Transcript GO/ADNI 2 MRI protocol
MRI ICAD 2010
Outline
ADNI 1 - Summarize most important results – internal and external ADNI investigators From ISAB summary of reasoning and pilot work behind final GO/ADNI 2 protocol Summarize QC procedures for new sequences Summarize parameters of sequences
Previous ADNI session
Dx, prediction, rates of change, sample size
Brewer/Dale – Freesurfer Barnes/Fox Schuff – all the above also APOE and CSF effects
ADNI 1 image analysis results
MRI has better longitudinal power to detect change than clinical instruments, resulting in smaller sample sizes for clinical trials in both MCI and AD patients Provided sample size estimates for powering clinical trials for MCI and AD, comparing various methods Measurement method matters: some MRI analysis methods had greater longitudinal power than others best performing MRI measures overall TBM, BSI, Freesurfer greater white matter hyperintensity load in AD than control and in MCI than control subjects who would be typically enrolled in therapeutic trials [Carmichael] use as co variate in clinical trials
Hua et al
Sample Sizes per Arm Needed to Power Treatment Study in AD/MCI
Citation Holland et al 2009 (51) Hua et al 2010 (52) Leung et al 2010 (53) Schuff et al 2009 (54) Vemuri et al 2010 (50) Wolz et al 2010 (55) Subjects 129 AD 299 MCI 50 AD 122 MCI 81 AD 96 AD 226 MCI 71 AD 149 MCI 126 AD 279 MCI Source of subjects Referral sample ADNI Referral sample ADNI Referral sample ADNI Referral sample ADNI Referral sample ADNI Referral sample ADNI Measurement Method Ctx thickness ERC ROI TBM temporal lobe KN-BSI Hippocampal volume (SNT), model includes 3 scans, Markov chain, APOE Ventricular –BSI Simultaneous 4D graph Segmentation Sample size required to detect treatment effects Assuming 24 month trial, 25% effect size, 80% power, scans every 6 mo; 45 AD per arm; 135 MCI per arm Assuming 12 month trial, 25% effect size, 80% power; 43 AD per arm; 82 MCI per arm Assuming 12 month trial, 25% effect size, 80% power; 81 AD per arm Assuming 12 month trial, 25% effect size, 90% power; 186 AD per arm; 341 MCI per arm Assuming 12 month trial, 25% effect size, 80% power, 2-sided 2 sample t-test at 0.05; 100 AD per arm; 186 MCI per arm Assuming 12 month trial, 25% effect size, 80% power, 2-sided 2 sample t-test at 0.05; 67 AD per arm; 206 MCI per arm
Cross Sectional Separation of Clinically Diagnosed AD vs. Controls
Citation Subjects Gerardin et al 2009 (27) Neuroimage CN 25 AD 23 Hinrichs et al 2009 (28) CN 94 AD 89 Kohannim et al 2010 (30) CN 213 AD 158 McEvoy et al 2009 (31) CN 139 AD 84 Walhovd et al. 2010 (32) 42 CN, 38 AD Source of subjects Referral sample ADNI Referral sample ADNI Referral sample ADNI Referral sample ADNI Referral sample ADNI Measurement Method Hippocampal shape metric Multi voxel classifier Multi voxel classifier Ct thickness; med and lat temporal, isthmus cingulated orbito frontal Ct thickness 85% Results Sens 96%, spec 92% AUROC 0.88
AUROC 0.89
Sens 83%, spec 93%
ADNI 1 image analysis results
MRI rates of change in cognitively normal subjects are greater in APOE e4 carriers than non-carriers [Schuff, 2009; Morra, 2009; Fjell, 2010] lower CSF A 42 was associated with a thinner cortex in cognitive healthy controls [Tosun, 2010] No difference between 1.5T and 3T in group-wise discrimination or sample sizes needed to power trials [Ho, 2009]
Association between low baseline CSF A
1-42 concentrations and cortical thickness in cognitive normal elderly
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Tosun, 2010
CSF AB and decreased brain volume in cognitively normal elderly (CDR 0) Fagan et al Annals 2009
Dynamic Biomarkers of the Alzheimer’s Pathological Cascade
Jack et al, Lancet Neurol 2010; 9: 119-28 Ab Amyloid = CSF Ab42 or amyloid PET imaging; Tau Mediated Neuron Injury and Dysfunction = CSF tau or FDG PET; Brain Structure = structural MRI
Annual change in global PIB ratio and ventricular volume by clinical diagnosis
PIB positive subjects (baseline global cortical PIB ≥ 1.5) are represented with triangles and PIB negative subjects (baseline global cortical PIB < 1.5) are represented with circles. Jack et al, Brain 2009 132 (Pt 5):1355-65
ADNI: Predicting time to conversion from MCI to AD from baseline biomarkers – univariately
Vemuri et al Neurology 2009 Model summaries from age-adjusted Cox proportional hazards models of time from aMCI to AD. The biomarker enters the model as restricted cubic spline with three knots.
