Mutations in the isocitrate dehydrogenase genes (IDH1/2) occur often in diffuse gliomas, where they are associated with abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Monitoring 2-HG levels could provide prognostic information in this disease, but detection strategies that are noninvasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy ( 1 H-MRS) acquisition scheme that uses an ultrahigh magnetic field (!7T) capable of noninvasively detecting 2-HG with quantitative measurements sufficient to differentiate mutant cytosolic IDH1 and mitochondrial IDH2 in human brain tumors. Untargeted metabolomics analysis of in vivo 1 H-MRS spectra discriminated between IDHmutant tumors and healthy tissue, and separated IDH1 from IDH2 mutations. High-quality spectra enabled the quantification of neurochemical profiles consisting of at least eight metabolites, including 2-HG, glutamate, lactate, and glutathione in both tumor and healthy tissue voxels. Notably, IDH2 mutation produced more 2-HG than IDH1 mutation, consistent with previous findings in cell culture. By offering enhanced sensitivity and specificity, this scheme can quantitatively detect 2-HG and associated metabolites that may accumulate during tumor progression, with implications to better monitor patient responses to therapy. Cancer Res; 76(1); 43-49. Ó2015 AACR.
In the healthy human brain, evidence for dissociable memory networks along the anterior-posterior axis of the hippocampus suggests that this structure may not function as a unitary entity. Failure to consider these functional divisions may explain diverging results among studies of memory adaptation in disease. Using task-based and resting functional MRI, we show that chronic seizures disrupting the anterior medial temporal lobe (MTL) preserve anterior and posterior hippocampal-cortical dissociations, but alter signaling between these and other key brain regions. During performance of a memory encoding task, we found reduced neural activity in human patients with unilateral temporal lobe epilepsy relative to age-matched healthy controls, but no upregulation of fMRI signal in unaffected hippocampal subregions. Instead, patients showed aberrant resting fMRI connectivity within anterior and posterior hippocampal-cortical networks, which was associated with memory decline, distinguishing memory-intact from memory-impaired patients. Our results highlight a critical role for intact hippocampo-cortical functional communication in memory and provide evidence that chronic injuryinduced functional reorganization in the diseased MTL is behavioral inefficient.
Right hemisphere activation during functional imaging studies of language has frequently been reported following left hemisphere injury. Few studies have anatomically characterized the specific right hemisphere structures engaged. We used functional MRI (fMRI) with verbal fluency tasks in 12 right-handed patients with left temporal lobe epilepsy (LTLE) and 12 right-handed healthy controls to localize language-related activity in the right inferior frontal gyrus (RIFG). During the phonemic task, LTLE patients activated a significantly more posterior region of the right anterior insula/frontal operculum than healthy controls (P = 0.02). Activation of the left inferior frontal gyrus (LIFG) did not differ significantly between the two groups. This suggests that, following left hemisphere injury, language-related processing in the right hemisphere differs from that with a functionally normal left hemisphere. The localization of activation in the left and right inferior frontal gyri was determined with respect to the anatomical sub-regions pars opercularis (Pop), pars triangularis (Ptr) and pars orbitalis (Por). In the LIFG, both healthy controls (8 out of 12) and LTLE patients (9 out of 12) engaged primarily Pop during phonemic fluency. Activations in the RIFG, however, were located mostly in the anterior insula/frontal operculum in both healthy controls (8 out of 12) and LTLE patients (8 out of 12), albeit in distinct regions. Mapping the locations of peak voxels in relation to previously obtained cytoarchitectonic maps of Broca's area confirmed lack of homology between activation regions in the left and right IFG. Verbal fluency-related activation in the RIFG was not anatomically homologous to LIFG activation in either patients or controls. To test more directly whether RIFG activation shifts in a potentially adaptive manner after left hemisphere injury, fMRI studies were performed in a patient prior to and following anatomical left hemispherectomy for the treatment of Rasmussen's encephalitis. An increase in activation magnitude and posterior shift in location were found in the RIFG after hemispherectomy for both phonemic and semantic tasks. Together, these results suggest that left temporal lobe injury is associated with potentially adaptive changes in right inferior frontal lobe functions in processing related to expressive language.
Understanding functional plasticity in memory networks associated with temporal lobe epilepsy (TLE) is central to predicting memory decline following surgery. However, the extent of functional reorganization within memory networks remains unclear. In this preliminary study, we used novel analysis methods assessing network-level changes across the brain during memory task performance in patients with TLE to test the hypothesis that hippocampal functions may not readily shift between hemispheres, but instead may show altered intra-hemispheric organization with unilateral damage. In addition, we wished to relate functional differences to structural changes along specific fibre pathways associated with memory function. Nine pre-operative patients with intractable left TLE and 10 healthy controls underwent functional MRI during complex scene encoding. Diffusion tensor imaging was additionally performed in the same patients. In our study, we found no evidence of inter-hemispheric shifts in memory-related activity in TLE using standard general linear model analysis. However, tensor independent component analysis revealed significant reductions in functional connectivity between bilateral MTL, occipital and left orbitofrontal regions among others in left TLE. This altered orbitofrontal activity was directly related to measures of fornix tract coherence in patients (P < 0.05). Our results suggest that specific fibre pathways, potentially affected by MTL neurodegeneration, may play a central role in functional plasticity in TLE and highlight the importance of network-based analysis approaches. Relative to standard model-based methods, novel objective functional connectivity analyses may offer improved sensitivity to subtle changes in the distribution of memory functions relevant for surgical planning in TLE.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.