Changes in brain function occur years before the onset of cognitive impairment

Abstract

To develop targeted intervention strategies for the treatment of Alzheimer's disease, we first need to identify early markers of brain changes that occur before the onset of cognitive impairment. Here, we examine changes in resting-state brain function in humans from the Baltimore Longitudinal Study of Aging. We compared longitudinal changes in regional cerebral blood flow (rCBF), assessed by (15)O-water PET, over a mean 7 year period between participants who eventually developed cognitive impairment (n = 22) and those who remained cognitively normal (n = 99). Annual PET assessments began an average of 11 years before the onset of cognitive impairment in the subsequently impaired group, so all participants were cognitively normal during the scanning interval. A voxel-based mixed model analysis was used to compare groups with and without subsequent impairment. Participants with subsequent impairment showed significantly greater longitudinal rCBF increases in orbitofrontal, medial frontal, and anterior cingulate regions, and greater longitudinal decreases in parietal, temporal, and thalamic regions compared with those who maintained cognitive health. These changes were linear in nature and were not influenced by longitudinal changes in regional tissue volume. Although all participants were cognitively normal during the scanning interval, most of the accelerated rCBF changes seen in the subsequently impaired group occurred within regions thought to be critical for the maintenance of cognitive function. These changes also occurred within regions that show early accumulation of pathology in Alzheimer's disease, suggesting that there may be a connection between early pathologic change and early changes in brain function.

Figure 1.

Study design. In the initial phase of the neuroimaging study, annual resting-state PET scans were administered through follow-up year 8 of the study. Participants also performed a battery of cognitive tests each year. A group of participants developed initial symptoms of cognitive impairment on an average corresponding to year 11 (symptom onset, mean ± SD, 10.9 ± 3.7 years from baseline; n = 22). Changes in brain activity before the onset of impairment were assessed in CI (scan interval examined, mean ± SD, 7.0 ± 1.7 years) and compared with those who remained CN (scan interval examined, mean ± SD, 7.4 ± 1.5 years; n = 99) throughout the study.

Figure 2.

Group differences at baseline. Axial slices showing regions where the CI group exhibited higher rCBF (red) and lower rCBF (blue) at the baseline assessment relative to the CN group. The higher rCBF in left occipital cortex (slice 2) and the lower rCBF in the right precentral gyrus (slice 4) did not remain significant after correction for MRI tissue volume.

Figure 3.

Longitudinal changes in rCBF. Regions showing differences in longitudinal rates of rCBF changes for the CI group relative to the CN group are shown on sagittal sections of the brain. Areas in yellow represent regions where CI show greater increases in rCBF over time relative to CN; areas in blue represent regions where CI exhibit greater decreases in rCBF over time. The group difference in insular decline (slice 4) did not remain significant after MRI tissue volume correction.

Figure 4.

Regional trajectories of rCBF change. The CI group shows different trajectories of rCBF of change over time relative to the CN group. Estimated trajectories of longitudinal change are shown for regions of greater rCBF increase in the CI group (orbitofrontal and anterior cingulate regions) and greater rCBF decrease in the CI group (parieto-occipital and lingual regions). All changes were linear in nature.