MMP-9 and symptom severity of ADHD

"The statistical regression analysis revealed a correlation between increased serum MMP-9 levels and severity of symptoms in the ADHD". That was the sentence that caught my eye taken from the paper by Halina Kadziela-Olech and colleagues [1] (open-access here) looking at serum matrix metalloproteinase-9 (MMP-9) levels in children with hyperkinetic disorder (HKD) [2] "a severe form of a syndrome which is referred to in DSM-IV... and the American literature as attention deficit hyperactivity disorder (ADHD)".

Hamlet @ Wikipedia 

MMP-9 is something that has already been talked about on this blog with autism in mind (see here) but basically refers to a protease which is involved in degrading proteins of the extracellular matrix [3] and other duties. As Kadziela-Olech et al  point out, there is some preliminary interest in MMP-9 with reference to "neuropsychiatric disorders" particularly with schizophrenia in mind [4]. Interestingly also is that quite a bit of the conversation about MMP-9 and its potential effects have focused on the blood-brain barrier [5] under certain circumstances, which is something that I've always been more than a little interested in (see here) particularly transport across this important barrier.

Anyhow, back to the paper in question:

• Analysis was conducted on 37 boys with HKD/ADHD all properly assessed, as were cognitive functions (via the WISC-R). Blood samples were donated and MMP-9 activity assessed by ELISA (see here).
• Results: bearing in mind there was no asymptomatic control group, it's pretty pointless for me to talk about the serum levels of detected MMP-9 in cases overall. Of more relevance were the various associations made between levels of MMP-9 and presented symptoms: "The MMP-9 levels were significantly associated with symptoms severity of HKD and of ADHD".
• In particular, MMP-9 levels seemed to correlate best with the impulsivity symptom domain when it came to HKD.

In the paper discussion, the authors do go through some of the possible ways that MMP-9 might relate to ADHD/HKD. Part of those discussions focus on blood-brain barrier (BBB) permeability and whether some of the reported risk factors for ADHD may affect MMP-9 expression onwards to a sort of 'leaky' BBB (sounds very familiar). I note also mention of minocycline as a MMP-9 inhibitor (see here) which may very well tie back into some of the research work being done with autism / Fragile X syndrome in mind, particularly given the overlap being reported between diagnoses like autism and ADHD. Some light reading around the topic of MMP-9 also reveals that there may be lots of other functions/relationships to had for this protease. With my cherry-picking hat on, I note the paper by Rodrigues and colleagues [6] talking about inflammation and in particular: "MMP-9 expression in the colon causes alterations in the fecal microbiome" given my interest in all-things gut microbiomics.

Ultimately however, quite a bit more work needs to be done in this area before anyone gets too carried away. Bearing in mind the Kadziela-Olech study was a snapshot study and as I said, without relevant control groups, there are some limitations on what can be said about the findings. Looking also at the plots correlating behavioural presentation and MMP-9 levels it's quite obvious that the relationship between the two variables is not altogether straight-forward despite what the statistics might suggest.

But don't let that deflect from their findings and the need for more research in this area...

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[1] Kadziela-Olech H. et al. Serum matrix metalloproteinase-9 levels and severity of symptoms in boys with attention deficit hyperactivity disorder ADHD/hyperkinetic disorder HKD. Eur Child Adolesc Psychiatry. 2014 Mar 17.

[2] Cameron M. & Hill P. Hyperkinetic Disorder: Assessment and Treatment. Adv Psychiatr Treat. 1996; 2: 94-102.

[3] Birkedal-Hansen H. et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4(2):197-250

[4] Yamamori H. et al. Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine. Neurosci Lett. 2013 Nov 27;556:37-41.

[5] Li YJ. et al. Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels. J Neuroinflammation. 2013 Jul 5;10:80.

[6] Rodrigues DM. et al. Matrix metalloproteinase 9 contributes to gut microbe homeostasis in a model of infectious colitis. BMC Microbiol. 2012 Jun 13;12:105.

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Kadziela-Olech H, Cichocki P, Chwiesko J, Konstantynowicz J, & Braszko JJ (2014). Serum matrix metalloproteinase-9 levels and severity of symptoms in boys with attention deficit hyperactivity disorder ADHD/hyperkinetic disorder HKD. European child & adolescent psychiatry PMID: 24633733