The purpose of the present study was to evaluate the performance of various parametric reference tissue models for quantification of [11C]PIB studies. Several models with and without fixing the reference tissue efflux rate constant (k'(2)) were investigated using both simulations and clinical data. The following parametric methods were evaluated: receptor parametric mapping (basis function implementation of the simplified reference tissue model with and without fixed k'(2)), reference Logan, and several multi-linear reference tissue methods (again with and without fixed k'(2)). In addition, standardised uptake value ratios with cerebellum (SUV(r)) were evaluated. Simulations were used to assess the effects of variation in flow (R(1)), fractional blood volume (V(b)) and binding potential (BP(ND)) itself on precision and accuracy of parametric BP(ND). For clinical studies, most parametric methods showed comparable performance, with poorest results for SUV(r). Best performance was obtained for receptor parametric mapping (RPM2) and one of the multi-linear reference tissue models (MRTM2), both with fixed k'(2): BP(ND) outcome was less affected by noise and the images showed better contrast than other tested methods. RPM2 and MRTM2 also provided best accuracy and precision in the simulation studies and are therefore the methods of choice for parametric analysis of clinical [11C]PIB studies.
"Head-to-head comparison of the analytical methods for both cross-sectional and longitudinal data showed that dynamic scans are superior to static scans in terms of accuracy, test–retest variability and image contrast [6,7]. Among dynamic scan protocols, receptor parametric mapping is preferred over the Logan distribution volume ratio due to better test–retest performance and lower susceptibility to statistical noise [6,8]. "
[Show abstract][Hide abstract] ABSTRACT: The possibility to map amyloid-beta, the Alzheimer's disease hallmark protein, in vivo opens the application for amyloid imaging in clinical trials with disease-modifying agents. Monitoring change in amyloid burden, particularly when potential amyloid-lowering drugs are at play, requires accurate analytical methods. Studies to date have used suboptimal methods that do not account for heterogeneous changes in flow associated with disease progression and potentially with anti-amyloid drugs. In this commentary, we discuss practical and methodological issues regarding longitudinal amyloid imaging and propose several quantitative, yet feasible, alternatives for reliable assessment of changes over time in amyloid burden.
Alzheimer's Research and Therapy 08/2013; 5(4):36. DOI:10.1186/alzrt195 · 3.98 Impact Factor
"The individual in vivo radioligand binding was examined by calculating the binding potential with a reference tissue approach using the cerebellum –. Parametric images of regional Aβ plaque burden for representative animals were created with the 2-step multilinear reference tissue model 2 (MRTM2, , ) as shown in Figure 2 and Figure S1. The binding potential values for neocortex estimated by the same model for the whole study collective showed highly significant separation of all transgenic animals from controls and a clear distinction of AD animals belonging to different study groups (Figure S10). "
[Show abstract][Hide abstract] ABSTRACT: In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [(11)C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [(11)C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [(11)C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice.
PLoS ONE 03/2012; 7(3):e31310. DOI:10.1371/journal.pone.0031310 · 3.23 Impact Factor
"Our two subjects with presenilin-1 mutations, in the absence of memory loss, both had higher RATIO PONS in the cortex and the cerebellum than the mean control values whereas RATIO CER underestimated the [ 11 C]PIB binding differences (Table 4). Studies have examined the reproducibility of [ 11 C]PIB using different methods of analysis (Aalto et al., 2009; Edison et al., 2009; Engler et al., 2006; Lopresti et al., 2005; Price et al., 2005) and have shown that reference tissue methods perform better than the arterial input method of analysis for discrimination of AD from healthy normals, while the target-to-cerebellum ratio performed better than the other simplified methods of analysis in terms of sensitivity and reproducibility (Yaqub et al., 2008). Here, the target-to-pons ratio demonstrated high sensitivity for detecting AD and gave comparable test–retest reproducibility to RATIO CER . "
[Show abstract][Hide abstract] ABSTRACT: 11C]PIB is the most widely used PET imaging marker for amyloid in dementia studies. In the majority of studies the cerebellum has been used as a reference region. However, cerebellar amyloid may be present in genetic Alzheimer's (AD), cerebral amyloid angiopathy and prion diseases. Therefore, we investigated whether the pons could be used as an alternative reference region for the analysis of [11C]PIB binding in AD. The aims of the study were to: 1) Evaluate the pons as a reference region using arterial plasma input function and Logan graphical analysis of binding. 2) Assess the power of target-to-pons ratios to discriminate controls from AD subjects. 3) Determine the test-retest reliability in AD subjects. 4) Demonstrate the application of target-to-pons ratio in subjects with elevated cerebellar [11C]PIB binding.
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