Thursday, 17 April 2014

Mitochondrial dysfunction as a neurobiological subtype of autism

The paper by Suzanne Goh and colleagues [1] reporting on "a possible neurobiological subtype of mitochondrial dysfunction in ASD [autism spectrum disorder]" is a worthy addition to the research roll call which has graced this blog down the years. Based on the analysis of brain lactate levels - a potential marker of mitochondrial dysfunction - via the analysis of lactate doublets on brain magnetic resonance spectroscopic imaging (MRSI), authors picked up a significantly higher rate of lactate in cases of autism spectrum disorder (ASD) when compared to age and sex-matched asymptomatic controls. I've talked lactate and autism before on this blog (see here) so very much welcomed this research looking specifically at brain levels of this stuff.

I'm writing this post having already scheduled a blog entry on the recent paper by Rose and colleagues [2] (open-access here) on the increasing complexity of mitochondrial dysfunction being seemingly present in some cases of autism. Given the findings from Goh et al I've decided to publish this entry first (just to confuse everyone even further) as yet again, my confusion on the topic of all-things mitochondrial has an opportunity to shine through.

So then, a few details from the Goh paper:

  • Based on imaging and other data derived from 75 participants diagnosed with an ASD (aged 5-60 years) contrasted with 96 typically-developing controls, the authors set about "assessing in-vivo evidence of mitochondrial dysfunction directly in the brains of a large sample of children and adults with ASD".
  • Whilst not an imaging man, I can tell you that they used proton multiplanar spectroscopic imaging (MPSI) to quantify endogenous brain chemistry and "regional cellular metabolism and function" specifically towards the detection of lactate. Actually, the talk of [lactate] doublets is not a million miles away from the results one gets as a consequence of a related chemical analytical technique, NMR, which brings back memories of some work from days gone by.
  • After laying down quite a few ground rules for what was and wasn't a readable result, the authors concluded that: "Lactate doublets were present at a significantly higher rate in participants with ASD (13%) than in typically developing controls (1%) (P = .001), providing in vivo evidence for the presence of mitochondrial dysfunction in the brains of individuals with ASD". In-vivo by the way, means in the living and contrasts with science done in a test-tube (in-vitro).
  • Age was a factor when it came to lactate levels, with elevations reported more often in adults than in children. This phenomenon has been talked about before in the research literature [3].
  • The authors go on to discuss the implications of their results. Bearing in mind the various situations where elevated brain lactate levels have been noted outside of just ageing, including as a result of issues like anxiety or panic disorder [4], they reiterate how their "strict exclusion critera and careful scanning procedures made such explanations less likely". Further they highlight how: "individuals with ASD should undergo evaluation for mitochondrial dysfunction, as novel and promising treatments are under development for mitochondrial disorders".

As per my link above, this is not the first time that lactate has appeared in the autism research literature. I'll for example, draw your attention to the paper by Al-Mosalem and colleagues [4] and their reporting that: "Lactate as an important energy metabolite for the brain was significantly higher in autistic patients compared to control showing about 40% increase". Bear in mind however that this and other results [5] have tended to look in plasma rather than directly what's going on in the brain as Goh et al did.

There's little more for me to say on this area of research aside from the need for further replicative investigations and perhaps a little more inquiry into the subgroup of people with autism who fall into this mitochondrial dysfunction category bearing in mind the continued focus on the plurality of autism (the autisms). That there may be interventions available for mitochondrial disorder when present [6] is another important point. As per related research in other conditions with a potential mitochondrial aspect to them (see here), at least one of the interventions - Coenzyme Q10 (ubiquinol) - is being looked at with some autism in mind [7] (open-access here) bearing in mind no medical or clinical advice is given or intended.

Music then to close. I'm thinkin' of something with a candy orientation given the time of year, so again, ladies and gentlemen, Mr Sammy Davis Jnr and The Candy Man.. (he can you know).

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[1] Goh S. et al. Mitochondrial Dysfunction as a Neurobiological Subtype of Autism Spectrum Disorder. Evidence From Brain Imaging. JAMA Psychiatry. 2014. April 9.

[2] Rose S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psychiatry. 2014 Apr 1;4:e377.

