Faculty Bibliography

BACKGROUND AND PURPOSE: To assess the sensitivity of non-localized, whole-head 1H-MRS to an individual's serial changes in total-brain NAA, Glx, Cr and Cho concentrations - metabolite metrics often used as surrogate markers in neurological pathologies. MATERIALS AND METHODS: In this prospective study, four back-to-back (single imaging session) and three serial (successive sessions) non-localizing, ~3min 1H-MRS (TE/TR/TI=5/104/940ms) scans were performed on 18 healthy young volunteers: 9 women, 9 men: 29.9+/-7.6 [mean+/-standard deviation (SD)] years old. These were analyzed by calculating a within-subject coefficient of variation (CV=SD/mean) to assess intra- and inter-scan repeatability and prediction intervals. This study was Health Insurance Portability and Accountability Act-compliant. All subjects gave Institutional Review Board-approved written, informed consent. RESULTS: The intra-scan CVs for the NAA, Glx, Cr and Cho were: 3.9+/-1.8%, 7.3+/-4.6%, 4.0+/-3.4% and 2.5+/-1.6%, and the corresponding inter-scan (longitudinal) values were: 7.0+/-3.1%, 10.6+/-5.6%, 7.6+/-3.5% and 7.0+/-3.9%. This method is shown to have 80% power to detect changes of 14%, 27%, 26% and 19% between two serial measurements in a given individual. CONCLUSIONS: Subject to the assumption that in neurological disorders NAA, Glx, Cr and Cho changes represent brain-only pathology and not muscles, bone marrow, adipose tissue or epithelial cells, this approach enables us to quantify them, thereby adding specificity to the assessment of the total disease load. This will facilitate monitoring diffuse pathologies with faster measurement, more extensive (~90%) spatial coverage and sensitivity than localized 1H-MRS.

A 32-year-old female with relapsing-remitting multiple sclerosis (MS) presented with severe new onset ataxia and diplopia. MRI showed a new inflammatory MS lesion that involved the right dorsal pons and extended into the adjacent superior cerebellar peduncle. The patient improved with aggressive immunotherapy; however, repeat MRI 3 months later revealed a new non-enhancing lesion in the left inferior medullary olive. The differential diagnosis for this new lesion included an MS lesion vs hypertrophic olivary degeneration, with infarct or neoplasm as the less likely considerations. We used track density imaging, which provides unprecedented anatomic details based on probabilistic tractography streamlines, to demonstrate apparent changes in the integrity of the dentato-rubro-olivary pathway (Guillain-Mollaret triangle) that were consistent with the diagnosis of hypertrophic olivary degeneration from the antecedent MS lesion involving the right superior cerebellar peduncle. Further medical therapy was avoided, and follow-up MRI 1 year later showed interval involution of the left olivary lesion. This case demonstrates the potential clinical utility of using track density imaging to detect lesion-induced alterations in brainstem connectivity and characterize neurodegeneration in patients.

H3K27 downregulates gene transcription. When H3K27 is trimethylated, it is tightly associated with inactive gene promoters. In malignant gliomas, the loss of histone H3K27 trimethylation is strongly associated with underlying K27M mutation; however the role of H3K27 in meningiomas has not been completely elucidated. Atypical and anaplastic meningiomas (WHO Grade II and III) are associated with higher risk of recurrence following gross total resection; however the molecular biology of anaplastic progression is not completely understood. We performed histological and molecular analysis of 14 WHO Grade II and III meningiomas and compared them with 6 locally invasive WHO Grade I meningiomas. Grade and atypical features were correlated with expression of histone H3K27 trimethylation by immunohistochemistry. Staining intensity (none, weak, moderate, strong) and extent of staining (0-100% of the tumor) were evaluated semi-quantitatively. We also tested the tumors for K27M mutation by mutation specific antibody. Out of 14 high grade meningiomas, 10 showed a complete loss of K27 trimethyl staining and 4 tumors showed small foci of preserved trimethyl staining, mostly in areas close to the dura; however staining intensity was weak. In contrary, all 6 (100%) WHO Grade I tumors showed preserved multifocal trimethyl mark expression in 25-50% of the tumor cells, with moderate (5) or strong (1) staining intensity. All tumors were negative for histone H3K27M mutation by immunohistochemistry. Atypical and anaplastic meningiomas show almost uniform loss of histone H3K27 trimethylation staining. However this loss of trimethylation is not caused by histone H3K27M mutation. Loss of histone H3K27 trimethylation leads to dysregulation of the PRC2 complex, which is involved in repression of non-cell-type specific promoters and may contribute to aggressive behavior. Clinically, loss of histone H3K27 trimethylation can be used as a diagnostic marker for a high grade meningiomaswhen histological features are inconclusive

Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

BACKGROUND: Previous reports have proposed an association between traumatic brain injury (TBI) and subsequent glioblastoma (GBM) formation. METHODS: We used literature searches and radiographic evidence from two patients to assess the possibility of a link between TBI and GBM. RESULTS: Epidemiological studies are equivocal on a possible link between brain trauma and increased risk of malignant glioma formation. We present two case reports of patients with GBM arising at the site of prior brain injury. CONCLUSION: The hypothesis that TBI may predispose to gliomagenesis is disputed by several large-scale epidemiological studies, but supported by some. Radiographic evidence from two cases presented here suggest that GBM formed at the site of brain injury. We propose a putative pathogenesis model that connects post-traumatic inflammation, stem and progenitor cell transformation, and gliomagenesis.

Tinnitus is an auditory perception of internal origin. Tinnitus is not a diagnosis but a symptom with many possible causes and correspondingly divergent pathophysiologic, anatomic, diagnostic, and therapeutic considerations. This article provides a summary of the imaging findings of structural causes of tinnitus.

Schwannomatosis is characterized by multiple non-intradermal schwannomas with patients often presenting with a painful mass in their extremities. In this syndrome malignant transformation of schwannomas is rare in spite of their large size at presentation. Non-invasive measures of assessing the biological behavior of plexiform neurofibromas in neurofibromatosis type 1 such as positron emission tomography (PET), CT scanning and MRI are well characterized but little information has been published on the use of PET imaging in schwannomatosis. We report a unique clinical presentation portraying the use of PET imaging in schwannomatosis. A 27-year-old woman presented with multiple, rapidly growing, large and painful schwannomas confirmed to be related to a constitutional mutation in the SMARCB1 complex. Whole body PET/MRI revealed numerous PET-avid tumors suggestive of malignant peripheral nerve sheath tumors. Surgery was performed on multiple tumors and none of them had histologic evidence of malignant transformation. Overall, PET imaging may not be a reliable predictor of malignant transformation in schwannomatosis, tempering enthusiasm for surgical interventions for tumors not producing significant clinical signs or symptoms.