bf-227 and Alzheimer-Disease

Although a battery of neuropsychological tests is often used in making a clinical diagnosis of Alzheimer's disease (AD), definitive diagnosis still relies on pathological evaluation at autopsy. The identification of AD biomarkers may allow for a less invasive and more accurate diagnosis as well as serve as a predictor of future disease progression and treatment response. Importantly, biomarkers may also allow for the identification of individuals who are already developing the underlying pathology of AD such as plaques and tangles yet who are not yet demented, i.e. "preclinical" AD. Attempts to identify biomarkers have included fluid and imaging studies, with a number of candidate markers showing significant potential. More recently, better reagent availability and novel methods of assessment have further spurred the search for biomarkers of AD. This review will discuss promising fluid and imaging markers to date.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Benzoxazoles; Biomarkers; Brain; Cerebrovascular Circulation; Humans; Isoprostanes; Microglia; Nitriles; Protease Nexins; Radiography; Receptors, Cell Surface; Regional Blood Flow; Stilbenes; tau Proteins; Thiazoles

Molecular imaging is a visualization of quantity and dynamics of molecules to understand the process of gene regulation and physiological function of the proteins in living tissue or cells. Examples of the research include the development and application of fluorescent proteins, quantum dots, nanoparticles for optical imaging, micro bubbles for ultrasound, ferromagnetic compounds for MRI and radiopharmaceuticals for positron emission tomography (PET). PET is most promising in this field, because of its high sensitivity of the measurement and easy applicability to humans. In this general remark, the topics will be concentrated on molecular imaging with PET for the diagnosis of Alzheimer's disease (AD) in early stage. 11C-MP4P (N-methlpiperidyl-4-propionate), is a probe for the measurement of acetylcholine esterase (AchE) activity in the human brain by PET. The AchE activities (k3) in early onset AD measured with PET was low in hippocampus, amygdale and wide spread neocortex including parietal and temporal cortex compared to those in age-matched control. The results indicated that the decrease of AchE activities is preceded by the decrease of blood flow. One of the topics in this research field is an imaging of aggregated amyloid Abeta in the AD brain. Kudo et al, screened more than 2,600 compounds and found several good probes for amyloid Abeta imaging, including BF-168 and BF-227. Okamura demonstrated that BF-168 specifically bind to the amyloid plaques in the brain of a transgenic mouse (PS1/APPsw). Furumoto et al successfully labeled BF-227 with C-11, and clinical PET studies using 11C-BF-227 is now ongoing at Tohoku University. Preliminary clinical study revealed that the compound accumulated in the tempo-parietal region of the brain in AD patient, although non-specific accumulation in the thalamus, basal ganglia and white matter was observed. The goal of this project is to detect AD at pre-clinical stage.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Benzoxazoles; Brain; Carbon Radioisotopes; Diagnostic Imaging; Humans; Mice; Molecular Probes; Piperidines; Plaque, Amyloid; Positron-Emission Tomography; Propionates; Thiazoles

This paper reviews the progress in developing amyloid imaging ligands to be used to measure amyloid in vivo in the brain of patients with Alzheimer's disease.. Four radioligands, [18F] 1,1-dicyano-2-[6-(dimethylamino)-2-naphtalenyl] propene or 18F-FDDNP, N-methyl [11C] 2-(4'-methylaminophenyl)-6-hydroxy-benzothiasole or 11C-PIB, 4-N-methylamino-4'-hydroxystilbene [11C] or SB13 and 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole or 11C-BF-227, have so far been studied in Alzheimer's disease patients and age-matched healthy controls by PET. A robust difference was observed between PIB retention in mild patients and controls. A 2-year follow-up study in mild patients showed a stable level of PIB retention and a decrease in cerebral glucose metabolism and cognition. 18F-FDDNP showed less difference between Alzheimer's disease patients and controls compared with PIB. Both ligands have detected increases in amyloid in the brain of patients with mild cognitive impairment.. The new PET amyloid imaging technique is a breakthrough in understanding the pathophysiological mechanisms and time course in amyloid deposits in the brain. The technique will enable early detection of Alzheimer's disease. PET amyloid imaging should be used in the evaluation of new antiamyloid therapies.

