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Biomedical subjects

Tohru Sawada

Publications and source records attributed to Tohru Sawada.

At least 19 recordsLinked to original sources
PubMed2006

Positive correlations between cerebral choline and renal dysfunction in chronic renal failure.

INTRODUCTION: Cerebral metabolism in chronic renal failure (CRF) patients has not been fully evaluated. This study examined cerebral metabolites in CRF, using proton magnetic resonance spectroscopy (MRS). METHODS: Subjects comprised 19 CRF patients and 21 healthy volunteers. Spectra were acquired from voxels of interest positioned in the parietal gray and white matter, and concentrations of the following cerebral metabolites were measured: N-acetyl group (NA), creatine + phosphocreatine (Cr), choline-containing compounds (Cho), myo-inositol and glutamate + glutamine. Among the 19 CRF patients, 9 who were started on hemodialysis (HD) underwent careful follow-up. Proton MRS was performed before and about 2 weeks after starting HD. In six patients in whom follow-up was possible, a third MRS was performed after about 18 months. RESULTS: The NA/Cr ratio was not significantly changed in CRF. However, elevations in the Cho/Cr ratio were found in both gray and white matter compared with controls. To the best of our knowledge, this is the first report of positive correlations between the Cho/Cr ratio in both regions and serum osmotic pressure. Compared with baseline data, no significant changes in cerebral metabolite ratios were found about 2 weeks after starting HD. About 18 months after starting HD, however, the elevated Cho/Cr ratio was significantly reduced in the gray matter and tended to be reduced in the white matter. CONCLUSIONS: Cho appear to play an important role in the regulation of cerebral metabolism to compensate for alterations in serum osmotic pressure in CRF, and HD may correct this abnormal cerebral metabolism.

Adult↗
PubMed2006

Magnetic resonance spectroscopic study of Alzheimer's disease and frontotemporal dementia/Pick complex.

Disease-specific metabolic changes in Alzheimer's disease and frontotemporal dementia/Pick complex were examined by proton magnetic resonance spectroscopy at 3.0 T. Spectra were acquired from posterior and anterior cingulate cortices and the parieto-occipital and frontal white matter. This study included eight Alzheimer's disease patients, 10 frontotemporal dementia/Pick complex patients and 14 healthy volunteers. N-acetylaspartate/creatine+phosphocreatine ratio was reduced in the posterior cingulate cortex in the Alzheimer's disease and frontotemporal dementia/Pick complex patients. The Alzheimer's disease patients, however, showed a posterior dominant decrease, whereas the frontotemporal dementia/Pick complex patients showed a frontal predominant decrease. These different distributions of metabolic changes may represent the underlying pathological processes in each disease. Our standardized protocol of proton magnetic resonance spectroscopy measurement may be helpful in differentiating these dementia subtypes.

Aged↗
PubMed2006

Interactive segmentation of the cerebral lobes with fuzzy inference in 3T MR images.

Measurement of volume and surface area of the frontal, parietal, temporal and occipital lobes from magnetic resonance (MR) images shows promise as a method for use in diagnosis of dementia. This article presents a novel computer-aided system for automatically segmenting the cerebral lobes from 3T human brain MR images. Until now, the anatomical definition of cerebral lobes on the cerebral cortex is somewhat vague for use in automatic delineation of boundary lines, and there is no definition of cerebral lobes in the interior of the cerebrum. Therefore, we have developed a new method for defining cerebral lobes on the cerebral cortex and in the interior of the cerebrum. The proposed method determines the boundaries between the lobes by deforming initial surfaces. The initial surfaces are automatically determined based on user-given landmarks. They are smoothed and deformed so that the deforming boundaries run along the hourglass portion of the three-dimensional shape of the cerebrum with fuzzy rule-based active contour and surface models. The cerebrum is divided into the cerebral lobes according to the boundaries determined using this method. The reproducibility of our system with a given subject was assessed by examining the variability of volume and surface area in three healthy subjects, with measurements performed by three beginners and one expert user. The experimental results show that our system segments the cerebral lobes with high reproducibility.

Algorithms↗
PubMed2006

Styrylbenzoazole derivatives for imaging of prion plaques and treatment of transmissible spongiform encephalopathies.

