Shinjiro Fukami

Region-specific reduction of A beta-degrading endopeptidase, neprilysin, in mouse hippocampus upon aging

Metabolism of amyloid‐β peptide (Aβ) is closely associated with the pathology and etiology of Alzheimers disease (AD). Neprilysin is the only rate‐limiting catabolic peptidase proven by means of reverse genetics to participate in Aβ metabolism in vivo. The aim of the present study is to assess whether possible spatial changes in neprilysin level in the brain with aging correlate to AD‐vulnerable regions. When neprilysin levels in various brain regions of 10‐, 80‐ and 132‐week‐old mice were evaluated by neprilysin‐dependent endopeptidase activity assay and Western blot‐based quantitative analysis, a clear change in neprilysin level with aging was observed in the hippocampal formation, in which the level was reduced by 20% at 132 weeks, compared to the 10‐week group. Quantitative immunohistochemical analysis confirmed a marked local reduction of neprilysin levels with aging at the outer molecular layer and polymorphic layer of the dentate gyrus, and the stratum lucidum of the hippocampus, where the densities were reduced by 56%, 82% and 83%, respectively, at 132 weeks compared to the 10‐week group. Thus, neprilysin was decreased selectively at the terminal zones and on axons of the lateral perforant path and the mossy fibers. These are the sites that show Aβ pathology in mutant amyloid precursor protein (APP) transgenic mice, and that show synaptic loss in AD. The immunoreactivities to synaptic vesicle protein‐2 and synaptophysin in the stratum lucidum and the dentate gyrus were unchanged, suggesting that a loss or decrease of synapses was not responsible for the decrease in the neprilysin levels. These observations suggest that downregulation of neprilysin is likely to be related to AD pathology and to the Aβ deposition associated with normal aging in humans.

Aβ-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Aβ pathology

Metabolism of amyloid-β peptide (Aβ) is closely associated with the pathology and etiology of Alzheimers disease (AD). Since neprilysin is the only rate-limiting catabolic peptidase proven by reverse genetics to participate in Aβ metabolism in vivo, we performed detailed immunohistochemical analysis of neprilysin in mouse brain using neprilysin-deficient mice as a negative control. The aim was to assess, at both the cellular and subcellular levels, where Aβ undergoes neprilysin-dependent degradation in the brain and how neprilysin localization relates to Aβ pathology in amyloid precursor protein (APP)-transgenic mice. In hippocampus, neprilysin was present in the stratum pyramidale and stratum lacunosum-moleculare of the CA1-3 fields and the molecular layer of the dentate gyrus. Confocal double immunofluorescence analyses revealed the subcellular localization of neprilysin along axons and at synapses. This observation suggests that after synthesis in the soma, neprilysin, a type II membrane-associated protein, is axonally transported to the terminals, where Aβ degradation is likely to take place. Among various cell types, GABAergic and metabotropic glutamate 2/3 receptor-positive neurons but not catecholaminergic or cholinergic neurons, expressed neprilysin in hippocampus and neocortex, implying the presence of a cell type-specific mechanism that regulates neprilysin gene expression. As expected, Aβ deposition correlated inversely with neprilysin expression in TgCRND8 APP-transgenic mice. These observations not only support the notion that neprilysin functions as a major Aβ-degrading enzyme in the brain but also suggest that down-regulation of neprilysin activity, which may be caused by aging, is likely to elevate local concentrations of Aβ at and around neuronal synapses.

IN VIVO GLIOMA GROWTH REQUIRES HOST-DERIVED MATRIX METALLOPROTEINASE 2 FOR MAINTENANCE OF ANGIOARCHITECTURE

Glioma, the most common form of brain tumor, has been shown mostly by in vitro studies to utilize matrix metalloproteinase (MMP) for invasive growth through degradation of the extracellular matrix. In order to examine the in vivo role of MMP, we established a rodent model of glioma progression using C6 rat glioma cells and analyzed the effect of tissue inhibitors of metalloproteinases (TIMPs). TIMP-2 rather than TIMP-1 caused significant reduction of the tumor size accompanied by the presence of degenerated blood vessels and ischemic necrosis. Because TIMP-2 inhibits MMP-2 preferentially, we then examined glioma growth in MMP-2-deficient mice and observed essentially identical consequences. While MMP-2 activity was present in the tumor and adjacent tissues of the wild-type mice, no MMP-2 activity was detected even in the tumor of the null mice, although C6 cells are known to express MMP-2. These observations suggest that glioma induces MMP-2 and utilizes its activity in the host tissue to support angiogenesis and to maintain angioarchitecture.

