Objective-Assess Aβ deposition longitudinally and explore its relationship with cognition and disease progression.Methods-Clinical follow-up was obtained 20 ± 3 months after [ 11 C]Pittsburgh compound B (PiB)-positron emission tomography in 206 subjects: 35 with dementia of the Alzheimer type (DAT), 65 with mild cognitive impairment (MCI), and 106 age-matched healthy controls (HCs). A second PiB scan was obtained at follow-up in 185 subjects and a third scan after 3 years in 57.Results-At baseline, 97% of DAT, 69% of MCI, and 31% of HC subjects showed high PiB retention. At 20-month follow-up, small but significant increases in PiB standardized uptake value Address correspondence to Dr Villemagne, Department of Nuclear Medicine and Centre for PET, Austin Health, 145 Studley Road, Heidelberg, Vic., 3084, Australia. villemagne@petnm.unimelb.edu.au. D.A. is Principle Investigator of the Australian Imaging, Biomarkers, and Lifestyle study of ageing.Additional Supporting Information can be found in the online version of this article. Potential Conflicts of InterestGE Healthcare holds a license agreement with the University of Pittsburgh based on the technology described in this article. W.E.K. and C.A.M. have received consultancy fees and royalties and have a grant pending from GE Healthcare. W.E.K. and C.A.M. are coinventors of PiB and, as such, have a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of the manuscript. All other authors have no conflicts of interest with this work, had full access to all of the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. NIH Public Access Author ManuscriptAnn Neurol. Author manuscript; available in PMC 2012 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript ratios were observed in the DAT and MCI groups, and in HCs with high PiB retention at baseline (5.7%, 2.1%, and 1.5%, respectively). Increases were associated with the number of apolipoprotein E ε4 alleles. There was a weak correlation between PiB increases and decline in cognition when all groups were combined. Progression to DAT occurred in 67% of MCI with high PiB versus 5% of those with low PiB, but 20% of the low PiB MCI subjects progressed to other dementias. Of the high PiB HCs, 16% developed MCI or DAT by 20 months and 25% by 3 years. One low PiB HC developed MCI.Interpretation-Aβ deposition increases slowly from cognitive normality to moderate severity DAT. Extensive Aβ deposition precedes cognitive impairment, and is associated with ApoE genotype and a higher risk of cognitive decline in HCs and progression from MCI to DAT over 1 to 2 years. However, cognitive decline is only weakly related to change in Aβ burden, suggesting that downstream factors have a more direct effect on symptom progression.In vivo amyloid imaging with positron emission tomography (PET) allows longitudinal study...

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Amyloid imaging with 18 F-labeled radiotracers will allow widespread use, facilitating research, diagnosis, and therapeutic development for Alzheimer disease. The purpose of the study program was to compare cortical amyloid deposition using 18 F-florbetaben and PET in controls and subjects with mild cognitive impairment (MCI), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), vascular dementia (VaD), Parkinson disease (PD), and Alzheimer disease (AD). Methods: One hundred nine subjects in 3 clinical studies at Austin Health were reviewed: 32 controls, 20 subjects with MCI, and 30 patients with AD, 11 with FTLD, 7 with DLB, 5 with PD, and 4 with VaD underwent PET after intravenous injection of 300 MBq of 18 F-florbetaben. Standardized uptake value ratios (SUVR) using the cerebellar cortex as a reference region were calculated between 90 and 110 min after injection. Results: When compared with the other groups, AD patients demonstrated significantly higher SUVRs (P , 0.0001) in neocortical areas. Most AD patients (96%) and 60% of MCI subjects showed diffuse cortical 18 F-florbetaben retention. In contrast, only 9% of FTLD, 25% of VaD, 29% of DLB, and no PD patients and 16% of controls showed cortical binding. Although there was a correlation between Mini Mental State Examination and b-amyloid burden in the MCI group, no correlation was observed in controls, FTLD or AD. Conclusion: 18 F-florbetaben had high sensitivity for AD, clearly distinguished patients with FTLD from AD, and provided results comparable to those reported with 11 C-Pittsburgh Compound B in a variety of neurodegenerative diseases.

Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau. Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD. We have previously reported 18 F-labeled THK-523 ( 18 F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel 18 F-labeled arylquinoline derivatives, 18 F-THK-5105 and 18 F-THK-5117, for use as tau imaging PET tracers. Methods: 18 F-labeled compounds were prepared from the corresponding tosylated precursors. The binding affinity of compounds to synthetic tau aggregates and tau-rich AD brain homogenates was determined by saturation and competition binding assays. The binding selectivity of compounds to tau pathology was evaluated by autoradiography of AD brain sections. The pharmacokinetics of compounds were assessed in biodistribution studies in normal mice. A 14-d toxicity study with intravenous administration of compounds was performed using rats and mice. Results: In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates. Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of 11 C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than 18 F-THK-523 and other reported 18 F-labeled radiotracers. THK-5105 and THK-5117 showed no toxic effects related to the administration of these compounds in mice and rats and no significant binding for various neuroreceptors, ion channels, and transporters at 1-mM concentrations. Conclusion: 18 Flabeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.

While considerable effort has focused on developing positron emission tomography β-amyloid imaging radiotracers for the early diagnosis of Alzheimer's 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 Alzheimer's 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%; P < 0.007) 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.