Recent prevalence of acquired forms of transmissible spongiform encephalopathies (TSEs) has urged the development of early diagnostic measures as well as therapeutic interventions. To extend our previous findings on the value of amyloid imaging probes for these purposes, styrylbenzoazole derivatives with better permeability of blood-brain barrier (BBB) were developed and analyzed in this study. The new styrylbenzoazole compounds clearly labeled prion protein (PrP) plaques in brain specimens from human TSE in a manner irrespective of pathogen strain, and a representative compound BF-168 detected abnormal PrP aggregates in the brain of TSE-infected mice when the probe was injected intravenously. On the other hand, most of the compounds inhibited abnormal PrP formation in TSE-infected cells with IC50 values in the nanomolar range, indicating that they represent one of the most potent classes of inhibitor ever reported. BF-168 prolonged the lives of mice infected intracerebrally with TSE when the compound was given intravenously at the preclinical stage. The new compounds, however, failed to detect synaptic PrP deposition and to show pathogen-independent therapeutic efficacy, similar to the amyloid imaging probes we previously reported. The compounds were BBB permeable and non-toxic at doses for imaging and treatment; therefore, they are expected to be of practical use in human TSE.

Animals↗
PubMed2006

NF-kappaB regulates B-cell-derived nerve growth factor expression.

In the mammalian brain, four neurotrophins have been identified: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5). NGF exerts an important role in the development and functions of the central and peripheral nervous system. However, it has recently been documented that several types of immune cells, such as mast cells, lymphocytes, basophils and eosinophils, produce, store and release NGF. Accumulating preclinical and clinical data indicate that dysfunctions of NGF and the other neurotrophins may contribute to impaired immune responses and concentration of NGF frequently correlates with disease severity. Thus, the aim of this study was to elucidate the potential signaling mechanisms of cytokine- neurotrophins interactions contributing to increased NGF levels. Our data show that the transcription factor NF-kappaB plays a pivotal role in regulating B-cell-derived NGF expression.

Animals↗
PubMed2005

Quinoline and benzimidazole derivatives: candidate probes for in vivo imaging of tau pathology in Alzheimer's disease.

Neurofibrillary tangles (NFTs), neuropil threads, and neuritic elements of senile plaques predominantly comprise hyperphosphorylated tau protein and represent pathological characteristics of Alzheimer's disease (AD). These lesions occur before the presentation of clinical symptoms and correlate with the severity of dementia. In vivo detection of these lesions would thus prove useful for preclinical diagnosis of AD and for tracking disease progression. The present study introduces three novel compounds, 4-[2-(2-benzoimidazolyl)ethenyl]-N,N-diethylbenzenamine (BF-126), 2-[(4-methylamino)phenyl]quinoline (BF-158), and 2-(4-aminophenyl)quinoline (BF-170), as candidate probes for in vivo imaging of tau pathology in the AD brain. When solutions of these compounds are injected intravenously into normal mice, these agents exhibit excellent brain uptake and rapid clearance from normal brain tissue. These compounds display relatively lower binding affinity to beta-amyloid fibrils and higher binding affinity to tau fibrils, compared with previously reported probe BF-168. In neuropathological examination using AD brain sections, BF-126, BF-158, and BF-170 clearly visualize NFTs, neuropil threads, and paired helical filament-type neuritis. Autoradiography using 11C-labeled BF-158 further demonstrated labeling of NFTs in AD brain sections. These findings suggest the potential usefulness of quinoline and benzimidazole derivatives for in vivo imaging of tau pathology in AD.

Aged↗
PubMed2004

Nerve growth factor (NGF) induces mRNA expression of the new transcription factor protein p48ZnF.

Apoptosis, the cell's intrinsic death program, plays a crucial role in the regulation of tissue homeostasis, and abnormal inhibition of apoptosis is an indicator of cancer and autoimmune diseases, whereas excessive cell death is implicated in neurodegenerative disorders such as Alzheimer's disease (AD). Using cDNA subtraction analysis, we compared p60TRP (p60 transcription regulator protein) expressing cells with control cells during the process of apoptosis and we identified the new zinc-finger protein p48ZnF that is predominantly located in the cytoplasm of the cell. Additionally, we demonstrate here that p48ZnF is up-regulated in rat neuronal PC12 cells upon stimulation with the neurotrophic factor NGF (50 ng/ml). These findings point to a possible pivotal role of p48ZnF in the control of neuronal survival.

