Cerebrospinal fluid proteomic analysis reveals dysregulation of methionine aminopeptidase-2 expression in human and mouse neurofibromatosis 1-associated glioma.

Individuals affected with the neurofibromatosis 1 (NF1) tumor predisposition syndrome are prone to the development of multiple nervous system tumors, including optic pathway gliomas (OPG). The NF1 tumor suppressor gene product, neurofibromin, functions as a Ras GTPase-activating protein, and has been proposed to regulate cell growth by inhibiting Ras activity. Recent studies from our laboratory have shown that neurofibromin also regulates the mammalian target of rapamycin activity in a Ras-dependent fashion, and that the rapamycin-mediated mammalian target of rapamycin inhibition ameliorates the Nf1-/- astrocyte growth advantage. Moreover, Nf1-deficient astrocytes exhibit increased protein translation. As part of a larger effort to identify protein markers for NF1-associated astrocytomas that could be exploited for therapeutic drug design, we did an objective proteomic analysis of the cerebrospinal fluid from genetically engineered Nf1 mice with optic glioma. One of the proteins found to be increased in the cerebrospinal fluid of OPG-bearing mice was the eukaryotic initiation factor-2alpha binding protein, methionine aminopeptidase 2 (MetAP2). In this study, we show that Nf1 mouse OPGs and NF1-associated human astrocytic tumors, but not sporadic pilocytic or other low-grade astrocytomas, specifically expressed high levels of MetAP2. In addition, we show that Nf1-deficient astrocytes overexpress MetAP2 in vitro and in vivo, and that treatment with the MetAP2 inhibitor fumagillin significantly reduces Nf1-/- astrocyte proliferation in vitro. These observations suggest that MetAP2 is regulated by neurofibromin, and that MetAP2 inhibitors could be potentially employed to treat NF1-associated tumor proliferation.

MRI in neurofibromatosis type I: using fluid-attenuated inversion recovery pulse sequences.

Cranial magnetic resonance imaging results of 14 patients with neurofibromatosis type I were examined with T2-weighted fluid-attenuated inversion recovery pulse sequences, as well as conventional T2-weighted spin-echo sequences. Definition was better in 62 of 79 lesions or groups of lesions on fluid-attenuated inversion recovery images than on T2-weighted spin-echo images. The lesions were demonstrated not only in the brainstem, cerebellum, globus pallidus, and cerebral white matter, but also in the hippocampus, pulvinar thalami, and splenium of the corpus callosum. The latter 3 lesions have not been demonstrated or emphasized in previous studies. It is concluded that fluid-attenuated inversion recovery imaging is more effective in detecting multiple lesions in patients with neurofibromatosis type I than conventional T2-weighted spin-echo imaging.

Long-term outcome after removal of spinal neurofibroma.

Spinal neurofibromas are uncommon, comprising approximately 3% of all spinal tumors. They occur both sporadically and in association with neurofibromatosis 1 (NF1; von Recklinghausen's disease). This study presents the clinical characteristics of 32 patients who underwent surgery for symptomatic spinal neurofibromas. Twenty-two of these patients showed clinical signs of NF1. The patients were typically younger (median age 31 years) than those with spinal schwannomas. The tumors were located mainly in the cervical region and tended to grow both extra- and intradurally. Patients with NF1 were prone to develop new spinal neurofibromas. A life-table analysis showed a reduced survival rate for these patients compared to that of the general population.

Citramalic acid in cerebrospinal fluid of patients with bacterial meningitis.

Cerebrospinal fluid (CSF) from uninfected patients and from patients with bacterial and viral meningitis was analyzed by gas-liquid chromatography, with use of a flame ionization detector, and by gas chromatography-mass spectrometry. The resulting profiles were consistent and reproducible. Hydroxy acids were the compounds found in greatest abundance in both normal and infected CSF. Control experiments to establish the sensitivity and efficiency of the extraction and derivatization methods are also presented. Constituents of CSF from patients with bacterial meningitis differed quantitatively and qualitatively from those of CSF from uninfected patients or patients with nonbacterial infections. CSF from seven of eight patients with bacterial meningitis contained citramalic acid, a compound not previously identified in either normal or infected CSF. The implications of these findings are discussed.