Modeling clustered activity increase in amyloid-beta positron emission tomographic images with statistical descriptors

Abstract

BackgroundAmyloid-beta (Aβ) imaging with positron emission tomography (PET) holds promise for detecting the presence of Aβ plaques in the cortical gray matter. Many image analyses focus on regional average measurements of tracer activity distribution; however, considerable additional information is available in the images. Metrics that describe the statistical properties of images, such as the two-point correlation function (S2), have found wide applications in astronomy and materials science. S2 provides a detailed characterization of spatial patterns in images typically referred to as clustering or flocculence. The objective of this study was to translate the two-point correlation method into Aβ-PET of the human brain using 11C-Pittsburgh compound B (11C-PiB) to characterize longitudinal changes in the tracer distribution that may reflect changes in Aβ plaque accumulation.MethodsWe modified the conventional S2 metric, which is primarily used for binary images and formulated a weighted two-point correlation function (wS2) to describe nonbinary, real-valued PET images with a single statistical function. Using serial 11C-PiB scans, we calculated wS2 functions from two-dimensional PET images of different cortical regions as well as three-dimensional data from the whole brain. The area under the wS2 functions was calculated and compared with the mean/median of the standardized uptake value ratio (SUVR). For three-dimensional data, we compared the area under the wS2 curves with the subjects’ cerebrospinal fluid measures.ResultsOverall, the longitudinal changes in wS2 correlated with the increase in mean SUVR but showed lower variance. The whole brain results showed a higher inverse correlation between the cerebrospinal Aβ and wS2 than between the cerebrospinal Aβ and SUVR mean/median. We did not observe any confounding of wS2 by region size or injected dose.ConclusionThe wS2 detects subtle changes and provides additional information about the binding characteristics of radiotracers and Aβ accumulation that are difficult to verify with mean SUVR alone.

Reference tissue normalization in longitudinal 18F-florbetapir positron emission tomography of late mild cognitive impairment

“…PET analysis using the wS 2 method also results in smaller standard errors and thus may be more suitable for detecting subtle changes due to the larger effect size. The theoretical framework of wS 2 is described in our previous work where this method was validated with 11 C-PiB PET data [ 24 ].…”

“…The wS 2 method is a statistical tool adopted from astronomy and materials science and can be used to detect specific changes in spatial patterns within Aβ-PET images that we refer to as increased clustering or flocculence . Our preliminary data [ 24 ] indicate the potential utility of this method for detecting longitudinal changes that are difficult to assess with conventional regional mean image values, which typically have large standard deviations.…”

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

“…Visual inspection of florbetapir PET images was as effective as SUVR in determining Aβ positivity [465]. Alternative automated methods such as Syngo-PET Aβ Plaque [466], and a method based on a two-point correlation metric, wS2 [467], were comparable to SUVR and offered some advantages such as the ability to detect subtle changes in patterns of Aβ deposition [468].…”

Longitudinal Positron Emission Tomography in Preventive Alzheimer's Disease Drug Trials, Critical Barriers from Imaging Science Perspective

“…Our group has also developed an alternative method to regional and voxel-based methods that enables monitoring different subjects with different topographic Aβ-PET radiotracer uptake profiles without averaging the voxel values (regional analysis) or requiring a reference population (voxel-based analysis). This method (74) is based on two-point correlation functions that capture longitudinal changes in Aβ-PET by detecting subtle changes in spatial radiotracer uptake patterns that are referred to as increased clustering or flocculence.…”

“…The global uptake has been used to classify subjects as amyloid positive or negative (34, 39) or to test the treatment efficacy of drugs (57, 64, 71). Similar to FDG-PET’s AD-signature ROI, the cortical Aβ-PET SUVR mean values are associated with large standard errors (74). In a single subject, the SUVR standard deviation indicates voxel intensity variations across the global ROI.…”