Monday, 15 September 2014

Zinc and copper and autism

The paper by Li and colleagues [1] looking at serum copper (Cu) and zinc (Zn) levels in a group of participants diagnosed with an autism spectrum disorder (ASD) is the source material for today's post. Highlighting how "mean serum Zn levels and Zn/Cu ratio were significantly lower in children with ASD compared with normal cases... whereas serum Cu levels were significantly higher" the continued focus on the metallome in autism carries on at a pace. I should at this point out that I'm not in favour of the use of the word 'normal' in this or any context (anyone who feels that they are normal, please make themselves known to the population at large).

"Bring me... the bore worms!"
Anyhow... I've talked zinc and autism / other conditions on this blog quite a few times (see here and see here). Alongside other more recent data [2] there is a growing realisation that zinc deficiency present in at least some diagnosed on the autism spectrum might have quite a few implications. With this thought in mind, I might also draw your attention to the recent paper by Chaves-Kirsten and colleagues [3] talking about how zinc might also show some connection to the protein kinase of the hour, mTOR (see here) and in particular reducing mTOR levels in a rodent model of autism. This follows other work in this area [4].

The Li paper alongside looking at individual levels of zinc and copper and how they seemed to correlate with presented symptoms according to the Childhood Autism Rating Scale (CARS) also talks about the zinc/copper ratio which is something that has been previously discussed in the peer-reviewed literature with reference to autism and various other conditions as per the excellent review by Osredkar & Sustar [5] (open-access). The paper by Faber and colleagues [6] for example, indicated that a low Zn/Cu ratio may "indicate decrement in metallothionein system functioning". They also talked about how issues with this ratio "may be a biomarker of heavy metal, particularly mercury, toxicity in children with ASDs" as per the various biological uses of metallothionein [7]. I know this moves discussions into some quite uncomfortable realms but science is science (see here) and one should not be afraid to have scientific discourse on any topic. Importantly too, the Faber results also seemed to show more than a passing similarity to those presented by Li et al. Same goes for the paper by Russo and colleagues [8].

The other interesting point recorded by Li and colleagues was their use of the good 'ole ROC curve as a means to indicate an "auxiliary diagnosis of autism". More frequently linked to a certain Egyptian-Saudi autism research group (see here), ROC curves - "a fundamental tool for diagnostic test evaluation" - basically plots the true positive rate against the false positive rate for a test. Li et al projected the cut-off value for the Zn/Cu ratio to be 0.665 for a diagnosis, with "a sensitivity of 90.0% and a specificity of 91.7%". Bearing in mind the relatively small participants included for analysis (n=60), those aren't bad figures for sensitivity and specificity remembering my recent discussions on the observation-based classifier (OBC) from Wall and colleagues [9] (see here) and what they got.

There's little more for me to say about the Li data that I haven't already said here and in other posts on this topic. If you want to read a little more about the possible role of zinc and copper in cases of autism, the report by Bjorklund [10] covers quite a bit of the literature on possible links. The next question is what might we be able to do about any issues in this area? [11]

So then, The Last of the Famous International Playboys? (not me of course..)

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[1] Li SO. et al. Serum copper and zinc levels in individuals with autism spectrum disorders. Neuroreport. 2014 Aug 26.

[2] Grabrucker S. et al. Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. Brain. 2014 Jan;137(Pt 1):137-52.

[3] Chaves-Kirsten GP. et al. Prenatal zinc prevents mTOR disturbance in a rat model of autism induced by prenatal lipopolysaccharide. Brain, Behavior & Immunity. 2014; 40: e11-e12.

[4] McClung JP. et al. Effect of supplemental dietary zinc on the mTOR signaling pathway in skeletal muscle from post-absorptive mice. FASEB J. 2006; 20 (Meeting Abstract Supplement) A627.

[5] Osredkar J. & Sustar N. Copper and Zinc, Biological Role and Significance of Copper/Zinc
Imbalance. Journal of Clinical Toxicology. 2011; S3.

