PET scanning as a biomarker for ketogenic diet response in autism? Not quite...

The case report findings reported by Iwona Żarnowska and colleagues [1] provide the blogging fodder today and an interesting idea: could PET imaging - "non-invasive positron emission tomography (PET) with 18 fluoro-deoxyglucose (18FDG PET) of the resting brain" - serve as "a biomarker in identifying individuals with autism who might benefit from the KD [ketogenic diet] due to underlying abnormalities related to glucose hypometabolism"?

'We need more research' is the conclusion reached by authors, who describe a case report of a 6-year old boy who seemed to regress into autism (yes, he regressed - "At the age of 2, he was developmentally on target in motor and cognitive skills, used language for communication, and displayed normal interests, social activities, and behaviours that were appropriate for his age") and was subsequently introduced to a ketogenic diet. The ketogenic diet (KD) has been discussed before on this blog in relation to autism (see here and see here for examples), and how "a very strict, high-fat, low-carbohydrate, adequate-protein and vitamin-supplemented diet with meals distributed evenly throughout the day" seems to have some important effects on behaviour for some.

Indeed, we are told that use of the KD diet for this young man diagnosed with autism and ADHD (attention-deficit hyperactivity disorder) seemed to *correlate* with some important changes to his behavioural presentation. So: "improvements in clinical outcomes were observed as early as 1 month after the classic KD initiation." The sorts of things reported included less hyperactive and aggressive behaviours and some important differences in his scores on schedules such as the CARS (Childhood Autism Rating Scale) focusing on autistic behaviours. Cognitively, there were also some positive changes reported too: "The intellectual development of the patient, as measured by the WISC-R at the age of 7 years and 5 months, also improved his Full Scale IQ increased from 82 to 99..., Verbal Scale IQ increased from 102 to 113..., and Performance Scale IQ increased from 62 to 83." All of this bearing in mind the 'case report' status of this study.

Then to the mention of that word 'biomarker' as PET scanning was conducted "before treatment (baseline study) and 11 months later on the KD (follow-up study)" and results compared. Although no expert on PET (see here for an overview) the aim was to look at glucose and where the glucose-like tracer 'stuck' in terms of parts of the brain. Researchers observed that at baseline, before the KD was put in place, there was evidence of "regional glucose hypometabolism... observed bilaterally in the mesial temporal lobes, basal ganglia, and cerebellum." At follow-up, when the various manifestations of the ketogenic diet had been in place for a year, they reported different findings based on PET scanning: "18F-FDG uptake decreased markedly and diffusely in the whole cerebral cortex with a relatively low reduction in basal ganglia." The authors add that such observations are not a million miles away from similar metabolic changes seen in others when a KD is put in place in relation to the management of epilepsy (a set of conditions where the KD has found a particular usefulness). The shift away from glucose metabolism in those brain areas is thought to represent "a metabolic shift from the utilization of glucose to utilization of ketone bodies as a primary source of energy" a key aim of the ketogenic diet.

Do the Żarnowska live up to their possible 'biomarker' discussions? Erm, I'm afraid not yet they don't. They do make some interesting observations about the use of a ketogenic diet in the context of a single case report including the label autism. They also present some interesting 'brain imaging' data gathered before and after the use of a KD. But as a biomarker? Not on this occasion. Not yet. But don't however discount the potential usefulness of the ketogenic diet in the context of [some] autism however...

To close, of course you know that it's Star Wars Day today. Don't you? 'Penny for your thoughts.'

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[1] Żarnowska I. et al.Therapeutic use of carbohydrate-restricted diets in an autistic child; a case report of clinical and 18FDG PET findings. Metabolic Brain Disease. 2018. April 11.

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"Schizophrenia confers a high endogenous risk for diabetes"

"Schizophrenia confers a high endogenous risk for diabetes, and the risk is further increased by both first-generation and second-generation antipsychotics."

So concluded Anto Rajkumar and colleagues [1] who relied on participant data in the thousands derived from several of those very helpful Scandinavian population registries (this time in Denmark) to add some further science to the idea that psychiatric diagnoses like schizophrenia seem to carry an elevated risk for all-manner of somatic conditions.

From a total population of 2.7 millions people born in Denmark between 1977 and 2013, researchers reported that: "14,118 (0.52%) developed diabetes, and 8,945 (0.33%) developed schizophrenia during follow-up (49,582,279 person-years)." When looking at the risk of developing diabetes (bearing in mind there is more than one type of diabetes) in those with schizophrenia not following any antipsychotic medication regime, researchers reported that: "The adjusted hazard ratio for diabetes was 3.07 (95% confidence interval [CI], 1.71–5.41) in antipsychotic-naive schizophrenia compared with the general population." In other words, compared with those without a diagnosis of schizophrenia, there was something of an increased risk of developing diabetes in those diagnosed with schizophrenia.

Then to the potential effect of antipsychotic medication, and as the authors note: "The risk for diabetes after starting antipsychotic treatment was significantly higher (adjusted hazard ratio, 3.64; 95% CI, 1.95–6.82) than the risk in antipsychotic-naive schizophrenia." The use of an adjusted hazard ratio means that researchers took into account potentially confounding variables such as a family history of diabetes known to potentially elevate the risk of the condition. The focus on medication is also perhaps the side of the whole schizophrenia-diabetes story that people might more readily recognise.

