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Human Amyloid-beta Imaging in Alzheimer’s Disease: Future Tracer Development. Chet Mathis. Departments of Radiology, Pharmacology, and Pharmaceutical Sciences University of Pittsburgh. Funding and Conflicts • NIH: NIA & NIMH • Alzheimer’s Association • US Department of Energy
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Human Amyloid-beta Imaging in Alzheimer’s Disease:Future Tracer Development Chet Mathis Departments of Radiology, Pharmacology, and Pharmaceutical Sciences University of Pittsburgh
Funding and Conflicts • • NIH: NIA & NIMH • • Alzheimer’s Association • • US Department of Energy • Dana Foundation • • GE Healthcare • - licensed technology from University of Pittsburgh • - conflict of interest as a co-inventor of technology • - PiB is freely available to academic investigators, but its • commercial use is subject to GE Healthcare approval Acknowledgments and Disclosures
AD Brain Frontal Cortex Elderly Control Brain Frontal Cortex X-34 The Definitive Biomarkers of AD: Amyloid-b Plaques & Neurofibrillary Tangles Imaged With the Highly Fluorescent Dye X-34 X-34 X-34 NFT Cerebral Amyloid Angiopathy Ab Plaque
Ab(1-40) Ki = 2 nM Ab(1-40) Ki = 300 nM Neutral Thioflavin-T Analogues HO H C S S C H 11CH3 3 3 N N + C H N H N 3 C H 3 Thioflavin-T [11C]PiB Klunk et al., Life Sci 2001; Mathis et al., Bioorg Med Chem Lett 2002; Klunk et al., J Neurosci 2003; Mathis et al., J Med Chem 2003; Klunk et al., Ann Neurology 2004; Mathis et al., Curr Pharm Design 2004
[11C]PiB in AD and Control Appearance inexpected graymatter areas Very littleretention Absence inareas wherethere isno amyloid Absence ofretention ingray matter
Dynamic Range of [11C]PiB 120% difference in signal in PCG of ave. AD vs ave. Control SUVR 2.4 0 Lopresti et al., J Nucl Med 2005; 46:1959-72
Time Future Clinical Imaging in Dementia MCI Normal Aging AD Cognitive Function Future Imaging Current Imaging Adapted from Small et al., Lancet Neurol 2008
Anticipated MCI Findings with PiB Control MCI AD
MCI’s Cover the Range of Amyloid Load Lopresti et al., J Nuclear Medicine 2005
Amyloid-Positivity Predicts Clinical Conversion in MCI -Forsberg et al., Neurobiol Aging 2008 -Wolk et al., Annals of Neurology2009 -Okello et al., Neurology 2009 -Rowe et al., ICAD 2009 1-2 years of follow-up in 115 MCI PiB+ AD Converters: 47/76 = 62% PiB- AD Converters: 2/39 = 5%
AD range Control AD Cntl range Frontal Parietal Lat. Temp Precuneus Mesial Temp Subcort. WM Some Elderly Controls are “PiB+”
Frequency of PiB+ Among Elderly Healthy Controls: AIBL Study n = 177 Age = 73.6 ± 7.6 MMSE = 28.8 ± 1.2 3.5 3.5 3.0 3.0 2.5 2.5 Neocortical SUVR40-70 Neocortical SUVR40-70 33% 2.0 2.0 1.5 1.5 1.0 1.0 HC ICAD 2009 V. Villamagne and C. Rowe
Prevalence of PiB+ in Cognitively Normal Aging • Overall 20-40% prevalence >60 y/o normal controls • 60-90 y/o increasing prevalence with age • <55 y/o very low occurrence • Caveats • PiB+ designation is somewhat artificial because amyloid exists • in a continuum in the brain • The detection threshold of PiB+ is not known
Logan DVR 2.0 1.0 Longitudinal Studies of a Cognitively Normal Elderly Control Baseline 1 Yr 2 Yr
3.4 3.4 3.4 3.2 3.2 3.2 3.0 3.0 3.0 2.8 2.8 2.8 2.6 2.6 2.6 2.4 2.4 2.4 2.2 2.2 2.2 2.0 2.0 2.0 1.8 1.8 1.8 1.6 1.6 1.6 1.4 1.4 1.4 1.2 1.2 1.2 1.0 1.0 1.0 0 0 0 20 20 20 37 37 37 Longitudinal PiB PET Follow-up Data Ab Burden Change from Baseline: AIBL Study Ctrl (n=65) MCI (n=35) AD (n=29) 1-4% per year Neocortical SUVR40-70 <1% per year Time (months) ICAD 2009 V. Villamagne and C. Rowe
Early Detection of Amyloid Deposits • Will become very important if effective therapies are available to prevent or slow AD progression • Current therapies showing the most promise • Active or passive Ab anti-body immunization • b- or g-Secretase inhibitors • Peripheral sink approaches
