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Clifford R. Jack, Jr., Dept Radiology Mayo Clinic Rochester MN

Serial Combined PIB PET and MRI in Alzheimer's Disease or Biomarkers of the Alzheimer's pathological cascade and clinical expression. Clifford R. Jack, Jr., Dept Radiology Mayo Clinic Rochester MN. Diagnosis of AD. Current criteria - McKhann 1984 Dementia

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Clifford R. Jack, Jr., Dept Radiology Mayo Clinic Rochester MN

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  1. Serial Combined PIB PET and MRI in Alzheimer's DiseaseorBiomarkers of the Alzheimer's pathological cascade and clinical expression Clifford R. Jack, Jr., Dept Radiology Mayo Clinic Rochester MN

  2. Diagnosis of AD • Current criteria - McKhann 1984 • Dementia • Progressive worsening of memory and other cognitive functions - abstract thinking, judgment, language, etc. • No disturbance of consciousness • Absence of other brain disease that could account for decline -- ie diagnosis of exclusion • Loss of functional independence • based solely on clinical grounds • Two-state model: AD pathology and clinical symptoms are synonymous

  3. No pathology pathology Dementia Relationship between AD pathology and dementia syndrome The two state view of early 1980’s normal D Knopman

  4. Imaging of “Two State” View AD 4 3 2 1 0 Control

  5. New knowledge since 1984 • Demographics – 1% 60s; 30% 80s; 50% 90s • Overlap with other pathologies – CVD, Lewy body Dz • Onset of dementia is gradual  intermediate cognitive state (MCI), not normal but not demented • AD syndrome vs AD pathology • 30% of cognitively normal elderly have AD pathology at autopsy – esp. amyloid plaques • Genetics & molecular pathways – amyloid cascade hypothesis • Different types of AD path have different relationships to symptoms – amyloid plaques vs NFT vs neurodegeneration • Biomarkers of AD path developed and validated • Temporal order of AD pathology and biomarkers

  6. New knowledge since 1984 • Demographics – 1% 60s; 30% 80s; 50% 90s • Overlap with other pathologies – CVD, Lewy body Dz • Onset of dementia is gradual  intermediate cognitive state (MCI), not normal but not demented • AD syndrome vs AD pathology • 30% of cognitively normal elderly have AD pathology at autopsy – esp. amyloid plaques • Genetics & molecular pathways – amyloid cascade hypothesis • Different types of AD path have different relationships to symptoms – amyloid plaques vs NFT vs neurodegeneration • Biomarkers of AD path developed and validated • Temporal order of AD pathology and biomarkers

  7. No pathology pathology Dementia Relationship between AD pathology and dementia syndrome The two state view of early 1980’s normal D Knopman

  8. Dementia The concept of Alzheimer’s disease across the cognitive continuum 2010 Biomarker & Clinical Biomarker Biomarker & Clinical normal Mild Cognitive Impairment D Knopman

  9. Objectives • to describe, and provide evidence in support, of a dynamic biomarker based model of AD progression • To place the role of biomarkers within this context • Clinical • Therapeutic trials

  10. AD Pathology: 4 categories • Amyloid plaques • Neurofibrillary tangles • Inflammation • Neurodegeneration • Loss, shrinkage of dendritic tree, synapses, neurons • Clinical symptoms * NFT and neurodegeneration are both neuronal processes and occur in same topographic distribution

  11. Imaging & CSF Biomarkers; 4 classes • Brain Amyloidosis • PET - amyloid plaque imaging • CSF AB 1-42 • Neuronal dysfunction and tau mediated injury • CSF t-tau and p-tau • FDG PET • Functional MRI (activation and resting state) • Neurodegeneration • Structural MRI • MR Spectroscopy • Diffusion MRI • Perfusion MRI • Inflammation – PET & MRS Biomarker Reviews Hampel, Alzheimer’s Dement 2008 Shaw, Nat Rev Drug Discov 2007

  12. Model of disease staging based on PIB & MRI Publications in 2008 and early 2009 • 11C PIB and Structural MRI Provide Complementary Information in Imaging of AD and Amnestic MCI.Brain 2008;131(Pt 3):665-680 • Serial PIB and MRI in normal, MCI, and AD: implications for sequence of pathological events in AD.Brain 2009 132(Pt 5):1355-65 • Objective: understand temporal relationships amyloid, neurodegeneration, cognition • 11C PIB biomarker of amyloid load • structural MRI biomarker of stage of neurodegeneration • Mormino et. al. Brain 2009; 132(Pt 5):1310-23

