OS08.4.A Retrospective analysis of in vivo 1H-magnetic resonance spectroscopy based on a machine learning approach enables reliable prediction of IDH mutation in patients with glioma

BACKGROUND Mutation of isocitrate dehydrogenase (IDH) is not only an important landmark in the development of low-grade gliomas, but also has prognostic significance and is a potential therapeutic target. There is a high need to determinate IDH mutation status at diagnosis and during the course of therapy in a non-invasive and reliable manner. We established a machine learning approach based on a support vector machine to detect IDH mutation status in in vivo standard 1H-magnetic resonance spectroscopy (1H-MRS) at 3T with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2–99.9%), and a specificity of 75% (95% CI, 42.85–94.5%) in a prospective monocentric clinical trial. Here, the same method is applied in a retrospective cohort at 1.5T and tested for transferability. MATERIAL AND METHODS Validation cohort. The validation cohort comprised 100 patients with glioma for which standard in vivo 1H-MRS spectra had been acquired between 2002 and 2007. Standard single voxel spectroscopy had been measured at 1.5T using a PRESS sequence with a TR of 1500ms and a TE of 30ms. One sample had to be excluded due to non-malignant histology and for 15 samples the IDH mutation status was not available. Therefore, the validation cohort comprised 84 samples, of which 35 were bearing an IDH mutation in immunohistochemistry (sequencing for confirmation is outstanding). Machine learning. To transfer our method to an independent validation cohort our previously established machine learning approach was first trained on all samples of the 3T group. The trained algorithm was then applied to the data of the validation cohort. Here, among other factors the different field strengths, with which the spectra were acquired (3T vs. 1.5T) had to be considered. RESULTS 27 samples of the validation cohort had to be excluded due to poor spectra quality. Our approach correctly detected IDH mutation status in 47 of 62 patients (75.8%), although the technical conditions were significantly different from our published prospective cohort. 17 of 30 patients bearing an IDH mutation were correctly identified, while 30 of 32 wild type patients were determined successfully. CONCLUSION Our approach to detect IDH mutation status has promising application in an unselected retrospective cohort, demonstrating transferability across different technical conditions. Further investigations to improve our technique and an advanced neuropathological processing of the samples are planned.

1H Magnetic Resonance Spectroscopy to Understand the Biological Basis of ALS, Diagnose Patients Earlier, and Monitor Disease Progression

At present, limited biomarkers exist to reliably understand, diagnose, and monitor the progression of amyotrophic lateral sclerosis (ALS), a fatal neurological disease characterized by motor neuron death. Standard MRI technology can only be used to exclude a diagnosis of ALS, but 1H-MRS technology, which measures neurochemical composition, may provide the unique ability to reveal biomarkers that are specific to ALS and sensitive enough to diagnose patients at early stages in disease progression. In this review, we present a summary of current theories of how mitochondrial energetics and an altered glutamate/GABA neurotransmitter flux balance play a role in the pathogenesis of ALS. The theories are synthesized into a model that predicts how pathogenesis impacts glutamate and GABA concentrations. When compared with the results of all MRS studies published to date that measure the absolute concentrations of these neurochemicals in ALS patients, results were variable. However, when normalized for neuronal volume using the MRS biomarker N-acetyl aspartate (NAA), there is clear evidence for an elevation of neuronal glutamate in nine out of thirteen studies reviewed, an observation consistent with the predictions of the model of increased activity of glutamatergic neurons and excitotoxicity. We propose that this increase in neuronal glutamate concentration, in combination with decreased neuronal volume, is specific to the pathology of ALS. In addition, when normalized to glutamate levels, there is clear evidence for a decrease in neuronal GABA in three out of four possible studies reviewed, a finding consistent with a loss of inhibitory regulation contributing to excessive neuronal excitability. The combination of a decreased GABA/Glx ratio with an elevated Glx/NAA ratio may enhance the specificity for 1H-MRS detection of ALS and ability to monitor glutamatergic and GABAergic targeted therapeutics. Additional longitudinal studies calculating the exact value of these ratios are needed to test these hypotheses and understand how ratios may change over the course of disease progression. Proposed modifications to the experimental design of the reviewed 1H MRS studies may also increase the sensitivity of the technology to changes in these neurochemicals, particularly in early stages of disease progression.

Reduced cortical GABA and glutamate in high schizotypy

Rationale Abnormal functioning of the inhibitory gamma-aminobutyric acid (GABA) and excitatory (glutamate) systems is proposed to play a role in the development of schizophrenia spectrum disorder. Although results are mixed, previous 1H-magnetic resonance spectroscopy (MRS) studies in schizophrenia and clinical high-risk samples report these metabolites are altered in comparison to healthy controls. Currently, however, there are few studies of these metabolites in schizotypy samples, a personality dimension associated with the experience of schizophrenia and psychosis-like symptoms. Objectives We investigated if GABA and glutamate metabolite concentrations are altered in people with high schizotypy. We also explored the relationship between resilience to stress, GABA metabolite concentrations and schizotypy. Methods We used MRS to examine GABA and glutamate levels in the medial prefrontal cortex in people with low and high schizotypy traits as assessed with the Schizotypal Personality Questionnaire. Resilience to stress was assessed using the Connor-Davidson Resilience Scale. Results Compared to individuals with low schizotypy traits, high schizotypy individuals showed lower cortical prefrontal GABA (F (1,38) = 5.18, p = 0.03, η2 = 0.09) and glutamate metabolite levels (F (1, 49) = 6.25, p = 0.02, η2 = 0.02). Furthermore, participants with high GABA and high resilience levels were significantly more likely to be in the low schizotypy group than participants with low GABA and high resilience or high GABA and low resilience (95% CI 1.07–1.34, p < .001). Conclusions These findings demonstrate that subclinical schizotypal traits are associated with abnormal functioning of both inhibitory and excitatory systems and suggest that these transmitters are implicated in a personality trait believed to be on a continuum with psychosis.