and risk of autism, mainly centred on insulin and the regulation of maternal glucose levels in relation to effects on offspring. The theory goes that foetal exposure to high levels of glucose results in an sustained overproduction of insulin which increase the requirement for oxygen inducing chronic intrauterine tissue hypoxia. Glucose has previously been mentioned on this blog (here).
Interestingly a similar process has also been suggested for schizophrenia** (which again has also been linked to maternal diabetes). Indeed the paper by Van Lieshout & Voruganti** (full-text) offers a couple of other possible explanations which might also be relevant to cases of autism including a role for those dastardly proinflammatory cytokines and/or oxidative stress. Similar findings also go for ADHD.
* Krakowiak P. et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. April 2012
DOI: 10.1542/peds.2011-2583
** Van Lieshout RJ. & Voruganti LP. Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms. Journal of Psychiatry & Neuroscience. 2008; 33: 395-404.
Sunday, 8 April 2012
Dust settled: autism, de novo mutations and older dads
On purpose I have left it a few days to post about the trio of studies published in Nature by Sanders and colleagues*, O'Roak and colleagues** and Neale and colleagues*** which have created big headlines like this one and this one on quite a few de novo mutations - as in not present in parents but present in children - being linked to the diagnosis of autism. A fourth study picked up by Time magazine (here) by Kerin and colleagues**** on moesin adds to the flavour. This last study coincidentally being in the same publication that contains an article suggesting that the predictive power of personal genome sequencing is likely to be a little bit more limited than many initially suspected. Who'd have thought it?
Back to the Nature articles, I let the dust settle a little for two main reasons: (1) just about everyone has an opinion about this work and its meaning, and (2) my first instinct was to say 'add them to the 2193 genes, 2806 SNPs/VNTRs, 4544 copy number variations, etc' already found and discussed in relation to autism.
I've talked about mutation and genes already quite a bit on this blog and how, whether diagnosed with autism or anything else or nothing at all, we are all a product of mutation and individually carry our own store of genetic mutations. Quite by chance I just saw one of the latest Marvel film adaptations, 'Thor' complete with cameo performance from the magnificent Stan Lee, who has whether knowingly or not, popularised mutation and in some respects relieved it of its quite negative connotations. After all, every kid wants to be Wolverine or Spiderman don't they?
Anyway a very, very short summary of the papers in question:
I have probably not been able to do justice to the complexity and obvious work that has gone into these studies with this very short summary. There was some overlap in the genetic areas of interest across the studies which, given the statistical odds involved, might be potentially very important. I must admit that I raised an eyebrow when these papers all came out pretty much simultaneously and only a few days after the CDC reported another increase in their estimates of prevalence of autism in the United States, up from 1 in 110 to 1 in 88 8-year olds - indeed 1 in 32 boys apparently in the State of Utah. I'm sure that the timing was just coincidence though.
I've said it before and will say it again, I am not a molecular biologist or anything related, so am very much an amateur when it comes to decoding the precise meaning of exomes and de novo mutations outside of some background reading. With this in mind, I translate these collective works as suggesting a few things (but don't quote me on this):
With the onset of epigenetics (changes to gene expression without changes to the genome), things are changing in the world of genetics. Autism research at the same time continues its fascination with this area of endeavour. The concept of an 'autism gene' covering everyone with autism (and the BAP?) is a distant memory (as are the millions of pounds/dollars/other currency pumped into this area down the years) to be replaced by an altogether more complicated picture emerging of spontaneous mutations, differing genetic profiles for individuals and genes and environment potentially acting variably but synergistically.
To finish, the UK is awash with Britain's Got Talent at the moment, and aside from asking 'where me keys, where me phone' a group called the Zimmers got me reminiscing about an old Beastie Boys classic... fight for your right to [fill in the blank].
* Sanders SJ. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. April 2012.
DOI: 10.1038/nature10945
** O’Roak BJ. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature. April 2012.
DOI: 10.1038/nature10989
*** Neale BM. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 2012.
DOI: 10.1038/nature11011
**** Kerin T. et al. A noncoding RNA antisense to moesin at 5p14.1 in autism. Science Translational Medicine. April 2012.
DOI: 10.1126/scitranslmed.3003479
Back to the Nature articles, I let the dust settle a little for two main reasons: (1) just about everyone has an opinion about this work and its meaning, and (2) my first instinct was to say 'add them to the 2193 genes, 2806 SNPs/VNTRs, 4544 copy number variations, etc' already found and discussed in relation to autism.
I've talked about mutation and genes already quite a bit on this blog and how, whether diagnosed with autism or anything else or nothing at all, we are all a product of mutation and individually carry our own store of genetic mutations. Quite by chance I just saw one of the latest Marvel film adaptations, 'Thor' complete with cameo performance from the magnificent Stan Lee, who has whether knowingly or not, popularised mutation and in some respects relieved it of its quite negative connotations. After all, every kid wants to be Wolverine or Spiderman don't they?
