Association Between Earliest Amyloid Uptake and Functional Connectivity in Cognitively Unimpaired Elderly

Abstract

Alterations in cognitive performance have been noted in nondemented subjects with elevated accumulation of amyloid-β (Aβ) fibrils. However, it is not yet understood whether brain function is already influenced by Aβ deposition during the very earliest stages of the disease. We therefore investigated associations between [18F]Flutemetamol PET, resting-state functional connectivity, gray and white matter structure and cognitive performance in 133 cognitively normal elderly that exhibited normal global Aβ PET levels. [18F]Flutemetamol uptake in regions known to accumulate Aβ fibrils early in preclinical AD (i.e., mainly certain parts of the default-mode network) was positively associated with dynamic but not static functional connectivity (r = 0.77). Dynamic functional connectivity was further related to better cognitive performance (r = 0.21-0.72). No significant associations were found for Aβ uptake with gray matter volume or white matter diffusivity. The findings demonstrate that the earliest accumulation of Aβ fibrils is associated with increased functional connectivity, which occurs before any structural alterations. The enhanced functional connectivity may reflect a compensatory mechanism to maintain high cognitive performance in the presence of increasing amyloid accumulation during the earliest phases of AD.

Keywords: Alzheimer’s disease; [18 f]flutemetamol; dynamic connectivity; resting-state fMRI.

Figure 1.

Brain regions which are most prone to earliest amyloid accumulation as identified in a recent analysis of the ADNI cohort (P < 0.05 FWE-corrected voxel level) (Palmqvist et al. 2017). The average [¹⁸F]Flutemetamol SUVR across these regions was extracted for each subject and used for further analysis.

Figure 3.

Associations between [¹⁸F]Flutemetamol SUVR extracted from regions shown in Fig. 1 and dynamic resting-state functional connectivity, adjusted for the covariates sex, age, APOE ε4 status and presence of SCD (P < 0.05 FWE corrected). Functional connectivity further showed a positive correlation with MMSE scores. Line thickness in connectogram is proportional to association strength (t-values). The r-values denote Pearson correlation coefficients after correction for covariates using regression. After correction the original mean values were added to the residuals to approximate the raw values, thus calculated values are relative and may exceed the maximum of the MMSE. BG, basal ganglia; CER, cerebellum; DA, dorsal attention; DM, default mode (red); FP, frontoparietal (green); FT, frontotemporal; HI, amygdala-hippocampus; SM: somatomotor (blue); VA, ventral attention; VI, visual.

Figure 2.

Dynamic functional connectivity states and number of subjects exhibiting each state (total sample n = 133). Average static (and dynamic) connections across all subjects (and states) showed strong overlap (r = 0.97). For each of the 6 states only those connections are shown, which are stronger than the common ones (i.e., >2 standard deviations stronger than the average). Line thickness is proportional to connectivity strength (z-score). Line thickness of average connections is downscaled by 200 for visualization and only the strongest 20% of connections are shown. See Figure 3 for abbreviations and color code.