Neuromuscular hamartoma is a possible primary pathology of oculomotor ophthalmoplegic migraine.

Background: Oculomotor ophthalmoplegic migraine (O-OPM) occurs in many children, and in some cases MRI shows a small mass in the root exit zone (REZ) of the oculomotor nerve. This mass is considered to result from nerve hypertrophy caused by repeated demyelination. Case results: A 51-year-old man has been on oral medication for O-OPM, which he had from 6 years of age. However, the frequency and intensity of his migraine attacks have gradually increased. Brain magnetic resonance imaging (MRI) revealed a small nodular mass in the REZ of the oculomotor nerve. The mass was initially diagnosed as oculomotor schwannoma and tumor resection was attempted. However, as the mass was tightly adhered to the oculomotor nerve and hemorrhagic, biopsy was performed. The pathological diagnosis was neuromuscular hamartoma. Conclusion: The small nodular mass in the REZ of the oculomotor nerve may be a hamartoma associated with congenital factors and may possibly be the primary pathology of O-OPM in this case.

Radiopathological characteristics of cerebellar malignant glioma in adults

Our aim was to extract the radiopathological features of cerebellar malignant glioma in adults from the four cases we encountered. All four cases (two men and two women, aged 52–80 years; mean age, 67 years) had a floating sensation or vertigo at the onset of their disease. Initially, these patients were given a diagnosis of cerebellar infarction or cavernous angioma, or had faint abnormalities in the cerebellum that were overlooked. These patients were followed up for 2–14 months (mean, 6 months), and the tumor was detected when their clinical symptoms deteriorated. The tumor was located in the hemisphere in one patient and in the vermis in three patients. MRI revealed ring-like enhancement in two patients and nodular enhancement in two patients. All patients underwent subtotal tumor resection, followed by postoperative radiochemotherapy. However, three patients died at 16 to 44 months (mean, 28 months), and cerebrospinal fluid (CSF) dissemination was observed in three patients. Two cases were classified as WHO grade III and two as WHO grade IV. The pathological features were typical of malignant glioma, partially presenting the features of low-grade glioma, such as pilocytic, astrocytic, or oligodendroglial components. Nuclear pleomorphism and vascular endothelial proliferation were prominent, and micronecrosis was relatively less evident. The MIB-1 index was 12%–40%, and most of the patients were p53 protein positive. At the onset of cerebellar malignant glioma, diagnostic imaging shows few signs of brain tumor. Thereafter, tumors grow in a short period of time, following a rapid clinical course. Because cerebellar malignant glioma is a rare disease, it is difficult to differentiate it from metastatic brain tumors and primary central nervous system lymphoma by preoperative imaging. Some patho logical features suggesting malignant transformation from low-grade glioma were detected.

A case of radiologically multicentric but genetically identical multiple glioblastomas

Surgery was performed in a 65-year-old male patient with malignant gliomas at two locations in the left and right cerebral hemispheres that showed no apparent continuity in imaging studies. Slight differences in histopathological appearance were seen between the tumors, and multicentric malignant glioma was diagnosed. Detailed genetic examination showed both the left- and right-side tumors to be of the IDH-1 wild type with a p53 mutation at the same locus. Whole genome analysis by comparative genomic hybridization revealed many of the same mutations to be present in both tumors. The O6-methylguanine-methyltransferase promoter in both cases was unmethylated, and the genetic profiles of both showed them to be homologous tumors. They were therefore inferred to be multiple gliomas from the same clone. There have been occasional reports of multicentric gliomas classified by diagnostic imaging. This report discusses the need to examine tumor origin by genomic profiling.

Primary medulla oblongata germinoma – an unusual posterior fossa tumors in young adults

We encountered 2 patients with germinoma arising from the medulla oblongata in whom preoperative radiological diagnosis was difficult. A 30-year-old woman presented due to aspiration pneumonia caused by bilateral lower cranial nerve palsies, and a 24-year-old man presented with headache caused by obstructive hydrocephalus. In both patients, there was a midline tumor that extended from the lower part of the fourth ventricle to the C1 lamina level. It was well-demarcated and homogeneously enhanced tumor with a slightly high density on plain CT scan. The preoperative diagnosis for both patients was ependymoma. The former patient had persistent lower cranial nerve palsies due to brain stem injury after tumor resection. Both patients achieved complete remission with adjuvant therapy. Fewer than 10 cases of germinoma affecting the medulla oblongata have been reported. Radiological findings resembling those of the pineal region germinoma were observed in the two patients reported here. We would like to stress the importance of remembering germinoma when making a preoperative differential diagnosis of fourth ventricular tumors in young adults.