[3] Ross JM. et al. High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. PNAS. 2010; 10.1073/pnas.1008189107

[4] Al-Mosalem OA. et al. Metabolic biomarkers related to energy metabolism in Saudi autistic children. Clin Biochem. 2009 Jul;42(10-11):949-57.

[5] Oliveira G. et al. Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol. 2005 Mar;47(3):185-9.

[6] Parikh S. et al. A Modern Approach to the Treatment of Mitochondrial Disease. Curr Treat Options Neurol. Nov 2009; 11(6): 414–430.

[7] Gvozdjáková A. et al. Ubiquinol improves symptoms in children with autism. Oxid Med Cell Longev. 2014;2014:798957.

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ResearchBlogging.org Goh, S., Dong, Z., Zhang, Y., DiMauro, S., & Peterson, B. (2014). Mitochondrial Dysfunction as a Neurobiological Subtype of Autism Spectrum Disorder JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.179

Wednesday, 16 April 2014

Joined by HDAC (inhibitors)

I'm treading quite carefully with this post which came about following my [non-expert] reading of the paper abstract from Anand Venkatraman and colleagues [1] on a potential downside to the use of HDAC (histone deacetylase) inhibitors for treating spinocerebellar ataxia type 1 (SCA1), a progressive disease affecting movement and other knock-on functions. This follows other work suggesting that certain HDAC inhibitors might offer some important new lines of investigation when it comes to at least some of the various types of spinocerebellar ataxia (SCA). For those who thought this was a blog about autism research, bear with me on this one...

HDACs represent a group of enzymes which go to work removing acetyl groups on histone tails which, as the paper by Patrick Grant [2] (open-access) very nicely illustrates, has the potential to do some rather important things to processes like gene expression (condensing chromatin and repressing transcription). I have kinda touched upon histones and the so-called histone code in a previous introductory post on the rise and rise of epigenetics (see here) with autism in mind.

The Venkatraman results focused on a mouse model, and how depletion/loss of a particular type of HDAC - HDAC3 - was in some cases: "highly deleterious both behaviorally, with mice showing early onset ataxia, and pathologically, with progressive histologic evidence of degeneration". They talk about "cautionary evidence that this approach could produce untoward effects" when it comes to the employment of "pharmacologic inhibition of HDAC3" via HDAC inhibitors in SCA.

Not to make too many sweeping generalisations or form associations which might not be there, but two things from the Venkatraman paper got my old(ish) grey matter fired up: (i) mention of HDAC inhibitors and the emerging story when it comes to prenatal exposure to valproate with a HDAC slant, and (ii) the focus on Purkinje cell function; as their paper title states: "The histone deacetylase HDAC3 is essential for Purkinje cell function". Both these points bring me back to some potentially important issues which might apply to at least some autism and related neurodevelopmental outcomes.

It is still very much an emerging picture but pregnancy use of valproate and 'adverse' offspring events/development is turning into something of a quite important association in recent times. So much so that the US FDA and UK MHRA have issued some guidance on this matter. Valproate has some history as a potential teratogen [3] bearing in mind my offering no medical or clinical advice on this matter aside from saying 'don't mess with epilepsy'. That valproate is also an HDAC inhibitor [4] (open-access) is another mechanism through which the drug might (a) find some new markets for conditions other than epilepsy, but also (b) impact on development and functions. Readers are invited to have a look through the paper by Katie Lloyd [5] (open-access) for a well-rounded overview of potential effects.

Then to the Purkinje cell story. I'm sure most people with an interest in autism will have heard about the cerebellum in relation to the condition at some point. Indeed, the paper by Fatemi and colleagues [6] (open-access) kinda sums up where we're at when it comes to the 'little brain' bearing in mind the need for further investigation and the greater focus on the plural 'autisms'. To talk about the cerebellum and autism also brings into the play those Purkinje cells which have also featured on several occasions on the autism research menu [7] and quite recently, with an epigenetic slant to the research (see here). Indeed, the paper by Jill James and colleagues [8] (open-access) on epigenetics and EN-2 is something I'd very much like to see more work on.

