Abstract
The positron emission tomography (PET) radiotracer Pittsburgh Compound B ([C-11]PiB) demonstrates a high affinity for fibrillary amyloid-beta (Aβ) aggregates. However, [C-11]PiB's in vivo sensitivity and specificity is an ongoing area of investigation in correlation studies with postmortem measures of Aβ pathology. One potential confound in PET-to-postmortem correlation studies is the limited spatial resolution of PET and resulting partial volume effects (PVEs). In this work, we evaluated the impact of three partial volume correction (PVC) techniques – the Meltzer, the modified Müller-Gärtner, and the Region-Based Voxel-Wise – on correlations between region-matched in vivo [C-11]PiB standardized uptake value ratios (SUVRs) and postmortem measures of Aβ pathology in a unique cohort of nine subjects. Postmortem Aβ pathology was assessed histologically as percent area coverage of 6-CN-PiB positive and Aβ immunoreactive (4G8 antibody) deposits. The application of all three PVC techniques resulted in minimally reduced PET-to-postmortem correlations relative to no PVC. However, correlations to both 6-CN-PiB and 4G8 percent area across all PVC techniques and no PVC were statistically significant at p < 0.01, suggesting that PVC is of minimal importance in understanding the relationship between Aβ PET and neuropathologically assessed Aβ. Thus, the utility of PVC in Aβ PET imaging should continue to be examined on an application-specific basis.
Highlights
Alzheimer's disease (AD) is characterized clinically by impaired cognitive function (Förstl and Kurz, 1999) and neuropathologically by extracellular amyloid-beta (Aβ) plaques, intracellular neurofibrillary tangles of hyper-phosphorylated tau protein, and synaptic/neuronal loss resulting in regional hypometabolism and cortical atrophy (Mirra et al, 1991)
To facilitate clinical diagnosis and early disease detection, several positron emission tomography (PET) radioligands were developed for imaging Aβ pathology in vivo, including 11C-radiolabelled Pittsburgh Compound B ([C-11]PiB) (Klunk et al, 2004; Engler et al, 2002), 18F-Florbetapir (Wong et al, 2010), 18F-Flutemetamol (Vandenberghe et al, 2010), and 18F-florbetaben (Rowe et al, 2008), the latter three of which have been FDA approved for clinical use (FDA approves 18F-florbetapir PET agent, 2012)
We examined the impact of three partial volume correction (PVC) techniques on [C-11]PiB PET measures and the correlation of [C-11]PiB PET measures with postmortem Aβ pathology load
Summary
Alzheimer's disease (AD) is characterized clinically by impaired cognitive function (Förstl and Kurz, 1999) and neuropathologically by extracellular amyloid-beta (Aβ) plaques, intracellular neurofibrillary tangles of hyper-phosphorylated tau protein, and synaptic/neuronal loss resulting in regional hypometabolism and cortical atrophy (Mirra et al, 1991). To address PVEs, several protocols were developed with variable success; these are referred to as partial volume correction (PVC) techniques and include: 1) the Meltzer method, which addresses spill-out of activity from the brain to CSF space but does not account for heterogeneity within tissue (Meltzer et al, 1990; Meltzer et al, 1999; Price et al, 2005; Lopresti et al, 2005); 2) the modified Müller-Gärtner (mMG) method, which addresses cross-contamination between GM and WM but does not account for heterogeneity within WM or GM (Rousset et al, 1998a); 3) the geometric transform matrix (GTM) method (Rousset et al, 1998b); and 4) the Region-Based Voxel-Wise (RBV) method (Thomas et al, 2011). We compared the effects of three PVC techniques on the correspondence between region-matched in vivo PET and postmortem measures of Aβ pathology in nine subjects who had an in vivo [C-11] PiB PET scan and later underwent postmortem neuropathology examination
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