Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2.

BACKGROUND: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. METHODS: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. RESULTS: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). CONCLUSIONS: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.

Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial.

BACKGROUND: The antiplatelet drug cilostazol is efficacious for prevention of stroke recurrence compared with placebo. We designed the second Cilostazol Stroke Prevention Study (CSPS 2) to establish non-inferiority of cilostazol versus aspirin for prevention of stroke, and to compare the efficacy and safety of cilostazol and aspirin in patients with non-cardioembolic ischaemic stroke. METHODS: Patients aged 20-79 years who had had a cerebral infarction within the previous 26 weeks were enrolled at 278 sites in Japan and allocated to receive 100 mg cilostazol twice daily or 81 mg aspirin once daily for 1-5 years. Patients were allocated according to a computer-generated randomisation sequence by means of a dynamic balancing method using patient information obtained at registration. All patients, study personnel, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was the first occurrence of stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage). The predefined margin of non-inferiority was an upper 95% CI limit for the hazard ratio of 1·33. Analyses were by full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT00234065. FINDINGS: Between December, 2003, and October, 2006, 2757 patients were enrolled and randomly allocated to receive cilostazol (n=1379) or aspirin (n=1378), of whom 1337 on cilostazol and 1335 on aspirin were included in analyses; mean follow-up was 29 months (SD 16). The primary endpoint occurred at yearly rates of 2·76% (n=82) in the cilostazol group and 3·71% (n=119) in the aspirin group (hazard ratio 0·743, 95% CI 0·564-0·981; p=0·0357). Haemorrhagic events (cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission) occurred in fewer patients on cilostazol (0·77%, n=23) than on aspirin (1·78%, n=57; 0·458, 0·296-0·711; p=0·0004), but headache, diarrhoea, palpitation, dizziness, and tachycardia were more frequent in the cilostazol group than in the aspirin group. INTERPRETATION: Cilostazol seems to be non-inferior, and might be superior, to aspirin for prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. Therefore, cilostazol could be used for prevention of stroke in patients with non-cardioembolic stroke. FUNDING: Otsuka Pharmaceutical.

Antiplatelet cilostazol is beneficial in diabetic and/or hypertensive ischemic stroke patients. Subgroup analysis of the cilostazol stroke prevention study.

BACKGROUND AND PURPOSE: Although antiplatelets are known to be effective for secondary prevention of cerebral infarction, the number needed to treat is rather large and the effects in stroke patients with complications such as hypertension or diabetes are inadequately defined. This study was conducted to examine the effect of such complications on recurrence of cerebral infarction, and to assess the effect of cilostazol, an antiplatelet agent, in these high-risk subjects. METHODS: A post hoc subgroup analysis of the already reported Cilostazol Stroke Prevention Study, which was a placebo-controlled double-blind trial, has been carried out to clarify the influence of various complications on recurrence in the placebo group and the effects of cilostazol in 1,095 patients with noncardioembolic ischemic cerebrovascular disease. Treatment continued for an average of 1.8 +/- 1.3 years (maximum 4.8 years). RESULTS: The recurrence rate of the diabetic stroke patients was significantly higher compared with the nondiabetics in the placebo group (9.4 vs. 4.7%/year, p = 0.01). Furthermore, our study showed that the relative risk reduction (RRR) for recurrence of infarction was 41.7% with cilostazol. This treatment provided a significant benefit in patients with lacunar infarction (RRR 43.4%, p = 0.04), with diabetes (RRR 64.4%, p = 0.008), or with hypertension (RRR 58.0%, p = 0.003). CONCLUSIONS: Diabetic patients are particularly at risk for recurrence of cerebral infarction. Cilostazol is useful for the prevention of the recurrence of vascular events in patients with lacunar infarction, and is probably effective in high-risk patients with diabetes and/or hypertension.

Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS): A randomized, double-blind, aspirin-controlled trial.