Again, not to make mountains out of molehills, but I did wonder whether there may be some science to do covering these potentially overlapping areas. I'm not necessarily saying that valproate = HDAC inhibition = impact on Purkinje cell numbers/maturation/functions = autism because I very much doubt it's going to be that simple or generalised despite some emerging [rodent] data [9]. With the increasing interest in all-things epigenetic however, also crossing over to autism research [10] (open-access), one might consider more inquiry into the HDACs, their inhibitors and effectors (and exposure timing) to be a potentially important part of that particular autism research tide? Whether even important ecosystems e.g. "the [gut] microbiota itself may be viewed as an epigenetic entity" [11] may also tie into some of the work in this area too?

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[1] Venkatraman A. et al. The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Hum Mol Genet. 2014 Mar 4.

[2] Grant PA. A tale of histone modifications. Genome Biology 2001, 2:reviews0003-reviews0003.6

[3] Alsdorf R. & Wyszynski DF. Teratogenicity of sodium valproate. Expert Opin Drug Saf. 2005 Mar;4(2):345-53.

[4] Göttlicher M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001; 20(24): 6969–6978.

[5] Lloyd KA. A scientific review: mechanisms of valproate-mediated teratogenesis. Bioscience Horizons 2013; 6 : hzt003

[6] Fatemi SH. et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum. 2012 Sep;11(3):777-807.

[7] Skefos J. et al. Regional alterations in purkinje cell density in patients with autism. PLoS One. 2014 Feb 24;9(2):e81255.

[8] James SJ. et al. Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Transl Psychiatry. 2013 Feb 19;3:e232.

[9] Moldrich RX. et al. Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice. Behav Brain Res. 2013 Nov 15;257:253-64.

[10] Lasalle JM. Autism genes keep turning up chromatin. OA Autism. 2013 Jun 19;1(2):14.

[11] Stilling RM. et al. Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis. Genes Brain Behav. 2014 Jan;13(1):69-86.

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ResearchBlogging.org Venkatraman A, Hu YS, Didonna A, Cvetanovic M, Krbanjevic A, Bilesimo P, & Opal P (2014). The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Human molecular genetics PMID: 24594842

Monday, 14 April 2014

Neurology of inflammatory bowel diseases

The paper by Ben-Or and colleagues [1] talking about a neurologic profile present in a small participant cohort of children and adolescents diagnosed with an inflammatory bowel disease (IBD) caught my eye recently. Their findings reporting that over two-thirds of their paediatric participant group diagnosed with IBD also "exhibited neurologic manifestations" provides some compelling preliminary evidence for further investigation in this area.

Outside of reports of headache and dizziness, the presentation of attention-deficit hyperactivity disorder (ADHD), hypotonia and "sensory complaints" comorbid to IBD shines a spotlight on the so-called 'gut-brain axis'. That being said the fact that "seizures and neuropsychiatric disorders were less characteristic" between IBD cases and asymptomatic controls may also have some important implications for various conditions including the primary topic of this blog, the autism spectrum conditions.

I'm not on this occasion going to dissect the Ben-Or findings too much aside from pointing you in the direction of some other research which may very well tie into their findings. I've talked before about research on other bowel-related conditions suggestive of potentially important neurological and behavioural links. Think coeliac disease and the the ataxia story as one example mentioned in a previous post (see here). I'd also draw your attention to some work in the autism research domain talking about a possible link between functional bowel habit issues and the presentation of anxiety and sensory symptoms (see here). Granted, it is a leap from a diagnosis of IBD to the presentation of constipation or diarrhoea not necessarily due to an IBD (or at least that's what was thought) but one might imagine that further investigation would be indicated in light of the Ben-Or data.

Reiterating the gut-brain link which seems to be appearing with ever-greater frequency these days, I'm minded to suggest that further research be directed to looking at the possible mechanisms to account for any relationship. The usual triad of issues: intestinal (gut) permeability, the gut microbiota and the gut mucosal immune system spring to mind as potential players in any relationship, but that's all I'll say on the matter for now.

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[1] Ben-Or O. et al. The Neurologic Profile of Children and Adolescents With Inflammatory Bowel Disease. J Child Neurol. 2014 Apr 2.

