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Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone-ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients. This was an investigator-initiated, researcher-blinded, randomized, crossover study in six adult GSDIIIa patients. Prior to exercise subjects ingested a carbohydrate drink (~66 g, CHO) or a ketone-ester (395 mg/kg, KE) + carbohydrate drink (30 g, KE + CHO). Subjects performed 15-minute cycling exercise on an upright ergometer followed by 10-minute supine cycling in a magnetic resonance (MR) scanner at two submaximal workloads (30% and 60% of individual maximum, respectively). Blood metabolites, indirect calorimetry data, and in vivo 31P-MR spectra from quadriceps muscle were collected during exercise. KE + CHO induced ANK in all six subjects with median peak βHB concentration of 2.6 mmol/L (range: 1.6-3.1). Subjects remained normoglycemic in both study arms, but delta glucose concentration was 2-fold lower in the KE + CHO arm. The respiratory exchange ratio did not increase in the KE + CHO arm when workload was doubled in subjects with overt myopathy. In vivo 31P MR spectra showed a favorable change in quadriceps energetic state during exercise in the KE + CHO arm compared to CHO in subjects with overt myopathy. Effects of ANK during exercise are phenotype-specific in adult GSDIIIa patients. ANK presents a promising therapy in GSDIIIa patients with a severe myopathic phenotype. Trial registration number: ClinicalTrials.gov identifier: NCT03011203.

A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise-induced rhabdomyolysis in patients with fatty acid oxidation (FAO) disorders. We hypothesised that ingestion of a ketone ester (KE) drink prior to exercise could serve as an alternative oxidative substrate supply to boost muscular ATP homeostasis. To establish a rational basis for therapeutic use of KE supplementation in FAO, we tested this hypothesis in patients deficient in Very Long-Chain acyl-CoA Dehydrogenase (VLCAD). Five patients (range 17-45 y; 4 M/1F) patients were included in an investigator-initiated, randomised, blinded, placebo-controlled, 2-way cross-over study. Patients drank either a KE + CHO mix or an isocaloric CHO equivalent and performed 35 minutes upright cycling followed by 10 minutes supine cycling inside a Magnetic Resonance scanner at individual maximal FAO work rate (fatmax; approximately 40% VO2max). The protocol was repeated after a 1-week interval with the alternate drink. Primary outcome measures were quadriceps phosphocreatine (PCr), Pi and pH dynamics during exercise and recovery assayed by in vivo 31P-MR spectroscopy. Secondary outcomes included plasma and muscle metabolites and respiratory gas exchange recordings. Ingestion of KE rapidly induced mild ketosis and increased muscle BHB content. During exercise at FATMAX, VLCADD-specific plasma acylcarnitine levels, quadriceps glycolytic intermediate levels and in vivo Pi/PCr ratio were all lower in KE + CHO than CHO. These results provide a rational basis for future clinical trials of synthetic ketone ester supplementation therapy in patients with FAO disorders. Trial registration: ClinicalTrials.gov. Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.

Purpose Glutamatergic models of psychosis propose that dysfunction of N -methyl- d -aspartate (NMDA) receptors, and associated excess of glutamate, may underlie psychotic experiences in people with schizophrenia. However, little is known about the specific relation between glutamate and auditory verbal hallucinations (AVH) in patients with psychosis. In this study, levels of glutamate + glutamine (Glx) in the left lateral prefrontal lobe were determined using proton magnetic resonance spectroscopy ( 1 H MRS) to calculate their association with AVH. Methods Sixty-seven patients with schizophrenia and thirty healthy control participants (HC) underwent magnetic resonance spectroscopy (MRS) to estimate levels of Glx in the white matter of the left prefrontal lobe. The spectrum was estimated from an 8 mm 3 voxel placed in the left lateral prefrontal region, belonging to both the cingulum and forceps minor. Patients with lifetime AVH (AVH group; n = 45) and patients without lifetime AVH were compared (NoAVH group; n = 22) to control participants. Results Levels of Glx were significantly different between the groups (F(2,94) = 5.27, p = 0.007). Planned comparisons showed that higher Glx levels were found in control participants than in the total patient group ( p = 0.010). However, patients with lifetime AVH had higher levels of Glx compared to patients without lifetime AVH ( p = 0.019). Creatin levels were similar in all three groups. We found no association between Glx and the severity of symptoms (item P3 of the PANSS or PANSS positive subscale). Conclusion The higher Glx levels in patients with lifetime AVH as compared to patients without lifetime AVH suggest a mediating role for Glx in AVH. Our results are consistent with a previous study that found similar decreased levels of Glx in patients with schizophrenia, and increased levels in an AVH group as compared to a NoAVH group. The role of the glutamatergic system deserves further investigation, for example in different brain regions and in relation to clinical variables.

Insight is impaired in most patients with psychosis and has been associated with poorer prognosis. The exact neural basis of impaired insight is still unknown, but it may involve disrupted prefrontal neural connectivity. Numerous studies have indeed found white matter (WM) abnormalities in psychosis. The association between prefrontal WM abnormalities and insight has not been studied yet by means of proton magnetic resonance spectroscopy (H-1-MRS). H-1-MRS can be used to measure N-acetylaspartate (NAA), which is considered to be a marker of neuronal integrity. We measured insight with the Birchwood Insight Scale (BIS) as well as item G12 of the Positive and Negative Syndrome Scale (PANSS) in 88 patients with psychosis. Prefrontal WM concentrations of NAA and ratios of NAA to creatine (Cr) were assessed with H-1-MRS. Nonparametric partial correlational analyses were conducted between NAA concentrations and insight controlling for illness duration, standardized antipsychotic dose, symptom scores, voxel grey matter content and voxel cerebrospinal fluid content. We found a significant correlation between reduced NAA/Cr ratios and poorer insight as measured with the BIS, which remained significant after additional correction for full width at half maximum, signal/noise and age. This is the first study reporting a relationship between lower prefrontal concentrations of a marker of neuronal integrity and impaired insight, providing further evidence that prefrontal pathology may play an important role in impaired insight in psychosis. This may be explained by the involvement of the prefrontal cortex in several executive and metacognitive functions, such as cognitive flexibility and perspective taking. (C) 2016 Elsevier B.V. All rights reserved.