[6] Faber S. et al. The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Biomarkers. 2009 May;14(3):171-80.

[7] Coyle P. et al. Metallothionein: the multipurpose protein. Cell Mol Life Sci. 2002 Apr;59(4):627-47.

[8] Russo AJ. et al. Plasma copper and zinc concentration in individuals with autism correlate with selected symptom severity. Nutr Metab Insights. 2012 Feb 28;5:41-7.

[9] Duda M. et al. Testing the accuracy of an observation-based classifier for rapid detection of autism risk. Transl Psychiatry. 2014 Aug 12;4:e424.

[10] Bjorklund G. The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp (Wars). 2013;73(2):225-36.

[11] Russo AJ. & Devito R. Analysis of Copper and Zinc Plasma Concentration and the Efficacy of Zinc Therapy in Individuals with Asperger's Syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) and Autism. Biomark Insights. 2011;6:127-33.

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ResearchBlogging.org Li SO, Wang JL, Bjørklund G, Zhao WN, & Yin CH (2014). Serum copper and zinc levels in individuals with autism spectrum disorders. Neuroreport PMID: 25162784

Friday, 12 September 2014

Insulin, growth hormone and risk of schizophrenia?

"Overall, the present findings suggest that metabolic and hormonal disturbances such as effects on insulin and growth hormone may represent a vulnerability factor to develop mental disorders". That was the conclusion reported by van Beveren and colleagues [1] (open-access) looking at "disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia".
"Years ago you served my father in the Clone Wars"

Drawing on data derived from participants taking part in the Genetic Risk and Outcome of Psychoses (GROUP) study [2] researchers looked at blood serum samples "to measure the levels of 184 molecules in serum from 112 schizophrenia patients, 133 siblings and 87 unrelated controls". Multiplex immunoassay was the analytical weapon of choice.

The results indicated that "10 proteins were present at significantly different levels between schizophrenia patients and controls" which can be seen here. The insulin synthesis pathway showed more than a passing connection to group differences as per the appearance of insulin and precursor molecules such as proinsulin and C-peptide (connecting peptide). Some of these pathway molecules were also reported to be altered in the sibling group(s) too. Growth hormone also featured as a potentially distinguishing marker, as did adiponectin among others.

The authors conclude (again) their findings for "the presence of a molecular endophenotype involving disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia". Perhaps even more interesting is their view of the body of work [3] suggesting that "antipsychotic drugs are known to increase peripheral glucose levels" and how, in light of their findings, "these effects may be intrinsically related to the therapeutic mechanism of action by increasing the peripheral blood glucose levels and thereby increasing glucose availability in the brain".

As the authors point out, there is still quite a bit more to do in this area including examining larger samples sizes and importantly, looking at blood glucose levels as a measure of insulin resistance to further complement their findings. I note however that issues with insulin function being potentially related to mood and other psychiatric conditions are nothing new as per the various literature in this area. Anderson and colleagues [4] for example, talked about a diagnosis of diabetes doubling the odds of comorbid depression. Bearing in mind, the possible interfering effect of medication, Verma and colleagues [5] found that in drug-naive (unmedicated) patients with first-episode psychosis there was a significantly increased likelihood of diabetes to be present compared with age and sex-matched asymptomatic control participants. I don't doubt however, that any relationship is going to be complicated.

Finally, and bearing in mind the prime directive of this blog (no medical or clinical advice given or intended), there is the question of how this research might translate into therapeutic intervention. A final quote from the authors on this and the possibility of: "novel disease prevention approaches, which could involve nutrition modification, stress reduction and pharmaco-therapeutic interventions, including the application of well-tolerated drugs that combat insulin resistance". Alongside the dietary aspect (which is something very favourable to this blog for lots of reasons), I am wondering whether we could also learn something from times gone by [6]? Perhaps even the appliance of prophylactic psychiatry [7]?

Music to close and Andrea Bocelli sings Funiculì, Funiculà...

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[1] van Beveren NJM. et al. Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia. Translational Psychiatry. 2014; 4: e430.