Anyway a very, very short summary of the papers in question:
- Sanders and colleagues* discussed exome sequencing for nearly a thousand individuals, including 200 people with a diagnosis of autism. Exome sequencing, I am reliably informed, relates to the analysis of exons, the parts of DNA which get translated into functional proteins. There is quite a good background description here. Their results identified several de novo mutations in brain-expressed genes to be present, with one mutation in the same gene present in 2 unrelated participants with autism but not in asymptomatic controls among other findings.
- O'Roak and colleagues** carried out similar exome analysis for a couple of hundred parent - child trios (trios implying mum, dad and child with autism, N=677). Their analysis suggested quite a few of the 248 de novo mutations, 126 classified as 'severely disruptive', they found were paternal in origin - from dads - and showed a positive correlation with paternal age consistent with other work on older dads perhaps being a risk factor for autism. I was interested in some elements of the last sentence of this paper abstract which talked about 'extreme locus heterogeneity' but at the same time providing ".. a target for future discovery, diagnostics and therapeutics". Make of that what you will.
- Neale and colleagues*** again sequenced exomes in 175 trios. They reported finding de novo mutations in less than half of their cases (46.3%) stating that ".. the overall rate of mutation is only modestly higher than the expected rate". Nevertheless, some clever proteomics work looking at how these mutation might fit together revealed some interesting interactions between the proteins encoded by the genes being looked at. They also suggested that carrying these mutations might up the risk of autism between 5 - 20 times compared with not having them. I was also interested in one of the gene candidates identified in this study, KATNAL2, which has been tentatively correlated with 'conscientiousness' as a personality trait (assuming you believe that personality is genetic). Dr Ben Neale, the lead author, has also summarised his team's results on a guest blog post here and done to my mind, quite a good job outside of all the hype.
I have probably not been able to do justice to the complexity and obvious work that has gone into these studies with this very short summary. There was some overlap in the genetic areas of interest across the studies which, given the statistical odds involved, might be potentially very important. I must admit that I raised an eyebrow when these papers all came out pretty much simultaneously and only a few days after the CDC reported another increase in their estimates of prevalence of autism in the United States, up from 1 in 110 to 1 in 88 8-year olds - indeed 1 in 32 boys apparently in the State of Utah. I'm sure that the timing was just coincidence though.
I've said it before and will say it again, I am not a molecular biologist or anything related, so am very much an amateur when it comes to decoding the precise meaning of exomes and de novo mutations outside of some background reading. With this in mind, I translate these collective works as suggesting a few things (but don't quote me on this):
- The genetics of autism are getting more and more complicated with every study published. It probably doesn't help that the diagnosis of autism is a subjective experience from a clinical viewpoint and autism is often surrounded by other comorbidities which are also likely to exert an effect on results. Exactly how this might change if and when the new 'sliding scale' DSM-V autism diagnostic criteria comes out will be interesting.
- These were studies on de novo mutations meaning that they did not originate from parents. I read one comment on a blog (here) by a commentator who drops by this blog now and again, RAJ, asking the very important question: where did all the heritability go? Does this mean that the autism of today is different from the autism of yester-year or is it all a question of technology, participant numbers, etc.?
- How and why do these de novo mutations appear is a question that should be on everyone's lips. Random is a word that crops us time and time again in relation to these mutations but with due respect, if we are talking about these mutations showing cause and effect in relation to autism risk, saying they just randomly appear leaves quite a big gap in the knowledge base. Again with my amateur status as a caveat, I do wonder about the involvement of environment and judging by the latest blog from Tom Inset at the NIMH, I'm not the only one. The paternal spotlight and in particular the older dads suggestion from the O'Roak study has put sperm in the cross-hairs, and lets face it, that opens up a myriad of possible environmental factors outside of just 'old sperm' as potentially showing some association (something again that RAJ has commented on in other posts on this blog).
- As per other studies on mutation in areas such as ADHD, whilst these are impressive studies utilising some impressive technologies, one perhaps needs to ask how common these mutations were in terms of autism as a whole. Yes, there were some interesting areas coming to light and yes, these should be priorities for future studies. As the paper from Neale and colleagues reported however, the overall rate of mutation was only marginally higher than what would be normally expected and one should perhaps not discount the influence of things like intellectual disability as accounting for at least some results (see here).
With the onset of epigenetics (changes to gene expression without changes to the genome), things are changing in the world of genetics. Autism research at the same time continues its fascination with this area of endeavour. The concept of an 'autism gene' covering everyone with autism (and the BAP?) is a distant memory (as are the millions of pounds/dollars/other currency pumped into this area down the years) to be replaced by an altogether more complicated picture emerging of spontaneous mutations, differing genetic profiles for individuals and genes and environment potentially acting variably but synergistically.
To finish, the UK is awash with Britain's Got Talent at the moment, and aside from asking 'where me keys, where me phone' a group called the Zimmers got me reminiscing about an old Beastie Boys classic... fight for your right to [fill in the blank].
* Sanders SJ. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. April 2012.
DOI: 10.1038/nature10945
** O’Roak BJ. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature. April 2012.
DOI: 10.1038/nature10989
*** Neale BM. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 2012.
DOI: 10.1038/nature11011
**** Kerin T. et al. A noncoding RNA antisense to moesin at 5p14.1 in autism. Science Translational Medicine. April 2012.
DOI: 10.1126/scitranslmed.3003479