The Australian Imaging Biomarkers and Lifestyle Flagship Study of - PowerPoint PPT Presentation

The Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing . (AUSTRALIAN ADNI) July 2013 UPDATE – Imaging Christopher Rowe MD – Neuroimaging stream leader

June 2013 The Australian Imaging 58 new participants Biomarkers and AV-45 Lifestyle Flagship Study Replacement Funded anon of Ageing. MCI and sMC 102 new participants Flutemetamol Funded by GE October 2006 Women ’ s Healthy Aging 105 new participants Florbetaben Program Funded by Bayer/Piramal 83 participants Flutemetamol Funded by GE 92 participants 823 not imaged 738 not imaged 632 not imaged AV-45 Original Funded anon Cohort 390 not imaged 288 imaged 230 imaged 172 imaged 141 participants MRI + 11C-PiB MRI + 11C-PiB MRI and 11C-PiB MRI and 11C-PiB Funded by CSIRO Funded by CSIRO Funded by SIEF Funded by SIEF 0 yrs 1.5 yrs 4.5 yrs 3 yrs 968 remain 824 remain 718 remain plus 1112 recruited 268 new

The Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing. 3 year Data Release 221 subjects (HC, MCI, AD) with baseline PiB PET and MRI now with 3 year clinical data - 1.5 and 3 year PiB PET in 173 with MRI in 148 - Data and Samples www.adni.loni.ucla.edu - Access Data

540 research groups granted access to AIBL@LONI through ADNI website Finland Sweden China Taiwan Denmark Japan UK Hong Kong Ireland Korea Germany Australia France New Zealand Spain Italy India Canada Belgium Pakistan USA Netherlands Saudi Arabia Colombia Switzerland Iran Mexico Poland Cuba Algeria Argentina Egypt Bulgaria Israel Turkey Includes access granted to the following companies : Abbott Labs, Abiant, ADM diagnostics, Astra Zeneca, Avid, BioClinica, Biogen Idec, Bristol-Myers Squibb, Cogstate Cytokinetics, Eisai, Elan, Eli Lilly, GE Health Care, General Resonance, Genetech, Imorphics, Iris Biotechnologies, Janssen, Johnson Johnson, M and M Scientific, Merck & Co, Mimvista, Pentara Corp, Pfizer, Philips, Predixion software, Rancho Biosciences, Servier, Siemens, Soft team solutions, UCB, United Biosource Corp.

PiB neocortical SUVR 3.00 Neocortical SUVR 2.50 99% 68% 31% 2.00 1.50 1.00 HC MCI AD 1.40 ± 0.4 1.91 ± 0.6 2.30 ± 0.4 ( n = 195 ) ( n = 92 ) ( n = 79 ) (n = 366)

Longitudinal PiB PET 6-year follow-up 2.8 78 yo HC male ( e 3/ e 3) 74 yo HC female ( e 3/ e 3) MMSE 25 2.5 MMSE 26 Neocortical SUVR MCI MCI MMSE 28 MMSE 29 MCI MMSE 29 MMSE 29 2.2 HC MMSE 30 MMSE 29 HC HC HC HC MMSE 29 MMSE 29 HC HC 1.9 73 yo HC female ( e 3/ e 3) 1.6 1.3 MMSE 29 MMSE 29 HC MMSE 30 MMSE 30 HC MMSE 29 1.0 HC HC HC 20 45 70 Time (months)

Relation between baseline A b burden and rates of A b deposition 3-5 year follow-up 0.06 0.05 Rate of A b deposition 0.04 0.03 0.02 0.01 R 2 = 0.23 ( p<0.0001 ) 0.00 1.0 1.5 2.0 2.5 3.0 Baseline A b burden

Rate of A b deposition vs MMSE 3-5 year follow-up HC 0.10 MCI Rate of A b deposition AD 0.05 0.00 -0.05 R 2 = 0.08 ( p=0.0006 ) 30 25 20 15 Baseline MMSE