Clearance APP g Ab Immunization Peripheral Sinks b # # Secretases Beta-Amyloid OLIGOMERS 1 2 Secretase Inhibitors PLAQUE NEUROTOXICITY Toxicity FIBRIL (b-pleated sheet) 3 Anti-oxidants, Vits E&C BRAIN INFLAMMATION Anti-Amyloid Therapeutic Targets
0.3 0.2 0.1 Change in [11C]PiB p = 0.003 0 -0.1 -0.2 Baseline 20 45 78 Week Change in Fibrillar Amyloid-β Load in Alzheimer’s Disease Subjects Treated with the Anti-body Bapineuzumab Phase II Results Rinne et al., Lancet Neurology 2010
Correlating PiB Retention In Vivo with A Levels Determined Post-Mortem CASE #1 • 61 year old female with severe AD • Followed for 1 year at Univ. of Pittsburgh ADRC • MMSE = 1 at last visit • Died 10 months after PiB scan Ikonomovic et al., Brain 2008
Correlation of PiB Retention In Vivo with A Levels Determined Post-Mortem Ikonomovic et al., Brain 2008
PiB Retention In Vivo Corelates Well with A Levels Determined Post-Mortem Frozen Tissue (right hemisphere) Frozen Tissue (right hemisphere) 2.6 2.0 In Vivo PiB Retention (DVR) 1.4 r = 0.73, p<0.0028 0.8 0 2.0 1.0 1.5 0.5 Total Insoluble Ab (pmol/mg tissue) Ikonomovic et al., Brain 2008
Ongoing Studies with PiB • World-wide • •>60 PET sites presently conducting PiB studies • •>8,000 PiB scans performed • Univ Pittsburgh • •>600 PiB scans performed • •Conducting longitudinal studies in normal aging, MCI & AD • •Correlating with FDG scans and cognitive scores • • Correlating PiB scans with post-mortem analyses • Selected World Sites • •Utilizing as a biomarker in anti-Ab drug trials
PiB for Amyloid Imaging • Two areas for improvement: • 20 min half-life of 11C radiolabel • non-specific retention in white matter
Studies with 18F-Labeled Amyloid Tracers • • Greater distribution potential than 11C-radiolabel • 110 min vs 20 min half-life • • Phase III human studies in progress at Avid, GEHC • & Bayer-Schering
1 8 F O H H C S 3 H N N C H 3 1 8 H N O F C H 3 N 1 8 O O H N O F O O New 18F-Labeled Amyloid Radiotracers KD = 2.2 nM AD brain 2007 [18F]3’F-PIB / GE-067 flutemetamol 2007 KD = 6.7 nM AD brain [18F]AV-1 / BAY94-9172 florbetaben 2008 KD = 3.1 nM AD brain [18F]AV-45 florbetapir
[18F]florbetaben AD Elderly Control Rowe et al., Lancet Neurol 2008;7:129–35
[18F]florbetapir Control AD Images courtesy of Dan Skovronsky, Avid Radiopharmaceuticals
2.5 2.5 0.5 0.5 Comparison of [18F]flutemetamol and [11C]PiB in the same control and AD subject CONTROL AD SUVR [18F]flutemetamol 90-120 min SUVR [11C]PiB 40-90 min
70% 120% AD AD 75% 69% 66% AD AD 75% 75% 36% NC NC NC NC Signal : AD vs. Normal Control in PCG Sub-CorticalWhite Matter Retention 3.0 2.5 SUVR 2.0 1.5 1.0 [11C]PiB [18F]florbetaben(BAY94-9172) (AV-1) [18F]flutemetamol(GE-067) (3’-F-PiB) [18F]florbetapir (AV-45) Wong et al., 2008 Lopresti et al., 2005 Mathis et al., 2007 Rowe et al., 2008 Ichise et al., 2008 Lin et al., 2010
Time Future Clinical Imaging in Dementia MCI Normal Aging AD Cognitive Function Future Imaging Current Imaging Adapted from Small et al., Lancet Neurol 2008
Future Challenges • Develop selective and potent NFT radioligands to complement Ab radioligands • Conduct definitive longitudinal studies to fully elucidate the time course and linkage of Ab deposition to cognitive decline • Define the detection sensitivity of Ab imaging agents in terms of regional concentrations of insoluble and total Ab • Use Ab imaging to identify subjects who would most benefit from anti-Ab therapies and document the efficacy of anti-Ab therapies and subsequent patient improvement or stabilization
Amyloid Imaging Project Collaborators • ADRC • Steve DeKosky, prev. Director • Oscar Lopez, current Director • Milos Ikonomovic • Ron Hamilton, Bill Paljug • GEHC • Gill Farrar • Kim Gallagher • PET Facility • Julie Price • Scott Mason • Daniel Holt • Brian Lopresti • Guo-feng Huang • Molecular Neuropharm Lab • Bill Klunk • Manik Debnath • Li Shao
[18F]FDDNP: 10% Increase in Signalin MTC of AD vs Control(binds to both Ab plaques and NFT) Shoghi-Jadid et al., AJGP 2002;10:24-35 Small et al., NEJM 2006;355:2652-63