Deleterious GRM1 Mutations in Schizophrenia

We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose documented role as a modulator of neuronal signalling and synaptic plasticity makes it a plausible schizophrenia candidate. In a recent study, this gene was shown to harbour a cluster of deleterious nsSNPs within a functionally important domain of the receptor, in patients with schizophrenia and bipolar disorder. Our Sanger sequencing of the GRM1 coding regions detected equal numbers of nsSNPs in cases and controls, however the two groups differed in terms of the potential effects of the variants on receptor function: 6/6 case-specific and only 1/6 control-specific nsSNPs were predicted to be deleterious. Our in-vitro experimental follow-up of the case-specific mutants showed that 4/6 led to significantly reduced inositol phosphate production, indicating impaired function of the major mGluR1signalling pathway; 1/6 had reduced cell membrane expression; inconclusive results were obtained in 1/6. Family segregation analysis indicated that these deleterious nsSNPs were inherited. Interestingly, four of the families were affected by multiple neuropsychiatric conditions, not limited to schizophrenia, and the mutations were detected in relatives with schizophrenia, depression and anxiety, drug and alcohol dependence, and epilepsy. Our findings suggest a possible mGluR1 contribution to diverse psychiatric conditions, supporting the modulatory role of the receptor in such conditions as proposed previously on the basis of in vitro experiments and animal studies

Comparison of [18F]-Fluoroethyltyrosine PET and the IDH status with Sodium MRI in Cerebral Gliomas

V56Comparison of [18F]-Fluoroethyltyrosine PET and the IDH status with Sodium MRI in Cerebral GliomasA. Shymanskaya1, W. A. Worthoff1, G. Stoffels1, J. Lindemeyer1, B. Neumaier2, P. Lohmann1, N. Galldiks3, K. J. Langen1, N. J. Shah11Forschungszentrum Jülich GmbH, Institute of Neuroscience and Medicine - 4, Jülich, Germany; 2Forschungszentrum Jülich GmbH, Institute of Neuroscience and Medicine - 5, Jülich, Germany; 3Forschungszentrum Jülich GmbH, Institute of Neuroscience and Medicine - 3, Jülich, GermanyZiel/Aim:O-(2-[18F]fluoroethyl)-L-tyrosine([18F]-FET) PET is used for the supportive diagnostics of cerebral gliomas. In this study, the relationship between the [18F]-FET-PET parameters, distribution of restricted (mainly intracellular) and unrestricted (mainly extracellular) sodium, and the mutational status of the enzyme isocitrate dehydrogenase (IDH) were investigated in patients with cerebral gliomas.Methodik/Methods:Ten patients with untreated gliomas and one patient with a recurrent glioblastoma were investigated by dynamic [18F]-FET-PET and sodium MRI using an enhanced SISTINA sequence to estimate sodium parameters in tumours. The enhanced SISTINA sequence uses single-quantum and triple-quantum-filtered imaging and allows simultaneous acquisition of signal originating from restricted and unrestricted sodium (1). IDH mutational status was determined after biopsy or resection. The untreated patients were analysed independently in two groups (5 patients each) dependent on their IDH mutational status.Ergebnisse/Results:Tumour-to-brain ratio (TBR) of weighted mainly intracellular sodium (NaR) was significantly lower in IDH mutated (p=0.01) than in IDH wildtype gliomas. Total sodium concentration in mmol/L (p=0.05), TBR of the total sodium concentration (NaT) (p=0.02), TBR of weighted unrestricted mainly extracellular sodium (NaNR) (p=0.003), and the ratio of NaT/NaR (p<0.001) were significantly higher in IDH mutated than in IDH wildtype gliomas. [18F]-FET parameters estimated from tracer dynamics curves (TBR, time-to-peak) correlated neither to the IDH status nor to the sodium distribution. The patient with a recurrent GBM exhibited an additional radiation injury with strong abnormalities in sodium MRI.Schlussfolgerungen/Conclusions:Acquired results show that sodium MRI shows stronger relation to the IDH mutational status than [18F]-FET-PET parameters in cerebral gliomas in this patient cohort. Further evaluation of the combination of the three diagnostic modalities in gliomas seems promising and requires higher patient number.Literatur/References:[1] Worthoff WA, Shymanskaya A, Shah NJ. Relaxometry and quantification in simultaneously acquired single and triple quantum filtered sodium MRI. Magn Reson Med. 2018;00:1-13. doi:10.1002/mrm.27387

Comparison of [18F]-Fluoroethyltyrosine PET and the IDH status with Sodium MRI in Cerebral Gliomas

Ziel/Aim:O-(2-[18F]fluoroethyl)-L-tyrosine([18F]-FET) PET is used for the supportive diagnostics of cerebral gliomas. In this study, the relationship between the [18F]-FET-PET parameters, distribution of restricted (mainly intracellular) and unrestricted (mainly extracellular) sodium, and the mutational status of the enzyme isocitrate dehydrogenase (IDH) were investigated in patients with cerebral gliomas.Methodik/Methods:Ten patients with untreated gliomas and one patient with a recurrent glioblastoma were investigated by dynamic [18F]-FET-PET and sodium MRI using an enhanced SISTINA sequence to estimate sodium parameters in tumours. The enhanced SISTINA sequence uses single-quantum and triple-quantum-filtered imaging and allows simultaneous acquisition of signal originating from restricted and unrestricted sodium (1). IDH mutational status was determined after biopsy or resection. The untreated patients were analysed independently in two groups (5 patients each) dependent on their IDH mutational status.Ergebnisse/Results:Tumour-to-brain ratio (TBR) of weighted mainly intracellular sodium (NaR) was significantly lower in IDH mutated (p=0.01) than in IDH wildtype gliomas. Total sodium concentration in mmol/L (p=0.05), TBR of the total sodium concentration (NaT) (p=0.02), TBR of weighted unrestricted mainly extracellular sodium (NaNR) (p=0.003), and the ratio of NaT/NaR (p<0.001) were significantly higher in IDH mutated than in IDH wildtype gliomas. [18F]-FET parameters estimated from tracer dynamics curves (TBR, time-to-peak) correlated neither to the IDH status nor to the sodium distribution. The patient with a recurrent GBM exhibited an additional radiation injury with strong abnormalities in sodium MRI.Schlussfolgerungen/Conclusions:Acquired results show that sodium MRI shows stronger relation to the IDH mutational status than [18F]-FET-PET parameters in cerebral gliomas in this patient cohort. Further evaluation of the combination of the three diagnostic modalities in gliomas seems promising and requires higher patient number.Literatur/References:[1] Worthoff WA, Shymanskaya A, Shah NJ. Relaxometry and quantification in simultaneously acquired single and triple quantum filtered sodium MRI. Magn Reson Med. 2018;00:1-13. doi:10.1002/mrm.27387

Multistage Background Field Removal (MUBAFIRE)—Compensating for B0 Distortions at Ultra-High Field

The investigation of tissue magnetic susceptibility and the resultant magnetic field offers a new avenue for quantitative tissue characterisation by MRI. One crucial step in mining the phase and field data for relevant tissue information is the correction of externally induced field shifts. This article outlines a multistep approach comprising several methodologies for background field removal. The virtues of B0 long-range variation detection and compensation of more localised external disturbances are unified in a sequential filter chain. The algorithm is tested by means of a numerical Monte Carlo simulation model and applied to in vivo measurements at 3T and 9.4T as well as to a fixed brain tissue measurement at 9.4T. Further, a comparison to conventional filter types has been undertaken