Pathologic Findings and Clinical Course of Midline Paraventricular Gliomas Diagnosed Using a Neuroendoscope

INTRODUCTION Removal of midline paraventricular gliomas is difficult because of their deep localization and invasive character, requiring biopsy for pathologic diagnosis. This study aimed to assess the pathologic findings and clinical course of midline paraventricular gliomas diagnosed using a neuroendoscope. METHODS This study was performed as a retrospective investigation using a neuroendoscope of 26 patients whose tumors were diagnosed as midline paraventricular gliomas. The main loci of the lesions were the thalamus (11 patients), tectum (6 patients), and other areas (9 patients). Of these 26 patients, 21 (81%) had accompanying obstructive hydrocephalus. Surgery was performed via the lateral ventricle using a flexible scope. For patients with obstructive hydrocephalus, we added endoscopic third ventriculostomy, septostomy, and/or plasty of the foramen of Monro. Pathologic diagnosis was determined according to hematoxylin-eosin staining and immunohistochemistry using anti-GFAP, anti-Ki-67, anti-H3-K27M, and anti-IDH1-R132H antibodies. RESULTS The pathologic diagnoses were grade I (5 patients), grade II (3 patients), grade III (6 patients), and grade IV (4 patients) gliomas. Six patients were diagnosed as having high-grade glioma, which was difficult to distinguish between grade III and grade IV. Two patients were undiagnosable. H3-K27M was strongly positive in 8 of 15 patients with high-grade glioma. All patients with high-grade gliomas died or received best supportive care within 2 years after surgery. CONCLUSIONS Neuroendoscopic surgery is useful for midline paraventricular gliomas in terms of the treatment of obstructive hydrocephalus, as well as pathologic diagnosis and genetic analysis, which are required under the World Health Organization 2016 classification.

A case of unruptured aneurysm of the internal carotid artery presenting as olfactory hallucinations

Background: Olfactory hallucination, a symptom of medial temporal lobe epilepsy, is rarely associated with unruptured intracranial aneurysms. Case Description: We encountered this situation in a 70-year-old woman with an unruptured aneurysm at the bifurcation of the internal carotid and posterior communicating artery. We were able to achieve epileptic control by craniotomy clipping and medial temporal lesionectomy. Conclusion: According to our knowledge, previous reports are limited to cases of large middle cerebral artery aneurysms compressing the lateral orbitofrontal cortex, and this is apparently the first report of a case where olfactory hallucinations occurred from direct stimulation of the entorhinal cortex by an internal carotid and posterior communicating artery bifurcation aneurysm. We examined the pathophysiology underlying the development of olfactory hallucinations. We found craniotomy clipping and focal resection to be useful from the standpoint of seizure control. Whether seizure control can also be obtained with intracranial aneurysm coiling should be investigated in the future.

Rapid De Novo Aneurysm Formation after Rathke Cleft Cyst Rupture.

BACKGROUND Spontaneous rupture of a Rathke cleft cyst is very rare, and rapid de novo aneurysm formation associated with pituitary apoplexy is rare. CASE DESCRIPTION A 66-year-old woman experienced severe left temporal pain. Magnetic resonance imaging showed a Rathke cleft cyst, and transsphenoidal surgery was planned. However, the patient suddenly developed severe headache, vomiting, visual disturbance, and a lowered level of consciousness about 3 weeks after the first onset. The clinical course and neuroradiologic characteristics suggested Rathke cleft cyst rupture. The patient received hormone replacement, and the visual abnormalities resolved. However, subsequent neuroradiologic evaluation demonstrated that a de novo aneurysm in the cavernous sinus portion of the internal carotid artery had formed within 8 days after rupture of the Rathke cleft cyst. This de novo aneurysm was not apparent on initial magnetic resonance angiography. CONCLUSIONS This case features a rare clinical presentation of rapid de novo aneurysm formation after Rathke cleft cyst rupture. The severe inflammation around the vasculature after rupture of the Rathke cleft cyst might have been involved in aneurysm formation.