CHI3L1, NTRK2, 1p/19q and IDH Status Predicts Prognosis in Glioma.

The aim of this study was to identify relevant biomarkers for the prognosis of glioma considering current molecular changes such as IDH mutation and 1p19q deletion. Gene expression profiling was performed using the TaqMan Low Density Array and hierarchical clustering using 96 selected genes in 64 patients with newly diagnosed glioma. The expression dataset was validated on a large independent cohort from The Cancer Genome Atlas (TCGA) database. A differential expression panel of 26 genes discriminated two prognostic groups regardless of grade and molecular groups of tumors: Patients having a poor prognosis with a median overall survival (OS) of 23.0 ± 9.6 months (group A) and patients having a good prognosis with a median OS of 115.0 ± 6.6 months (group B) (p = 0.007). Hierarchical clustering of the glioma TCGA cohort supported the prognostic value of these 26 genes (p < 0.0001). Among these genes, CHI3L1 and NTRK2 were identified as factors that can be associated with IDH status and 1p/19q co-deletion to distinguish between prognostic groups of glioma from the TCGA cohort. Therefore, CHI3L1 associated with NTRK2 seemed to be able to provide new information on glioma prognosis.

N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia.

The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule-associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19-7 neuroprogenitors lacking folate. Compared with controls, N-homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N-homocysteinylation dissociated tau and MAPs from ß-tubulin, and MS analysis showed that it targets lysine residues critical for their binding to ß-tubulin. N-homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days-old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy-thiolactone, the substrate of N-homocysteinylation. Experimental inactivation of MARS prevented the N-homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from ß-tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N-homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A nonradiated grade II glioma that underwent delayed malignant transformation to a gliosarcoma with meningeal growth and dissemination.

BACKGROUND: Secondary gliosarcomas are rare tumors, especially those arising from a World Health Organization (WHO) grade II glioma not irradiated. We report a case with subtotal resection for a WHO grade II oligoastrocytoma, without adjuvant treatment, whose metaplastic transformation into gliosarcoma suddenly occurred 4 years later with meningeal dissemination. We show a favorable outcome after therapeutic management of this rare entity. PATIENT: A 46 year-old woman underwent surgery for a right premotor WHO grade II oligoastrocytoma discovered incidentally. Because of a subtotal resection with only 1 cc of residue, no complementary therapy was given, and the patient enjoyed a normal life for 4 years. In the meantime, the magnetic resonance images performed every 6 months showed a very low growth rate. Suddenly, the tumor switched toward a gliosarcoma profile with meningeal dissemination. RESULTS: Reoperation, radiotherapy, and chemotherapy were performed, enabling a control of the disease with 15 months of follow-up (i.e., with radiologic shrinkage of the multiple lesions and preservation of quality of life). CONCLUSION: A delayed sarcomatous transformation can acutely occur with a low proliferation index in a nonirradiated WHO grade II oligoastrocytoma. Furthermore, an aggressive therapeutic strategy can allow control of secondary gliosarcomas, even in cases of leptomeningeal spreading.

Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy.

IMPORTANCE: Idiopathic narcolepsy with cataplexy is thought to be an autoimmune disorder targeting hypothalamic hypocretin neurons. Symptomatic narcolepsy with low hypocretin level has been described in Ma antibody­associated encephalitis; however, the mechanisms underlying such an association remain unknown. OBSERVATIONS: We described a 63-year-old man with clinical criteria for diencephalic encephalitis with sleepiness, cataplexy, hypocretin deficiency, and central hypothyroidism, together with brainstem encephalitis reflected by supranuclear ophtalmoparesis and rapid eye movement sleep behavior disorder with underlying abnormalities on brain magnetic resonance imaging. An autoimmune process was demonstrated by the detection of antibodies against Ma protein. Death occurred 4 months after disease onset without any tumor detected. Neuropathology, immunohistochemistry, and immunoreactivity results were compared with those obtained in idiopathic narcolepsy-cataplexy and with normal control brains. The principal findings revealed almost exclusive inflammation and tissue injury in the hypothalamus. The type of inflammatory reaction suggests cytotoxic CD8+ T lymphocytes being responsible for the induction of tissue injury. Inflammation was associated with complete loss of hypocretinergic neurons. Autoantibodies of the patient predominantly stained neurons in the hypothalamus and could be absorbed with Ma2. CONCLUSIONS AND RELEVANCE: The encephalitic process, responsible for narcolepsy-cataplexy and hypocretin deficiency, reflects a CD8+ inflammatory-mediated response against hypocretin neurons.

