Changes in brain function occur years before the onset of cognitive impairment.
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.
Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei 100, Taiwan, Department of Radiology, Johns Hopkins Hospital, Baltimore, Maryland 21287, and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224.
Lori L
LL
Beason-Held
Joshua O
JO
Goh
Yang
Y
An
Michael A
MA
Kraut
Richard J
RJ
O'Brien
Luigi
L
Ferrucci
Susan M
SM
Resnick
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology* / Q000523:psychology; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging*; D002560:Cerebrovascular Circulation / Q000502:physiology; D003072:Cognition Disorders / Q000000981:diagnostic imaging* / Q000523:psychology; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D013997:Time Factors