Reference region selection and the association between the rate of amyloid accumulation over time and the baseline amyloid burden

Relative quantitative analysis of amyloid plaque burden in Alzheimer's disease (AD) patients can be reported as standardized uptake value ratio (SUVR) from positron emission tomography (PET). Here, the SUVR is the ratio of the mean amyloid radioligand retention in a composite (COMP) neocortical volume of interest (VOI) to that in a reference VOI, such as the cerebellum, brainstem (BST)/pons, or white matter (WM). Some longitudinal PET investigations show that the rate of amyloid accumulation to follow-up has an inverted U relationship with baseline amyloid SUVR relative to cerebellar or brainstem/pons reference VOIs. The corresponding association with SUVR relative to WM is unknown. To test the possible benefits of WM normalization, we analyzed [F-18]-AV45 PET data from 404 subjects in the AD Neuroimaging Initiative (ADNI) database at baseline and 2-year follow-up (144 cognitively normal controls, 225 patients with mild cognitive impairment, and 35 AD patients). Reference regions included subcortical WM as well as conventional cerebellar gray matter (CBL), and BST. We tested associations between each subject's inter-session change (a dagger) of SUVR and their baseline SUVR by applying linear, logarithmic, and quadratic regression analyses. Unscaled standardized uptake values (SUVs) were correlated between VOIs at baseline and follow-up, and within VOIs in the longitudinal run. The association between a dagger SUVR and baseline SUVR relative to WM reference was best described by an inverted U-shaped function. Correlation analyses demonstrated a high regional and temporal correlation between COMP and WM VOI SUVs. For WM normalization, we confirm that the rate of amyloid accumulation over time follows an inverted U-shaped function of baseline amyloid burden. Reference region selection, however, has substantial effects on SUVR results. This reflects the extent of covariance between SUVs in the COMP VOI and those in the various reference VOIs. We speculate that PET labeling of amyloid deposition within target regions is partially confounded by effects of longitudinal changes of cerebral blood flow (CBF) on tracer delivery. Indeed, CBF may be the leading factor influencing longitudinal SUV changes. We suggest that SUVR relative to WM may be more robust to changes in CBF, and thus fitter for sensitive detection of amyloid accumulation in intervention studies.