The natural history of A b deposition in sporadic AD MCI + 3.0 AD HC+ Neocortical SUVR cb 2.5 * Mean SUVR AD+ (2.33) 2.0 0.043 SUVR/yr (95%CI 0.037-0.049 SUVR/yr) 1.5 19.2 yr (95%CI 17-23 yrs) Mean SUVR HC- 12.0 yr (1.17) (95%CI 10-15 yrs) 1.0 HC MCI- 0 10 20 30 40 - Time (years)

Relationship between “ abnormality ” and CDR of 1.0 CDR 1.0 abnormal A b deposition Hippocampal volume Episodic memory Biomarker magnitude Grey matter volume Non-memory cut-off normal -30 -25 -20 -15 -10 -5 0 Time (years) non-demented demented

Risk of decline over 3 years: Positive vs negative amyloid scan HC MCI ( n=183 ) ( n=87 ) 77% (46/60) to AD 25% 29% (8/27) to MCI/AD to dementia POSITIVE NEGATIVE NEGATIVE POSITIVE ( n=27) (n=130) (n=53) (n=60) Odds Ratio 4.8 Odds Ratio 7 (p = 0.001) ( p< 0.001) (OR increases to 14 if non-AD dementia removed)

MCI to AD over 3 years (n=87; 59% progressed) MCI positive Odds Ratio PPV NPV for marker 48 HV 4 0.67 0.65 ApoE- e 4 50 5 0.74 0.66 61 CVLT<-1.5 11 0.80 0.74 60 PiB 15 0.77 0.82 PiB+ e 4 47 16 0.79 0.81 35 PiB+HV 44 0.83 0.90 na 43 PiB+ CVLT 0.86 1.00

Predictive value of low (<1.4) vs intermediate vs high (>1.9) PiB binding 3.00 Neocortical SUVR PPV 82% 2.50 PPV 35% 2.00 PPV 17% PPV 44% 1.50 1.00 HC MCI AD ( n = 183 ) ( n = 87 ) ( n = 79 ) RASAD March 2012

CVLT-II Delayed Recall over 36 mths 14 14 PiB -ve n =122, SUVR = 1.16 12 12 Mild Cognitive Impairment 10 10 CVLT-II Delayed Recall PiB -ve 8 PiB +ve 8 n = 16, SUVR = 1.18 n = 55, SUVR = 1.95 Healthy Older Persons 6 6 PiB +ve n = 32, SUVR = 2.21 4 4 2 2 Baseline 18 months 36 months Baseline 18 months 36 months

Initial A b burden is a better predictor of progression from MCI to AD than the rate of A b accumulation Rates of A b deposition p = 0.001 p < 0.0001 A b burden non-converters converters non-converters converters OR = 5.4 OR = 15

17-23yrs Preclinical Stage CDR 1 1 2 3 Abnormal 5-8yrs 9-12yrs Biomarker magnitude 1-3yrs 1-2yrs A b Amyloid Neuronal Injury Cognitive Symptoms Cut-points Normal Cognitively Normal MCI Dementia Clinical disease stage

HC to MCI or AD over 3 years (n=183; 13% progressed) HC positive OR PPV NPV for marker 46 HV 2.2 0.20 0.90 74 e4 2.1 0.18 0.91 22 EM<-0.5 4.2 0.32 0.90 53 PiB 4.8 0.26 0.93 34 PiB+e4 5.7 0.29 0.93 17 PiB+HV 10 0.47 0.92 10 PiB+EM 16 0.50 0.94 AIBL composite EM Z-score <-1 (n=49), OR 11, PPV 35%, NPV 96% without correction for age or education.

Future Directions for AIBL Imaging • Further refine prognostic value and comparative effectiveness of imaging biomarkers • Replace 11 C-PiB with 18 F-NAV4694 • Add Tau imaging • Create a new pool of amyloid scan positive HC and MCI for early intervention trials • Use AIBL infrastructure to support the A4 and DIAN therapy trials

Tau, Aβ and glucose metabolism in Alzheimer's disease patient 18 11 [ F]FDG 18 [ F]THK - 5105 [ C] PiB 0 1.5 3 0 0.6 1.2 0 1 2 SUVR SUVR SUVR

Acknowledgements and thanks AIBL is a large collaborative study and a complete list of contributors and the management committee can be found at www.aibl.csiro.au This research is funded in part by the Science and Industry Endowment Fund. We thank all who took part in the study.