[2] Korver N. et al. Genetic Risk and Outcome of Psychosis (GROUP), a multi-site longitudinal cohort study focused on gene-environment interaction: objectives, sample characteristics, recruitment and assessment methods. Int J Methods Psychiatr Res. 2012 Sep;21(3):205-21.

[3] Wirshing DA. et al. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002 Oct;63(10):856-65.

[4] Anderson RJ. et al. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001 Jun;24(6):1069-78.

[5] Verma SK. et al. Metabolic risk factors in drug-naive patients with first-episode psychosis. J Clin Psychiatry. 2009 Jul;70(7):997-1000.

[6] Anderson K. et al. Salsalate, an old, inexpensive drug with potential new indications: a review of the evidence from 3 recent studies. Am Health Drug Benefits. 2014 Jun;7(4):231-5.

[7] Sawa A. & Seidman LJ. Is Prophylactic Psychiatry around the Corner? Combating Adolescent Oxidative Stress for Adult Psychosis and Schizophrenia. Neuron. 2014; 83: 991-993.

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ResearchBlogging.org van Beveren NJ, Schwarz E, Noll R, Guest PC, Meijer C, de Haan L, & Bahn S (2014). Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia. Translational psychiatry, 4 PMID: 25158005

Thursday, 11 September 2014

Treating autism in the first year of life

I had been waiting y'know. Waiting a while for the paper by Sally Rogers and colleagues [1] to finally appear quite a few days after the media headlines about 'reducing', 'reversing' and even 'eliminating' the signs and symptoms of autism in early infancy had appeared. Personally, I prefer the New Scientist headline: 'Early autism intervention speeds infant developmentgiven the text of the paper. I should perhaps also add the words 'for some' to that sentence as you will hopefully see...

I'm sure most people have already read about the study ins and outs: take an intervention called 'Infant Start' (IS), a relation of the Early Start Denver Model (ESDM), and apply it with a small (very small) group of "symptomatic" young infants (n=7, aged between 6-15 months old) showing signs and symptoms of autism. Plot baseline measures and progress of those children under IS using various psychometric tools including something like the Autism Observation Scale for Infants (AOSI) and old reliable: the ADOS (the Autism Diagnostic Observation Schedule) compared against four comparison groups. One of those control groups included those with similar early autism symptoms as judged by "elevated AOSI scores and clinician concerns" but who did not receive IS; a so-called "declined referral (DR) group" (n=4). Record results and report outcome based on said 12-week program and added extra sessions a few months down the line.

The headline conclusion: "At 36 months, the treated group had much lower rates of both ASD [autism spectrum disorder] and DQs [developmental quotients] under 70 than a similarly symptomatic group who did not enroll in the treatment study". Further: "the pilot study outcomes are promising". I should add that when it came to the "final visit" and "based on standardized assessments and clinical judgement" 2 of the 7 children in the IS group did eventually receive a diagnosis of ASD/PDD-NOS (pervasive developmental disorder not otherwise specified). This compared with 3 of the 4 children in the DR group who met criteria for ASD/PDD-NOS (the other child "presented with intellectual disability"). Insofar as DQ - specifically "overall DQ at or below 70 at 36 months" - well, one child in the IS group fell into this category compared with 3 children in the DR group (note to authors, you've called this the 'DE' group... sorry to be pedantic). You can um-and-ah about the links between ASD and PDD-NOS for example, but suffice to say that any effect from IS was not universal across all participants included in the trial. If you'd like a few more details about the trial and results, I'll refer you to the press release from UC Davis (see here).

Of course this is not the first time that this type of very early intervention has been discussed in the peer-reviewed domain. Take for example another paper by Rogers and colleagues [2] (open-access) talking about the use of ESDM with a cohort of 14-24 month old toddlers "at risk for autism spectrum disorders". The results on that occasions were slightly less dramatic than the more recent ones with the caveat that "both younger child age at the start of intervention and a greater number of intervention hours were positively related to the degree of improvement in children's behavior for most variables". I talked about this in a previous post (see here). Indeed it appears that age at start of intervention might be an important variable after all.

