Toshiro Inubushi

Phosphorus-31 magnetic resonance spectroscopy and ventricular enlargement in bipolar disorder

Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) was used to examine whether reduced levels of phosphomonoesters (PME) were correlated with ventricular enlargement in 40 patients with bipolar disorder and 60 age-matched normal control subjects. Ventricular enlargement was assessed by magnetic resonance imaging (1H-MRI) using the following three methods: Evans ratio (ER), Huckman number (HN), and minimum distance of caudate nuclei (MDCN). Although MDCN and ER were significantly larger in the patient group, no significant correlations were found between 31P-MRS and 1H-MRI. PME was negatively correlated with age in bipolar disorder. Decreased levels of PME were found only in bipolar I disorder. Intracellular pH was positively correlated with duration of lithium treatment. These results suggest that the observed PME reduction was not related to ventricular enlargement, but the issue should be further studied with volumetric MRI analysis.

Correlations of phosphomonoesters measured by phosphorus-31 magnetic resonance spectroscopy in the frontal lobes and negative symptoms in schizophrenia

Frontal lobe dysfunction has been linked to negative symptoms of schizophrenia. We used phosphorus-31 magnetic resonance spectroscopy (31P-MRS) to examine phosphorous metabolism in frontal brain regions in 26 schizophrenic patients compared with 26 sex- and age-matched control subjects. The relative signal intensities of phosphorous metabolites in frontal regions did not differ significantly between schizophrenic patients and control subjects. However, phosphomonoester levels were significantly decreased in frontal regions of 12 schizophrenic patients who had high scores on negative symptom subscales from the Brief Psychiatric Rating Scale (i.e., emotional withdrawal, motor retardation, and blunted affect) compared with 14 patients with low negative symptom scores on the same subscales and control subjects. The correlations between negative symptoms and phosphorous metabolism in the frontal lobes support the hypofrontality hypothesis in schizophrenia.

Lateralized abnormality of high-energy phosphate and bilateral reduction of phosphomonoester measured by phosphorus-31 magnetic resonance spectroscopy of the frontal lobes in schizophrenia

Magnetic resonance spectroscopy (one-dimensional chemical shift imaging) was used to measure membrane phospholipid metabolism and high-energy phosphate metabolism in the left and right frontal lobes of 27 schizophrenic patients. In the schizophrenic patients, the phosphomonoester peak area was decreased in bilateral frontal lobes compared with that in age-matched normal subjects. On the other hand, the peak area of beta-adenosine triphosphate was increased in the left frontal lobe in the schizophrenic group. The phosphocreatine peak area was increased in the left frontal lobe of schizophrenic patients with high scores on the Scale for the Assessment of Negative Symptoms (SANS).

Prevalence of cavum septum pellucidum detected by MRI in patients with bipolar disorder, major depression and schizophrenia

The incidence of cavum septum pellucidum (CSP), which has been widely regarded as a developmental anomaly of little clinical importance in neuropathology, was examined in 113 patients with affective disorders (69 with bipolar disorder and 44 with major depression), 40 schizophrenic patients, and 92 control subjects by magnetic resonance imaging (MRI). Significantly higher incidence of Grade 3-4 CSP (moderate to large) compared with the controls was found only in the schizophrenics. When a broader interpretation of CSP, including indeterminant (Grade 1) and small (Grade 2) CSP was used, three additional patients with bipolar disorder were found to have Grade 1-2 CSP, and the total prevalence of Grade 1-4 CSP in the patients with bipolar disorder was significantly higher than that in the control subjects but slightly lower than that in the schizophrenic patients. CSP was not observed in any patient with major depression. There were no differences between the patients with and without CSP in age, sex, education, or the duration of illness. These findings are consistent with the hypothesis that neurodevelopmental abnormality may be present in schizophrenia, and such an abnormality may also be present in some patients with bipolar disorder.