Topics: Alzheimer Disease; Amyloid; Aniline Compounds; Animals; Benzothiazoles; Benzoxazoles; Brain; Carbon Radioisotopes; Fluorine Radioisotopes; Humans; Longitudinal Studies; Mice; Mice, Transgenic; Molecular Structure; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Three-dimensional stereotactic surface projection (3D-SSP) analyses have been widely used in dementia imaging studies. However, 3D-SSP sometimes shows paradoxical results on amyloid positron emission tomography (PET) analyses. This is thought to be caused by errors in anatomical standardization (AS) based on an (18)F-fluorodeoxyglucose (FDG) template. We developed a new method of 3D-SSP analysis for amyloid PET imaging, and used it to analyze (11)C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227) PET images of subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD).. The subjects were 20 with MCI, 19 patients with AD, and 17 healthy controls. Twelve subjects with MCI were followed up for 3 years or more, and conversion to AD was seen in 6 cases. All subjects underwent PET with both FDG and BF-227. For AS and 3D-SSP analyses of PET data, Neurostat (University of Washington, WA, USA) was used. Method 1 involves AS for BF-227 images using an FDG template. In this study, we developed a new method (Method 2) for AS: First, an FDG image was subjected to AS using an FDG template. Then, the BF-227 image of the same patient was registered to the FDG image, and AS was performed using the transformation parameters calculated for AS of the corresponding FDG images. Regional values were normalized by the average value obtained at the cerebellum and values were calculated for the frontal, parietal, temporal, and occipital lobes. For statistical comparison of the 3 groups, we applied one-way analysis of variance followed by the Bonferroni post hoc test. For statistical comparison between converters and non-converters, the t test was applied. Statistical significance was defined as p < 0.05.. Among the 56 cases we studied, Method 1 demonstrated slight distortions after AS of the image in 16 cases and heavy distortions in 4 cases in which the distortions were not observed with Method 2. Both methods demonstrated that the values in AD and MCI patients were significantly higher than those in the controls, in the parietal, temporal, and occipital lobes. However, only Method 2 showed significant differences in the frontal lobes. In addition, Method 2 could demonstrate a significantly higher value in MCI-to-AD converters in the parietal and frontal lobes.. Method 2 corrects AS errors that often occur when using Method 1, and has made appropriate 3D-SSP analysis of amyloid PET imaging possible. This new method of 3D-SSP analysis for BF-227 PET could prove useful for detecting differences between normal groups and AD and MCI groups, and between converters and non-converters.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Benzoxazoles; Carbon Radioisotopes; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Imaging, Three-Dimensional; Male; Plaque, Amyloid; Positron-Emission Tomography; Reference Standards; Thiazoles

In previous studies, patients with idiopathic normal-pressure hydrocephalus (iNPH) occasionally showed Alzheimer's pathology in frontal lobe cortical biopsy during cerebrospinal fluid shunt surgery or intracranial pressure monitoring. In clinical practice, the differential diagnosis of iNPH from Alzheimer's disease (AD) can be problematic, particularly because some iNPH cases exhibit AD comorbidity. In this study, we evaluated amyloid deposition in the brains of patients with iNPH before shunt surgery, and investigated the association between brain amyloid deposits and clinical improvement following the surgery.. Amyloid imaging was performed in patients with iNPH or AD and also in healthy control subjects by using positron emission tomography (PET) and a radiolabeled pharmaceutical compound, (11)C-BF227. Using the cerebellar hemispheres as reference regions, the standard uptake value ratio (SUVR) of the neocortex was estimated and used as an index for amyloid deposition. In patients with iNPH, clinical symptoms were assessed before shunt surgery and 3 months after surgery.. Five of the 10 patients with iNPH had neocortical SUVRs that were as high as those of AD subjects, whereas the SUVRs of the 5 patients were as low as those of healthy controls. A significant inverse correlation between neocortical SUVRs and cognitive improvements after shunt surgery was observed in iNPH.. The amount of amyloid deposits ranges widely in the brains of patients with iNPH and is associated with the degree of cognitive improvement after shunt surgery.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Analysis of Variance; Benzoxazoles; Cerebrospinal Fluid Shunts; Female; Humans; Hydrocephalus, Normal Pressure; Image Processing, Computer-Assisted; Japan; Magnetic Resonance Imaging; Male; Middle Aged; Neocortex; Positron-Emission Tomography; Retrospective Studies; Statistics as Topic; Thiazoles