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ResearchBlogging.org Ben-Or O, Zelnik N, Shaoul R, Pacht A, & Lerner A (2014). The Neurologic Profile of Children and Adolescents With Inflammatory Bowel Disease. Journal of child neurology PMID: 24700662

Friday, 11 April 2014

Dad's obesity and risk of offspring autism

In this post I'm talking about the paper by Pål Surén and colleagues [1] (open-access here) and their suggestion that "paternal obesity is an independent risk factor for ASDs [autism spectrum disorders] in children". I do so not with the intent of stigmatising parents and specifically parents with weight issues, which tend to be present for many more reasons than just food and exercise (see here), but merely to highlight how parental physical health may show some relationship to offspring cognitive and developmental progress. Indeed, the findings from Surén et al are to viewed in the context of some other related research in this area (see here).
By the water @ Renoir @ Wikipedia 

Quite a nice summary of the Surén work can be found here and here. The basics are: MoBa (see here), questioning parents particularly fathers about their physical health while their partner was pregnant, following up offspring and their subsequent development - specifically whether they had received a diagnosis of "autistic disorder", Asperger syndrome or pervasive developmental disorder not otherwise specified (PDD-NOS).

The results: well, the rate of autism reported (0.45%) was interesting. Certainly compared to other prevalence estimates we've been hearing about recently, quite a different figure was noted altogether (see here) allowing for age differences in case ascertainment. Then to the primary findings: "The risk of autistic disorder was 0.27% (25 of 9267) in children of obese fathers and 0.14% (59 of 41 603) in children of fathers with normal weight (BMI <25), generating an adjusted OR of 1.73 (95% CI: 1.07–2.82)". And with regards to Asperger syndrome: "The risk was 0.38% (18 of 4761) in children of obese fathers and 0.18% (42 of 22 736) in children of normal-weight fathers, and the adjusted OR was 2.01 (95% CI: 1.13–3.57)". Ergo, potentially double the risk of offspring autism when fathers were categorised as overweight or obese based on body mass index (BMI).

It goes without saying that the suggestion of a link between paternal weight and offspring risk of autism is by no means proved by this latest research. Think correlation not being the same as causation as one reason why we should not just accept the results of this work at face value irrespective of how enthusiastic researchers might be about their data and what they were able to control for as potential interfering variables. That also BMI has it's 'issues' when it comes to defining healthy weight is another reason for caution where muscle mass for example, is not accounted for in such a simplistic formula.

But all that doesn't mean the results are not interesting...

In recent times I've noticed quite a bit more research looking at the potential role of father's health and wellbeing on offspring development treading in the footsteps of how ageing might play a role. Take for example the recent opinion piece in Nature titled 'Sins of the father' which introduces another side to the Surén results: the science of epigenetics. The paper by Lambrot and colleagues [2] is as good an example as any on how a father's nutritional status with folate in mind, might impact on offspring health. I'm not asking you to take this as fact; merely that the focus on maternal nutrition and offspring outcome might not be the only important variable in any relationship.

Harking back to another paper by the Surén research group (including Drs Hornig and Lipkin) [3] reveals nutrition to be something that the authors had probably thought about with the current results in mind. On that occasion, the focus was on the elevated risk of autism in cases of a short inter-pregnancy interval (see here) and mention of a "depletion of micronutrients" as a possible factor. Shadows indeed of the work of the late David Barker and his foetal programming hypothesis.

I do believe there are more investigation to be done building on the Surén results. I've already made mention of folate in the father-offspring relationship given the link between the folate cycle and the availability of methyl groups for the process of DNA methylation, an important epigenetic process. One might also wonder about the body of work looking at more traditional genetic issues in the genes involved in that cycle such as everyone's favourite Scrabble gene and enzyme:  Methylenetetrahydrofolate reductase (MTHFR) and its growing links with some autism (see here). Could issues with MTHFR present in fathers confer susceptibility to offspring autism, or weight issues pertinent to an elevated risk via epigenetic mechanisms? That being said, I'm sure that any relationship is going to be complicated and not necessarily relevant to every child diagnosed with an autism spectrum condition.

Music to close. In memory of author Sue Townsend and her Adrian Mole series of books... Profoundly in Love with Pandora.

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[1] Surén P. et al. Parental Obesity and Risk of Autism Spectrum Disorder. Pediatrics. 2014. April 7.

[2] Lambrot R. et al. Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nature Comms. 2013; 4: 2889.

[3] Gunnes N. et al. Interpregnancy interval and risk of autistic disorder. Epidemiology. 2013 Nov;24(6):906-12.