Capsule type medical robot with magnetic drive in abdominal cavity

This paper describes the development of a medical robot that remains in the abdominal cavity in order to monitor sites of medical interest, and discusses robot travel operations and specifications. A long and narrow piece of ferromagnetic material was placed inside the robot, after which an external magnetic field was used to set the robot in motion. We developed a prototype robot, and conducted experiments in order to verify our proposed concept and the drive principles of the robot. In vivo experiments in a rabbit model showed that solenoids produced sufficient magnetic force to enable the robot to travel through the abdominal cavity, verifying the motion principles. The appropriate shape of the robot was confirmed in the experiments, and the friction between the robot and the organs and the abdominal wall was measured. Using a modified prototype of the robot, we conducted clinical experiments in the rabbit model in which a surgeon operated the XYZ axis stages in order to adjust the position of the subject for the experiment and moved the robot to the liver. Robot travel from the insertion point to the liver was verified on X-rays. The long travel distance of the robot was enabled by its improved shape and through the use of accurate magnetic field imaging.

Relationship of Lithium Concentrations: in the Brain Measured by Lithium-7

Lithium concentrations in the brain were measured in 14 manic patients with bipolar disorder (12 with bipolar disorder, manic, and 2 with bipolar disorder, not otherwise specified, by DSM-III-R) by the use of lithium-7 magnetic resonance spectroscopy ([7Li]MRS). The reduction of Petterson Mania Rating Scale 4 weeks after the initiation of lithium treatment was not significantly correlated with concentrations in serum (r = 0.33), but was correlated with concentrations in the brain (r = 0.64; p < 0.05). These results suggest that the treatment response to lithium in manic patients with bipolar disorder is more closely related to the lithium concentration in the brain as measured by [7Li]MRS than to the concentration in serum.

Acute focal cerebral ischemia in rats studied by diffusion-weighted magnetic resonance imaging—An experimental study

BACKGROUNDnTemporary occlusion of the cerebral artery is occasionally repeated during neurosurgical operations, but the safety of such a procedure remains to be studied further.nnnMETHODnWe studied early changes and reversibility of focal cerebral ischemia and the cumulative effects of repeated ischemic insults in rats using magnetic resonance imaging (MRI).nnnRESULTSnDiffusion-weighted magnetic resonance images (DWI) and determination of signal intensity ratio (SIR) proved to be a valuable measure of studying early changes and reversibility of transient focal cerebral ischemia and cumulative adverse effects of repeated ischemic insults. DWIs showed marked intensity changes shortly after focal cerebral ischemia, while T2-weighted images failed to show hyperintensities until 2.5 hours after the onset of permanent ischemia. The critical period of ischemia in this model was 60 minutes. However, 20 minutes ischemia, when repeated twice with 60 minutes reperfusion in between, showed irreversible damage.nnnCONCLUSIONnRepeated insults of focal regional cerebral ischemia may cause irreversible tissue damage even if each ischemic period is less than the critical one.

Development of a novel 19F MRI probe for detecting amyloid deposition in Alzheimer's disease