  13. Cross sectional group-wise comparison global cortical PiB and hippocampal volume Jack et al, Brain 2008;131:665-680

  14. Cross sectional group-wise comparison global cortical PiB and hippocampal volume Jack et al, Brain 2008;131:665-680

  15. Annual change in global PIB ratio and ventricular volume by clinical diagnosis Mayo plus ADNI data Jack et al , Brain 2009 132 (Pt 5):1355-65

  16. Summary: Data derived from imaging consistent with model of typical late onset AD with 3 main features • significant plaque deposition occurs prior to neuro degeneration and clinical decline • Dissociation: Change in cognition is closely coupled to rate of neurodegenerative progression, not to rate of amyloid deposition • Bi-phasic disease process: amyloid dynamic early vs. neurodegeneration dynamic mid to late stage Brain 2008;131(Pt 3):665-680, and Brain 2009 132(Pt 5):1355-65

  17. Graphical model of the dynamic biomarkers of AD pathological progression Jack et al, Brain 2009 132 (Pt 5):1355-65 Brain 2009 132(Pt 5):1355-65 Proposed model relating imaging (pathology) and clinical presentation over an individual’s adult lifetime.

  18. Graphical model of the dynamic biomarkers of AD pathological progression Jack et al , Brain 2009 132 (Pt 5):1355-65 Brain 2009 132(Pt 5):1355-65 Proposed model relating imaging (pathology) and clinical presentation over an individual’s adult lifetime.

  19. Expand Model: Imaging & CSF Biomarkers; “big 5” • Brain Amyloidosis • PET - amyloid plaque imaging • CSF AB 1-42 • Neuronal dysfunction and tau mediated injury • CSF t-tau and p-tau • FDG PET • Functional MRI (activation and resting state) • Neurodegeneration • Structural MRI • MR Spectroscopy • Diffusion MRI • Perfusion MRI • Inflammation – PET & MRS Biomarker Reviews Hampel, Alzheimer’s Dement 2008 Shaw, Nat Rev Drug Discov 2007

  20. PIB and CSF AB42roughly equivalent measures of brain amyloid Fagan 2006 Forsberg 2008 Jagust 2009

  21. Evidence tau changes in normal subjects “destined to decline”: PIB and CSF Tau, normal elderlyFagan et al EMBO Molecular Medicine 2009

  22. Evidence brain volume changes in normal subjects “destined to decline” - CSF AB and brain volume in cognitively normal elderly (CDR 0): Fagan et al Annals 2009

  23. Cortical Thickness in PIB + vs – elderly controls: Dickerson et al Cereb Cortex 2009

  24. MRI correlates with cognitive impairment better than CSF Vemuri et al Neurology 2009

  25. Serial Biomarker Measures: MRI dynamic late, CSF tau intermediate:Vemuri Neurology 2010

  26. Non-linearity: Rate of atrophy accelerates as approach dementia: Chan et al, Lancet 2003

  27. temporal ordering of biomarkers • Amyloid imaging [Mintun, 2006; Aizenstein, 2008; Klunk 2004; Rowe 2007; Mormino 2009] • CSF A42 [Peskind, 2006; Shaw, 2009; Fagan, 2007; Li, 2007; Fagan 2009; Vemuri 2009] • CSF tau [Bouwman 2007; de Leon 2006; Wahlund 2003; Stefani 2006; Sluimer 2008; Hansson 2006; Sunderland 1999; Blennow 2003; Vemuri 2009] • FDG PET[Minoshima, 1997; Chetelat, 2002; de Leon, 2001; Reiman, 1996; Small 1995] • MRI [Fox 1997; Fox 1999; Kaye, 1997; Killiany 2000; Dickerson 2009] • Conclusions • Biomarker abnormalities precede clinical symptoms • Amyloid biomarkers become abnormal first • Little evidence for ordering of amyloid imaging vs CSF AB42 • FGD PET changes before MRI [Reiman 1998] • Little evidence for ordering of FDG PET vs CSF tau • MRI last onset but correlates with clinical Sx longest [Vemuri, 2009] • Non-linear functions (over long period) [Chan 2003; Carlson 2008]

