SUPPLEMENTARY INFORMATION In format provided by Frank et al. (JULY 2010)

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1 Table 1 Imaging bios for Alzheimer s Visual rating High correlation with Multicenter studies have Accuracy for longitudinal hippocampus volume (R 2 been performed, but changes only at chance about 0.9, diagnostic stability has level 1 accuracy for Alzheimer s not systematically been versus controls assessed between 80 and 90% 1, prediction of Alzheimer s in MCI not assessed Hippocampus volume Entorhinal cortex (ERC) Manual volumetry High test-retest reliability 3, diagnostic accuracy for Alzheimer s vs. controls between 80 and 90% 4, prediction of Alzheimer s in MCI with 70 to 80% accuracy 5 Automated volumetry Manual volumetry High correlation with manual volumetry (R 2 > 0.8) 8. Group discrimination Alzheimer s versus Controls 83%, MCI versus Controls 73% (post hoc probability only) 9 No additional benefit in identifying patients with manifest Alzheimer s. Accuracy of prediction of Alzheimer s in MCI increased by a few percent compared Multicenter variability below 5%, low for longitudinal data 6 Atrophy rates of 3-7% per annum in Alzheimer s compared to 0.9%-1.4% in healthy controls 7 Method has been established and applied to small samples, rate of atrophy predicts subsequent cognitive decline in nondemented elderly with about 80% accuracy 10 Rates of ERC atrophy 5- times greater in Alzheimer s than in controls 12 Needs to be systematically analyzed in trials Has already been employed as secondary endpoint in Only small scale studies so far Only employed in small scale studies so far Useful for diagnostic at baseline 2, no use for follow up Best established imaging bio to date; variability of longitudinal needs to be assessed Methods still need major observer input, needs to assessed in larger and samples Probably no added value over hippocampus volumetry in RCT given the laborious methodology

2 to hippocampus volumetry 11 Whole brain volume Regional grey matter Cortical thickness Automated measurement Voxel based morphometry Deformation based morphometry Automated detection based on cortical curvature Main application for longitudinal Consistent pattern of brain atrophy in Alzheimer s and MCI, but lacks an established statistical model to determine individual risk for a single subject Consistent pattern of brain atrophy in Alzheimer s and MCI 16, statistical models for individual risk prediction have been suggested (predicts Alzheimer s in MCI with 80% accuracy) 17, discriminates between MCI and controls with 90% accuracy 18 90% accuracy in the discrimination between Alzheimer s patients and controls 20 Employed in studies, but stability has not systematically been assessed Multicenter variability below 5% for crosssectional data 14, not assessed for longitudinal data Atrophy rate of 2.5% per year in Alzheimer s patients compared to % in healthy controls 13 Accelerated rates of regional grey matter atrophy in patients with MCI who later converted to Alzheimer s 15, no statistical model for risk prediction Spread of atrophy through the brain in Alzheimer s 19, but no individual measure of effect size to interpret the findings of a clinical trial Rates of atrophy on average 0.18 mm per year in Alzheimer s 21 Already employed in in the context of Limited heuristic value due to global nature of measurement Needs a statistical model for individual risk prediction Promising as it assesses changes across the entire brain with high spatial resolution, needs further study in larger mono- and samples Promising endpoint in as it offers a direct assessment of effect sizes expressed in a meaningful metric Basal forebrain Thickness and Significant difference Promising