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ResearchBlogging.org Suren, P., Gunnes, N., Roth, C., Bresnahan, M., Hornig, M., Hirtz, D., Lie, K., Lipkin, W., Magnus, P., Reichborn-Kjennerud, T., Schjolberg, S., Susser, E., Oyen, A., Smith, G., & Stoltenberg, C. (2014). Parental Obesity and Risk of Autism Spectrum Disorder PEDIATRICS DOI: 10.1542/peds.2013-3664

Thursday, 10 April 2014

Gluten exposure and "feelings of depression"?

Could exposure to dietary gluten affect a person's moods or emotional state?

Well, if the paper by Simone Peters and colleagues [1] (open-access here) is to be believed the answer may very well be yes, at least in some cases, as they report a link between gluten consumption and feelings of depression under [short-term] experimental conditions. If replicated, such a finding may have profound consequences for how we view our relationship between food and mental health and wellbeing.
Bread Ma'am? @ Wikipedia 

I was initially drawn to the Peters paper as a function not only of the subject matter but also the authorship team. Mention of Jessica Biesiekierski in amongst the list of contributors immediately brought back memories of another ground-breaking paper of hers [2] reporting that "Non-celiac gluten intolerance may exist" (see here).

For those who might not know about non-coeliac gluten sensitivity (NCGS), this is a suggestion that outside of the classical connection between gluten and the autoimmune condition coeliac (celiac) disease, there exists something of a spectrum of gluten-related health issues. Some of these issues might have far-reaching implications for an array of conditions including that of autism... at least some autism (see here).

The Peters paper is open-access but a few details might be worthwhile mentioning:

  • This was a gold-standard trial in terms of being randomised, double-blind, placebo-controlled and including a cross-over component. What this means is that participants with irritable bowel syndrome (IBS) who were negative for coeliac disease (CD) (though not necessarily tested for the serology of CD) were "asked that they continue on a GFD [gluten-free diet] low in FODMAPS [Fermentable, Oligo-, Di-, Mono-saccharides And Polyols]" for the study duration. Participants were then divided up into groups to receive one of three dietary challenges to their gluten-free diet: gluten supplement (16g/day), whey supplement (16g/day) or placebo for 3 days followed by a wash-out period and then onto the next dietary supplement regime. Neither participants nor researchers knew who got what challenge when.
  • As well as adherence to the gluten-free diet and gastrointestinal (GI) symptoms being assessed, salivary cortisol secretions were measured alongside mental state as per the use of the State Trait Personality Inventory (STPI), a self-report measure.
  • Results: bearing in mind the relatively small participant group examined (n=22) and the various complications one might expect from undertaking a dietary trial, there was an "increase in [the] STPI state depression score following gluten ingestion compared to placebo". The depression scores were also higher when comparing gluten and whey supplements but did not reach statistical significance. 
  • No differences were found with regards to cortisol concentrations across the groups and time-frames nor for GI symptoms.
  • The authors conclude that: "Short-term exposure to gluten specifically induced current feelings of depression with no effect on other indices or on emotional disposition". They added: "Such findings might explain why patients with non-coeliac gluten sensitivity feel better on a gluten-free diet despite the continuation of gastrointestinal symptoms".

I have to say that as preliminary as these results might be, I'm quite excited at the implications from them. Yes, I have some professional interest in the relationship between gluten and our mental health / psychology and the so-called gut-brain axis (see here) so am perhaps biased, but to see some research utilising the gold-standard of evidence-based medicine coming up with the findings that they did is something rather grand. As per my opening sentences, replication, replication, replication is the next stop and then we can get really excited.

I note the authors do speculate on why they got the results they did. Cortisol is kinda ruled out as a cause as a function of their findings of no significant change. I might however draw your attention to other findings in this area which should be kept in mind. Serotonin (5-HT) also gets a mention as a potential explanatory reason, which is also interesting bearing in mind the mood connection with this neurotransmitter with appropriate caveats.

Then to some other interesting avenues for further study such as those trillions of beasties which call us and our gut home: the gut microbiota and their potential connection to our mood and psychology (see here). And how about a possible role for gluten exorphins and further the suggestion that opiate antagonists such as naltrexone might be a useful thing to look at? I'd perhaps also be minded to suggest that another possibility not discussed by the authors might be that of intestinal hyperpermeability (leaky gut) also playing a potential role given what we know about gut permeability and gluten [3]. More investigations like this please.

