1. Agenda: - Update on master tracers’ segmentation check - Update validation vs pathology - PMT application submission of “Study on the validation of VSRAD” (dr M. Nishikawa) - Benchmark: possible issues for platform XI PMT meeting – July 3, 2012

2. Benchmark Images ADNI scans: 2 x 5 Scheltens’s atrophy score x 2 sides x 2 magnet strengths (1.5-3T) Total per rater: 40 hippos 5 Master Tracers’ segmentations: Mapped in overlap on correspondent MRI Checked and reported causes for overlapping discrepancies at 1.5T Improved Harmonized Protocol in many points Masters asked to correct if they agree, or to discuss the issue if they disagree with the corrections

3. Benchmark Images Overlapping agreement Volume ICCs 1.5T images: 0.71 3T images: 0.75

5. Validation vs Pathology

6. Validation versus pathology Tracer (to be defined whether GP will segment all datasets, or if each centre will provide its tracer - waiting for LA answer on privacy issues) Segmentation based on Harmonized Protocol: 60 ante mortem 46 postmortem MRIs 106 images Analysis based on the information available for each dataset Mayo Clinic ~50 AD + MCI + CTRL dataset with pathologically confirmed diagnosis (Braak’s stages), antemortem left hippocampal measurement (Manual and Freesurfer) Only volumetric measures to be shared Mony DeLeon 9 AD + 4 CTRL at 1.5T (T1) 13 postmortem and 2 AD antemortem 9 AD + 1 CTRL at 1.5T (PD) 10 postmortem and 8 AD antemortem (Neuron, plaque and tangle counts, Braak’s stages, abeta, tau, histological volumetry, CA1 definition only on PD), 3mm, coronal, no 3D navigation one side hippocampal measurement (Manual. MIDAS) Images and volumetric measures can be shared Liana Apostolova (23 hippos at 7T) CA1 neuronal counts, tau and Abeta immunoreactivity measures

7. Validation versus pathology Originally designated sample: (Bobinski et al., 2000) 11 AD + 4 CTRL postmortem MRI and quantitative histology de Leon: 9 AD + 4 CTRL at 1.5T (T1) and 9 AD + 1 CTRL at 1.5T (PD) 23 postmortem and 10 AD antemortem Neuron, plaque and tangle counts, Braak’s stages, abeta, tau, histological volumetry (CA1 definition only on PD) 3mm, coronal, no 3D navigation one side hippocampal measurement (Manual, MIDAS) Jack: ~50 AD + MCI + CTRL antemortem MRIs with pathologically confirmed diagnosis (Braak’s stages). Volumes of left Hippocampus (Manual and Freesurfer). No post-mortem hippocampal measurement Liana? 23 (one side only) 7T 60-hour postmortem scans (in progress: CA1 neuronal counts, tau and Abeta immunoreactivity measures)

8. “Study on the validation of VSRAD” Dr. Masami Nishikawa VSRAD (Voxel-based Specific Regional analysis system for Alzheimer’s Disease): automatic VBM-based software for hippocampal atrophy. Project aim: to validate the new version of VSRAD, comparing it versus the Harmonized Protocol as the gold standard method to manually measure hippocampal volume. Subjects: 22 AD, 19 MCI, 18 controls + 3 healthy volunteers that served as human phantoms for the pilot E-ADNI project (Frisoni et al., 2008): scanned by the 7 different machines. Hippocampal segmentations carried out on these subjects will serve not only the aims of the present project, but will also contribute to provide data that will add to the validation of the Harmonized Protocol. PMT application submission

9. Benchmark Maps: CSF exclusion Harmonized Protocol criteria: internal CSF pools must be properly and independently segmented and excluded MultiTracer: using one label generates higher variability in segmentations, since every tracer will "connect" somehow the internal pool to the external CSF Solution: To segment the internal pools with an additional label, that will be used to subtract both volume and segmented voxels.

10. Benchmark Maps: plausible variability

11. Papers describing the project Survey of protocols (preliminary phase; published, JAD 2011) Operationalization (preliminary phase; I revision, Alzheimer’s & Dementia, MS n. ADJ-D-12-00094) Axes check short report (Brescia Team, in progress) Delphi consensus (Brescia Team, in progress) Master tracers’ practice and reliability (Brescia Team, in progr) Development of certification platform (Duchesne and coll) Validation data and Protocol definition + Protocol (Brescia Team) Validation vs pathology (TBD) DONE IN PROGRESS PLANNED

12. VALIDATION VS CURRENT PROTOCOLS ASSESSMENT OF SOURCES OF VARIANCE TRAINING SET DEVELOPMENT VALIDATION VS PATHOLOGY GOLD STANDARD Harmonized Protocol ADNI scans: 2 x 5 Scheltens’s atrophy score x 2 sides x 2 magnet strengths (1.5-3T) Total per rater: 40 hippos Harmonized Protocol ADNI scans: 2 sides x 5 Scheltens’s atrophy scores x 3 time points (bl-1y-2y) x 3 scanners (+ retracing @ bl) x 2 magnet strengths (1.5-3T) Total per rater: 240 hippos Assessment of variance due to rater and center Local Protocol ADNI scans: 2 x 5 Scheltens’s atrophy scores x 2 sides x 2 magnet strengths (1.5-3T) Harmonized Protocol ADNI scans: 2 x 5 Scheltens’s atrophy score x 2 sides x 2 magnet strength (1.5-3T) Total per rater: 40 hippos Harmonized Protocol: Pathological datasets: Mayo Clinic and NYU Total: about 40 hippos Training ADNI scans: 10 at 1.5T x 2 sides x 7 SUs x 2 tracing rounds Total per rater: 40 hippos 20 naïve tracers5 master tracers 1 tracer REFERENCE PROBABILISTIC MASKS with 95% C.I. QUALIFICATION Best 5 naïve tracers Assessment of variance due to side, trace-retrace, atrophy, time, scanner, rater TRAINING SET Assessment of agreement with volume on pathology or ex vivo MRI and correlation with neuronal density

13. GANTT