Measurement of longitudinal β-amyloid change with 18F-florbetapir PET and standardized uptake value ratios.
The accurate measurement of β-amyloid (Aβ) change using amyloid PET imaging is important for Alzheimer disease research and clinical trials but poses several unique challenges. In particular, reference region measurement instability may lead to spurious changes in cortical regions of interest. To optimize our ability to measure (18)F-florbetapir longitudinal change, we evaluated several candidate regions of interest and their influence on cortical florbetapir change over a 2-y period in participants from the Alzheimer Disease Neuroimaging Initiative (ADNI).


METHODS
We examined the agreement in cortical florbetapir change detected using 6 candidate reference regions (cerebellar gray matter, whole cerebellum, brain stem/pons, eroded subcortical white matter [WM], and 2 additional combinations of these regions) in 520 ADNI subjects. We used concurrent cerebrospinal fluid Aβ1-42 measurements to identify subgroups of ADNI subjects expected to remain stable over follow-up (stable Aβ group; n = 14) and subjects expected to increase (increasing Aβ group; n = 91). We then evaluated reference regions according to whether cortical change was minimal in the stable Aβ group and cortical retention increased in the increasing Aβ group.


RESULTS
There was poor agreement across reference regions in the amount of cortical change observed across all 520 ADNI subjects. Within the stable Aβ group, however, cortical florbetapir change was 1%-2% across all reference regions, indicating high consistency. In the increasing Aβ group, cortical increases were significant with all reference regions. Reference regions containing WM (as opposed to cerebellum or pons) enabled detection of cortical change that was more physiologically plausible and more likely to increase over time.


CONCLUSIONS
Reference region selection has an important influence on the detection of florbetapir change. Compared with cerebellum or pons alone, reference regions that included subcortical WM resulted in change measurements that are more accurate. In addition, because use of WM-containing reference regions involves dividing out cortical signal contained in the reference region (via partial-volume effects), use of these WM-containing regions may result in more conservative estimates of actual change. Future analyses using different tracers, tracer-kinetic models, pipelines, and comparisons with other biomarkers will further optimize our ability to accurately measure Aβ changes over time.
Helen Wills Neuroscience Institute, University of California, Berkeley, California Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California slandau@berkeley.edu.
Susan M
SM
Landau
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
Allison
A
Fero
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
Suzanne L
SL
Baker
Radiology Department, University of Michigan, Ann Arbor, Michigan.
Robert
R
Koeppe
Avid Radiopharmaceuticals, Inc., Philadelphia, Pennsylvania; and.
Mark
M
Mintun
Banner Alzheimer's Institute, Phoenix, Arizona.
Kewei
K
Chen
Banner Alzheimer's Institute, Phoenix, Arizona.
Eric M
EM
Reiman
Helen Wills Neuroscience Institute, University of California, Berkeley, California Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
William J
WJ
Jagust
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000814:Aniline Compounds; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001931:Brain Mapping / Q000379:methods; D002531:Cerebellum / Q000473:pathology; D005026:Ethylene Glycols; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007700:Kinetics; D008137:Longitudinal Studies; D008297:Male; D059906:Neuroimaging / Q000379:methods; D011149:Pons / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D012016:Reference Values; D015203:Reproducibility of Results
D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D015415:Biomarkers; D005026:Ethylene Glycols; D019275:Radiopharmaceuticals; C545186:florbetapir
Alzheimer’s disease; PET imaging; amyloid