So, where next with this research? Well, aside from some discussions reiterating how useful it would be to have something to aid early diagnosis (see here) bearing in mind that it has not been conclusively proven that all autism is present from birth (see here), discussions have turned to why such early intervention might have had the effect that it had. Brain plasticity has been mentioned, and how critical periods in early development might be particularly amenable to such intensive intervention. Of course, without the all-important "testing the treatment’s efficacy" under more controlled conditions and with larger groups, one cannot discount some role for chance in the recent findings. Not buying that as an answer? How about differing developmental trajectories then?

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[1] Rogers SJ. et al. Autism Treatment in the First Year of Life: A Pilot Study of Infant Start, a Parent-Implemented Intervention for Symptomatic Infants. Journal of Autism and Developmental Disorders. 2014. 12 September.

[2] Rogers SJ. et al. Effects of a brief Early Start Denver model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2012 Oct;51(10):1052-65.

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ResearchBlogging.org S. J. Rogers, L. Vismara, A. L. Wagner, C. McCormick, G. Young, & S. Ozonoff (2014). Autism Treatment in the First Year of Life: A Pilot Study of Infant Start, a Parent-Implemented Intervention for Symptomatic Infants Journal of Autism and Developmental Disorders : 10.1007/s10803-014-2202-y

Omega-3 fatty acids rescues Fragile X phenotypes in Fmr1-Ko mice

"These results demonstrate that n-3 PUFAs dietary supplementation, although not a panacea, has a considerable therapeutic value for FXS [Fragile X syndrome] and potentially for ASD [autism spectrum disorder], suggesting a major mediating role of neuroinflammatory mechanisms".

A view @ Wikipedia 
That was the conclusion reached by Susanna Pietropaolo and colleagues [1] who "evaluated the impact of n-3 PUFA dietary supplementation in a mouse model of fragile X syndrome (FXS), i.e., a major developmental disease and the most frequent monogenic cause of ASD". Looking at the Fmr1-KO mouse model of FXS, a mouse specifically bred to mimic the silencing of the FMR1 gene noted in FXS (see here) with onwards adverse effects for the production of FMRP, researchers looked at what happened when diets were "enriched or not with n-3 PUFAs from weaning until adulthood when they were tested for multiple FXS-like behaviors". The results seemed to indicate that "n-3 PUFA supplementation rescued most of the behavioral abnormalities displayed by Fmr1-KO mice, including alterations in emotionality, social interaction and non-spatial memory, although not their deficits in social recognition and spatial memory". Neuroinflammatory imbalances noted in the knock-out mice were also positively affected by omega-3 supplementation.

I don't need to remind you that the Pietropaolo study was a study of mice and one needs to be quite careful about extrapolating animal results when it comes to humans. That being said, given the quite extensive work that has been done on FXS and the detailing of it's molecular background, one might assume that the current results are treated with a little less scepticism than in relation to other more idiopathic 'types' of autism. Still, proper trials with people are indicated as per other research.

Omega-3 fatty acids have been discussed before on this blog with autism in mind (see here). The collected literature on their usefulness as supplements for autism is rather mixed at present [2] despite some emerging evidence on their involvement in various biological processes in cases of autism (see here). That being said, I'm not getting too down on omega-3 fatty acids in light of some associations being made with specific skills over and above any condition-specific relationship and some new light being shed on their use in other conditions [3]. I'm yet to find anything like an experimental trial of fatty acids in real people with FXS but did chance(!) upon the study by Lachance and colleagues [4] (open-access) talking about the use of fenretinide (N-(4-hydroxyphenyl) retinamide (4HPR)) in the test-tube and effects "associated with the normalization of arachidonic acid/docosahexaenoic acid ratio in macrophages". The effect talked about translates as a down-regulation in the "production of arachidonic acid (AA), a pro-inflammatory omega-6 polyunsaturated fatty acid, and to increase levels of omega-3 polyunsaturated docosahexaenoic acid (DHA), which has an anti-inflammatory effect". Mmm... possibly some new targets to replace quite a few disappointments when it comes to FXS therapeutics (see here).