s / Neuroscience Research 71S (2011) e46–e107 e85 in the development of PET imaging radiotracers such as [18F]FDDNP, [11C]Pittsburgh Compound-B (PiB), and [11C]BF-227, resulted in successful detection of amyloid deposition in the living human brains. Recently we developed a novel ligand, [18F]THK-523, for in vivo imaging of tau proteins. In this study, we characterized the binding properties of THK-523 and other imaging probes to synthetic protein fibrils and human brain tissue in vitro. Methods: In vitro radioligand binding assays were conducted using synthetic A 40 and K18 K280 tau fibrils. Non-specific binding was determined by the mixture of 2 M unlabeled compounds. In vitro autoradiography was conducted using AD hippocampal brain sections to examine the radioligand binding to neuropathological lesions at tracer concentrations (low nM range). Results: In vitro binding assay indicated that [18F]THK-523 bound to tau fibrils with higher affinity than A 40 fibrils, while [18F]BF-227 bound to tau fibrils with lower affinity than that to A 40 fibrils. Autoradiographic analysis indicated that [18F]THK-523 accumulated in CA1 region of AD hippocampus, which contains high density of tau deposits. On the other hand, [18F]FDDNP showed low binding affinity to both A 40 and tau fibrils and did not accumulate in any regions of AD hippocampus. Conclusion: This study demonstrated the unique binding property of [18F]THK-523 to AD pathology in the brain, indicating that [18F]THK-523 is a candidate probe for in vivo tau imaging. doi:10.1016/j.neures.2011.07.361 O3-J-3-2 Identification of S-nitrosylated proteins induced by MPTP Kentaro Ozawa , Gozoh Tsujimoto WDDC, Grad. Sch. of Pharm., Kyoto Univ., Kyoto, Japan Recently it has been shown S-nitrosylation is involved in the regulation of numerous signalling pathways in a wide range of pathophysiological condition including neurodegenertion diseases. To evaluate the importance of S-nitrosylation in pathogenesis of neurodegeneration diseases, we have developed proteomic methods after purifing S-nitrosyalted proteins. We treated the human neuroblastoma cell line SH-SY5Y with or without 1methyl-4-phenylpyridinium (MPP+), which causes Parkinson’s disease-like symptoms, and purified S-nitorosylated proteins by modified Biotin-Switch method. Then we isolated proteins by 2D gel electrophoresis and identified several proteins whose S-nitrosylation is increased by MPTP by mass spectrometry. This research might be a clue to understanding pathogenesis mechanism of sporadic neurodegeneration, and therefore, might have significant therapeutic benefit. Research fund: KAKENHI (20117008). doi:10.1016/j.neures.2011.07.362 O3-J-3-3 Amyloidogenic processing of APP is enhanced in Alcadein -deficient mice Tohru Yamamoto 1 , Naoya Gotoh 1, Yuhki Saito 1, Saori Hata 1, Fumio Matsuzaki 2, Toshiharu Suzuki 1 1 Lab. of Neurosci., Faculty of Pharm. Sci., Hokkaido Univ., Sapporo, Japan 2 Center for Developmental Biology, RIKEN, Kobe, Japan Alcadein (Alc ) is an evolutionary conserved transmembrane protein preferentially expressed in nerve tissues, and functions as a cargo of Kinesin-1. We have shown that Amyloid-beta precursor protein (APP) forms a complex with Alc through X11-like (X11L) membrane scaffold proteins, and endogeneous amyloidogenic metabolism of APP is enhanced in the brains of X11 family-deficient mice. Accumulating evidences including our observations indicate that X11 family proteins suppress amyloidogenic metabolism of APP in vivo. However, it is still elusive if Alc , the other component of the complex, affect the metabolism of APP. To assess whether Alc is coexpressed with APP and X11L, we verified the expression of these proteins in mouse brains at cellular resolution. We confirmed that APP, X11L, and Alc proteins co-existed in neurons of mouse brain including hippocampus, piriform cortex, and cerebral cortex. To further investigate the function of Alc in the context of APP metabolism in vivo, we generated Alc -deficient mice. The mice carrying Alc -null allele were successfully generated and we backcrossed them to C57BL6 mice for more than 10 generations to obtain a functionally congenic strain to avoid possible complications derived from different genetic background. The resultant congenic Alc -deficient mice reached adulthood without displaying obvious abnormalities, and were fertile. We analyzed the metabolism of endogeneous APP using the resultant strain, and found that amyloidogenic metabolites such as A and CTF were significantly increased in the Alc -deficient mice brains. Furthermore, transgenic mice expressing human APP751swe, exhibited more amyloid plaques in Alc -deficient background. These results indicate that Alc suppresses amyloidogenic processing of APP in vivo as well as X11 family proteins. Our observations strongly suggest that Alc is involved in APP metabolism, which could be a novel target molecule for elucidating AD pathogenesis. doi:10.1016/j.neures.2011.07.363 O3-J-3-4 Development of a novel 19F MRI probe for detecting amyloid deposition in Alzheimer’s disease Daijiro Yanagisawa 1,4 , Shigehiro Morikawa 2, Hiroyasu Taguchi 1, Akihiko Shiino 3, Toshiro Inubushi 3, Ikuo Tooyama 1 1 Mol. Neurosci. Res. Ctr., Shiga Univ. Med. Sci., Otsu, Japan 