Nobuyuki Okamura

18F-THK523: a novel in vivo tau imaging ligand for Alzheimer’s disease

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimers disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with β-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimers disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight β-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; Pu2009<u20090.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.

Comparison study of amyloid PET and voxel-based morphometry analysis in mild cognitive impairment and Alzheimer's disease.

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 Alzheimers 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.

Amyloid PET in mild cognitive impairment and Alzheimer’s disease with BF-227: comparison to FDG–PET

We recently developed a novel PET tracer, 11C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole ([11C]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 [11C]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 [11C]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 [11C]BF-227-PET has a possibility to be a useful technology for early detection of AD pathology and also even in the MCI stage.

In vivo detection of prion amyloid plaques using [11C]BF-227 PET

PurposeIn vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain.MethodsThe binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Sträussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [11C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer’s disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention.ResultsBinding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain.ConclusionAlthough [11C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs.

Discrete cortical regions associated with the musical beauty of major and minor chords

Previous research has demonstrated that the degree of aesthetic pleasure a person experiences correlates with the activation of reward functions in the brain. However, it is unclear whether different affective qualities and the perceptions of beauty that they evoke correspond to specific areas of brain activation. Major and minor musical keys induce two types of affective qualities—bright/happy and dark/sad—that both evoke aesthetic pleasure. In the present study, we used positron emission tomography to demonstrate that the two musical keys (major and minor) activate distinct brain areas. Minor consonant chords perceived as beautiful strongly activated the right striatum, which has been assumed to play an important role in reward and emotion processing, whereas major consonant chords perceived as beautiful induced significant activity in the left middle temporal gyrus, which is believed to be related to coherent and orderly information processing. These results suggest that major and minor keys, both of which are perceived as beautiful, are processed differently in the brain.

Brain histamine H1 receptor occupancy of loratadine measured by positron emission topography: comparison of H1 receptor occupancy and proportional impairment ratio.

We have evaluated the sedative properties of H1‐antihistamines by using positron emission tomography (PET) and 11C‐doxepin. The purpose of the present study was to measure histamine H1 receptor occupancy (H1RO) of loratadine 10u2009mg in patients with allergic rhinitis and to compare this occupancy with that of d‐chlorpheniramine 2u2009mg, a first‐generation antihistamine. We also compared our PET findings with the proportional impairment ratio reported by McDonald et al.

In vivo Detection of Amyloid Plaques in the Mouse Brain using the Near-Infrared Fluorescence Probe THK-265

Noninvasive detection of amyloid-β (Aβ) deposits in the brain would be beneficial for an early and presymptomatic diagnosis of Alzheimers disease (AD). We developed THK-265 as a candidate near-infrared fluorescence (NIRF) probe for the in vivo detection of amyloid deposits in the brain. The maximal emission wavelength of THK-265 was greater than 650nm and it showed high quantum yield and molar absorption coefficients. A fluorescence binding assay showed its high binding affinity to Aβ fibrils (Kd = 97 nM). THK-265 clearly stained amyloid plaques in AD neocortical brain sections and showed a moderate log p value (1.8). After intravenous administration of THK-265 in amyloid-β protein precursor (AβPP) transgenic mice, amyloid deposits in the brain were clearly labeled with THK-265. Furthermore, in vivo NIRF imaging demonstrated significantly higher fluorescence intensity in the brains of AβPP transgenic mice than in those of wild-type mice. As THK-265 showed profound hyperchromic effect upon binding to Aβ fibrils, good discrimination between AβPP transgenic and wild-type mice was demonstrated even early after THK-265 administration. Furthermore, the fluorescence intensity of THK-265 correlated with amyloid plaque burden in the brains of AβPP transgenic mice. These findings strongly support the usefulness of THK-265 as an NIRF imaging probe for the noninvasive measurement of brain amyloid load.

Effects of a sedative antihistamine, D-chlorpheniramine, on regional cerebral perfusion and performance during simulated car driving.

The sedative side effects of antihistamines have been recognized to be potentially dangerous in car driving, but the mechanism underlying these effects has not yet been elucidated to date. The aim of the present study is to examine regional cerebral blood flow (rCBF) responses during a simulated car‐driving task following oral administration of D‐chlorpheniramine using positron emission tomography (PET) and [15O]H2O, based on a single‐blind cross‐over study‐design.

Advances in molecular imaging for the diagnosis of dementia.

BACKGROUNDnThere is an urgent need for early diagnosis and treatment of dementia to ease caregiver burden and medical costs associated with the increasing number of affected patients. Molecular imaging with target-specific ligands is contributing to the early diagnosis of dementia and the evaluation of anti-dementia therapy.nnnOBJECTIVEnThis article reviews recent advances in the molecular imaging field applied to dementia. To illustrate the utility of molecular imaging in the clinical management of dementia, results from recently published papers using new imaging probes are compared with those from conventional imaging strategies.nnnCONCLUSIONnThe recent development of β-sheet binding agents including FDDNP, PIB, SB-13, BF-227 and BAY94-9172 enables the non-invasive detection of amyloid deposition in the brain. These agents would be useful for the early and accurate diagnosis of Alzheimers disease, patient selection for disease-modifying therapeutic trials and monitoring the effect of anti-amyloid therapy. Also, monitoring neurotransmitter function contributes to the differential diagnosis of dementia and refinement of treatment protocols. New targets for molecular imaging are focusing on protein misfolding diseases associated with the neurotoxic deposition of aggregated tau, α-synuclein and prion proteins.