Music to close. Fontella Bass and Rescue Me.

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[1] Pietropaolo S. et al. Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice. Psychoneuroendocrinology. 2014 Jul 9;49C:119-129.

[2] James S. et al. Omega-3 fatty acids supplementation for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2011 Nov 9;(11):CD007992.

[3] Hawkey E. & Nigg JT. Omega-3 fatty acid and ADHD: Blood level analysis and meta-analytic extension of supplementation trials. Clin Psychol Rev. 2014 Jun 2;34(6):496-505.

[4] Lachance C. et al. Fenretinide corrects the imbalance between omega-6 to omega-3 polyunsaturated fatty acids and inhibits macrophage inflammatory mediators via the ERK pathway. PLoS One. 2013 Sep 12;8(9):e74875.

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ResearchBlogging.org Pietropaolo S, Goubran MG, Joffre C, Aubert A, Lemaire-Mayo V, Crusio WE, & Layé S (2014). Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice. Psychoneuroendocrinology, 49C, 119-129 PMID: 25080404

Wednesday, 10 September 2014

Donepezil and D-cycloserine rescue behaviours in VPA exposed animals

In a post not-so-long-ago I talked about an interesting piece of research by Ahn and colleagues [1] suggesting that a ketogenic diet might yet hold some promise to "modify complex social behaviors and mitochondrial respiration" affected in the "prenatal valproic acid (VPA) rodent model of ASD [autism spectrum disorder]". The idea being that exposure to valproic acid (valproate) during the nine months that made us might carry some heightened risk for adverse effects on offspring development (see here) and a dietary change might rescue some functions.
"Daisy, Daisy, give me your answer do"

Well, the floodgates have well and truly opened when it comes to looking at various pharmacological agents that 'might' also rescue abilities thought to be affected by prenatal valproate exposure as today I discuss two papers.

First up is the paper by Wellmann and colleagues [2] which reported that: "D-cycloserine normalized the VPA-induced increase in play fighting in males and also increased social motivation in females". Second is the paper by Kim and colleagues [3] (open-access here) who observed: "Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring".

Aside from reiterating that these were studies of rodents and not humans, I was slightly taken aback by the reported findings. Cycloserine is normally packaged as an antibiotic but, as with many medicines these days, the pharmacological effects of the compound seem to extend far beyond the intended (antimicrobial) action [4]. I've talked about D-cycloserine before on this blog (see here) and some rather interesting research linking administration to several conditions. With autism in mind, I'll bring to your attention the paper by Urbano and colleagues [5] as one example of how far and wide this pharmaceutic is venturing. As to mode of action, well, I'd be clutching at straws if I was to hazard any guess. I might suggest that something around glutamate metabolism might be something to look at [6] which coincides with one of the proposed actions of D-cycloserine [7].

Donepezil (Aricept®) falls under the category of acting as a reversible acetylcholinesterase inhibitor (AChEI). More usually indicated for dementia and particularly Alzheimer's disease [8] Kim et al describe how "prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring". You can, therefore, perhaps see the logic in using donepezil as an AChEI particularly when one takes into account how other AChE inhibitors have been studied with autistic behaviours in mind [9]. Indeed, this is not the first time that donepezil has specifically been talked about in relation to autism, mouse models of autism, as per the findings from Karvat & Kimchi [10] and their discussions based on the BTBR 'dangermouse' where: "i.p. [intraperitonealinjection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner". And there is the promise of more to come with this medicine.

Reiterating that the Wellmann and Kim results (and the Ahn results) are based on studies of rodents not people, these are an interesting datasets crying out for further replication and study. Scientific glimmers are appearing which provide further data on what biological functions might be affected by prenatal valproate exposure and importantly, what might be done to [safely] rescue certain functions. But we're not there yet... and I haven't even mentioned epigenetics [11] ...

