Altered ghrelin levels in boys with autism

"Honey, it's the '90s, remember?"

Saudi Arabia and autism research? It must be at least one author from the research tag-team that is Mostafa and Al-Ayadhi.

Indeed, in today's post it is Laila Al-Ayadhi featured on the paper by Felwah S. Al-Zaid and colleagues [1] (open-access) who concluded on: "a potential role for the hormone ghrelin in the pathogenesis of autism".

Ghrelin, by the way, is often called the 'hunger hormone' as a result of its effects in relation to energy homoeostasis. Alongside another hormone called leptin (which has also been implicated in cases of autism) the long-and-short of food intake regulation seem to be covered by these hormones [2].

The Al-Zaid paper is open-access but I'll direct you to a few important points...

• A case-control study, authors looked at various measures for 31 boys diagnosed with autism compared with 28 age- and sex-matched controls.
• Alongside various anthropometric measures, plasma and serum levels of "acyl ghrelin (AG), des-acyl ghrelin (DG), total testosterone (TT), free testosterone (FT), leptin and growth hormone (GH)" were measured. These were single spot measures with samples taken "after an overnight fast". 
• Results: the autism group were on average heavier than controls but aside from that, no other physical measure was significantly different (mean height was greater in the autism group but just escaped significance). Both acyl ghrelin and des-acyl ghrelin levels were significantly lower in the autism group. By contrast, leptin levels were higher in the autism group (as per other independent findings) and free and total testosterone levels were significantly elevated compared to controls. Taking into account the effect of weight and it's link to adiposity, authors also showed that an analysis of a smaller subgroup (autism, n=27; controls, n=28) where mean weight was controlled for, found a similar trend in hormone levels (see this link to Table 3 of the paper) bearing in mind how body fat can influence the parameters.
• Various correlational analyses were completed on the data but given the relatively small participant groups and the use of spot samples I'm not particularly minded to read too much into these findings at this time.
• The authors conclude that their study: "contributes significantly to the understanding of hormonal dysregulation in the pathophysiology of autism, as it provides baseline data regarding hormonal profiles in autism and substantiates potential clinical interventions".

Small participants numbers and a "lack of female subjects with autism" kinda prohibit me from reading too much into these findings as they stand. I've already made mention of the research trend when it comes to elevated leptin levels and autism (see the paper from Rodrigues and colleagues [3] as one example). Likewise, testosterone levels and autism have received quite a bit of autism research attention down the years (see here). Indeed, elevations in testosterone levels not described in-utero with some potential relationship to foetal programming, has been the stuff of controversy in autism research circles [4].

Going back to the primary ghrelin findings and the observations of lower levels detected in their autism group, the authors speculate on some of the hows and whys of their findings. Gastrointestinal (GI) issues get a call-out and how some of the variety of GI issues noted in cases of autism "could affect the gastric mucosa and interfere with the normal function of ghrelin-secreting cells". although no particulars about GI issues are included in their descriptions of their cohort. One additional issue that I would perhaps add to the whole inflammation, dysbiosis et al discussions would be how ghrelin seems to play some role in GI motility [5] too. That being said, 'wide-ranging' is perhaps the best way to describe what biological processes ghrelin might impact on [6].

I was a touch surprised that the more usual role for ghrelin in terms of hunger and energy homoeostasis was not given more prominence in the Al-Zaid article on autism. Food and feeding patterns are important topics when it comes to autism as per discussions on the extremes sometimes noted in cases of autism (see here) and the increasingly important issue of weight (see here) (which also seemed to be picked up in the authors' findings). One might speculate that hunger and signals linked to hunger might be similarly tied into at least some of the feeding issues reported in autism?

As I seem to do in many discussions these days, I'll reiterate that there is quite a bit more to see and do in research terms on the relationship between ghrelin and related hormones and autism. The additional suggestion from Ghanizadeh [7] about the ghrelin being a "promising therapeutic target for co-occurring autism and epilepsy" might also be worthy of greater inspection.