Objective: Given that aripiprazole acts as a partial agonist on the dopamine receptor, it may have unique effects on brain neuro-metabolism, specifically in the prefrontal cortex. In this exploratory study, we investigated the effect of aripiprazole compared to risperidone on prefrontal metabolite levels (Glx, NAA, Creatine, Choline and myo-Inositol) and changes in gray and white matter volume (GMV and WMV) in patients with a psychotic disorder. We hypothesized that patients treated with aripiprazole would show increased levels of Glx and NAA and preserved brain volumes, in contrast to risperidone. Methods: In this randomized, single blind study, patients (n=24) treated with either risperidone or aripiprazole underwent magnetic resonance spectroscopy (1H-MRS) and high-resolution anatomical scans (3T) at baseline and after 9 weeks. LC Model was used to determine the absolute spectral metabolite levels and SPM12 was to perform voxel based morphometry analyses. Both metabolite levels and brain volumes were compared between treatment groups. Results: We found a trend for a different effect of both antipsychotics on Glx levels, whereby risperidone reduced Glx levels compared to aripiprazole. Moreover, patients treated with aripiprazole showed a decreased GMV in the precentral gyrus, caudate and lateral frontal regions and increased WMV in the precentral gyrus and a non-significant but consistent pattern of prefrontal WM increases, in contrast to risperidone. Conclusion: Our results point to possibility of different effects of aripiprazole on brain volume and metabolism compared to risperidone. Studies in larger samples are needed to shed more light on the robustness and nature of such differences.

Glutamatergic models of psychosis propose that dysfunction of N-methyl-d-aspartate (NMDA) receptors, and associated excess of glutamate, may underlie psychotic experiences in people with schizophrenia. However, little is known about the specific relation between glutamate and auditory verbal hallucinations (AVH) in patients with psychosis. In this study, levels of glutamate+glutamine (Glx) in the left lateral prefrontal lobe were determined using proton magnetic resonance spectroscopy (Sixty-seven patients with schizophrenia and thirty healthy control participants (HC) underwent magnetic resonance spectroscopy (MRS) to estimate levels of Glx in the white matter of the left prefrontal lobe. The spectrum was estimated from an 8mmLevels of Glx were significantly different between the groups (F(2,94)=5.27, p=0.007). Planned comparisons showed that higher Glx levels were found in control participants than in the total patient group (p=0.010). However, patients with lifetime AVH had higher levels of Glx compared to patients without lifetime AVH (p=0.019). Creatin levels were similar in all three groups. We found no association between Glx and the severity of symptoms (item P3 of the PANSS or PANSS positive subscale).The higher Glx levels in patients with lifetime AVH as compared to patients without lifetime AVH suggest a mediating role for Glx in AVH. Our results are consistent with a previous study that found similar decreased levels of Glx in patients with schizophrenia, and increased levels in an AVH group as compared to a NoAVH group. The role of the glutamatergic system deserves further investigation, for example in different brain regions and in relation to clinical variables.

While retrieving additional information from patients’ medical files for another study, it became clear that one patient who was actually using valproate and levetiracetam, was previously processed as a lithium user. Below you will find the corrected version of the subjects’ characteristics Table 1, as well as corrected results of the explorative analyses of this study where lithium use was involved and an updated version of Fig. 7, summarizing the explorative analysis results of the left hippocampus. The altered text of the concerned paragraphs are set in boldface. The cited references are as in the original report.

H-Magnetic Resonance Spectroscopy (1H-MRS) can offer insights in various neuropathologies by measuring metabolite levels in the brain. In the current study we investigated the levels of glutamate + glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate + glutamic acid (NAA + NAAG; neuronal viability) in the prefrontal cortex of patients with a psychotic disorder and people at Ultra High Risk (UHR) for psychosis. A 1H-MRS spectrum was acquired in 31 patients with a recent onset psychotic disorder and 60 with a chronic state, 16 UHR patients and 36 healthy controls. Absolute metabolite levels were calculated using LCModel with a reference water peak. Groups were compared while taking into account age and partial volume effects. Moreover, we investigated associations with positive and negative symptoms, duration of illness and antipsychotic treatment in patients. The most notable finding is that chronicity of schizophrenia was related to decreased levels of Glx and NAA. On the other hand, although on an exploratory note, UHR showed increased levels of prefrontal Glx and NAA levels with increasing age. Our results may indicate an initial Glx and NAA increase and subsequent decrease during illness progression that may be related to the neurotoxic effects of glutamate.

Background: The hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning.Materials and methods: Twenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [C-11]-(R)PK11195 neuroinflammation positron emission tomography scan.Results: In contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA) + N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr) + phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA + NAAG concentration, between alcohol use and NM + NAAG concentration, between microglial activation and the depression score and a negative relation between Cr + PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally.Conclusion: Compared to HCs, the decreased NAA + NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis. (C) 2015 Elsevier Inc. All rights reserved.