Alzheimer Disease↗
PubMed2004

Development of a hyperpolarized 129Xe system on 3T for the rat lungs.

MRI (magnetic resonance imaging) with 129Xe has gained much attention as a diagnostic methodology because of its affinity for lipids and possible polarization. The quantitative estimation of net detectability and stability of hyperpolarized 129Xe in the dissolved phase in vivo is valuable to the development of clinical applications. The goal of this study was to develop a stable hyperpolarized 129Xe experimental 3T system to statistically analyze the dissolved-phase 129Xe signal in the rat lungs. The polarization of 129Xe with buffer gases at the optical pumping cell was measured under adiabatic fast passage against the temperature of an oven and laser absorption at the cell. The gases were insufflated into the lungs of Sprague-Dawley rats (n = 15, 400-550 g) through an endotracheal tube under spontaneous respiration. Frequency-selective spectroscopy was performed for the gas phase and dissolved phase. We analyzed the 129Xe signal in the dissolved phase to measure the chemical shift, T2*, delay and its ratio in a rat lungs on 3T. The polarizer was able to produce polarized gas (1.1+/-0.47%, 120 cm3) hundreds of times with the laser absorption ratio (25%) kept constant at the cell. The optimal buffer gas ratio of 25-50% rendered the maximum signal in the dissolved phase. Two dominant peaks of 211.8+/-0.9 and 201.1+/-0.6 ppm were observed with a delay of 0.4+/-0.9 and 0.9+/-1.0 s from the gas phase spectra. The ratios of their average signal to that of the gas phase were 5.6+/-5.2% and 4.4+/-4.7%, respectively. The T2* of the air space in the lungs was 2.5+/-0.5 ms, which was 3.8 times shorter than that in a syringe. We developed a hyperpolarized 129Xe experimental system using a 3T MRI scanner that yields sufficient volume and polarization and quantitatively analyzed the dissolved-phase 129Xe signal in the rat lungs.

Administration, Inhalation↗
PubMed2004

Styrylbenzoxazole derivatives for in vivo imaging of amyloid plaques in the brain.

Progressive deposition of senile plaques (SPs) is one of the major neuropathological features of Alzheimer's disease (AD) that precedes cognitive decline. Noninvasive detection of SPs could, therefore, be a potential diagnostic test for early detection of AD patients. For imaging SPs in the living brain, we have developed a series of styrylbenzoxazole derivatives that achieve high binding affinity for amyloid-beta (Abeta) fibrils. One of these compounds, 6-(2-Fluoroethoxy)-2-[2-(4-methylaminophenil) ethenyl]benzoxazole (BF-168), selectively binds SPs in AD brain sections and recognizes Abeta1-42-positive diffuse plaques as well as neuritic plaques in AD brain sections. Intravenous injection of BF-168 in PS1/APP and APP23 transgenic mice resulted in specific in vivo labeling to both compact and diffuse amyloid deposits in the brain. In addition, (18)F-radiolabeled BF-168 demonstrated abundant initial brain uptake (3.9% injected dose/gm at 2 min after injection) and fast clearance (t(1/2) = 24.7 min) after intravenous administration in normal mice. Furthermore, autoradiograms of brain sections from APP23 transgenic mice at 180 min after intravenous injection of [(18)F]BF-168 showed selective labeling of brain amyloid deposits with little nonspecific binding. These findings strongly suggest that styrylbenzoxazole derivatives are promising candidate probes for positron emission tomography and single-photon emission computed tomography imaging for early detection of amyloid plaque formation.