An unusual song from Ween to close... Push th' Little Daisies. Having said that, Ween are/were an unusual band...

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[1] Ahn Y. et al. The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder. Dev Neurosci. 2014 Jul 8.

[2] Wellmann KA. et al. D-Cycloserine Ameliorates Social Alterations That Result From Prenatal Exposure To Valproic Acid. Brain Res Bull. 2014 Aug 14. pii: S0361-9230(14)00120-8.

[3] Kim JW. et al. Subchronic Treatment of Donepezil Rescues Impaired Social, Hyperactive, and Stereotypic Behavior in Valproic Acid-Induced Animal Model of Autism. PLoS One. 2014 Aug 18;9(8):e104927.

[4] Rodrigues H. et al. Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis. PLoS One. 2014 Jul 3;9(7):e93519.

[5] Urbano M. et al. A trial of D-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder. Clin Neuropharmacol. 2014 May-Jun;37(3):69-72.

[6] Bristot Silvestrin R. et al. Animal model of autism induced by prenatal exposure to valproate: altered glutamate metabolism in the hippocampus. Brain Res. 2013 Feb 7;1495:52-60.

[7] Hashimoto K. Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets. 2014 Sep;18(9):1049-63.

[8] McGleenon BM. et al. Acetylcholinesterase inhibitors in Alzheimer’s disease. British Journal of Clinical Pharmacology. 1999; 48: 471-480.

[9] Ghaleiha A. et al. Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2013 Oct 15;28(7):677-685.

[10] Karvat G & Kimchi T. Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism. Neuropsychopharmacology. 2014 Mar;39(4):831-40.

[11] Tordjman S. et al. Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry. 2014 Aug 4;5:53.

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ResearchBlogging.org Wellmann KA, Varlinskaya EI, & Mooney SM (2014). D-Cycloserine Ameliorates Social Alterations That Result From Prenatal Exposure To Valproic Acid. Brain research bulletin PMID: 25130667



ResearchBlogging.org Kim JW, Seung H, Kwon KJ, Ko MJ, Lee EJ, Oh HA, Choi CS, Kim KC, Gonzales EL, You JS, Choi DH, Lee J, Han SH, Yang SM, Cheong JH, Shin CY, & Bahn GH (2014). Subchronic Treatment of Donepezil Rescues Impaired Social, Hyperactive, and Stereotypic Behavior in Valproic Acid-Induced Animal Model of Autism. PloS one, 9 (8) PMID: 25133713

Tuesday, 9 September 2014

The gondii and generalised anxiety disorder

Toxoplasma gondii (T. gondii) has been absent from discussions on this blog for a while now. I'm going to remedy that today with this post talking about the paper from Markovitz and colleagues [1] who concluded: "T. gondii infection may play a role in the development of GAD [generalized anxiety disorder]".
"You have saved our lives. We are eternally grateful"

Based on participants taking part in the Detroit Neighborhood Health Study exposure to T. gondii "defined by seropositivity and IgG antibody levels" was measured in approaching 500 people. Psychiatric diagnoses including depression, PTSD (posttraumatic stress disorder) and GAD were ascertained and data analysed to see if there was anything correlation-wise between T. gondii exposure and the various conditions.

The results suggested that T. gondii exposure was "associated with a 2 times greater odds of GAD" when taking into account various potential confounding variables. Those with some of the highest antibody levels to T. gondii were over three times at greater risk of GAD, potentially suggesting a dose-response relationship. Ergo, "T. gondii infection is strongly and significantly associated with GAD" but with more research to do.

Although no expert on GAD, I was a little puzzled by the Markovitz results. My previous musings on T. gondii and how it manages to alter rodent behaviour would seem to imply that this protozoan has an opposite effect on animal anxiety (i.e. reducing or modifying anxiety and predation-related fear [2]). Of course mice/rats are mice/rats and not humans but one might have expected something of an opposite effect [3].