2 Department Fundamental Nursing, Shiga Univ. Med. Sci., Otsu, Japan 3 Biomed. MR Sci. Res. Ctr., Shiga Univ. Med. Sci., Otsu, Japan 4 JSPS, Tokyo, Japan According to amyloid cascade hypothesis, determining the level of amyloid (A ) deposition in the brain would be informative for evaluating Alzheimer’s disease (AD) progression and monitoring their response to anti-amyloid therapy. We have developed a novel 19F-containing curcumin derivative (named FMeC1) as a potential 19F magnetic resonance (MR) imaging (MRI) probe for amyloid imaging. This study investigated whether FMeC1 is suitable to detect A deposition in the Tg2576 mouse, a model of AD. We used a 7.0 T horizontal-bore MR scanner and a home-built circular-type surface coil measuring 1.6 cm in diameter to collect the data. For 19F MRI, free induction decay (FID) data of 19F chemical shift imaging were collected with a 40,000 Hz SW, 24 mm × 24 mm FOV, 1-s TR, 200 s phase encoding time, and 68 acquisitions for each central 44 phase encoding step out of 8 × 8 steps. When Tg2576 mice at 20–22 months of age were peripherally injected with FMeC1, dosedependent increasing in the level of 19F signal was observed in 19F MR spectra obtained from the whole head. 19F MR image showed remarkable levels of 19F signal in the brain of Tg2576 mice after the injection of FMeC1 at a dose of 200 mg/kg. In contrast, there are no significant 19F signals in the brain of FMeC1-injected wild-type mice. Histological analysis of FMeC1-injected Tg2576 mouse brain showed strong fluorescence signal for FMeC1 in the cortex and hippocampus, and most of this signal was colocalized with the A immunoreactivity. Moreover, FMeC1 exhibited an affinity for senile plaques in human brain sections. These results suggest the potential benefit of 19F MRI with FMeC1 as a novel method for detecting A deposition in the brain. Research fund: This study was supported in part by the JST Practical Application Research Program and by JSPS KAKENHI (22300153). doi:10.1016/j.neures.2011.07.364 O3-J-4-1 Vaccination with a non-human sequence amyloid oligomer mimic results in improved cognitive function and reduced plaque deposition in Tg2576 mice Suhail Rasool , Hilda Martinez Coria, Leonoid Breydo, Jessica Wu, Saskia Milton, Andy Tran, Ricardo Albay, Charles Glabe Department of Molecular Biology and Biochemistry University of California, Irvine, USA Accumulation of beta-amyloid (A ) is an important molecular event in Alzheimers disease (AD). It is now well known that vaccination of humans and transgenic animals against fibrillar A prevents amyloid accumulation in plaques and preserves cognitive function in transgenic mouse models. However, autoimmune side effects have halted the development of vaccines based on A . We have reported that the immune response to amyloid oligomers is largely directed against epitopes that are common to many different amyloid oligomers and independent of amino acid sequence. Here we have examined whether we can exploit this generic immune response to develop a vaccine that targets amyloid oligomers using a non-human amyloid oligomer sequence. To study the effect of vaccination against generic oligomer epitopes, a random sequence oligomer (3A) was selected that form oligomers that react with the oligomer specific A11 antibody. Oligomer mimics formed from this 3A peptide, A oligomers, islet amyloid polypeptide (IAPP) oligomers, & A fibrils were used to vaccinate Tg2576 mice, which develop a progressive accumulation of plaques and cognitive impairment. We vaccinated Tg2576 mice monthly with the above antigens and examined various cognitive parameters at 14 months of age. We found that all vaccinated mice have a significant improvement in cognitive function compared to controls, including the non-human random sequence. Vaccination also markedly reduced total plaque load (A burden) in the Tg2576 mouse brains. We conclude that amyloid A sequence is not necessary to produce a protective immune response as IAPP and the random 3A peptide give rise to an immune response that recognizes A oligomers. Vaccination against a nonhuman amyloid oligomer epitope may be an effective strategy for developing

Evaluation of water molecules in the cold-preserved rat liver by proton magnetic resonance imaging.

Hypothermically preserved rat livers were studied with proton magnetic resonance imaging (1H-MRI) under proton density-, spin-lattice relaxation time-, spin-spin relaxation time- and diffusion-weighted (P-W, T1-W, T2-W and D-W) conditions. Relative signal intensities (RSI) of the liver to distilled water in terms of P-W, T1-W, T2-W and D-W increased time-dependently during 12 h hypothermic (4 degrees C) preservation with saline, while these parameters did not increase during preservation with University of Wisconsin (UW) solution. One-hour Wiggers hypotensive treatment before the harvesting increased the RSIs of P-W, T2-W and D-W, and the subsequent 12-hour preservation with UW solution did not improve the increased RSIs. These results suggest that 1H-MRI has potential application in evaluating the biophysical changes of water molecules in the liver graft, which were measured by placing the harvested liver in a plastic bag under a magnetic field at a low temperature.