To examine the usefulness of the early phase [(11)C]BF-227 positron emission tomography (PET) for (1) conferring additional diagnostic value by providing perfusion-like information and (2) obtaining the appropriate anatomical standardization (AS) using three-dimensional stereotactic surface projection (3D-SSP) method.. This study included 20 mild cognitive impairment (MCI), 19 Alzheimer's disease (AD), and 17 normal cognitive (NC) subjects. Early- and late-phase BF-227 PET images were obtained 0-10 and 40-60 min after the injection, respectively. AS for late-phase BF-227 images were performed by 2 methods: (1) method A, for AS of late-phase BF-227 images using (8)F-fluorodeoxyglucose (FDG) images of the same subject and (2) method B, for AS of late-phase BF-227 images using early phase BF-227 images.. Method B was successfully used for AS in all cases. The Z score maps of 3D-SSP analyses of FDG PET and early phase BF-227 PET for AD and MCI groups showed a typical AD-like pattern. Regional analyses revealed that the early phase BF-227 PET showed significant differences between AD and NC, and MCI and NC.. The early phase BF-227 PET images showed significant abnormal findings for the AD and MCI groups. AS of late-phase BF-227 images using early phase BF-227 images were successful, and enabled appropriate 3D-SSP analyses.

Topics: Aged; Alzheimer Disease; Benzoxazoles; Brain; Carbon Radioisotopes; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Imaging, Three-Dimensional; Male; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Thiazoles

Two methods are commonly used in brain image voxel-based analyses widely used for dementia work-ups: 3-dimensional stereotactic surface projections (3D-SSP) and statistical parametric mapping (SPM). The methods calculate the Z-scores of the cortical voxels that represent the significance of differences compared to a database of brain images with normal findings, and visualize them as surface brain maps. The methods are considered useful in amyloid positron emission tomography (PET) analyses to detect small amounts of amyloid-β deposits in early-stage Alzheimer's disease (AD), but are not fully validated. We analyzed the (11)C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227) amyloid PET imaging of 56 subjects (20 individuals with mild cognitive impairment [MCI], 19 AD patients, and 17 non-demented [ND] volunteers) with 3D-SSP and the easy Z-score imaging system (eZIS) that is an SPM-based method. To clarify these methods' limitations, we visually compared Z-score maps output from the two methods and investigated the causes of discrepancies between them. Discrepancies were found in 27 subjects (9 MCI, 13 AD, and 5 ND). Relatively high white matter uptake was considered to cause higher Z-scores on 3D-SSP in 4 subjects (1 MCI and 3 ND). Meanwhile, in 17 subjects (6 MCI, 9 AD, and 2 ND), Z-score overestimation on eZIS corresponded with high skull uptake and disappeared after removing the skull uptake ("scalping"). Our results suggest that non-specific uptakes in the white matter and skull account for errors in voxel-based amyloid PET analyses. Thus, diagnoses based on 3D-SSP data require checking white matter uptake, and "scalping" is recommended before eZIS analysis.

Topics: Aged; Alzheimer Disease; Amyloid; Artifacts; Benzoxazoles; Cognitive Dysfunction; Dementia; Demography; Female; Humans; Male; Positron-Emission Tomography; Skull; Thiazoles; White Matter

Although diabetes mellitus (DM) is considered to be one of the most consistent risks for developing dementia, it is not known if the pathology in dementia patients with DM is similar to or distinct from typical pathological features of Alzheimer's disease (AD). To discover the mechanism of developing dementia in AD patients with DM in a living state, we studied the distribution of amyloid β (Αβ) protein of diabetic AD patients.. To evaluate the accumulation of Aβ, we examined 14 normal controls, four diabetic patients with AD and 11 non-diabetic patients with AD by positron emission tomography (PET) using BF-227, a currently developed Aβ tracer.. The analysis of PET images among the three groups showed an abundant aggregated Aβ accumulation in the cerebral cortex of both AD patients with and without DM. The extent and distributions of BF-227 accumulation in diabetic AD patients were not significantly different from these of non-diabetic AD patients.. These results suggest that the degree and extent of Aβ deposition is not significantly different between AD with DM and AD alone.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Benzoxazoles; Brain; Case-Control Studies; Diabetes Complications; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Thiazoles

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Benzoxazoles; Cerebral Cortex; Humans; Positron-Emission Tomography; Thiazoles

