Simplified parametric methods for [11C]PIB studies
ABSTRACT 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.
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- "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 . "
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.NeuroImage 01/2012; 60(3):1716-23. DOI:10.1016/j.neuroimage.2012.01.099 · 6.36 Impact Factor
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- "(R)-[ 11 C]verapamil BP ND values in the two patients that were visually classified as PIB negative were in the range of the PIB-positive patients with Alzheimer's disease. Quantitatively, however, these two patients did show some amount of increased [ 11 C]PIB binding with RPM2-derived (Yaqub et al., 2008) global C]PIB BP ND values of 0.19 and 0.34, respectively. Although this is increased compared with healthy controls, it is still below the threshold of [ 11 C]PIB BP ND of 0.54 for being [ 11 C]PIB positive (Tolboom et al., 2010). "
ABSTRACT: A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-β in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-β from the brain may lead to these elevated amyloid-β levels. One of the clearance pathways of amyloid-β is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-β. P-glycoprotein function can be assessed in vivo using (R)-[(11)C]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[(11)C]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimer's disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[(11)C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic Alzheimer's disease and suggests that decreased P-glycoprotein function may be involved in the pathogenesis of Alzheimer's disease.Brain 11/2011; 135(Pt 1):181-9. DOI:10.1093/brain/awr298 · 10.23 Impact Factor
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- "The simulated data are adopted from published clinical data,  . Specifically, arterial input function and rate constants of two tissue reversible compartmental model for PIB tracer are used. "
ABSTRACT: Logan's graphical analysis (LGA) is a widely-used approach for quantification of biochemical and physiological processes from Positron emission tomography (PET) image data. A well-noted problem associated with the LGA method is the bias in the estimated parameters. We recently systematically evaluated the bias associated with the linear model approximation and developed an alternative to minimize the bias due to model error. In this study, we examined the noise structure in the equations defining linear quantification methods, including LGA. The noise structure conflicts with the conditions given by the Gauss-Markov theorem for the least squares (LS) solution to generate the best linear unbiased estimator. By carefully taking care of the data error structure, we propose to use structured total least squares (STLS) to obtain the solution using a one-dimensional optimization problem. Simulations of PET data for [11C] benzothiazole-aniline (Pittsburgh Compound-B [PIB]) show that the proposed method significantly reduces the bias. We conclude that the bias associated with noise is primarily due to the unusual structure of he correlated noise and it can be reduced with the proposed STLS method.