Music to close. Iggy Pop and Lust for Life.

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[1] Al-Zaid FS. et al. Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation. Sci Rep. 2014 Sep 26;4:6478.

[2] Klok MD. et al. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007 Jan;8(1):21-34.

[3] Rodrigues DH. et al. Changes in Adipokine Levels in Autism Spectrum Disorders. Neuropsychobiology 2014;69:6-10

[4] Geier DA. & Geier MR. A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies. Neuro Endocrinol Lett. 2007 Oct;28(5):565-73.

[5] Greenwood-Van Meerveld B. et al. Ghrelin as a target for gastrointestinal motility disorders. Peptides. 2011 Nov;32(11):2352-6.

[6] Delporte C. Structure and physiological actions of ghrelin. Scientifica (Cairo). 2013;2013:518909.

[7] Ghanizadeh A. Ghrelin as a promising therapeutic target for co-occurring autism and epilepsy. Epilepsy Behav. 2011 Feb;20(2):420-1.

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Al-Zaid FS, Alhader AA, & Al-Ayadhi LY (2014). Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation. Scientific reports, 4 PMID: 25257829

Brains, epigenetics and neuron numbers

In a post a few months back on 'what do we know about autism' I discussed some of the various views and opinions that certain professionals have about autism spectrum conditions. Although not exactly a complete picture of such a heterogeneous condition like autism, summarising what we know (and don't know) about 'general autism' at least provides a starting point for where research might want to 'project' itself in future.

In among the various findings, research on the brain and autism figured heavily; highlighting the issue of head size and brain growth alongside the fact that autism is not, generally speaking, due to a localised brain issue. With this in mind, a few interesting studies have been published in recent days which require some comment.

The first study by probably one of the most well-known names in autism brain research, Eric Courchesne and colleagues* suggested that in one part of the brain, the prefrontal cortex, children with autism might have more brain cells (neurons) than control children.  Based on examination of post-mortem prefrontal brain tissue, the numbers of neurons were counted from 7 children with autism and compared with 6 controls. The results suggested that the total numbers of neurons were increased in the autism group, and specifically in the dorsolateral prefrontal cortex. This alongside findings of a heavier brain in autism compared to controls.

Bearing in mind the small participant numbers and the fact the neurons can only really be counted when someone is deceased, there is some interest in this paper. The prefrontal cortex (I am reliably informed) is linked to quite a few things including social and communicative behaviours; areas with more than a passing relationship to autism. I would hasten to add that there are lots of other correlated functions and behaviours to this area as there is with other brain areas. You might think, more neurons = better functioning in these areas but unfortunately things are not so straight-forward, hence the reason why we tend prune our brain cells during certain points of our lives. Efficiency it seems trumps quantity.

The second paper, by Shulha and colleagues** also looked at brains and indeed the same region of the brain as Courchesne and colleagues, the prefrontal cortex, looking to characterise the epigenetic signature of autism. Epigenetics is basically environment; changes to gene activity not down to changes in DNA. Looking at post-mortem brain tissue from 16 people with autism and 16 controls, they examined samples for a specific epigenetic signature, histone methylation, and found many, many loci affected by altered histone methylation, most of which were not down to DNA mutation. In most cases, genes were switched on or off for reasons other than mutation (SNPs).

In both these papers, there is an interesting intersection between brain, genes and environment. The prefrontal cortex is one of the majority of brain areas that develop early on in-utero hence speculation has turned to some prenatal factor as potentially being involved. My mind wanders back to the study on vits and SNPs at this point, as one of a number of potentially interesting correlations. I do wonder if we ought also to be looking back at some older research on a possible role for disordered endogenous opioid peptide chemistry as potentially being involved in their role as neuronal pruning agents. Without trying to sound too 'he does not know what he is talking about' how about any involvement from the caspases also?

* Courchesne E. et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. Novemeber 2011.
** Shulha HP. et al. Epigenetic signatures of autism. Archives of General Psychiatry. November 2011.