Strategies for the generation of parametric images of [11C]PIB with plasma input functions considering discriminations and reproducibility
Introduction
Alzheimer's disease (AD) is characterised by the demonstration of amyloid plaques and neurofibrillary tangles in the brain. The clinical diagnosis of AD is based on the NINCDS-ADRDA (McKhann et al., 1984) and DSM 1V criteria. With the introduction of [11C]PIB or Pittsburgh compound B, it is now possible to detect amyloid plaque deposition in vivo with Positron Emission Tomography (PET) in subjects with AD. Modification of the amyloid binding histological dye, thioflavin-T led to the finding that neutral benzothiazoles also bind to amyloid with high affinity and additionally cross the blood–brain barrier (Klunk et al., 2001). Specifically, the benzothiazole amyloid binding agent 2-(4′ methylaminophenyl) benzothiazole (called BTA-1) and related compounds bind to amyloid-beta (Aβ) peptide fibrils with low nanomolar affinity, enter the brain in amounts sufficient for imaging with PET and clear rapidly from normal brain tissue (Mathis et al., 2002, Mathis et al., 2003, Wang et al., 2002). At the low nanomolar concentrations typically used in PET studies, BTA-1 binds to amyloid plaques in post mortem brain slices but not to intracellular neurofibrillary tangles. In vitro studies suggest that, while BTA-1 binds to fibrillar Aβ deposits found in the cortex and striatum, it does not bind to amorphous Aβ deposits found in cerebellum (Mathis et al., 2003).
The first PET imaging study in humans showed that [11C]PIB standard uptake values (SUV) were increased twofold in cortical association areas of AD patients compared to healthy control subjects (Klunk et al., 2004). The first tracer kinetic modelling report on [11C]PIB binding in humans concluded that graphical analysis of reversible binding (Logan et al., 1990) using a plasma input function was the method-of-choice providing stable region-of-interest results and robust parametric images (Price et al., 2005). Subsequently, the same laboratory reported that a 90 min target-to-cerebellum [11C]PIB uptake ratio produced the largest effect size while graphical analysis of reversible binding (Logan et al., 1996) using a cerebellar time-activity curve as the input function produced the most reproducible distribution volume ratios (Lopresti et al., 2005).
Several authors have now studied the generation of parametric maps of [11C]PIB binding with simplified methods, i.e. not requiring a plasma input function, for the discrimination between healthy controls and subjects with AD or mild cognitive impairment (MCI) (Mikhno et al., 2008, Ng et al., 2007, Ziolko et al., 2006, Zhou et al., 2007). In a recent paper, Yaqub et al. (2008) presented an exhaustive comparison of simplified parametric methods for the analysis of [11C]PIB studies and concluded that the modified simplified reference tissue model (Wu and Carson, 2002) was the method of choice.
The evaluation of [11C]PIB kinetics in many of the approaches employed in the above listed publications is based on the apparent reversibility of [11C]PIB binding to Aβ over the time course of a 90 min PET scan. However, Bacskai et al. (2003) found in a multiphoton imaging study in transgenic mice that PIB remained associated with amyloid deposits for several days. Based on analysis of data from the first [11C]PIB scans in humans which were acquired over 60 min, Blomquist proposed the use of an irreversible graphical model for the quantification of tracer uptake (Patlak et al., 1983) to generate parametric maps of [11C]PIB accumulation (Blomquist et al., 2005, Blomquist et al., 2008, Hinz et al., 2005b).
Another important aspect in the analysis of [11C]PIB binding is the selection of a reference region representing non-specific signal such as the cerebellum, white matter or pons. While a cerebellar reference may be valid for sporadic Alzheimer's disease, pathologies such as Prion disease can result in a significant amount of amyloid in the cerebellum (Mead et al., 2006, Watanabe and Duchen, 1993). A recent [11C]PIB PET report has also suggested that there is significant amyloid deposition in familial AD (Kaufer et al., 2008). In these conditions, finding a suitable reference region could potentially be difficult. A reference region should always be validated as being effectively void of specific binding in proportion to the specific binding in the target area before using it for the quantification of imaging studies (Asselin et al., 2007). As more mild cognitive impairment patients and patients with subjective memory impairment are studied, and various longitudinal studies are examined, it is important to use analysis methods with maximum discriminative power and to establish the reproducibility of the methods of analysis.
In this study we used three of the most common kinetic modelling methods employing an arterial plasma input function to generate parametric maps of [11C]PIB binding (Logan plot, Patlak plot, spectral analysis) and compared their test–retest reproducibility in a group of AD subjects and their ability to discriminate between a group of AD subjects and controls.
Section snippets
Subjects
For the discriminative part of the study, 12 sporadic AD subjects and 10 age and gender matched control subjects were selected (Table 1). In order to examine test–retest reproducibility 5 of these AD subjects underwent a repeat [11C]PIB scan within an interval of less than 6 weeks. These [11C]PIB scans were acquired as a part of a previously published larger research study comparing [18F]FDG and [11C]PIB PET in AD (Edison et al., 2007). All subjects were recruited from the Imperial College
Input function
In Fig. 1, the observed time courses of the ratio of plasma activity concentration over whole blood activity concentration (POB ratio) from the 10 discrete arterial blood samples are plotted for the two cohorts. Immediately after radiotracer injection the POB ratio quickly rises to reach a plateau at a nearly constant value of about 1.45. The two cohorts did not statistically differ in their POB time courses. Such time courses of POB ratios are characteristic for radiotracers that passively
Discussion
Our measurements of the parent fraction (Fig. 3) appear to be in reasonable agreement with the previously published results by Price et al. (2005). This is of some importance as the fraction of radioactivity in arterial plasma due to unmetabolised [11C]PIB decreases rapidly. The mean parent fraction of [11C]PIB was found to be about 75% after 5 min, 28% after 15 min, 10% after 40 min and less than 5% after 90 min scan time in our study of 22 subjects. Due to difficulties with the sensitivity of
Acknowledgments
We gratefully acknowledge the excellent work of Safiye Osman with the bioanalysis and quality control teams. We would like to particularly thank Andy Blythe and Dave Turton for their efforts in characterising and minimising the stickiness properties of [11C]PIB. Leonhard Schnorr, Hope McDevitt, and Andreanna Williams receive our thanks for their making the scans possible. We are very grateful to Prof. Martin Rossor for his help with the recruitment of Alzheimer's disease subjects for this
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