BACKGROUND AND PURPOSE: The antiplatelet agent sarpogrelate is a selective inhibitor of 5-hydroxytryptamine receptors. The purpose of this study was to compare the efficacy and safety of sarpogrelate with those of aspirin in Japanese ischemic stroke patients. METHODS: In total, 1510 patients with recent cerebral infarction (1 week to 6 months after onset) were randomly assigned to receive either sarpogrelate (100 mg TID) or aspirin (81 mg/d). Mean follow-up period was 1.59 years. The primary efficacy end point was recurrence of cerebral infarction. Clusters of serious vascular events (stroke, acute coronary syndrome, or vascular event-related death) were selected as secondary end points. The aim of the primary efficacy analysis was to demonstrate the noninferiority of sarpogrelate with respect to aspirin, with the criterion that the upper limit of the 95% CI of the hazard ratio (sarpogrelate vs aspirin) for recurrence of cerebral infarction should not exceed 1.33. RESULTS: Cerebral infarction recurred in 72 patients (6.09%/y) in the sarpogrelate group and in 58 (4.86%/y) in the aspirin group (hazard ratio=1.25; 95% CI, 0.89 to 1.77; P=0.19). A serious vascular event occurred in 90 (7.61%/y) and in 85 (7.12%/y) patients, respectively (hazard ratio=1.07; 95% CI, 0.80 to 1.44; P=0.65). The overall incidences of bleeding events were 89 (11.9%) and 131 (17.3%), respectively (P<0.01). CONCLUSIONS: Sarpogrelate was not noninferior to aspirin for prevention of recurrence of cerebral infarction. Bleeding events were significantly fewer with sarpogrelate than aspirin. The effect of aspirin in Japanese patients was similar to that in Western studies.

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.

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.

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.

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.

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.

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.

Highly diffusion-sensitized tensor imaging of unilateral cerebral arterial occlusive disease.

BACKGROUND AND PURPOSE: Selective neuronal death is a well-recognized histopathologic sequel to moderate ischemic brain damage. However, radiologic visualization of these changes has not been established, even with diffusion tensor imaging (DTI). We sought to determine whether DTI with b values > or =1900 s/mm(2) reveals occult diffusion abnormalities in patients with cerebral arterial occlusive disease. METHODS: Six patients (five men, one woman; mean age +/- standard deviation, 66 +/- 8 years) with unilateral internal carotid or middle cerebral arterial occlusive disease but not parenchymal T2 hyperintensity underwent 3T fast DTI with b < or = 1300 s/mm(2) and slow DTI with b > or = 1900 s/mm(2). We postprocessed mean diffusibility and fractional anisotropy (FA) images from the fast and slow DTI datasets. Standardized asymmetry indices (AIs) were used to identify regional asymmetries. Diagnostic accuracy among the DTI modalities was assessed by means of receiver operating characteristic analysis. RESULTS: In hemispheres ipsilateral to occluded vessel, AIs were significantly elevated on fast mean-diffusibility images of white matter at the levels of the internal capsule (95% confidence interval [CI]: 1.00, 1.09; P = .045) and corona radiata (95% CI: 1.01, 1.12; P = .034). AIs were significantly decreased on slow FA images at the internal capsule (95% CI: 0.84, 0.98; P = .018) and white matter at the internal capsule level (95% CI: 0.92, 1.00, P = .043). The slow FA map had the highest accuracy (89.8%) for detecting the hemisphere ipsilateral to arterial occlusion. CONCLUSION: Slow FA maps acquired by using DTI with high b values are useful for visualizing ischemic brain damage in apparently normal WM.

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.

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.

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.

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.

APP, NGF & the 'Sunday-driver' in a Trolley on the Road.

Alzheimer's disease (AD) is one of the most common and challenging neurodegenerative diseases in humans and is characterized by: progressive impairment in cognitive function, degeneration of cholinergic neurons of the basal forebrain (CBF), neurofibrillary tangles and amyloid beta-peptide (Abeta) depositions. The amyloid precursor protein (APP) is a transmembrane protein of which abnormal processing produces Abeta that is associated with the pathogenesis of AD. Neurotrophic factors have attracted much attention for their potential as a remedy for neurological disorders. In this regard, nerve growth factor (NGF) has generated a great interest as a potential target for the treatment of AD. This interest is based on the observation that CBF neurons, which provide the major source of cholinergic innervation to the cerebral cortex and hippocampus, undergo selective and severe degeneration in advanced AD and that the survival of CBF neurons depends upon NGF and its receptors, namely, trkA and p75NTR. This review focuses on recent findings about APP, NGF and their potential signaling-connections to the protein encoded by the 'Sunday-driver' (SYD) gene.

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.

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.

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.