We recently developed a novel PET tracer, (11)C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole ([(11)C]BF-227), and had success with in vivo detection of amyloid plaques in Alzheimer's disease (AD) brains (Kudo et al. in J Nucl Med 8:553-561, 2007). We applied this tracer to subjects with mild cognitive impairment (MCI) and AD in order to elucidate the status of amyloid plaque deposition in MCI and compared the diagnostic performance of BF-227-PET with that of FDG-PET in AD cases. We studied 12 aged normal (AN) subjects, 15 MCIs and 15 ADs with PET using [(11)C]BF-227. PET images were obtained after administration of BF-227 and the regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of BF-227 binding. AD patients showed increased uptake of [(11)C]BF-227 in the neocortical areas and striatum as well as decreased glucose metabolism in temporoparietal, posterior cingulate and medial temporal areas. MCI subjects showed a significant increase in BF-227 uptake in the neocortical areas similar to AD, and the most significant difference of BF-227 retention was observed in the parietal lobe if its retentions for MCI were compared to those for AD and AN. On the other hand, glucose hypometabolism in MCI was confined to cingulate and medial temporal cortices. Neocortical BF-227 uptake negatively correlated with glucose metabolism. Receiver operating characteristic (ROC) analysis indicated higher specificity and sensitivity with BF-227-PET than those with FDG-PET for differential diagnosis between AD and normal control. We conclude that [(11)C]BF-227-PET has a possibility to be a useful technology for early detection of AD pathology and also even in the MCI stage.

Topics: Aged; Alzheimer Disease; Amyloid; Benzoxazoles; Brain; Brain Mapping; Carbon Radioisotopes; Cognition Disorders; Diagnosis, Differential; Female; Fluorodeoxyglucose F18; Glucose; Humans; Male; Plaque, Amyloid; Positron-Emission Tomography; ROC Curve; Sensitivity and Specificity; Thiazoles

To determine early brain changes in the distribution of an amyloid positron emission tomography (PET) probe, (11)C-labeled BF-227 or [(11)C]BF-227, in order to accurately predict the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD).. Amyloid plaque burden was evaluated using [(11)C]BF-227 PET in AD, MCI and aged normal controls. A voxel-based analysis of [(11)C]BF-227 PET images was performed to characterize the culprit brain lesion in patients with MCI who were destined to progress to AD, referred to as MCI converters (MCI-C). In addition, binding characteristics of BF-227 to amyloid deposits were examined using postmortem AD brain samples.. Voxel-based statistical analyses of the BF-227 PET images clearly demonstrated an abnormal distribution of BF-227 mainly in the posterior association area in MCI-C and patients with AD. BF-227 uptake in the lateral temporal cortex was consistently observed in almost all MCI-C and patients with AD, and it distinguished MCI-C from MCI nonconverters. BF-227 binding strongly correlated with dense amyloid-β protein plaque density, but not with diffuse plaque density in the frontal cortex.. BF-227 uptake in the lateral temporal cortex is a reliable indicator that can be used for predicting prognosis in patients with MCI.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Benzoxazoles; Carbon Radioisotopes; Cerebral Cortex; Data Interpretation, Statistical; Disease Progression; Educational Status; Evidence-Based Medicine; Female; Humans; Male; Plaque, Amyloid; Positron-Emission Tomography; Sex Factors; Thiazoles; Wechsler Scales

Two techniques employed for the early diagnosis of dementia are the imaging of amyloid-beta protein using positron emission tomography (PET) and voxel-based morphometry analysis of MRI (VBM-MRI). The purpose of this study was to evaluate the clinical utility of amyloid PET and VBM-MRI for the early diagnosis and tracking of the severity of Alzheimer's disease (AD). The neuritic plaque burden and gray matter losses were evaluated using [11C]BF-227-PET and VBM-MRI in 12 healthy controls, 13 subjects with mild cognitive impairment (MCI), including 6 who converted to AD and 7 who did not convert, and 15 AD patients. The AD patients and the MCI converters exhibited a neocortical retention of BF-227 and parahippocampal gray matter loss shown by VBM-MRI. The MCI converters were more clearly distinguished from the MCI non-converters in BF-227-PET than VBM-MRI. The combined sample of the MCI converters and AD patients showed a significant correlation of MMSE scores with the global gray matter loss, but not with the BF-227 retention. These findings suggest that amyloid PET using [11C]BF-227 is better suited for the prediction of conversion from MCI to AD, while VBM-MRI appears to be better suited for tracking the severity of dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Benzoxazoles; Brain; Carbon Radioisotopes; Cognition Disorders; Early Diagnosis; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Neocortex; Nerve Fibers, Unmyelinated; Neuropsychological Tests; Parahippocampal Gyrus; Plaque, Amyloid; Positron-Emission Tomography; Severity of Illness Index; Signal Processing, Computer-Assisted; Thiazoles

