In this prospectively observed cohort of nondemented older adults, we found longitudinal increases in fibrillar Aβ deposition as detected by [11C]PiB-PET. Change in Aβ varied across individuals, with some showing no change and others showing annual increase as high as 11.2 % over 2.1 year follow-up. Variability in the annual rate of change was affected by global cDVR at initial PiB-PET, and increases were greater in nondemented older adults with elevated Aβ level compared with minimal Aβ level at the initial evaluation. The ROI analysis showed that longitudinal increases in [11C]PiB retention were observed in the prefrontal, parietal, lateral temporal, occipital and anterior and posterior cingulate regions.
Using cDVR as a global index of [11
C]PiB retention, we found increases in fibrillar Aβ deposition over time. This finding, together with a prior report of serial changes in [11
provides evidence of longitudinal increases in Aβ deposition in nondemented older adults. The mean overall rate of increase in cortical [11
C]PiB retention was only 0.011 DVR per year, a 0.9% increase from baseline DVR. Combined with findings by Jack et. al.4
, this suggests that the overall magnitude of change in [11
C]PiB retention in older adults, at least over short follow-up, is small.
However, we observed variability in rates of change in [11
C]PiB retention. On an individual level, we observed increases up to 11.2% DVR over 2.1 years, exceeding the +/− 6.2 % test-retest variability reported for the simplified reference tissue model in [11
C]PiB-PET studies20, 22
. On the other hand, some nondemented older adults show no increases in [11
C]PiB retention. To further investigate this variability, we evaluated whether increases in [11
C]PiB retention over time differ from the initial [11
C]PiB retention. Annual change in cDVR was significantly greater in older adults with an elevated [11
C]PiB retention compared to minimal [11
C]PiB retention at the initial PET scan. Cortical distribution volume ratio increased by a mean of 0.03 per year in older adults with elevated cDVR at initial evaluation, whereas those with minimal initial [11
C]PiB retention showed no significant increase over time. These differential rates of [11
C]PiB retention are consistent with models of longitudinal change proposing variable rates of Aβ deposition in nondemented older adults13, 23
Understanding factors that explain the variability in level and change over time in [11
C]PiB retention may help differentiate between normal aging and cognitive impairment. Several models propose that accelerated Aβ deposition predicts which individuals will convert to AD13, 14, 23, 24
. However, in the present study, 5 of 19 individuals who remain cognitively healthy (e.g. CDR = 0) show longitudinal increases greater than 0.02 DVR per year, values comparable to increases in [11
C]PiB retention in the 4 older adults with CDR=0.5. Continued prospective follow-up of this cohort will determine whether individuals with greater change in [11
C]PiB retention will ultimately show accelerated cognitive decline and will clarify the relationships between trajectories of Aβ deposition, age, and cognitive status.
Investigation of the regional patterns of longitudinal increases in [11
C]PiB retention is especially important in the group of nondemented older adults with lower and more localized regions of [11
C]PiB retention. Except for the medial temporal gyrus, annual increases in [11
C]PiB retention were observed in most cortical regions. These increases were detected not only in those with elevated baseline cDVR but also in the whole group of nondemented older adults. Of the cortical regions, the posterior cingulate gyrus had the highest annual increase in [11
C]PiB retention of 1.3% DVR. Increases in [11
C]PiB retention in the orbitofrontal gyrus were significant only when older adults with elevated vs minimal baseline cDVR were compared, suggesting that at least in this sample, the magnitude of increase in [11
C]PiB retention in the orbitofrontal gyrus may be relatively low compared with that in other regions. These findings extend those of previous cross-sectional studies8, 9
of early Aβ deposition and may provide insights into the relationships of global and regional Aβ deposition with cognitive decline25
and changes in brain networks10, 26
This study has several limitations. Given the small magnitude of annual change in [11C]PiB retention and its variability, investigation of large numbers of nondemented older adults is needed to understand the role of Aβ deposition in the context of neuropsychological, genetic, and biomarker data. Longer term follow-up is needed to investigate the trajectories of [11C]PiB retention and provide data about progression of disease. Nevertheless, this study of a well-characterized, prospectively observed community based sample provides detailed evaluation of [11C]PiB retention changes in nondemented older adults, including the regional patterns of changes in [11C]PiB retention.
The findings of increased [11
C]PiB retention over time have several implications. First, the study suggests that over short-term follow-up, Aβ deposition may be a gradual process, at least in nondemented adults. Second, there is substantial variability in the rates of [11
C]PiB retention among nondemented older adults, which underscores the potential utility of the measure. Older adults with minimal baseline [11
C]PiB deposition have little increase in [11
C]PiB retention over time and, as such, may represent the 20% to 56% of nondemented individuals with no or minimal amounts of Aβ on postmortem evaluation11, 27
. Third, given the small magnitude of overall change over time, regionally directed investigations may provide a better understanding of the interrelationship of AD biomarkers, cognition, and ultimately the molecular and cellular mechanism underlying the earliest stage of Aβ deposition. Larger samples with longer follow-up will be neeeded to better characterize the trajectories of fibrillar Aβ deposition in vivo and to define factors that render some individuals vulnerable and others resilient to Aβ deposition.