Alzheimer Disease↗
PubMed2004

Endogenous dopamine release induced by repetitive transcranial magnetic stimulation over the primary motor cortex: an [11C]raclopride positron emission tomography study in anesthetized macaque monkeys.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been used as a treatment for neuropsychiatric disorders such as depression and Parkinson's disease (PD). Despite the growing interest in therapeutic application of rTMS, precise mechanisms of its action remain unknown. With respect to PD, activation of the mesostriatal dopaminergic pathway is likely to be a candidate mechanism underlying the therapeutic effects; however, modulating effects of rTMS over the primary motor cortex (M1) on the dopaminergic system have not been studied. METHODS: We used [11C]raclopride positron emission tomography to measure changes of extracellular dopamine concentration after 5Hz rTMS over the M1 in eight anesthetized monkeys. RESULTS: rTMS over the right M1 induced a reduction of [11C]raclopride binding potential (BP) in the bilateral ventral striatum, including the nucleus accumbens, and a significant increase of BP in the right putamen; no significant BP reduction was found in the dorsal striatum. These data indicate that rTMS over the motor cortex induces a release of endogenous dopamine in the ventral striatum. CONCLUSIONS: Our results suggest that therapeutic mechanisms of rTMS may be explained in part by an activation of the mesolimbic dopaminergic pathway, which plays critical roles in rewards, reinforcement, and incentive motivation.

Animals↗
PubMed2004

Long-term effect of motor cortical repetitive transcranial magnetic stimulation [correction].

Repetitive transcranial magnetic stimulation (rTMS) recently has been assessed as a noninvasive treatment modality for movement and psychiatric disorders, whereas the mechanism underlying the therapeutic effects is not fully understood. Studies in rodents showed lasting functional changes in some selected regions, such as limbic-associated structures, but unfocused brain stimulation did not clarify the regional effects. To address the topographical and temporal profiles of the effects on glucose metabolism in primate brain, we performed rTMS and repeated (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) before, during, and up to 16 days after rTMS in anesthetized cynomologous monkeys. We delivered a total of 2,000 pulses of 5 Hz-rTMS over the right precentral gyrus using a small-sized eight-figured coil that induced a localized electrical field. Voxel-based analysis in a standard space of the macaque brain showed statistically robust changes in FDG uptake: a decrease in the motor/premotor cortices and an increase in the limbic-associated areas involving the anterior/posterior cingulate, and orbitofrontal cortices. Interestingly, these uptake changes continued for at least 8 days and the magnitude of the lasting effects in the limbic-related areas was negatively correlated across subjects with those in the motor/premotor cortices. The results demonstrate that motor rTMS has a long-term lasting effect on motor-related regions and distant limbic-related areas via functional connections.

Animals↗
PubMed2004

In vivo labeling of amyloid with BF-108.

Detection of aggregated amyloid-beta (Abeta) with a non-invasive imaging modality such as positron emission tomography (PET) was suggested to be ideal for the diagnosis of Alzheimer's disease (AD) prior to the onset of clinical symptoms. We have been searching for imaging probe candidates with a high affinity for aggregated Abeta in vitro and in vivo and high lipophilicity, a characteristic that allows for the permeation of the blood-brain barrier (BBB). As analyzed by Thioflavin T (ThT) assay and octanol/water partition coefficient test (PC), 3-diethylamino-6-(2-fluoroethyl)ethylaminoacridine (BF-108) were found to have high affinity for Abeta aggregates in vitro and high lipophilicity. Intravenously administrated BF-108 labeled Abeta aggregates injected into the amygdala as observed under a fluorescence microscope, showing this compound's permeability of BBB and an ability to label Abeta in vivo. BF-108 also labeled neuritic senile plaques (SPs), neurofibrillary tangles, and amyloid-laden vessels in temporal and hippocampal sections from AD patients. Following intravenous administration of BF-108 to an APP23 transgenic (TG) mouse, in vivo labeling of endogenous plaques was seen in brain sections by fluorescence microscopy. These properties suggest the potential utility of BF-108 for in vivo imaging of AD pathology.

Acridines↗
PubMed2004

Functional imaging of gustatory perception and imagery: "top-down" processing of gustatory signals.

By recalling gustatory memories, it is possible to generate vivid gustatory perceptions in the absence of gustatory inputs. This gustatory image influences our gustatory processing. However, the mechanism of the "top-down" modulation of gustatory perception in the human is still unclear. Our findings propose a new perspective on the neural basis of gustatory processing. Although gustatory imagery and gustatory perception shared common parts of neural substrates, there was an asymmetrical topography of activation in the insula: the left insula was predominantly activated by gustatory imagery tasks. In addition, the middle and superior frontal gyri were not activated by gustatory perception but they participated in the generation of gustatory hallucinations. These regions in the frontal cortex may mediate the "top-down" control of retrieving gustatory information from the storage of long-term memories.