If all that wasn't enough to convince you that schizophrenia - medicated and unmedicated - might show a rather important relationship with diabetes, perhaps the results reported by Pillinger and colleagues [2] might ease your scepticism and the suggestion (from the authors) that "higher levels of insulin, and increased levels of insulin resistance" are a facet of quite a few cases of schizophrenia alongside demonstrating that "people with schizophrenia had higher levels of glucose in the blood." On the basis of these and various other studies, the onus is on regular screening for diabetes and its symptoms alongside other related measures (see here for example) when it comes to schizophrenia under multiple 'medicated or not' conditions.

Music to close, and having bumped into the excellent film 'Stand By Me' again recently, the song of the same name...

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[1] Rajkumar AP. et al. Endogenous and Antipsychotic-Related Risks for Diabetes Mellitus in Young People With Schizophrenia: A Danish Population-Based Cohort Study. Am J Psychiatry. 2017 Jan 20:appiajp201616040442.

[2] Pillinger T. et al. Impaired Glucose Homeostasis in First-Episode Schizophrenia: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2017 Jan 11.

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Rajkumar AP, Horsdal HT, Wimberley T, Cohen D, Mors O, Børglum AD, & Gasse C (2017). Endogenous and Antipsychotic-Related Risks for Diabetes Mellitus in Young People With Schizophrenia: A Danish Population-Based Cohort Study. The American journal of psychiatry PMID: 28103712

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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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

Five serum metabolites and schizophrenia

This post extends my fascination with all things metabolomics, biomarkers and behaviourally-defined conditions. This is quite an apt post for me at the moment given that the all-singing, all-dancing Q-ToF mass spectrometer we have at work is currently receiving a little TLC from the appropriate engineer after a few days being under the weather (P.S. get well soon xxx).

I have previously talked about research presented on schizophrenia and the hunt for suitable biomarkers on this blog. Remembering back to the casein antibody link and the more recent offering on amino acids, a new study has just emerged by Yang and colleagues* with the rather interesting suggestion that just five serum markers (and one urinary marker) might be able to separate schizophrenia from not-schizophrenia equivalent to diagnostic interview.... read on.

The paper which is open-access is pretty comprehensive (aren't they always) but I will try and summarise the methods and main findings here:

• Serum and urine samples from Chinese participants diagnosed with schizophrenia (various onset psychosis) were compared with asymptomatic controls. The absence of diabetes, heavy alcohol consumption and being two weeks mood-stabilising drug free were prerequisites for study entry.
• Enrolled participants were allocated to a training set (N=124) or a test set (N=98). Sample combinations were analysed by gas chromatography - Time of Flight mass spectrometry (GC-ToF) and NMR. These methods and their important accompanying software, represent gold-standards in metabolomic analysis; the ToF bit gives you accurate mass of your compounds (mass-to-charge ratio of an ion) and the NMR, structural information about your compounds of interest.
• Principal component analysis (PCA) provided some information on how the various compounds related to the groups, and after applying a filter on the data, the detected compounds were whittled down to those which gave most discriminating power between schizophrenia and not-schizophrenia. 
• In the end five compounds detected in serum were deemed most important to discriminating schizophrenia in this participant group: glycerate, eicosenoic acid, beta-hydroxybutyrate, pyruvate and cystine. With this compound set, the receiver operating characteristics (AUC) were 0.945 in the training samples and 0.895 for the test samples. When a urinary compound was added to the set (beta-hydroxybutyrate), the AUC went to 1 (which represents a perfect classification) in both training and test sets.

OK you can perhaps see why this paper and its data is so exciting. Move over diagnostic interview, hello serum and urine analysis? The authors delve a little deeper into the compounds reported in their findings and their potential relationship to schizophrenia. At least three of the compounds recorded are tied into the degradation of glyceride and fatty acids which might point to energy metabolism as being implicated in schizophrenia. Some of this might (might!) also link back to related findings in certain types of autism and in particular talk of mitochondrial issues? Cystine is also discussed a little more in the paper and again, some familiar words to autism in relation to things like glutathione and homocysteine; I also wonder whether the findings of low cystine in urine and high in serum might also tie into some of the sulphation issues so unfortunately lost from the current autism research landscape.

As always there are some important things to say about this study before we get too carried away. First is the population used; all Chinese. Whether such markers are applicable to populations outside of China remains to be seen. Second is the relatively small participant group looked at and issues relating to any comorbidity which have not really been fully addressed. Finally are the comparisons of the findings with other, similar studies. The Rujescu findings mentioned in my last post on amino acids suggested that four amino acids might be discriminatory for schizophrenia. As far as I can tell, none of these amino acids, in either plasma or urine, showed up on the current paper (allowing for point one on different peoples and different profiles).

I will perhaps read and re-read the current paper just to make sure that I am seeing all that is being said. Likewise I might just flick through some of the autism research in this area (such as the Yap paper from last year) just to see if there are any other areas of 'overlap'.

* Yang J. et al. Potential metabolite markers of schizophrenia. Molecular Psychiatry. October 2011.