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[1] Peters SL. et al. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity – an exploratory randomised clinical study. Alimentary Pharmacology & Therapeutics. 2014. doi: 10.1111/apt.12730

[2] Biesiekierski JR. et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011 Mar;106(3):508-14.

[3] Vazquez-Roque MI. et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology. 2013 May;144(5):903-911.e3.

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ResearchBlogging.org Peters SL, Biesiekierski JR, Yelland GW, Muir JG, & Gibson PR (2014). Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity - an exploratory randomised clinical study. Alimentary pharmacology & therapeutics PMID: 24689456

Tuesday, 8 April 2014

Chronic Fatigue Syndrome and various factors

The paper by Kate Lievesley and colleagues [1] documenting various "predisposing, precipitating and perpetuating factors in Chronic Fatigue Syndrome in children and adolescents" caught my eye recently. Based on a review of the research literature around the topic of Chronic Fatigue Syndrome (CFS) [in childhood], the authors set about detailing some of the important factors linked to the condition and in doing so, highlighted how physiology and psychology might combine when it comes to aetiology and pathology.

View from... @ Wikipedia 
I'll immediately lay my opinion out on CFS. Like its counterpart, myalgic encephalomyelitis (ME), I am a great believer in physiology being a driving force behind the presentation of these 'overlapping fatigue conditions' [2]. I've read too much about issues with the immune system (see here), mitochondrial dysfunction (see here) and the -omic of the hour, the gut microbiome (see here) (with more to come apparently) to be involved so as to reach any other satisfying opinion. Neuroinflammation is the latest thing to be added to the list of correlates. The fact also that an anti-viral therapy also seems to impact on some cases of CFS, a 'subset' of cases of CFS (see here), further enhances that previous sentence, bearing in mind no medical or clinical advice is given or intended.

By saying all that though, I don't doubt however that the presentation of CFS also contains a psychological element to it. This could be due to the impact that the various symptoms have on a person day-in-day-out and the effect on their quality of life (impacted by something like resilience for example), or it could be part of that physiology-behaviour axis [3] that seems to be sprouting up everywhere these days. Debates continue in this area.

The Lievesley paper makes a number of important points in their review. So:

  • "Studies suggested that many children and adolescents with CFS reported that their illness began with an infection and there was some objective and prospective evidence to support this". Aetiology is an important research area for CFS. The authors note that EBV (Epstein-Barr virus) is linked to the onset of CFS in quite a few reports and certainly there are some well-documented cases in the research literature as per the case report by Geller & Giclas [4]. Indeed, the Montoya results [5] looking at the use of the anti-viral valganciclovir relied on "elevated IgG antibody titers against HHV-6 and EBV" for participant entrance to their trial. That being said, other infectious agents have also been mentioned in the peer-reviewed literature also.
  • "The strongest and most consistent finding was that rates of psychiatric co-morbidity, predominantly anxiety and depressive disorders, were higher in young people with CFS compared to healthy controls or illness control groups". This is where controversy can creep into the topic of CFS. Those who know a little bit about the history of CFS will already have come across some of the 'discussions' about the PACE trial [6] and the subsequent results that have followed [7]. The idea behind PACE was to test various combinations of adaptive pacing therapy (APT), graded exercise therapy (GET) and/or cognitive behaviour therapy (CBT) on the presentation of CFS. The results suggested some significant effects to be had, but the trial has been the topic of various discussions too. With my cold, objective scientific hat on, there is some evidence that CBT can impact on the presentation of issues like anxiety and depression. Even in a condition like autism where anxiety can in some instances be utterly disabling, there is emerging evidence on the value of the talking therapies compared with treatment-as-usual [8]. That being said, I'd also like to think that issues like anxiety and depression might also benefit from more biological-based intervention, such as the use of probiotic therapy reported by Rao and colleagues [9]. Physiology and psychology united together.
  • "Preliminary evidence suggested a link between CFS and a family history of CFS...". I've on purpose snipped this sentence down from it's original manifestation focusing on personality traits et al in relation to cognitive styles and CFS. Again, drawing on the experiences of autism research down the years and how the word 'refrigerator' set autism research back decades, I don't want to discuss such concepts here. What I will focus on is the potentially important issue of genes and CFS and where that might take us. Genes have certainly turned up when it comes to the presentation of CFS [10]. It is not at the point where science has been able to say conclusively that CFS is a genetic condition, but certainly there may be candidates for further inspection when it comes to risk. The science of epigenetics, as per a comment in the article by Landmark-Høyvik and colleagues [11] is "nonexistent" (and that paper was written in 2010). But there may be clues that epigenetics is involved in at least some cases of ME/CFS as per the very preliminary work on HERVs (human endogenous retroviruses) (see here) and not forgetting the growing interest in transgenerational epigenetic inheritance although with caveats. I don't doubt we are, once again, looking at some variable interaction between genetics and environment across CFS as per lots of other conditions.

