Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB

Abstract

Objective: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Abeta) deposition in vivo in individuals without dementia.

Method: [(11)C]PiB images were obtained to measure fibrillar Abeta burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [(11)C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations.

Results: [(11)C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions.

Conclusions: Higher Abeta deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Abeta deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.

Figures

Figure 1 Distribution of mean cortical [11C]PiB retention in older adults without dementia by tertile of mean distribution volume ratio Individuals in the highest tertile are shown as red triangles, in the middle by black circles, and the lowest by blue squares. The 6 older adults with CDR = 0.5 are shown by circled symbols.

Figure 2 Predicted longitudinal trajectories by tertile of PiB mean distribution volume ratio for cognitive tests showing significant longitudinal decline in association with higher Aβ burden Mean trajectories for each tertile are shown by bolded lines, and trajectories for participants with CDR = 0.5 are shown as dashed lines. (A) Verbal episodic memory, immediate recall (p < 0.01); (B) verbal episodic memory, delayed recall (p < 0.01); (C) Mental Status (p = 0.01); (D) executive function measured by Trails B in CDR = 0 individuals (p = 0.02). Note that higher scores reflect poorer performance for Trails B. CDR = Clinical Dementia Rating; MMSE = Mini-Mental State Examination; VM = verbal memory.

Figure 3 Voxel-based associations between regional Aβ load and slopes of longitudinal changes in episodic memory and mental status (A) CVLT immediate recall; (B) CVLT delayed recall; (C) MMSE. CVLT = California Verbal Learning Test; MMSE = Mini-Mental State Examination.

Figure 4 Voxel-based associations between regional Aβ load and slopes of longitudinal change in executive function Declining performance on Trails B over time is more robustly related to [11C]PiB retention in normal older adults. (A) Whole sample including 6 individuals with Clinical Dementia Rating = 0.5; (B) subset of 51 individuals with CDR = 0.