Thursday, 2 August 2012

The mixed up world of brain-derived neurotrophic factor and autism

I have to say that I am becoming quite settled with my new found interest in blogging after some 16 months of running this blog. Indeed as hopeful as I am that my posts are accurate, balanced and of some interest to at least someone, the whole process of writing a blog entry is also quite good for me and my learning curve on the multitude of research that has been, and continues to be done on autism and things related. Makes you wonder whether blogging would ever count as CPD?

A case in point is this entry on the various research examining a role / connection between brain-derived neurotrophic factor (BDNF) and autism. I've heard mention of BDNF down the years but never considered myself to be fully capable of saying what the stuff is and what has been found in relation to autism. I'm trying to remedy that situation with this post, so let's see how I do.

BDNF is probably best described as a protein, a member of the neurotrophin family, and a growth factor for neurons and synapses. Quite a good overview of the neurotrophins can be found here* by Allen & Dawbarn (full-text). The link between BDNF and neuronal health is perhaps why the molecule has found quite a bit of interest in autism research circles and in particular, its proposed link to the serotonergic system - serotonin having quite a long history in relation to autism.

It is worth point out that BDNF levels and function are known to be influenced by several factors. So, age and gender seem to be able to affect levels of BDNF (here) as does specific pathology such as depression and schizophrenia (here) depending on where you look and what medium you look in. The neuronal 'plasticity' relationship to BDNF (among quite a few other actions I might add) seems to have been taken up by quite a few authors; particularly adult plasticity, contributory perhaps to the more lifelong view of brain plasticity which predominates these days over older theories of 'after childhood, set in stone'.

With autism in mind, there is a body of evidence on BDNF which suggests a few things albeit not exactly consistently:

  • I am a little bit unsure whether BDNF is meant to be 'generally' high or low in cases of autism. Accepting the factors which can influence BDNF listed above, there seems to be some conflicting evidence on findings related to blood/plasma. So for example, this paper by Al-Ayadhi** (full-text), an author mentioned in previous posts, reported lower levels of serum BDNF in their cohort of children with autism. This contrasts with this paper by Connolly and colleagues*** who reported elevations in BDNF. Just to complicate matters further Lisa Croen and colleagues**** (full-text) reported no significant differences in blood concentrations of BDNF in either mums mid-pregnancy nor their young offspring subsequently diagnosed with autism compared with asymptomatic and learning disability control participants. I might be comparing apples and oranges at different times of year, but suffice to say that results are not yet clean-cut.
  • When it comes to genes and BDNF in cases of autism, the waters aren't really any less muddy. This paper by Correia and colleagues***** reported elevations in plasma BDNF in their autism cohort but the source of the increase did not seem to stem from issues with the BDNF gene. Without being an expert on all things genetic, I think this finding might also tie into the results published by Garcia and colleagues****** who suggested that BDNF elevations might not be "transcriptionally driven" (see here for a summary of mRNA). There are other studies looking at other features of BDNF seemingly reporting contrasting findings such as decreased BDNF and anti-apoptotic function (here) and SNPs in the BDNF gene in autism (here and here). The message continues: it's complicated.

One could perhaps suggest that the various results relating to BDNF in autism mirror quite a few other areas of research insofar as not being able to make consistently reproducible statements of fact about autism. Having said that there are perhaps lessons to be learned from compounds such as BDNF in terms of fluctuating levels throughout the lifetime, differences depending on the tissue or biological medium being analysed and some degree of individual responsiveness behind the various findings so far. The fact that BNDF levels might also show involvement in other conditions, such as depression for example, is also worth bearing in mind.

Finally, and without trying to tie every single finding in autism back to gut bacteria or other of my areas of interest, there may yet be something in this relationship accounting for at least some of the BDNF findings in autism. I note for example this paper by Bercik and colleagues******* (similar work commented on here) which suggested that in mice at least, disruption of the gut microflora by antibiotic use seemed to increase brain levels of BDNF.

An example of a real gut-brain interface in action?

----------

* Allen SJ, Dawbarn D. Clinical relevance of the neurotrophins and their receptors. Clinical Science. 2006; 110: 175.191.

** Al-Ayadhi LY. Relationship between Sonic hedgehog protein, brain-derived neurotrophic factor and oxidative stress in autism spectrum disorders. Neurochemical Research. 2012; 37: 394-400.

*** Connolly AM. et al. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy. Biological Psychiatry. 2006; 59: 354-363.

**** Croen LA. et al. Brain-derived neurotrophic factor and autism: maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) Study. Autism Research. 2008; 1: 130-137.

***** Correia CT. et al. Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism. Genes, Brain & Behavior. 2010; 9: 841-848.

****** Garcia KL. et al. Altered balance of proteolytic isoforms of pro-brain-derived neurotrophic factor in autism. Journal of Neuropathology & Experimental Neurology. 2012; 71: 289-297.

******* Bercik P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011; 141: 599-609.