William Jagust University of California, Berkeley and Lawrence Berkeley National Laboratory Things to Standardize Acquisition Timing, subject state, radiopharmaceutical, instrumentation Reconstruction Processing Scanner differences Radiopharmaceutical differences Quantitation methodology Standardizing Processing Image Standardization Orientation, voxel size, resolution FDG ROI selection Amyloid Imaging Tracers: [11C]PIB, [18F]Florbetapir, [18F]Flutemetamol Processing: ROI Selection, Reference regions, normalization vs native space, templates vs tailored Effects of Processing: FDG (ADNI MCI Patient) Raw 30 min data Baseline 36 month follow up Standard orientation, voxel size 8 mm Resolution Standardized ROIs Identification of ROIs from voxelwise analyses in the literature Peak voxels plotted in MNI coordinates, smoothed, thresholded Post Cingulate Gyrus L Inf Temporal Gyrus L Angular Gyrus R Angular Gyrus R Inf Temporal Gyrus “Meta-ROIs” Hypometabolic Convergence Index (HCI) PALZ T-sum Landau et al Neurobiol Aging 2011 Proportion remaining nondemented Composite “MetaROI” Performance Hypometabolic MCIs Hazard ratio = 2.95 p = 0.02 Baseline FDG vs ADAS-Cog Change FDG Change vs ADAS-Cog Change Landau et al Neurology 2010 Caroli et al, J Nucl Med 2012 FDG-PET in ADNI2/GO (N=931) 60/259 23% positive Frequency 52/209 25% positive 109/220 50% positive 227/243 93% positive MetaROI average 1.22 threshold: 82% sensitivity, 70% specificity for AD vs Controls (Landau et al, Neurology 2010) PIB (2.12) Florbetapir (2.00) PIB+/Florbetapir + (MCI) PIB (1.19) Florbetapir (1.04) PIB-/Florbetapir(Normal) ADNI (Freesurfer) Processing ADNI and Avid Processing Avid Processing ADNI PIB (N=32) GE PIB (N=40) ADNI Florbetapir (N=32) GE Flutemetamol (N=40) ADNI Florbetapir (N=324) AVID Autopsy Data Comparing Tracers 1 same subjects studied with both tracers or 2 Compare 2 tracers to the same third tracer Comparing Methods Analyze data 2 ways ADNI (Freesurfer) Processing Florbetapir and PIB in ADNI • Freesurfer Processing • Cerebellar Gray matter Reference ROI • Mean 1.5 years apart • • • • Cortical ROI: frontal, parietal, cingulate, temporal grey matter average N=32 6 normals 22 MCI (5 converted) 4 AD Cerebellar Grey Reference ROI PIB vs Florbetapir Cerebellar Gray Matter Reference Freesurfer Processing Florbetapir Threshold 1.28 PIB Threshold of 1.47 (Jagust et al, Neurology 2009) PIB and Florbetapir Grey and White Distributions 30 30 PIB White 1.54-2.46 PIB Gray 1-2.68 (mean ± 2stdev) (min, max) 20 20 10 10 1 1.5 30 2 2.5 White Matter Florbetapir White = 1.58 – 2.78 31 30 1.5 2 Gray Matter (min, max) 20 20 10 10 1.5 2 3 Florbetapir Gray = 0.87 – 2.23 (mean ± 2stdev) 1 2.5 2.5 31 1.5 2 2.5 3 Freesurfer: Grey matter vs whole cerebellum 1.13 1.28 1.47 (PIB) = 1.28 (Florbetapir) = 1.13 (Florbetapir, Whole Cerebellum Reference) We can convert from PIB to Florbetapir Values We can convert from a cerebellar grey reference to a whole cerebellar reference How about different processing streams? Avid also works up Florbetapir data - how does their processing compare? And….Avid has imaging-Neuropathology correlations! 1.091.17 Joshi et al J Nucl Med 2012: 1.10 = 95% CI upper interval for subjects < 55 Clark et al, JAMA 2011 324 ADNI subjects Freesurfer processing (whole cerebellar reference) Avid processing (whole cerebellar reference) 1.11 1.10 ADNI GO/2 Florbetapir (N=602) Frequency 56/194 29% positive 1.11 threshold (ADNI Data processed with freesurfer and cerebellar reference) 89/212 42% positive 83/132 63% positive 51/64 80% positive Florbetapir cortical mean Effect of Reference Region PIB-Florbetapir Comparisons (so far) Florbetapir (1.10) Avid Processing 0.9 1.0 Florbetapir (1.13) Freesurfer Whole Cerebellum 1.1 Florbetapir (1.11) Freesurfer Whole Cerebellum 1.2 1.3 Florbetapir (1.28) Freesurfer Cerebellar Gray Autopsy Thresholds 1.4 1.5 PIB (1.47) Freesurfer Cerebellar Gray [18F]Flutemetamol AD Control 40 Subjects (20 AD/20 MCI) Studied with PIB and Flutemetamol as part of GE phase II study PIB and Flutemetamol 1.47 1.47 Flutemetamol: Cerebellar Gray vs Whole Cerebellum 1.20 1.47 Effect of Reference Region PIB-Flutemetamol Florbetapir to Flutemetamol Florbetapir 1.11 (Clark Autopsy Threshold) = PIB 1.27 PIB 1.27 = Flutemetamol 1.21 PIB, Florbetapir, Flutemetamol Autopsy Thresholds Florbetapir (1.10) Avid Processing 0.9 1.0 Florbetapir (1.13) Freesurfer Whole Cerebellum Florbetapir (1.11) Freesurfer Whole Cerebellum 1.1 1.2 Flutemetamol (1.20) Freesurfer Whole Cerebellum 1.3 Florbetapir (1.28) Freesurfer Cerebellar Gray Flutemetamol (1.20) Freesurfer Whole Cerebellum 1.4 1.5 PIB (1.47) Freesurfer Cerebellar Gray Flutemetamol (1.47) Freesurfer Cerebellar Gray PIB Cerebellar Gray Reference = 1.5 Florbetapir Cerebellar Gray Reference = 1.3 Flutemetamol Cerebellar Gray Reference = 1.5 Florbetapir Whole Cerebellar Reference = 1.1 Flutemetamol Whole Cerebellar Reference = 1.2 Florbetapir Autopsy Value = 1.1 Flutemetamol Autopsy value = 1.2 What is not the Case Although numerical values can be compared, that does not mean they are “correct” in detecting Ab Tracer performance characteristics differ in ways we still do not fully understand: false negative and positive rates will differ Factors such as instrument resolution, sensitivity, reconstruction algorithms will affect results These are research-focused analyses and are not ready for clinical prime time Summary Pre-specified FDG ROIs are a statistically powerful analytic tool Analysis of amyloid images is most strongly affected by reference region Processing pipelines don’t seem to make much difference Thresholds for [18F] agents based on either PIB or autopsy results are remarkably consistent Acknowledgements ADNI Susan Landau Bob Koeppe Rick Margolin Mark Schmitt Core Leaders Site PIs Participants Avid Radiopharmaceuticals Dan Skrovonsky Mark Mintun Mike Pontecorvo Abhinay Joshi Chris Breault GE Healthcare Lennart Thurfjell Ben Thomas (UCL)
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