There is little more for me to add to this quite rambling post. I would echo the authors' call for further 'prospective' research into CFS, although ensuring that physiology and psychology take the research journey hand in hand. Certainly with the estimates of 1 in 100 school-aged children potentially presenting with CFS at least here in the UK, one would expect quite a bit more research commitment to be put into finding out what causes CFS and what one can do to ameliorate the condition and the obvious distress that it causes bearing in mind the idea of a 'spectrum' of fatigue conditions as kinda hinted at by Porter and colleagues [12].

Now, how about a spot of NOFX and Happy Guy (who is 'just a man' and not a scientist we are told).

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[1] Lievesley K. et al. A review of the predisposing, precipitating and perpetuating factors in Chronic Fatigue Syndrome in children and adolescents. Clin Psych Rev. 2014. March 1.

[2] Whiteley P. et al. Correlates of Overlapping Fatigue Syndromes. J Nutr Enviro Med. 2004; 14: 247-259.

[3] McCusker RH. & Kelley KW. Immune–neural connections: how the immune system’s response to infectious agents influences behavior. J Exp Biol 2013; 216: 84-98.

[4] Geller RD. & Giclas PC. Chronic fatigue syndrome and complement activation. BMJ Case Rep. 2009; 2009: bcr08.2008.0819.

[5] Montoya JG. et al. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013 Dec;85(12):2101-9.

[6] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. Mar 5, 2011; 377(9768): 823–836.

[7] White PD. et al. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Med. 2013.

[8] Storch EA. et al. The effect of cognitive-behavioral therapy versus treatment as usual for anxiety in children with autism spectrum disorders: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry. 2013 Feb;52(2):132-142.e2.

[9] Rao AV. et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog. 2009; 1: 6.

[10] Kaushik N. et al. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. J Clin Pathol. Aug 2005; 58(8): 826–832.

[11] Landmark-Høyvik H. et al. The genetics and epigenetics of fatigue. PM R. 2010 May;2(5):456-65.

[12] Porter N. et al. A Comparison of Immune Functionality in Viral versus Non-Viral CFS Subtypes. J Behav Neurosci Res. 2010 Jun 1;8(2):1-8.

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ResearchBlogging.org Lievesley, K., Rimes, K., & Chalder, T. (2014). A review of the predisposing, precipitating and perpetuating factors in Chronic Fatigue Syndrome in children and adolescents Clinical Psychology Review DOI: 10.1016/j.cpr.2014.02.002

Sunday, 6 April 2014

Vitamin D deficiency and more and risk of ADHD

"Vitamin D – could it stop 'modern’ diseases?" was one of the headlines I read quite recently as more pressure is being applied on the sunshine vitamin to perform when it comes to our health and welbeing. Indeed, not so long ago I posted an entry updating where we're at when it comes to the 'sunshine' vitamin D and the autism spectrum conditions. The conclusion buried in that post was that whilst there is some interesting work potentially linking vitamin D and autism, there is still more to do from a research perspective and as yet, very few conclusions can be made about any link outside of vitamin D deficiency not necessarily being a stranger to some cases of autism for whatever reason.
Starry, starry night @ Wikipedia

One of the other themes that was touched upon in that post was the question of whether issues with vitamin D noted in cases of autism may actually tie more strongly into some of the comorbidity which can also present alongside the core triad/dyad of symptoms. I used the example of depression in that case, extrapolating from the observations made by Anglin and colleagues [1] in their systematic review and meta-analysis of the combined peer-reviewed data up to 2011, knowing that the presence of autism and depression have some overlap in the research literature. I'll be talking more about this depression-vitamin D link/suggestion in a forthcoming post.

