Not quite PIB-positive, not quite PIB-negative: Slight PIB elevations in elderly normal control subjects are biologically relevant

Abstract

Researchers employing Pittsburgh Compound B positron emission tomography (PIB-PET) imaging have consistently indentified old normal control (oNC) subjects with elevated tracer uptake, suggesting the presence of beta-amyloid deposition in these individuals. However, a consensus regarding the level at which PIB reveals a biologically meaningful signal does not exist (ie. an appropriate cutoff value for PIB positivity remains unclear). In this exploratory study, we sought to investigate the range of PIB distribution volume ratio (DVR) values present in our oNC cohort (N = 75, age range = 58–97). oNC subjects were classified based on global PIB index values (average DVR across prefrontal, parietal, lateral temporal and cingulate cortices) by employing two approaches: (1) an iterative outlier approach that revealed a cutoff value of 1.16 (IO-cutoff) and (2) an approach using data from a sample of young normal control subjects (N = 11, age range = 20–30) that yielded a cutoff value of 1.08 (yNC-cutoff). oNC subjects falling above the IO-cutoff had values similar to AD subjects (“PIB+”, 15%). Subjects falling between the 2 cutoffs were considered to have ambiguous PIB status (“Ambig”, 20%) and the remaining oNC were considered “PIB-“ (65%). Additional measures capturing focal DVR magnitude and extent of elevated DVR values were consistent with the classification scheme using PIB index values, and revealed evidence for elevated DVR values in a subset of PIB- oNC subjects. Furthermore, there were a greater proportion of ambiguously elevated values compared to low values, and these elevated values were present in regions known to show amyloid deposition. The analyses presented in this study, in conjunction with recently published pathological data, suggest a biological relevance of slight PIB elevations in aging.

Introduction

Following the landmark human ¹¹C-labeled Pittsburgh Compound B positron emission tomography (PIB-PET) study in 2004 (Klunk et al., 2004), many researchers have applied amyloid imaging to investigate the relevance of beta-amyloid (Aβ) deposition in cognitively normal elderly “controls” (NC) (Rabinovici and Jagust, 2009). Consistent with data from post-mortem examination, these studies have re-affirmed that many NCs have extensive Aβ deposition. Furthermore, elevated PIB in NCs has been associated with differences in brain structure (Bourgeat et al., 2010, Dickerson et al., 2009, Fotenos et al., 2008, Jack et al., 2008, Mormino et al., 2009, Oh et al., 2010, Storandt et al., 2009) and brain function (Hedden et al., 2009, Mormino et al., 2009, Sheline et al., 2009, Sperling et al., 2009, Vannini et al., 2011), as well as subsequent decline in memory and conversion to AD (Morris et al., 2009, Storandt et al., 2009, Villemagne et al., 2011), suggesting that Aβ in NCs is not benign and may reflect an early stage of AD development.

Although PIB scans from some NC subjects display uptake indistinguishable from a typical AD scan, less-obvious cases exist that show sub-AD levels of tracer uptake. A major difficulty in assessing the relevance of these slightly elevated PIB values is that the conversion between actual plaque burden and tracer uptake is unclear. Comparison of PIB values to Aβ detected in brain tissue (via postmortem examination and brain biopsy) has shown that elevated PIB uptake is present in cases with high quantities of neuritic Aβ plaques, however the concordance between these measurements is inconclusive in subjects with evidence of low Aβ burden (Bacskai et al., 2007, Cairns et al., 2009, Ikonomovic et al., 2008, Leinonen et al., 2008). The ideal approach would involve comparison of postmortem measurements of Aβ with PIB in NCs, but these data are extremely difficult to obtain, and nearly impossible to obtain with a short delay between scanning and autopsy in NC individuals. To our knowledge, one study directly comparing PIB uptake with postmortem levels of Aβ in cognitively normal controls has been published (Sojkova et al., 2011). In this study, 3 of the 6 NC subjects showed slightly elevated pre-mortem PIB values and had a moderate CERAD rating in at least 1 of 3 regions examined at autopsy. Although limited by sample size, this data suggests that low levels of PIB uptake in NCs may reflect the presence of low quantities of Aβ deposition before AD-comparable levels are reached.

Given the limited data in older NCs, it is not surprising that a consensus regarding “PIB+” categorization is not established. For example, some groups have treated PIB as a continuous variable (Mormino et al., 2009, Pike et al., 2007) whereas other groups have dichotomized subjects into PIB- and PIB + groups (Aizenstein et al., 2008, Dickerson et al., 2009, Fotenos et al., 2008, Jack et al., 2008, Rowe et al., 2010). A cutoff value for group dichotomization is avoided by treating PIB as a continuous variable, however, the skewed distribution of this variable violates the assumptions of least-square regression and it is likely that there are low PIB values that merely reflect noise. Furthermore, there is variability in categorization approaches amongst studies that dichotomize into PIB + and PIB- groups [hierarchical clustering (Rowe et al., 2010), iterative outlier removal (Aizenstein et al., 2008), etc.]. Moreover, classification into PIB + and PIB- is often dependent on the distribution of PIB values present in the NC group under investigation rather than on a group of subjects lacking Aβ deposition. Therefore, we cannot be confident that resulting PIB- subjects are definitively negative for Aβ.

To this end, we acquired PIB-PET data from a group of subjects 20 to 30 years of age under the assumption that these individuals have no Aβ deposition and therefore the corresponding PET signal should only reflect noise. Although the age at which Aβ deposition begins is unknown, it has been shown that deposition is minimally present in early life. For instance, Braak and Braak reported that only 1 of 61 subjects below age 35 had any evidence of Aβ (Braak and Braak, 1997). Furthermore, a separate study reported 7 of 114 subjects under age 50 had sparse CERAD ratings; no subjects under age 50 had moderate or frequent plaques (Kok et al., 2009). It is therefore highly unlikely that 20–30 year olds will have appreciable Aβ deposition and therefore are an appropriate representation of true PIB- scans. Thus, the goal of this study was to investigate the presence of slightly elevated PIB values by employing different techniques to define positive scans and evaluate the likelihood that slight elevations in PIB uptake represent biologically significant Aβ deposition.