Can a gluten-free diet positively affect cognitive performance?

No, I am not suggesting that a gluten-free diet is the new nootropic (cognitive enhancer) of choice with the title of this post despite previous media headlines on the subject.

"Got gluten?"☺  @ Wikipedia 

I am however very, very interested in the results reported by Irene Lichtwark and colleagues [1] (open-access here) which suggested that in "newly diagnosed coeliac disease, cognitive performance improves with adherence to the gluten-free diet in parallel to mucosal healing".

For those who might not be familiar with coeliac (celiac) disease (CD), I wrote a sort of training post about what we (think we) know about the condition a few months back (see here). An autoimmune condition managed in the most part by the lifelong use of a gluten-free (GF) diet, CD remains the focal point of an increasing 'spectrum' of conditions where gluten might play some kind of role (see here) including those linked to brain and behaviour (see here). Indeed the Lichtwark paper starts with the assumption that outside of the classical genetic, gastrointestinal (GI) and immunological markers/effects of CD, there is a growing recognition that other biological systems may be affected, something I've talked about before on this blog.

The Lichtwark paper is open-access but as ever, here are a few pointers:

• A small participant group of 11 adults (mean age 30 years old) diagnosed with CD but not yet commencing with a GF diet were followed over the course of 1 year. Various assessments were periodically carried out at weeks 0 (baseline), week 12 and week 52 over the course of a GF diet being introduced/used. This included duodenal biopsies to assess the intensity of mucosal damage based on the Marsh criteria, a measure of intestinal permeability (IP) (yes, leaky gut) and various other tests, some of which are linked to the serology of CD (see here). Interestingly, vitamin D and vitamin B12 were also part of the testing suite.
• Various cognitive assessments were also included in the study covering aspects of memory, attention and language abilities, alongside a patient report measure on the presence of anxiety and depressive symptoms (something very topical at the moment).
• Results: bearing in mind this was a pilot study and involved only participants with CD all of whom were [knowingly] following a GF diet, there were some interesting points raised. The classical markers of CD saw their usual change as expected following use of a GF diet (compliance to which was described as excellent). The authors also note that: "IP was elevated in three participants, one of these at baseline the other two at week 12". Further: "All IP levels were within the normal range at 52 weeks".
• Based on the results of cognitive testing: "Four of the eight cognitive tests demonstrated a significant improvement in performance between time 0 and 52 weeks". These were predominantly tests in areas of attention, motor skills and verbal fluency. The authors note that this may be "the beginnings of an evidence-base for the ill-defined, yet frequently reported symptoms of brain fog in CD".
• The paper also reports some initial correlation values between some psychometric test scores and the CD histological and serological data. Obviously with 11 participants you would probably not imagine the correlation values, whether positive or negative, to be 'up there' but some of them were described as significant, and at better than just p<0.05.

Of course there is lots more to do in this area not least a larger and more controlled trial looking at the possibility of a relationship between CD, the GF diet and cognitive performance. The fact also that this was a study of adult CD also leaves questions to be answered about whether similar effects might be noticeable for paediatric cases of CD which appear to be on the rise. The other question resides in that murky grey area of non-coeliac gluten sensitivity (NCGS) and, assuming that this is a real phenomena (see here), whether a GF diet might also aid cognitive performance for cases there too? The paper by Volta and colleagues [2] (open-access) talks about a "foggy mind" as being apparent in some of their identified cases of NCGS...

This is not the first time that cognition has been talked about with CD in mind. "A possible association exists between progressive cognitive impairment and celiac disease, given the temporal relationship and the relatively high frequency of ataxia and peripheral neuropathy, more commonly associated with celiac disease". That was the conclusion of the study by Hu and colleagues [3]. Interestingly, they reported that out of a total of 13 participants, 3 people "improved or stabilized cognitively with gluten withdrawal". Terrone and colleagues [4] reported that in a paediatric cohort of kids recently diagnosed with CD, a measure of "cognitive, emotional and behavioural problems" was statistically higher than in another group of participant with CD symptoms controlled following the use of a GF diet. I was also quite interested to see that they reported a lower frequency of "chronic fatigue" in their CD remission group which brought back memories of a distant blog post I wrote on a similar topic (see here).

But the research is not yet cut-and-dried on the issue of cognitive dysfunction and untreated CD and any role for a GF diet. Take for example the small study by Hallert & Aström [5] (open-access here) who concluded "no consistent signs of cognitive impairment" to be found in their cohort. These results should also be take in light of other findings such as those by Casella and colleagues [6] looking at cognitive performance in older adults diagnosed with CD following a GF diet who concluded that: "Cognitive performance is worse in elderly coeliac disease than control patients, despite prolonged gluten avoidance in coeliacs". It's complicated.

Just before I leave you to further ponder the Lichtwark results, a few final points raised by the authors are also worthwhile mentioning. They speculate on the possible mechanisms by which "cognition might be impaired in patients with untreated CD". They do kinda rule out nutrient deficiencies on the basis of no association detected in their cohort with some of the nutritional parameters looked at. Personally, I don't think we can rule this out altogether at the moment given what we are still learning about good nutrition and behavioural and cognitive indicators (see here for one example). Inflammation and in particular, cytokine involvement receives a more favourable review to account for the results which should also be investigated further (see here). One final hypothesis revived by the authors is that of opioid peptides and any potential effects on "higher brain functions". I know brows become furrowed when the words 'opioid-excess' are talked about with reference to particular conditions, but given my own interest in this area, and recently our very preliminary paper on the formulation of low doses of the opiate blocker naltrexone into a cream [7] (see here), an intriguing question emerges about whether a GF diet might be the only avenue to enhancing cognitive performance under such circumstances? Oh and then there is the leaky gut angle too. At least one author [8] has asked the question of whether intestinal hyperpermeability might show some involvement in cognitive dysfunction albeit not necessarily directly pertinent to the issues of CD. More to do methinks.

To close, for those of you who might remember the film 'Limitless' and the fictional nootropic NZT-48, just think you could have it all. But also remember: "discontinued use will result in death". (And no, it's not real, not yet anyway).

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[1] Lichtwark IT. et al. Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity. Aliment Pharmacol Ther. 2014 May 28.

[2] Volta U. et al. An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Medicine 2014, 12:85.

[3] Hu WT. et al. Cognitive impairment and celiac disease. Arch Neurol. 2006 Oct;63(10):1440-6.

[4] Terrone G. et al. The Pediatric Symptom Checklist as screening tool for neurological and psychosocial problems in a paediatric cohort of patients with coeliac disease. Acta Paediatr. 2013 Jul;102(7):e325-8.

[5] Hallert C. & Aström J. Intellectual ability of adults after lifelong intestinal malabsorption due to coeliac disease. J Neurol Neurosurg Psychiatry. 1983 Jan;46(1):87-9.

[6] Casella S. et al. Cognitive performance is impaired in coeliac patients on gluten free diet: a case-control study in patients older than 65 years of age. Dig Liver Dis. 2012 Sep;44(9):729-35.

[7] Dodou K. et al. Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay. Pharm Dev Technol. 2014 May 2.

[8] Brenner SR. Hypothesis: intestinal barrier permeability may contribute to cognitive dysfunction and dementia. Age Ageing (2010) 39 (2): 278-279.

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Lichtwark IT, Newnham ED, Robinson SR, Shepherd SJ, Hosking P, Gibson PR, & Yelland GW (2014). Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity. Alimentary pharmacology & therapeutics PMID: 24889390