White matter reference region in PET studies of ¹¹C-Pittsburgh compound B uptake: Effects of age and amyloid-β deposition

Amyloid-β (Aβ) deposition as seen on PET using an Aβ-binding agent is a critical diagnostic biomarker for Alzheimer disease (AD). Some reports suggest using white matter (WM) as a reference region for quantification of serial Aβ PET studies; however, nonspecific WM retention in Aβ PET in people with dementia or cognitively unimpaired (CU) has been widely reported and is poorly understood. Methods: To investigate the suitability of WM as a reference region and the factors affecting WM ¹¹C-Pittsburgh compound B (¹¹C-PiB) uptake variability, we conducted a retrospective study on 2 large datasets: a longitudinal study of participants (n 5 577) who were CU, had mild cognitive impairment, or had dementia likely due to AD; and a crosssectional study of single-scan PET imaging in CU subjects (n 5 1,349). In the longitudinal study, annual changes in WM ¹¹C-PiB uptake were assessed, and in the cross-sectional study, WM ¹¹C-PiB uptake was assessed relative to subject age. Results: Overall, we found that WM ¹¹C-PiB uptake showed age-related increases, which varied with the WM regions selected. Further, variable annual WM ¹¹C-PiB uptake changes were seen with different gray matter (GM) ¹¹C-PiB baseline uptake levels. Conclusion: WM binding increases with age and varies with GM ¹¹C-PiB. These correlations should be considered when using WM for normalization in ¹¹C-PiB PET studies. The cerebellar crus¹¹Crus2 showed no increase with age and cerebellar GM1WM showed minimal increase, supporting their use as reference regions for cross-sectional studies comparing wide age spans. In longitudinal studies, the increase in WM uptake may be minimal in the short-term and thus using WM as a reference region in these studies seems reasonable. However, as participants age, the findings may be affected by changes in WM uptake. Changes in WM ¹¹C-PiB uptake may relate to disease progression, warranting examination of the causes of WM ¹¹C-PiB uptake.