title: Optimizing regions-of-interest composites for capturing treatment effects on brain amyloid in clinical trials.
abstract: BACKGROUND
  Pittsburgh Compound B (PiB) positron emission tomography (PET) neuroimaging is a powerful research tool to characterize amyloid evolution in the brain. Quantification of amyloid load critically depends on (i) the choice of a reference region (RR) and (ii) on the selection of regions of interest (ROIs) to derive the standard uptake value ratios (SUVRs).
  
  
  OBJECTIVE
  To evaluate the stability, i.e., negligible amyloid accumulation over time, of different RRs, and the performance of different PiB summary measures defined by selected ROIs and RRs for their sensitivity to detecting longitudinal change in amyloid burden.
  
  
  METHODS
  To evaluate RRs, cross-sectional and longitudinal analyses of focal regional and composite measures of amyloid accumulation were carried out on the standardized PiB-PET regional data for cerebellar grey matter (CER), subcortical white matter (SWM), and pons (PON). RRs and candidate composite SUVR measures were further evaluated to select regions and develop novel composites, using standardized 2-year change from baseline.
  
  
  RESULTS
  Longitudinal trajectories of PiB4-average of anterior cingulate (ACG), frontal cortex (FRC), parietal cortex, and precuneus-demonstrated marked variability and small change from baseline when normalized to CER, larger changes and less variability when normalized to SWM, which was further enhanced for the composite in PON-normalized settings. Novel composite PiB3, comprised of the average SUVRs of lateral temporal cortex, ACG, and FRC was created.
  
  
  CONCLUSIONS
  PON and SWM appeared to be more stable RRs than the CER. PiB3 showed compelling sample size reduction and gains in power calculations for clinical trials over conventional PiB4 composite.
authors.affiliation: Janssen Research & Development LLC, Pharmaceutical Companies of Johnson & Johnson, USA.
authors.forename: Volha
authors.initials: V
authors.lastname: Tryputsen
authors.affiliation: Janssen Research & Development LLC, Pharmaceutical Companies of Johnson & Johnson, USA.
authors.forename: Allitia
authors.initials: A
authors.lastname: DiBernardo
authors.affiliation: Janssen Research & Development LLC, Pharmaceutical Companies of Johnson & Johnson, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Samtani
authors.affiliation: Janssen Research & Development LLC, Pharmaceutical Companies of Johnson & Johnson, USA.
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Novak
authors.affiliation: Janssen Research & Development LLC, Pharmaceutical Companies of Johnson & Johnson, USA.
authors.forename: Vaibhav A
authors.initials: VA
authors.lastname: Narayan
authors.affiliation: Janssen Research & Development LLC, Pharmaceutical Companies of Johnson & Johnson, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Raghavan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000682:Amyloid / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D008137:Longitudinal Studies; D008297:Male; D059906:Neuroimaging / Q000379:methods*; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: D000682:Amyloid
keywords: ${11}^C$-PiB; Alzheimer's disease; amyloid imaging; brain; pons