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Optimizing Longitudinal Amyloid-β PET Measurement: The Challenges of Intensity Normalization

Accurate measurement of amyloid-b (Ab) PET tracer retention has become an increasingly important feature of neuroimaging research in Alzheimer disease (AD). Although initial Ab PET work mostly focused on abnormal/normal (1/2) categorization, the field has moved toward more precise measurement techniques in order to detect Ab at and even below the positivity threshold in hopes of understanding the initial stages of pathologic change as well as points of potential effective intervention. Clinical trials such as A4 using PET to screen for Ab positivity rely on the definition of an SUV ratio (SUVR) threshold or threshold range that can identify those who are early enough in the course of disease to still benefit from an Ab-targeting therapy (1). In addition, recent research has emphasized the earliest detection of Ab pathology, how it changes over time, and how it relates to neurodegenerative and cognitive changes (2–6), all of which depend on the accurate and precise measurement of Ab on a continuous scale. Although the selection of a reference region may appear to be a technical detail in PET image analysis, it has a major influence on Ab PET SUVRs. Cross-sectional Ab PET analyses have frequently used the cerebellar cortex or the whole cerebellum (white plus gray matter) because these regions are known to be relatively free of Ab in AD. Few studies have compared PET SUVRs calculated using different regions with one another, but existing work suggests that different reference regions are far from interchangeable (7,8). For example, longitudinal florbetapir PET cortical SUVRs calculated using a whole cerebellum reference region are only minimally predictive of the same cortical change calculated using a white matter (WM) reference region (9). This reinforces the idea that reference region selection is a methodologic decision worthy of careful consideration since it is likely to significantly influence study findings. For longitudinal studies in particular, in which accumulation may be less than 1% per year, the reference region that is selected may determine whether any change is detected at all. Several studies have reported that longitudinal florbetapir PET (9–11) and Pittsburgh compound B (PiB) PET (12) SUVRs are more stable and more plausible (e.g., roughly linear, nondecreasing) when the reference region contains WM than when it does not (e.g., whole cerebellum alone). WM may result in more stable signal because it is larger, less influenced by registration problems or poor regional definition or segmentation, and less vulnerable to problems with scatter correction related to proximity to the bottom of the field of view. On the other hand, WM signal is poorly understood, complicating its utility as a reference region. Most Ab pathology in AD is located in the cortex, but Ab pathology has also been observed in WM (13,14). In Ab PET imaging, tracer retention in WM is frequently as high as in the cortex and is considered nonspecific. This WM retention may be explained by slower tracer clearance compared with gray matter (15), tracer lipophilicity (16), and the b-pleated sheet structure of myelin-binding protein (17). However, PiB retention is also reduced in WM lesions (18,19). Importantly, these factors are ligand-specific and could account for differing proportions of WM signal depending on which ligand is used. Furthermore, isolating WM from cortical signal is challenging because of the low spatial resolution of PET; elevated signal in the cortex can influence WM signal and vice versa. Selection of an optimal reference region is further complicated by the lack of a gold standard for longitudinal measurement. Nonetheless, reference region stability over time and over the course of disease is a critical feature. In this issue of The Journal of Nuclear Medicine, Lowe et al. perform an unusually comprehensive set of PiB PET analyses to determine whether WM is an acceptable reference region for measuring cortical PiB retention throughout middle to older age and at different degrees of Ab burden (20). The authors use both cross-sectional and longitudinal analyses across the spectrum of disease to show that WM retention (but not cerebellar crus or whole cerebellum retention) increases with age and at moderate levels of cortical Ab (SUVR of about 1.9–2.1). The authors performed several critical analyses to examine cortical and WM regions separately and minimize signal contamination that would complicate interpretation of WM signal. First, they performed 2-compartment partial-volume correction, which adjusts for the influence of cerebral spinal fluid on neighboring WM or gray matter but not for the influence of WM on gray matter or vice versa. To address the latter issue, the authors examined periventricular WM separately from the rest of subcortical WM, because periventricular regions are far enough away from the cortex to eliminate the influence of cortex on WM via partialvolume effects. Compared with subcortical WM that neighbors cortex, periventricular WM regions were less elevated with older age and at moderate levels of cortical Ab, supporting the assumption Received Sep. 7, 2018; revision accepted Sep. 10, 2018. For correspondence or reprints contact: Susan M. Landau, 118 Barker Hall MC #3190, University of California Berkeley, Berkeley, CA 94720-3190. E-mail: slandau@berkeley.edu Published online Sep. 13, 2018. COPYRIGHT© 2018 by the Society of Nuclear Medicine and Molecular Imaging. DOI: 10.2967/jnumed.118.212662