The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse.

Dominant optic atrophy is a rare inherited optic nerve degeneration caused by mutations in the mitochondrial fusion gene OPA1. Recently, the clinical spectrum of dominant optic atrophy has been extended to frequent syndromic forms, exhibiting various degrees of neurological and muscle impairments frequently found in mitochondrial diseases. Although characterized by a specific loss of retinal ganglion cells, the pathophysiology of dominant optic atrophy is still poorly understood. We generated an Opa1 mouse model carrying the recurrent Opa1(delTTAG) mutation, which is found in 30% of all patients with dominant optic atrophy. We show that this mouse displays a multi-systemic poly-degenerative phenotype, with a presentation associating signs of visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia and cardiomyopathy. Moreover, we found premature age-related axonal and myelin degenerations, increased autophagy and mitophagy and mitochondrial supercomplex instability preceding degeneration and cell death. Thus, these results support the concept that Opa1 protects against neuronal degeneration and opens new perspectives for the exploration and the treatment of mitochondrial diseases.

Occipital WHO grade II gliomas: oncological, surgical and functional considerations.

BACKGROUND: Diffuse WHO grade II glioma (GIIG) involving the occipital lobe is a rare entity. Its surgical resection remains controversial as it implies inducing a permanent visual deficit. For the first time to our knowledge, we report a consecutive surgical series of patients who underwent an occipital lobectomy for an LGG invading visual structures. METHOD: Six right-handed patients harboring a GIIG revealed by seizures (normal examination except a quadrantanopsia in one case) and located within the occipital lobe (4 left and 2 right tumors) were submitted to surgery. Before making this decision, the benefit-to-risk ratio of the resection was extensively discussed with the patient and his/her family, especially concerning the price to pay to remove the tumor, that is, to voluntarily generate a permanent hemianopsia. All the procedures were performed under awake condition using intraoperative electrostimulation, in order to pursue the resection until sensory-motor and/or language structures were encountered. FINDINGS: An extensive occipital lobectomy was achieved in the six patients, with identification and preservation of sensory-motor pathways in the two cases with a right tumor and detection of language pathways in the four cases with a left tumor. The mean extent of resection was 93% (range: 91-100%). All patients experienced an expected postoperative deficit of the visual field (homonymous hemianopsia). Nonetheless, the six patients resumed a normal social and professional life (KPS at 90 in the 6 cases) with a mean follow-up of 58 months (range: 3-147 months)--with adjuvant treatment in three cases (in addition to a reoperation in two of them). CONCLUSIONS: Our findings suggest that, despite a definitive hemianopsia, an extensive surgical resection can be considered in the rare cases of occipital GIIG involving the primary visual structures, with patients able to maintain a normal life--except regarding the medico-legal problem of driving.

Discrepancies between preoperative stereoencephalography language stimulation mapping and intraoperative awake mapping during resection of focal cortical dysplasia in eloquent areas.

BACKGROUND/AIMS: To compare the reliability of preoperative stereoencephalography (SEEG) and intraoperative electrostimulation regarding functional mapping, and to select the indication for surgery for focal cortical dysplasia (FCD) in language areas. METHODS: The authors present the case of a 21-year-old, right-handed female, suffering from chronic pharmacologically resistant epilepsy since the age of 8. MRI showed a subcortical hypersignal on FLAIR and T(2) sequences at the posterior end of the left superior temporal sulcus compatible with an FCD. SEEG invasive monitoring was performed to precisely identify the epileptogenic zone (EZ) and for functional language mapping. RESULTS: The stimulation of the contacts implicated in the EZ through SEEG leads induced language disturbances, which were not reproducible. Surgery was performed under local anesthesia with awake corticosubcortical mapping. Direct intraoperative stimulation in the EZ, including FCD, did not induce language disturbances. Thus, EZ could be removed completely without any postoperative language deficit. CONCLUSIONS: The present case suggests that when language disturbances which occur during invasive SEEG functional mapping, in eloquent areas, are not reproducible, resection can be considered using intraoperative electrical mapping, without inducing permanent language impairment. This may be explained by a certain degree of plasticity and reshaping of functional areas associated with a congenital lesion and chronic epilepsy.