Analysis of [11C]PIB PET data
Pittsburgh Compound B (PIB, PiB, or 6-OH-BTA-1) is a derivative of thioflavin T, and both bind to amyloid-β; [11C]PIB has been successfully used as a PET radiopharmaceutical to in vivo visualization and quantification of extracellular amyloid-β deposits, especially in Alzheimer's disease (AD) patients. Cortical PIB uptake is associated with age, APOE genotype, and gender even in "healthy ageing" (Scheinin et al., 2014). Individuals with memory impairment but negative PIB PET do not exhibit AD pathology upon postmortem examination (Scheinin et al., 2018). Uptake is increased in mild cognitive impairment (MCI) (Kemppainen et al., 2007). [11C]PIB PET can reliably detect amyloid-β pathology among patients with idiopathic normal pressure hydrocephalus (Rinne et al., 2019).
[11C]PIB binding to amyloid-β in the grey brain matter is specific and reversible. [11C]PIB binding in white matter has a non-specific and non-saturable component (Fodero-Tavoletti et al., 2009), possibly due to the high lipid content of the white matter, and a specific component due to affinity to the β-sheet structure present in the myelin. [11C]PIB PET allows longitudinal evaluation of white matter in healthy individuals (Veronese et al., 2015), and can be used to quantify myelin loss and regeneration in the white matter of MS patients (Stankoff et al., 2011; Bodini et al., 2016).
The uptake in white matter is much lower than in grey matter, but due to slower kinetics in white matter, the uptake is prominent at later time points, which may impede the quantification of amyloid-β deposits in the grey matter in case of considerable partial volume effect. Partial volume correction decreases [11C]PIB binding estimates in cortical grey matter more in healthy subjects than in patients with high amyloid-β deposition (Matsubara et al., 2016).
The recommended analysis methods for quantification of amyloid load in the brain are
- MTGA for reversible uptake (Logan plot) with reference tissue input
- Simplified reference tissue model (SRTM) with constrained k'2
- Late-scan tissue-to-reference tissue ratio (SUVR), with cerebellar cortex as reference region (Chen et al., 2017).
Cardiac amyloidosis PET studies have been analyzed using FUR (Antoni et al., 2013; Kero et al., 2016). SUV calculation has been used in analysis of PIB uptake in gastrocnemius muscle in inclusion body myositis (Maetzler et al., 2011).
Dynamic PET study is required to apply MTGA and SRTM, while only a short late-scan is needed for SUVR method. Dynamic study is also required to estimate BPND using Washout Allometric Reference Method (WARM); WARM is not affected by regional perfusion differences. All methods can be calculated pixel-by-pixel, providing parametric maps for further analysis. Sato et al. (2013) have also proposed a method for estimating k3 using reference tissue model and 40-min dynamic PET scan.
If cerebellum cannot be used as a reference region, either arterial sampling or an image-derived arterial input function (Su et al, 2015), or supervised clustering procedure (Ikoma et al., 2013) is required.
Logan plot with [11C]PIB
Distribution volume ratio (DVR), or binding potential (BPND = DVR-1), can be calculated with Logan plot without arterial plasma data sampling, using cerebellar cortex as input (Mintun et al. 2006; Li et al. 2008). Reference region k2 was set to 0.2 min-1, but this value had only minimal impact on the results (Mintun et al. 2006). However, it may advance the time when Logan plot reaches linearity, thus reducing the required total scan length.
Estimate the regional DVR using logan with option
-k2=0.2 and set fit time from 20 minutes to a end time common to all PET studies.
Simplified reference tissue model (SRTM) has also been used to compute DVR or BPND images. The original SRTM has been enhanced by applying constraint for reference region k2 (Yaqub et al., 2008; Zwan et al., 2014; Sojkova et al., 2015).
Amyloid load can be quantified by computing region-to-cerebellum ratio over 60 to 90 minutes (Lopresti et al., 2005; Kemppainen et al. 2006; Kemppainen et al., 2014), either regionally with dftratio or pixel-by-pixel with imgratio. Optimal time range was thoroughly studied by McNamee et al. (2009); their suggestion was to use 40-60-min period in studies limited by low injected dose, but otherwise the 50-70-min period because of greater measurement stability, especially for longitudinal multisite studies.
Advantages of the ratio approach are 1) large effect sizes for Alzheimer's disease (AD) and control group differences (Lopresti et al., 2005), and 2) possibility to obtain the required data from a single relatively short scan. However, ratio is dependent on the uptake period and sensitive to changes in perfusion (van Berckel et al., 2013).
In cognitively intact individuals cerebellar grey matter is preferred reference tissue compared to pons (Adamczuk et al., 2016). AD patients may have also cerebellar plaques, which may render cerebellum vulnerable as a reference area. Therefore, it may be necessary to calculated results also by using pons as a reference area (Koivunen et al., 2008). In data-driven diagnostic classification, statistical analysis suggests that normalization by cerebellar grey matter and pons yields identical classification accuracy of AD (96% accuracy, 96% sensitivity, 95% specificity), while normalization by white matter performed less well, not outperforming CSF biomarkers (Oliveira et al., 2018).
With another amyloid-β tracer, [18F]florbetapir, cerebral white matter was found to be better reference region than cerebellum or pons (Chen et al., 2015a).
Amyloid tracers have high lipophilicity, which makes them good perfusion surrogates. Cerebral perfusion is lower in Alzheimer's disease than in healthy volunteers, but permeability-surface area product is unchanged, supporting the use of the unidirectional blood-brain clearance of [11C]PIB in tracking blood flow changes (Gjedde et al., 2013).
From a dynamic PET scan with arterial blood sampling the compartmental model parameter K1 can be estimated, and it reflects cerebral blood flow (Blomquist et al., 2008; Chen et al., 2015b). In clinical setting the blood sampling is usually omitted; then the first phase of the scan, for example the first 6 min p.i., can be used to calculate SUVR between the regions of interest and cerebellum (Forsberg et al., 2012), or preferably R1 from SRTM analysis is used as marker of relative perfusion changes (Chen et al., 2015b; Sojkova et al., 2015).
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Updated at: 2019-03-19
Created at: 2008-08-04
Written by: Vesa Oikonen