Neurotensin, autism and tail-chasing Bull Terrriers?

I'm not kidding.

The paper by Tsilioni and colleagues [1] (open-access) did indeed look at serum levels of neurotensin and corticotropin-releasing hormone (CRH) in a cohort of children diagnosed with an autism spectrum disorder (ASD) alongside levels in tail-chasing Bull Terrier dogs as compared to unaffected [non tail-chasing] Bull Terriers (BTs) and Labrador Retriever dogs. You may well smirk or even laugh at such research but, as per the recent [preliminary] broccoli chemical - autism study (see here), unusual research may yet offer some interesting insights into some of the biology of at least some of the autism spectrum.

Meg's gravy is famous.

Mention of neurotensin and autism really can only mean the involvement of one researcher: Prof. Theoharis Theoharides and his continuing interest in this area [2]. Indeed, the only thing seemingly missing from the Tsilioni paper is some analysis of another of Prof. Theoharides' interests: mast cells and autism (see here); although I do note that the authors mention how: "NT [neurotensin] is a vasoactive peptide isolated from the brain and is implicated in immunity. It is increased in the skin following acute stress, triggers skin mast cells (MCs) and increases skin vascular permeability in rodents through MC activation".

The Tsilioni paper is open-access but a few pointers might be in order:

• Greek children diagnosed with an ASD (N=40) fulfilling quite a few inclusion criteria provided a fasting blood sample. Similar samples were also provided by "normotypic" controls (I assume this means asymptomatic for ASD).
• "Serum from unaffected (n=18) and affected BTs (n=14) and unaffected Labrador retriever dogs (n=6) was collected at various facilities accessible to the owners and was sent to the senior Author’s laboratory on dry ice". Apparently a behavioural survey was used to classify Bull Terriers into affected and unaffected groups.
• Analysis for NT and CRH levels was completed on samples based on ELISA preceded by some clean-up steps. Results were presented to also include: "whether there is any relationship between the number of ASD children with GI [gastrointestinal] symptoms and high serum NT levels and whether it is more than expected by chance".
• So: group serum NT levels were significantly elevated in the cohort of children with ASD compared to controls (see here). As per the scatterplot shown in that last link however, this elevation was not noted for every child with autism; by my count about 11 children in the ASD group showed results above the upper 95% confidence interval (CI) for that particular group. The presence of GI symptoms also seemed to moderate this relationship: "There is a strong correlation between the number of ASD children with GI symptoms and high serum NT levels".
• Group serum CRH levels were also elevated for the ASD group compared to controls (see here) (12 of which seemed to show a similar pattern to that previously described).
• Bull Terriers affected by that tail-chasing behaviour - "reminiscent of stereotypic spinning exhibited by autistic children" - also showed group elevations in the levels of serum NT and CRH when compared to control dogs. The authors suggest that this: "supports the premise that these dogs could represent at least an autism endophenotype" from an animal model point of view (see this table for further information).

Outside of trying to model autism or more precisely behaviours associated with autism in another animal model other than rodents (see here) or monkeys (see here), the authors provide other clues for their report of a [potential] canine model: "This dog breed may be useful in the investigation of the diagnosis, pathogenesis and treatment of ASD. NTR and/or CRHR-1 antagonists, as well as MC blockers, could provide possible therapeutic approaches for stress-induced ASD. For instance, the natural flavonoid luteolin is known to inhibit mast cell-mediated allergic inflammation, and a dietary supplement containing luteolin was recently reported to significantly benefit children with ASD". That last sentence on luteolin as a potential intervention option for autism comes from other work published by the authors [3] in need of further, controlled study.

The evidence is starting to stack up suggesting that there may be more to see when it comes to NT and CRH levels in relation to at least some cases of autism (the autisms?). That GI symptoms (which are becoming much more readily accepted as being elevated in frequency when it comes to autism) might be a moderating variable of the presence of those peptide hormones is another potentially important feature in terms of how such pathology seems to interplay with behavioural symptoms (see here). I would like to see a little more focus on how other behavioural signs and symptoms (autism+) might also be affecting NT and/or CRH levels when it comes to cases of autism, and indeed, how this work overlaps with other reports of NT for example, in other conditions [4] potentially acting as "an endogenous antipsychotic drug" and more [5]

Music then. The Sound of Silence by S & G.

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[1] Tsilioni I. et al. Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism. Transl Psychiatry. 2014 Oct 14;4:e466.

[2] Angelidou A. et al. Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflammation. 2010 Aug 23;7:48.

[3] Theoharides TC. et al. A case series of a luteolin formulation (NeuroProtek®) in children with autism spectrum disorders. Int J Immunopathol Pharmacol. 2012 Apr-Jun;25(2):317-23.

[4] Boules M. et al. Diverse roles of neurotensin agonists in the central nervous system. Front Endocrinol (Lausanne). 2013 Mar 22;4:36.

[5] Boules MM. et al. Elucidating the Role of Neurotensin in the Pathophysiology and Management of Major Mental Disorders. Behav. Sci. 2014; 4: 125-153.

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Tsilioni I, Dodman N, Petra AI, Taliou A, Francis K, Moon-Fanelli A, Shuster L, & Theoharides TC (2014). Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism. Translational psychiatry, 4 PMID: 25313509