I want to continue that theme in today's post discussing the study by Bener and Kamal [2] (open-access here) who concluded: "Vitamin D deficiency was considerably higher in ADHD [attention deficit hyperactivity disorder] children compared to healthy children". Before anyone takes offence at the authors' use of the words 'healthy children' to denote their control group, I would have been minded to suggest the words 'asymptomatic controls' if I were writing this paper. I should perhaps also direct you to another paper by some of the same authors which also presents data on what appears to be the same cohort [3].

Their results, based on a case-control study including various direct and indirect measures covering physicians notes and biochemical data for children/young adults living in Qatar, included a number of potentially important snippets of information not least: "Multivariate logistic regression analysis revealed that household income, poor relationship between parents, mothers' occupation, consanguinity, BMI in percentiles, low duration of time under sun light, physical activity, low serum calcium level and low vitamin D level were considered as the main risk factors associated with the ADHD after adjusting for age, gender and other variables" (sorry for the long quote).

Looking at some of these factors linked to ADHD risk, I was immediately taken by their BMI (body mass index) data and in particular: "Overweight (7.7% vs 9.4%) and obesity (4.6% vs 7.7%) were significantly lower in ADHD children compared to their counterparts". This kinda flew in the face of other data which have started to emerge suggesting that ADHD may actually increase the risk of weight issues, as per the findings from Fliers and colleagues [4] for example. Of course I accept that we are looking at different populations, different genetics with very different eating habits and different environments so one has to be slightly cautious before making too much of a leap. But it is an interesting disparity and may be something important in future.

Back to the vitamin D issue identified in the Bener/Kamal paper, it was also interesting to note that quite a few of the other nutritional measures employed during the study also came up with lower results when compared to controls. So, group average levels of calcium, phosphorus, magnesium and potassium in serum were all lower compared to controls. This did make me wonder whether there is a more general micronutrient deficiency present in the ADHD cases over and above just something specific to vitamin D. I'll for example, take you back to a fairly recent post I did on the Julia Rucklidge paper talking about 'a vitamin-mineral mix for ADHD' (see here) as perhaps being pertinent here too.

A quick search around the accompanying research landscape suggests that vitamin D is still something of an unexplored area when it comes to cases of ADHD. That one of the only other studies done on vitamin D and ADHD is another study by Rucklidge and colleagues [5] is coincidental, although also potentially important given their observation within their cohort that: "Among the nutrients recorded at baseline, substantial deficiencies (27%) were only observed for vitamin D".

If one is to accept that ADHD or ADHD-like behaviours can and do feature across some cases of autism (see here) it is possible to see how problematic it might be to disentangle which condition or which behavioural characteristics of each condition, may show the strongest connection to something like a vitamin D deficiency. I'm not ruling out autism or autistic behaviours as being the primary driver of risk for vitamin D issues but to say anything further at this point time in terms of a causal relationship (whichever way) is perhaps a little premature despite some research eagerness. And given what seems to emerging when it comes to other dietary-based interventions 'for autism' with a side of ADHD, I'd be minded to say the focus on exactly what are the primary effects of such strategies in diagnostic terms should be near the top of any research agenda. RDoC anyone?

To close, taken from one of my favourite operas, Toreador! [song]

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[1] Anglin RE. et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013 Feb;202:100-7.

[2] Bener A. & Kamal M. Predict attention deficit hyperactivity disorder? Evidence -based medicine. Glob J Health Sci. 2013 Nov 27;6(2):47-57.

[3] Kamal M. et al. Is high prevalence of vitamin D deficiency a correlate for attention deficit hyperactivity disorder? ADHD Attention Deficit and Hyperactivity Disorders. 2014. DOI: 10.1007/s12402-014-0130-5

[4] Fliers EA. et al. ADHD is a risk factor for overweight and obesity in children. J Dev Behav Pediatr. 2013 Oct;34(8):566-74.

[5] Rucklidge JJ. et al. Moderators of treatment response in adults with ADHD treated with a vitamin-mineral supplement. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Apr 3;50:163-71.

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ResearchBlogging.org Bener A, & Kamal M (2013). Predict attention deficit hyperactivity disorder? Evidence -based medicine. Global journal of health science, 6 (2), 47-57 PMID: 24576365