RELATIONSHIPS BETWEEN TAU BURDEN MEASURED USING AV1451 PET, REGIONAL CEREBRAL GLUCOSE METABOLISM, AND COGNITIVE STATUS

Abstract

In amyloid positive (Am+) subjects at all stages of the AD pathway, the expression of an AD-like pattern of hypometabolism detected using a multivariate FDG classifier correlates with the rate of subsequent cognitive decline (Figure 1), supporting clinical trial enrichment. However, the pathology underlying Am+ subjects negative for an AD-like pattern is unknown. Using AV1451 PET scans, we studied the temporal and spatial relationship between FDG AD-like pattern expression and tau burden with the goal of understanding these differences. The AV1451 scans of 36 ADNI2 subjects (Table 1) were downloaded with their closest MRI, AV45, FDG, CSF Abeta, tau, and ptau, demographic, and cognitive data. Regions of interest were measured in structures aligned with Braak stages I–VI (Scholl, 2016). SUVRs were calculated using cerebellar cortex (AV1451) and pons (FDG), and Z-scores generated using Normal Am- references. FDG scans were scored for expression of an AD-like pattern using a multivariate AD Progression classifier (FDG CV1). AV1451 and FDG PET scores and patterns were compared across diagnostic and amyloid classes, and between subjects who expressed an AD like FDG pattern vs. those who did not. Using a threshold of z-score ≥2, only NL and SMC subjects with Am+ PET were Tau PET+ with Braak stage-like progression. Most Tau- subjects were negative for a FDG CV1 pattern. Compared to Am-Tau- subjects, Tau+ subjects expressed a tau pattern highly similar to AD hypometabolism (FDG CV1 pattern), differing in sensorimotor cortex (Figure 2). In Tau+ subjects, greater FDG CV1+ pattern expression was associated with greater deposition in FDG CV1 regions (Figure 3). Two of three Am+Tau+ subjects who were FDG CV1- had atypical, asymmetric tau patterns or relatively minimal tau burden and showed corresponding atypical hypometabolism (Figure 4). Regional glucose metabolism decline is associated with tau deposition in this preliminary data set, consistent with other findings (Ossenkoppele, 2016). Typical vs. atypical tau patterns and their extent may help to explain the correlation between FDG CV1 and subsequent rate of clinical decline, and to understand whether cognitive decline arises from tau or the extent of neurodegenerative response to burden. a) FDG CV1 pattern: Blue = hypometabolism, Red = hypermetabolism (preservation), relative to whole brain. Higher CV1 score corresponds to greater pattern expression. b) 36 month MMSE scores for Late MCI subjects stratified by baseline CV1. Subjects negative for AD-like pattern at baseline typically remain stable in contrast to higher scoring subjects who decline at greater rates. SPM-t comparison of Am+ Tau+ subjects with AD-like FDG CV1 vs. Am- Tau- subjects (p<0.005 uncorrected, N=5 Tau+,9 Tau-). Comparison of Am+ Tau+ subjects who exhibit AD-like hypometabolism vs. those who do not. AV1451 scan of Am+ Tau+ EMCI subject with atypical deposition pattern superimposed on MRI reference (with two different axial slices). Subject was negative for a typical AD-like pattern, but had hypometabolism in regions overlapping those with tau, including amygdala, lingual gyrus, fusiform gyrus, parahippocampus, and additionally in cerebellum and subcortical white matter relative to pons. Brightest color intensity corresponds with greater tau z-score (z = 4 to 5).