Adult↗
PubMed2004

Identification of rTid-1, the rat homologue of the drosophila tumor suppressor l(2)tid gene.

Active cell death ('apoptosis' or 'programmed cell death') is essential in the development and homeostasis of multicellular organisms and abnormal inhibition of apoptosis is an indicator of cancer and autoimmune diseases, whereas excessive cell death is implicated in neurodegenerative disorders such as Alzheimer's disease (AD). Here we demonstrate new isoforms of the rat homologue of the drosophila tumor suppressor l(2)tid gene (rTid-1). Moreover, we show that rTid-1 interacts isoform-specifically with the heat-shock-cognate-glucose-regulated protein hscGRP75 and neither induces nor inhibits directly neuronal apoptosis. This finding points to a pivotal role of Tid-1 in the control of cellular survival.

Animals↗
PubMed2004

Amyloid imaging probes are useful for detection of prion plaques and treatment of transmissible spongiform encephalopathies.

Diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders. A thioflavin derivative, 2-[4'-(methylamino)phenyl] benzothiazole (BTA-1) and a Congo red derivative, (trans, trans),-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB) are representative chemicals of these probes. In this report, the two chemicals were studied in transmissible spongiform encephalopathies (TSE). Both BTA-1 and BSB selectively bound to compact plaques of prion protein (PrP), not only in the brain specimens of certain types of human TSE, but also in the brains of TSE-infected mice when the probes were injected intravenously. The chemicals bound to plaques in the brains were stable and could be detected for more than 42 h post-injection. In addition, the chemicals inhibited abnormal PrP formation in a cellular model of TSE with IC(50) values of 4 nM for BTA-1 and 1.4 micro M for BSB. In an experimental mouse model, the intravenous injection of 1 mg BSB prolonged the incubation period by 14 %. This efficacy was only observed against the RML strain and not the other strains examined. These observations suggest that these chemicals bind directly to PrP aggregates and inhibit new formation of abnormal PrP in a strain-dependent manner. Both BTA-1 and BSB can be expected to be lead chemicals not only for imaging probes but also for therapeutic drugs for TSEs caused by certain strains.

Amyloid↗
PubMed2004

A novel imaging probe for in vivo detection of neuritic and diffuse amyloid plaques in the brain.

Extensive deposition of neuritic and diffuse amyloid plaques in the brain is a critical event for the pathogenesis of Alzheimer's disease (AD) and considered to start before the appearance of clinical symptoms. In vivo detection of these brain beta-amyloid (Abeta) deposits using positron emission tomography (PET), therefore, would be a useful marker for presymptomatic detection of AD. To develop a new agent for PET probe of imaging neuritic and diffuse amyloid deposits, novel fluorescent compounds, including styryl-fluorobenzoxazole derivatives, were examined. These compounds showed a high binding affinity for both synthetic Abeta1-40 and Abeta1-42 aggregates. Some of these compounds also displayed distinct staining of neuritic and diffuse amyloid plaques in AD brain sections. A biodistribution study of styryl-fluorobenzoxazole derivatives in normal mice exhibited excellent brain uptakes (4.5-5.5% injected dose/g at 2 min postinjection). Furthermore, iv administration of BF-145, a styryl-fluorobenzoxazole derivative, demonstrated specific in vivo labeling of compact and diffuse amyloid deposits in an APP23 transgenic mouse brain, in contrast to no accumulation in a wild-type mouse brain. These findings suggest that BF-145 is a potential candidate as a probe for imaging early brain pathology in AD patients.

Aged↗
PubMed2004

The splicing regulatory protein p18SRP is down-regulated in Alzheimer's disease brain.

Alzheimer's disease (AD) is the most common neurodegenerative disorder of aging, accounting for an estimated two-thirds of all cases of senile dementia. Using bioinformatics, the yeast two-hybrid-system, reverse transcription polymerase chain reaction, and fluorescence microscopy analysis, we demonstrate here that the new putative splicing regulatory protein p18SRP is a lysine-rich zinc finger domain-containing protein that interacts with the serine-arginine (SR)-rich splicing regulatory protein SRrp86. The additional finding of its down-regulation in the brain of AD subjects points to a possible pivotal role of p18SRP in the control of cellular survival.

Aged↗