After completion of the PET scan and the reconstruction of the dynamic images from the emission scan, an integral or sum image is generated in order to perform a co-registration with a structural volumetric magnetic resonance image as shown in Figure . This then allows the accurate definition of volumes of interest (VOIs) on the brain imaging data. Automated methods using atlases defined on brain templates are used as well as VOIs being manually outlined, particularly in cases with high levels of brain atrophy.
Figure 3 Sagittal image sections from a control subject and an Alzheimer's disease patient. Sagittal image sections from (left) a control subject and (right) an Alzheimer's disease (AD) patient. Positron emission tomography (PET) images (colour scale in the centre) (more ...)
Using the set of VOIs defined, the dynamic PET images are then sampled and tissue time-activity curves generated. As is illustrated in Figure these tissue time-activity curves represent the measured activity concentration averaged across the VOI - which implies that, in the ensemble of volume elements (voxels) comprising a VOI, all voxels share the same parameters of the underlying physiological and biochemical processes, and only differ as they are different realisations of the same random process. This means that special attention has to be paid to tissue heterogeneity when VOIs are defined, and often magnetic resonance images segmented in different tissue classes (grey matter, white matter and cerebrospinal fluid) are employed for the definition of homogeneous VOIs. As an example, the difference in the [11C]PIB signal between cerebellar grey matter and cerebellar white matter is highlighted in Figure .
Figure 4 Tissue time-activity curves. Tissue time-activity curves (TACs) from the two subjects shown in Figure 3 for four regions: cerebellar grey matter (cerebellum), frontal cortex, temporoparietal cortex and occipital cortex. (Left) Age-matched control subject. (more ...)
The purpose of tracer kinetic analysis (centre top box in Figure ) is to disentangle the different processes that jointly result in the tissue response curves obtained [19
]. For amyloid imaging studies, the contributions to consider are as follows. First, tracer delivery and washout - as the amyloid imaging markers currently used (for example, [11
F] BAY94-9172 and florbetapir ([18
F]AV-45)) are thought to cross the blood-brain barrier by passive diffusion, the delivery to and washout from brain tissue of these radiotracers is governed by cerebral blood flow. A second contribution is specific binding - the association, and dissociation for reversibly binding ligands, of the radioligand with the target (that is, Aβ). Another contribution is nonspecific binding - referring to any nonsaturable binding that occurs to other sites than Aβ (for example, to membranes or lipid fractions). A fourth contribution is radiolabelled metabolites - several of the [18
F]-labelled radiotracers used for amyloid imaging have been reported to form radiolabelled metabolites in vivo
that are also able to cross the blood-brain barrier [20
]; part of the radioactivity signal measured in brain tissue is therefore due to the contamination with radiolabelled metabolites. Finally, vascular activity - owing to the spatial resolution of the positron cameras of several millimetres, any VOI defined in the brain contains a few per cent blood volume; the spill in of activity from the vasculature therefore needs to be accounted for.
Using mathematical modelling and parameter estimation methods, system parameters such as rate constants, volumes of distribution or binding potentials [21
] can be estimated from the dynamic imaging data. The outcome parameters chosen should, of all the contributions listed above, reflect the specific binding to the maximum possible extent and should be insensitive to the other confounders. For example, it has been shown for [11
C]PIB that the accumulation rate did not correlate with cerebral blood flow [22
]. The parameter estimates can either be obtained regionally for each VOI, or they can be calculated for each voxel individually and then again represented as an image that is often referred to as a parametric map [23
] (Figure ). Parametric maps can then be interrogated for parameter changes that do not correspond to the anatomically predefined VOIs.
Figure 5 Parametric maps. Parametric images from the [11C]Pittsburgh Compound B ([11C]PIB) scans of the two subjects shown in Figure 3: top images, control subject; bottom images, Alzheimer's disease (AD) patient. Images generated with spectral analysis; colour (more ...)
A variety of modelling approaches exists and they have been applied to amyloid imaging studies with [11
C]PIB. These approaches range from compartmental models [24
], through graphical analyses such as Logan plots [25
] or Patlak plots [26
], to spectral analysis [28
] and reference tissue models [29
]. In reference tissue models, the tissue time-activity curve of a region without specific binding is used as a substitute for the plasma input function. For studies of sporadic AD the cerebellar grey matter is widely used as a reference region because postmortem investigations confirmed negligible concentrations of Aβ in cerebellar grey matter in this disease. However, careful validation of the reference region is required for each disease population.
One of the commonly used methods of analysis is the target to cerebellar ratio, commonly referred to as the RATIO method. Different groups have used different time points to create RATIO images from 40 to 60 minutes, from 40 to 70 minutes and from 60 to 90 minutes. These different time points largely give comparable results, however - and at later time points, while the signal increases, the noise also increases. Again, in different studies, different RATIO values have used as cut-off points [31
]. Some studies have used a strict cut-off value of two standard deviations above the control mean for individual regions, while other studies have used much more liberal cut-off values and a RATIO value of 1.4 or even 1.5. Even though different scanners differ slightly, it is generally accepted that a RATIO value above 1.5 is clearly abnormal.
Less sophisticated but technically much simpler to perform than dynamic scans are static acquisitions. In this procedure, the time-course of activity is not measured but only an integral (sum) image of tissue activity of a certain period after tracer injection is acquired. By then it is assumed that the tracer has reached a state of pseudo-equilibrium so that the tissue activity-concentration ratio can be used as an apparent volume of distribution ratio [33
] (Figure ).
Figure 6 Ratio maps. Ratio images from the [11C]Pittsburgh Compound B ([11C]PIB) scans of the two subjects shown in Figure 3: top images, control subject; bottom images, Alzheimer's disease (AD) patient. Images generated by dividing the mean activity concentration (more ...)