Biomarker STAND-score Aβ 1-42 log(t-tau) Model χ 2 (P)*
19.0 (<0.001) 8.2 (0.02) 6.8 (0.03)
Nonlinearity χ 2 (P)†
1.5 (0.22) 5.4 (0.02) 5.0 (0.03)
Q3 vs. Q1 HR (95% CI) ‡
2.6 (1.7, 4.2) 0.8 (0.5, 1.3) 1.7 (1.1, 2.6)
C-index
0.69
0.62
0.60
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log(p-tau 181P ) log(t-tau/Aβ 1-42 )
6.6 (0.04) 11.0 (0.004) 1.5 (0.22) 8.5 (0.004) * 3 degree of freedom likelihood ratio test of biomarker significance given that age is in the model 1.8 (1.1, 2.9) 2.0 (1.1, 3.4) † 1 degree of freedom likelihood ratio test of nonlinearity of biomarker effect given that age is in the model ‡ Hazard ratio (95% CI) comparing the third quartile (75th percentile) to the first quartile (25th percentile) of the biomarker.
0.61
0.62
§ The concordance index (C-index) in a survival model is analogous to the AUROC in a logistic model and represents the estimated probability the model will correctly predict which of two patients has the longer time until conversion from aMCI to dementia.
Effect of APOE on biomarkers •AB chaperone •Hypothesis is e4 would selectively affect amyloid biomarker Vemuri et al, ePub Annals of Neurology, 2010
Conclusions concerning image corrections
Metric is sample size per arm to detect a 25% rate reduction in AD – question is, do image corrections reduce technical variance in a meaningful way?
3D Grad warp ~ 10% SS reduction (Gunter, Med Phys, 2009) Scaling correction ~ 12% SS reduction (Clarkson, NI, 2009), image registration (vs phantom) is preferred method Intensity correction improves longitudinal precision – esp multi array coils and 3T (Leow NI 2006; Boyes, NI 2008)
Conclusions ADNI phantom
value of scanner monitoring - 20% of all ADNI-1 scans would have been affected by errors of various types had each scanner not been monitored [Gunter, 2009] Designed ADNI phantom. Has been adopted as the starting point for quantitative MRI phantom by ISMRM and NIST
Outline
ADNI 1 - Summarize most important results – internal and external ADNI investigators From ISAB summary of reasoning and pilot work behind final GO/ADNI 2 protocol Summarize QC procedures for new sequences Summarize parameters of sequences
GO/ADNI 2 MRI protocol - rational
ADNI 1 carry forward subjects: methodological consistency
maintain MRI
same 1.5T scanner, using ADNI 1 1.5T protocol Discontinue dual 3T/1.5T scans for those in “3T arm”
new GO/ADNI 2 enrollees: protocol modernize and expand MRI
3T limit ~ 30-40 minutes (limits # possible sequences in protocol) only product sequences – ie no WIPs Core protocol on all scanners, and vendor specific “experimental” sub studies
GO/ADNI 2 MRI 3T Protocol
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3D T1 volume unaccelerated Phillips, IR SPGR GE) (MPRAGE Siemens and 3D T1 volume 2X accelerated FLAIR long TE 2D gradient echo Experimental: Siemens (ASL), GE (DTI), Phillips (resting state EPI-BOLD) Phantom (once per day if > 1 ADNI patient)
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GO/ADNI 2 MRI Core Protocol
All newly enrolled GO (and ADNI 2) subjects All vendor systems 3D T1 volume (MPRAGE Siemens and Phillips, IR SPGR GE) Each MRI exam will contain both an accelerated and a non accelerated 3D T1 acquisition – * not back-to-back, (3.6%) exam “salvage rate” FLAIR (instead of PD/T2) – better measures of WMH long TE 2D gradient echo clinical trials population?
(e.g., TE = 20 ms) acquisition for micro hemorrhage detection what is natural history (prevalence and incidence) if MCH and superficial siderosis in a
Comparison 3T 3D T1 35 yo volunteer Phillips MPRAGE unaccel 9:06 Phillips MPRAGE accel 5:35 GE MPRAGE (ADNI-1) 9:17 GE IR-FSPGR (ADNI-GO) 9:41 GE IR-FSPGR (ADNI-GO) 5:34
Micro Hemorrhages Long TE gradient echo scan Superficial Hemosiderosis
GO/ADNI 2 experimental sub-studies – every subject gets one type
*vendor specific – each not done in every subject Why? (1) impossible to standardize without WIPs, (2) no product available, (3) limit 30 - 40 min arterial spin labeling (ASL) perfusion - Siemens diffusion tensor imaging (DTI) – GE resting state functional connectivity – Phillips purpose - to evaluate the feasibility of acquiring useful data in a multi-center (but single vendor) setting - are these techniques useful for clinical trials? Mission of ADNI.
QC of experimental sequences
Will only repeat exam for quality failure of un accelerated 3D T1 more scans with quality problems in GO/ADNI 2 than ADNI 1 QC information will be more important Raw images vs maps Raw images – QCed at Mayo for protocol compliance, completeness, head coverage, bulk motion, susceptibility artifacts Maps QCed by individual labs (Thompson, DeCarli, Jack, Schuff) that upload numeric data
DTI - Color Coded FA Maps
From Kantarci et al, in press Neurology
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GO/ADNI 2 protoocls
http://www.loni.ucla.edu/ADNI/Research/Cores/inde x.shtml