That being said, this is not the first time that anxiety (human anxiety) has been mentioned alongside T. gondii as per the paper by Groër and colleagues [4] (open-access). In that case authors concluded that: "Higher T gondii immunoglobulin G titers in infected women were related to anxiety and depression during pregnancy". Some clarification is perhaps needed in this area...

To close, music I've probably linked to before but it's so good I'm gonna do it again: REM and It's the End of the World...

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[1] Markovitz A. et al. Toxoplasma gondii and anxiety disorders in a community-based sample. Brain Behav Immun. 2014 Aug 11. pii: S0889-1591(14)00418-8.

[2] Kaushik M. et al. The role of parasites and pathogens in influencing generalised anxiety and predation-related fear in the mammalian central nervous system. Horm Behav. 2012 Aug;62(3):191-201.

[3] Gonzalez LE. et al. Toxoplasma gondii infection lower anxiety as measured in the plus-maze and social interaction tests in rats A behavioral analysis. Behav Brain Res. 2007 Feb 12;177(1):70-9.

[4] Groër MW. et al. Prenatal depression and anxiety in Toxoplasma gondii-positive women. Am J Obstet Gynecol. 2011 May;204(5):433.e1-7.

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ResearchBlogging.org Markovitz A, Simanek AM, Yolken R, Galea S, Koenen KC, Chen S, & Aiello AE (2014). Toxoplasma gondii and anxiety disorders in a community-based sample. Brain, behavior, and immunity PMID: 25124709

Monday, 8 September 2014

Homocysteine, MTHFR and schizophrenia studied AND meta-analysed

"Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia". Further: "The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia".
MTHFR (again!) @ Paul Whiteley

So said the results of the study and meta-analysis carried out by Akira Nishi and colleagues [1] (open-access) looking at the 'big H' alongside everyone's genetic Scrabble favourite MTHFR (methylenetetrahydrofolate reductase (NAD(P)H)).

The Nishi paper represents pretty good scientific value for money given that authors not only looked at plasma levels of total homocysteine in nearly 400 participants diagnosed with schizophrenia compared with nearly 1000 controls, they also genotyped for the MTHFR C677T polymorphism [2] (describing an amino acid substitution which reduces the activity of the enzyme methylenetetrahydrofolate reductase and results in elevated homocysteine levels) in a further 1700 participants with schizophrenia compared against over 3000 asymptomatic controls. For good measure, the authors then carried out a meta-analysis of the scientific literature looking at homocysteine and schizophrenia as a function of gender. Phew.

As per the opening paragraph, authors reported "significantly elevated plasma total homocysteine levels in patients with schizophrenia compared with controls, in both male and female subjects". The results of their meta-analysis confirmed such elevations in homocysteine "although antipsychotic medication might influence this outcome". Combined with the association made between a diagnosis of schizophrenia and the MTHFR SNP studied, all adds up to "disrupted 1-carbon metabolism [having] an important role in the pathophysiology of schizophrenia".

I don't mind saying that the Nishi results are really rather interesting to me. The links between schizophrenia and homocysteine have been talked about previously on this blog (see here) including the potential usefulness of folic acid and vitamin B12 for some cases of schizophrenia (see here). Nishi et al also talk about another potentially important part of their results with some mention of DNA methylation, something which also crosses over into other areas of research interest too (see here).

And so the evidence continues to stack up for the big H and MTHFR in some cases of schizophrenia...

Music then. The Pixies and Debaser.

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[1] Nishi A. et al. Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association
Studies of the MTHFR C677T Polymorphism in Schizophrenia. Schizophrenia Bulletin. 2014; 40: 1154-1163.

[2] Gilbody S. et al. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. 2007 Jan 1;165(1):1-13.

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ResearchBlogging.org Nishi A, Numata S, Tajima A, Kinoshita M, Kikuchi K, Shimodera S, Tomotake M, Ohi K, Hashimoto R, Imoto I, Takeda M, & Ohmori T (2014). Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in Schizophrenia. Schizophrenia bulletin PMID: 24535549