Association of hypometabolism and amyloid levels in aging, normal subjects

Abstract

Objective: We evaluated the relationship of amyloid, seen on Pittsburgh compound B (PiB)-PET, and metabolism, seen on [(18)F]-fluorodeoxyglucose (FDG)-PET, in normal subjects to better understand pathogenesis and biomarker selection in presymptomatic subjects.

Methods: Normal participants (aged 70-95 years; 600 with PiB-PET, FDG-PET, and MRI) were included. We performed a cross-sectional evaluation and subcategorized participants into amyloid-negative (<1.4), high-normal (1.4-1.5), positive (1.5-2.0), and markedly positive (>2.0) PiB standardized uptake value ratio groups representing different levels of amyloid brain load. Associations with metabolism were assessed in each group. Relationships with APOE ε4 carriage were evaluated.

Results: Hypometabolism in "Alzheimer disease (AD)-signature" regions was strongly associated with PiB load. Hypometabolism was greater with more positive PiB levels. Additional, more-diffuse cortical hypometabolism was also found to be associated with PiB, although less so. No hypermetabolism was seen in any subset. No significant incremental hypometabolism was seen in APOE-positive vs -negative subjects.

Conclusions: Hypometabolism in PiB-positive, cognitively normal subjects in a population-based cohort occurs in AD-signature cortical regions and to a lesser extent in other cortical regions. It is more pronounced with higher amyloid load and supports a dose-dependent association. The effect of APOE ε4 carriage in this group of subjects does not appear to modify their hypometabolic "AD-like" neurodegeneration. Consideration of hypometabolism associated with amyloid load may aid trials of AD drug therapy.

Figure 1. Global cortical PiB vs regional FDG

Age- and sex-adjusted mean FDG within each PiB group for the 47 regions of interest. The regions are sorted by level of significance. The estimates assume an 80-year-old subject and represent the average FDG for both men and women. The right side of the plot indicates the FDR-corrected p value for a “dose-effect” test of whether the log of PiB is associated with regional FDG after accounting for age and sex. FDG = [¹⁸F]-fluorodeoxyglucose; FDR = false discovery rate; PiB = Pittsburgh compound B.

Figure 2. ROI analysis of hypometabolism stratified by APOE status

Age- and sex-adjusted mean FDG for APOE ε4 carriers and noncarriers by region. The regions are sorted by level of significance based on unadjusted p values. The estimates assume an 80-year-old subject with PiB of 1.4 and represent the average FDG for both men and women. The first column of p values on the right side of the plot is FDR-corrected p values from a test of APOE after adjusting for age, sex, and PiB. The second column shows unadjusted p values. An asterisk is used to indicate regions in which APOE was significant at the p < 0.10 level after adjusting for age and sex but not PiB. FDG = [¹⁸F]-fluorodeoxyglucose; PiB = Pittsburgh compound B; ROI = region of interest.

Figure 3. Regional hypometabolism associated with regional PiB

Age- and sex-adjusted mean FDG within each regional PiB tertile. The regions are sorted by level of significance. The estimates assume an 80-year-old subject and represent the average FDG for both men and women. The right side of the plot indicates the FDR-corrected p value for a “dose-effect” test of whether the log of regional PiB is associated with regional FDG after accounting for age and sex. FDG = [¹⁸F]-fluorodeoxyglucose; FDR = false discovery rate; PiB = Pittsburgh compound B.

Figure 4. Theoretical relationship of brain amyloid load and hypometabolism in AD

Theoretical dose relationship of brain amyloid load (blue SUVR) and hypometabolism (red SUVR) predicted in normal subjects from these data. The biomarker relationships are estimated for relative to future disease status categorizations as “early symptoms” and “dementia” on the x-axis timeline. The SUVR projections are based on the initial SUVR relationships starting at a PiB SUVR of 1.5 and thereafter projected based on previously determined yearly change rates for PiB and FDG SUVR values in this population. AD = Alzheimer disease; FDG = [¹⁸F]-fluorodeoxyglucose; PiB = Pittsburgh compound B; SUVR = standardized uptake value ratio.