Amyloid-beta (Abeta) plaques are a pathological hallmark of Alzheimer's disease and a current target for positron emission tomography (PET) imaging agents. Whilst [(11)C]-PiB is currently the most widely used PET ligand in clinic, a novel family of benzoxazole compounds have shown promise as Abeta imaging agents; particularly BF227. We characterised the in vitro binding of [(18)F]-BF227 toward alpha-synuclein to address its selectivity for Abeta pathology, to establish whether [(18)F]-BF227 binds to alpha-synuclein/Lewy bodies, in addition to Abeta plaques. In vitro [(18)F]-BF227 saturation studies were conducted with 200 nM alpha-synuclein or Abeta(1-42) fibrils or 100 microg of Alzheimer's disease, pure dementia with Lewy bodies or control brain homogenates. Non-specific binding was established with PiB (1 microM). In vitro binding studies indicated that [(18)F]-BF227 binds with high affinity to two binding sites on Abeta(1-42) fibrils (K(D1) = 1.31 and K(D2) = 80 nM, respectively) and to one class of binding sites on alpha-synuclein fibrils (K(D) = 9.63 nM). [(18)F]-BF227 bound to Abeta-containing Alzheimer's disease brain (K(D) = 25 +/- 0.5 nM), but failed to bind to Abeta-free dementia with Lewy bodies or age-matched control homogenates. Moreover, BF227 labelled both Abeta plaques and Lewy bodies in immunohistochemical/fluorescence analysis of human Alzheimer's disease and Parkinson's disease brain sections, respectively. This study suggests that [(18)F]-BF227 is not Abeta-selective. Evaluation of BF227 as a potential biomarker for Parkinson's disease is warranted.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Benzoxazoles; Brain; Fluorine Radioisotopes; Humans; Immunohistochemistry; Lewy Bodies; Lewy Body Disease; Peptide Fragments; Protein Binding; Substrate Specificity; Thiazoles

Extensive deposition of dense amyloid fibrils is a characteristic neuropathologic hallmark in Alzheimer's disease (AD). Noninvasive detection of these molecules is potentially useful for early and precise detection of patients with AD. This study reports a novel compound, 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227), for in vivo detection of dense amyloid deposits using PET.. The binding affinity of BF-227 to amyloid-beta (Abeta) fibrils was calculated. The binding property of BF-227 to amyloid plaques was evaluated by neuropathologic staining of AD brain sections. Brain uptake and in vivo binding of BF-227 to Abeta deposits were also evaluated using mice. For clinical evaluation of (11)C-BF-227 as a PET probe, 11 normal (healthy) subjects and 10 patients with AD participated in this study. Dynamic PET images were obtained for 60 min after administration of (11)C-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of (11)C-BF-227 retention. The regional tracer distribution in AD patients was statistically compared with that of aged normal subjects on a voxel-by-voxel basis.. BF-227 displayed high binding affinity to synthetic Abeta1-42 fibrils (K(i) [inhibition constant], 4.3 +/- 1.5 nM). Neuropathologic staining has demonstrated preferential binding of this agent to dense amyloid deposits in AD brain. Moreover, a biodistribution study of this agent revealed excellent brain uptake and specific labeling of amyloid deposits in transgenic mice. The present clinical PET study using (11)C-BF-227 demonstrated the retention of this tracer in cerebral cortices of AD patients but not in those of normal subjects. All AD patients were clearly distinguishable from normal individuals using the temporal SUV ratio. Voxel-by-voxel analysis of PET images revealed that cortical BF-227 retention in AD patients is distributed primarily to the posterior association area of the brain and corresponded well with the preferred site for neuritic plaque depositions containing dense Abeta fibrils.. These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Animals; Benzoxazoles; Female; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Progressive accumulation 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 or presymptomatic detection of AD patients. For this purpose, many attempts have been made to visualize AD-specific pathological changes in the living brain. Currently, a most practical method for the in vivo measurement of SP depositions is using positron emission tomography (PET) and contrast agent that specifically label SPs. We have developed a novel compound 2-[2-(2-dimethylaminothiazol-5-yl) ethenyl]-6-[2-(fluoro)ethoxy] benzoxazole (BF-227) as a candidate for an amyloid imaging probe for PET. BF-227 displayed high affinity to synthetic amyloid beta fibrils and clearly stained both SPs and diffuse plaques in AD brain sections. Intravenous administration of [11C]BF-227 into normal mice indicated that this labeled tracer readily penetrated the blood brain barrier (BBB) and was washed out quickly from brain tissue. Currently, we have investigated the clinical trial of [11C]BF-227 in healthy subjects and AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzoxazoles; Early Diagnosis; Humans; Mice; Plaque, Amyloid; Positron-Emission Tomography; Thiazoles