3 atrophy signal intensity of between Alzheimer s substantia patients and inniminata controls 22, correlates with response to cholinergic treatment 23 BOLD-signal MRS FDG-PET fmri pre-post comparison Single voxel proton spectroscopy, spectroscopic imaging (chemical shift imaging) ROI and voxel based analysis The reliability of fmri data is high within subjects between imaging sessions 24 NAA in the hippocampus is reduced in Alzheimer s and already at the MCI stage in those subjects, who later decline to dementia 29 Good reproducibility of regional values with coefficients of variability about 16.5% for absolute values Scanner differences accounted for less than 10% of the total variability. Quality control protocols exist for longitudinal and multicentre studies 25 Below 5% (NAA) over 5 sites with different MRscanner 30, 31 types Multicenter stability of FDG-PET was shown to be high 33 Specific effects of cholinergic treatment on regional brain activation in attention networks in Alzheimer s 26, 27. Cholinergic treatment led to time dependent changes in hippocampus activation during a face recognition task 28 Increase of NAA during treatment with cholinesterase inhibitors in Alzheimer s. The treatment response correlated with NAA changes and low initial NAA predicted positive treatment outcome 32 Reduction of metabolism about 16-19% over 3 years in association cortices in Alzheimer s compared to no decline in small scale studies Evaluated in studies in the context of Evaluated in studies in the context of predictive for the integrity of the cholinergic systems, requires further validation on clinico-pathologcial studies Promising secondary endpoint due to wide availability. Initial studies on multicentre fmriimaging are positive and appear promising MRS provides complementary information to structural and functional MRI Potentially very stable and valid, however, limited due to costs and availability

4 in normal controls. Effects of piracetam and cholinergic treatment on cortical metabolism in Alzheimer s 34, 35 Amyloid-PET PIB High sensitivity in detecting amyloid plaques and vascular amyloid in human brain in-vivo 36 Cholinergic system PET Acetylcholineesterase s (C-11-N-methyl- 4-piperidylacetate (MP4A) and C-11-N- methyl-4- piperidylpropionate (MP4P)) For all currently available cholinesterase inhibitors at standard clinical dose the average reduction of cerebral AChE activity is in the range of 30 to 40% No further increase of 11C-PIB uptake during progression of Alzheimer s 37 The degree of AChE inhibition was correlated with clinical improvement of cognition in Alzheimer s 38 Potentially, interesting diagnostic pending further follow-up studies in PIB-positive healthy elderly subjects and MCI patients, not clear if useful as a surrogate endpoint Potentially interesting bio to determine the mode of action of a new compound

5 References: 1. Ridha, B.H. et al. Application of automated medial temporal lobe atrophy scale to Alzheimer. Arch Neurol 64, (2007). 2. Devanand, D.P. et al. Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer. Neurology 68, (2007). 3. Byrum, C.E. et al. Accuracy and reproducibility of brain and tissue volumes using a magnetic resonance segmentation method. Psychiatry Res 67, (1996). 4. Jack, C.R., Jr. et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's. Neurology 49, (1997). 5. Wang, P.N., Lirng, J.F., Lin, K.N., Chang, F.C. & Liu, H.C. Prediction of Alzheimer's in mild cognitive impairment: a prospective study in Taiwan. Neurobiol Aging 27, (2006). 6. Jack, C.R., Jr. et al. MRI as a bio of progression in a therapeutic trial of milameline for AD. Neurology 60, (2003). 7. Barnes, J. et al. A meta-analysis of hippocampal atrophy rates in Alzheimer's. Neurobiol Aging 30, (2009). 8. Csernansky, J.G. et al. Preclinical detection of Alzheimer's : hippocampal shape and volume predict dementia onset in the elderly. Neuroimage 25, (2005). 9. Colliot, O. et al. Discrimination between Alzheimer, mild cognitive impairment, and normal aging by using automated segmentation of the hippocampus. Radiology 248, (2008). 10. Rusinek, H. et al. Regional brain atrophy rate predicts future cognitive decline: 6-year longitudinal MR imaging study of normal aging. Radiology 229, (2003). 11. Pennanen, C. et al. Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiol Aging 25, (2004). 12. Ezekiel, F. et al. Comparisons between global and focal brain atrophy rates in normal aging and Alzheimer : Boundary Shift Integral versus tracing of the entorhinal cortex and hippocampus. Alzheimer Dis Assoc Disord 18, (2004). 13. Fox, N.C., Cousens, S., Scahill, R., Harvey, R.J. & Rossor, M.N. Using serial registered brain magnetic resonance imaging to measure progression in Alzheimer : power calculations and estimates of sample size to detect treatment effects. Arch Neurol 57, (2000). 14. Ewers, M. et al. Multicenter assessment of reliability of cranial MRI. Neurobiol Aging 27, (2006). 15. Chetelat, G. et al. Using voxel-based morphometry to map the structural changes associated with rapid conversion in MCI: a longitudinal MRI study. Neuroimage 27, (2005). 16. Thompson, P.M. et al. Cortical change in Alzheimer's detected with a -specific population-based brain atlas. Cereb Cortex 11, 1-16 (2001). 17. Teipel, S.J. et al. Multivariate deformation-based analysis of brain atrophy to predict Alzheimer's in mild cognitive impairment. Neuroimage 38, (2007). 18. Davatzikos, C., Fan, Y., Wu, X., Shen, D. & Resnick, S.M. Detection of prodromal Alzheimer's via pattern classification of MRI. Neurobiol Aging 29, (2006). 19. Thompson, P.M. et al. Tracking Alzheimer's. Ann N Y Acad Sci 1097, (2007).

