The kynurenine pathway and some autism

"Our data indicated that there were alterations to the KP [kynurenine pathway] in ASD [autism spectrum disorder]. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted."

Those were some of the rather interesting results reported by Chai Lim and colleagues [1] suggesting that when it comes to tryptophan metabolism in relation to autism, the continued sole focus on serotonin and melatonin (see here) might not be the best overall research strategy.

Detailing results based on the examination of an: "Immunological profile and the KP metabolic signature" for a small group of Omani children diagnosed with autism (n=15) and their "age-matched healthy siblings" (n=12), researchers reported their findings. That specific detail about "increased production of the downstream metabolite, quinolinic acid" may indeed be an important one given connections with things like activated microglia for example [2] and the rise and rise of the 'constant gardener' with autism in mind (see here).

Obviously further studies are required to confirm the Lim findings in light of converse findings [3] (albeit reported in cerebrospinal fluid). Mention that their results might "help rationalize the efficacy of sulforaphane treatment in ASD" (yes, broccoli sprouts and autism) is another aspect in need of further investigation in these days of plural autisms (see here) and a focus on 'best' and 'non' responders to the various intervention strategies put forward with autism in mind (see here). One might also need to further expand the links between autism and schizophrenia on the basis of any kynurenine-glutamatergic link (see here).

I might finally add that as quite a fan of the need for more research into the aromatic amino acids (tryptophan, tyrosine and phenylalanine) when it comes to a label like autism (see here), I'm also of the opinion that what goes on in our deepest, darkest recesses might also be a place to look when it comes to this research. Those trillions of wee beasties that call our gut home - the gut microbiota - may seemingly have quite an effect on some of the processes involved in something like tryptophan metabolism (see here) an onwards the (bio)chemistry of how the kynurenine pathway might tie into at least some autism. Investigation of the mechanism pertinent to such processes and whether 'changing' the gut microbiota environment might impact on them, seem to be important areas of further work. Oh and speaking of tryptophan metabolites, I'll be coming to the findings reported by Dieme and colleagues [4] quite soon...

Music: Oliver Cheatham - Get Down Saturday Night (although I was slightly underwhelmed by the film Ex Machina).

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[1] Lim CK. et al. Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity. Autism Res. 2015 Oct 24.

[2] Heyes MP. et al. Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. Biochemical Journal. 1996;320(Pt 2):595-597.

[3] Zimmerman AW. et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol. 2005 Sep;33(3):195-201.

[4] Dieme B. et al. Metabolomics study of urine in autism spectrum disorders using a multiplatform analytical methodology. J Proteome Res. 2015 Nov 5.

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Lim CK, Essa MM, de Paula Martins R, Lovejoy DB, Bilgin AA, Waly MI, Al-Farsi YM, Al-Sharbati M, Al-Shaffae MA, & Guillemin GJ (2015). Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity. Autism research : official journal of the International Society for Autism Research PMID: 26497015

Yes folks... broccoli chemical impacts on autism presentation

Please do not adjust your set. Broccoli, or least a chemical found in broccoli called sulforaphane has, under placebo-controlled, double-blind experimental conditions, been reported to impact on the presentation of autism according to the paper by Kanwaljit Singh and colleagues [1] (open-access).

Eat your greens @ Fir0002/Flagstaffotos

I had to do a bit of a double-take myself when I first read about these results (see here). Indeed, even the authors themselves seemed to be a little taken aback by their own findings if other media on this study is to be believed (see here). Still peer-reviewed science is peer-reviewed science and that goes just as much for this study as any other.

The paper is open-access but a few details might be useful:

• The study was previously registered in the US ClinicalTrials.gov database (see here). It involved comparing "capsules of sulforaphane-rich broccoli sprout extracts" with "indistinguishable placebo capsules" containing microcrystalline cellulose (wood pulp) in a small group of young men (aged 13-27 years) diagnosed with an autism spectrum disorder (ASD) administered daily over 18 weeks. As I mentioned, the study was also double-blind.
• Various measures - behavioural and physiological - were recorded at baseline (prior to study start) and at choice points during the 18 week study period. The results of the behavioural measures including the Aberrant Behaviour Checklist (ABC) and Social Responsiveness Scale (SRS) completed by parents/caregivers and the Clinical Global Impression Severity (CGI-S) and the Clinical Global Impression Improvement (CGI-I) scales completed by "study physicians" are included in the main paper results and conclusions.
• Results: well, first and foremost there were a few adverse events reported during the trial. The authors note that: "Sulforaphane treatment effectively improved core aberrant behaviors of ASD, and was safe and well-tolerated". But... "the sulforaphane group gained significantly more weight over the 18-wk period, compared with placebo" and there was mention of "single unprovoked seizures" occurring in two participants taking the active treatment. These seizures may well be unconnected to the sulforaphane capsules but one cannot rule out the possibility that they were connected.
• Forty participants completed the trial, or at least "part of the outcome measure evaluations" boiling down to "14 placebo and 26 sulforaphane". The statistical evaluation undertaken involved looking at "the differences between scores of individuals at 4, 10, 18, and 22 wk from their respective average pretreatment values". But the authors also undertook a separate intention-to-treat analysis that "included all 44 participants".
• The headlines: "many of the participants who were treated with sulforaphane in this study had statistically significant and clinically meaningful improvements during treatment with sulforaphane". With all due respect to parent/caregiver reports, I was particularly drawn to the fact that study physicians although blinded to who was on active treatment and who was taking a placebo were able to rate "13 of the 40 participants" as showing noticeable improvements in behaviour and sociability and "all were receiving sulforaphane". That's quite a feat by any study's standard.
• The authors conclude: "The substantial improvements of individual ASD patients’ trajectories were conspicuous and suggest that further investigation of sulforaphane in ASD is promising".

These are interesting results crying out for further independent [longer term] replication. The fact also that this was a trial of adolescents and adults with autism also fills a gap in the autism research market alluded to in previous posts on this blog (see here). 

Mechanism of effect? Well, there does seem to be quite a bit more to do in this area. The authors note that sulforaphane "was selected because it upregulates genes that protect aerobic cells against oxidative stress, inflammation, and DNA-damage, all of which are prominent and possibly mechanistic characteristics of ASD". Oxidative stress does indeed appear on the research radar when it comes to autism, at least some autism (see here) and sulforaphane fits the bill in terms of its potential 'protective' effects [2]. I've also talked about such mechanisms with another source of sulforaphane in mind (see here). That all being said, I don't doubt that there may be other biological processes at work.

So, in conclusion 'eat your greens' might very well be an important phrase for some on the autism spectrum. Whether eating the source material carries the same effect or will be equally well received as taking a daily pill is another matter...

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[1] Singh K. et al. Sulforaphane treatment of autism spectrum disorder (ASD). PNAS. 2014. October 13.

[2] Guerrero-Beltrán CE. et al. Protective effect of sulforaphane against oxidative stress: recent advances. Exp Toxicol Pathol. 2012 Jul;64(5):503-8.

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Kanwaljit Singh, Susan L. Connors, Eric A. Macklin, Kirby D. Smith, Jed W. Fahey, Paul Talalay, & Andrew W. Zimmerman (2014). Sulforaphane treatment of autism spectrum disorder (ASD) PNAS : 10.1073/pnas.1416940111