6 20. Lerch, J.P. et al. Automated cortical thickness measurements from MRI can accurately separate Alzheimer's patients from normal elderly controls. Neurobiol Aging 29, (2008). 21. Lerch, J.P. et al. Focal decline of cortical thickness in Alzheimer's identified by computational neuroanatomy. Cereb Cortex 15, (2005). 22. Teipel, S.J. et al. Measurement of basal forebrain atrophy in Alzheimer's using MRI. Brain 128, (2005). 23. Hanyu, H., Tanaka, Y., Sakurai, H., Takasaki, M. & Abe, K. Atrophy of the substantia innominata on magnetic resonance imaging and response to donepezil treatment in Alzheimer's. Neurosci Lett 319, (2002). 24. Loubinoux, I. et al. Within-session and between-session reproducibility of cerebral sensorimotor activation: a test--retest effect evidenced with functional magnetic resonance imaging. J Cereb Blood Flow Metab 21, (2001). 25. Friedman, L. & Glover, G.H. Report on a fmri quality assurance protocol. J Magn Reson Imaging 23, (2006). 26. Kircher, T.T., Erb, M., Grodd, W. & Leube, D.T. Cortical activation during cholinesterase-inhibitor treatment in Alzheimer : preliminary findings from a pharmaco-fmri study. Am J Geriatr Psychiatry 13, (2005). 27. Bokde, A.L.W. et al. Decreased activation along the dorsal visual pathway after a 3-month treatment with galantamine in mild Alzheimer. J Clin Psychopharmacol 29, (2009). 28. Goekoop, R., Scheltens, P., Barkhof, F. & Rombouts, S.A. Cholinergic challenge in Alzheimer patients and mild cognitive impairment differentially affects hippocampal activation--a pharmacological fmri study. Brain 129, (2006). 29. Chao, L.L. et al. Reduced medial temporal lobe N-acetylaspartate in cognitively impaired but nondemented patients. Neurology 64, (2005). 30. Träber, F. et al. A reproducibility study of single-voxel (1)H-MRS of the medial temporal lobe. Eur Radiol 16, (2006). 31. Jessen, F. et al. A (1)H- MRS study of the medial temporal lobe in AD and MCI. Neurology 72, (2009). 32. Jessen, F. et al. Treatment monitoring and response prediction with proton MR spectroscopy in AD. Neurology 67, (2006). 33. Herholz, K. et al. Comparability of FDG PET studies in probable Alzheimer's. Journal of Nuclear Medicine 34, (1993). 34. Heiss, W.D. et al. Effect of piracetam on cerebral glucose metabolism in Alzheimer's as measured by positron emission tomography. Journal of Cerebral Blood Flow & Metabolism 8, (1988). 35. Teipel, S.J. et al. Effects of donepezil on cortical metabolic response to activation during (18)FDG-PET in Alzheimer's : a double-blind cross-over trial. Psychopharmacology (Berl) 187, (2006). 36. Edison, P. et al. Amyloid, hypometabolism, and cognition in Alzheimer : an [11C]PIB and [18F]FDG PET study. Neurology 68, (2007). 37. Engler, H. et al. Two-year follow-up of amyloid deposition in patients with Alzheimer's. Brain 129, (2006). 38. Bohnen, N.I. et al. Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's. J Neurol Neurosurg Psychiatry 76, (2005).