  28. 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

  29. Biomarker-based disease modeling • Provides a framework that relates temporal changes in AD biomarkers with clinical disease stage and with each other • Some details of model will undoubtedly change • However, certain principles will stand up • Biomarkers measure specific aspects of AD path • Temporally ordered: amyloid => neuronal => cognition • Temporal ordering: both onset and ceiling; not start-stop but displaced in time • Combination of biomarkers needed for comprehensive staging • Non linear function of time

  30. Objectives • to describe, and provide evidence in support, of a dynamic biomarker based model of AD progression • To place the role of biomarkers within this context • Clinical diagnosis • Therapeutic trials

  31. Diagnostic role of biomarkers in typical late onset AD • Pre clinical – pathology present, but no (minimal) symptoms - biomarkers are only indicator • Amyloid biomarker required, others supportive • Mild Cognitive Impairment • identify etiology of impairment • likelihood that patient will progress to AD in short interval (i.e. time to event) • Dementia (meets clinical criteria for AD dementia) • increase (or decrease) confidence that clinically determined dementia is due to AD pathology

  32. Implications of the pathological specificity of biomarkers for anti amyloid trials in MCI/AD • initiating molecular pathway amyloid dysmetabolism  inclusion should be based on evidence of the presence of amyloid in the brain  amyloid PET imaging or CSF A42 • Target efficacy, amyloid reduction  amyloid biomarker (PET amyloid imaging) • However, objective is to treat brain amyloidosis with intent to affect cognition. Change in Aβ amyloid load over time has little relationship to change in cognition in demented (Elan study) • Cognitive outcome is expensive target – more so in mildly affected • Therapeutic outcome  neurodegenerative measures, MRI, CSF tau, FDG PET

  33. ADNI: sample size per arm to detect a 25% reduction in rate (0 -12 months) of decline in AD MRI,FDG PET, cognitive tests, in AD, n=30

  34. Implications of the pathological specificity of biomarkers for anti amyloid trials in MCI/AD • initiating molecular pathway amyloid dysmetabolism  inclusion should be based on evidence of the presence of amyloid in the brain  amyloid PET imaging or CSF A42 • Target efficacy, amyloid reduction  amyloid biomarker (PET amyloid imaging) • However, objective is to treat brain amyloidosis with intent to affect cognition. Change in Aβ amyloid load over time has little relationship to change in cognition in demented (Elan study) • Cognitive outcome is expensive target – more so in mildly affected • Therapeutic outcome neurodegenerative measures, MRI, CSF tau, FDG PET

  35. Implications of pathological cascade for therapy: treatment vs prevention 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

  36. Implications of pathological cascade for therapy: treatment vs prevention 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

  37. Anti amyloid clinical trials in cognitively normal P Aisen • Are the right subjects enrolled? • Amyloid biomarker for inclusion • Is intervention effective? • Neurodegenerative biomarker for outcome • can be adequately powered with much smaller sample sizes (less expensive) than trials in MCI and AD using conventional clinical endpoints

  38. Dynamic Biomarkers of the Alzheimer’s Pathological Cascade – model for chronic degenerative conditions 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

  39. Acknowledgments • AG11378 • AG19142 • AG16574 • AG06786 • ADNI • Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program • Alexander Family Professorship in Alzheimer's disease research

  40. Ronald C. Petersen* David Knopman Brad Boeve Joe Parisi Walter Rocca Rosebud Roberts Bob Ivnik Glenn Smith Shane Pankratz Yonas Geda Selam Negash Mayo Rochester ADRC and Study of Aging Mayo Jacksonville Dennis Dickson Neil Graff-Radford Tannis Ferman

  41. Kejal Kantarci Jeff Gunter Matthew Senjem Prashanthi Vemuri Jennifer Whitwell Mary Machulda Matt Bernstein Heidi Edmonson Stephen Weigand Heather Wiste Scott Przybelski Guang Zeng Ankit Master Denise Reyes Bret Borowski Greg Preboske Chad Ward Brian Gregg Paul Lewis Kaely Steinert Ramesh Avula Don Gerhart Dan Heard Scott Squires Samantha Wille AJ Spychalla Mayo Aging and Dementia Imaging Research (ADIR) Lab 2010

  42. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade Lancet Neurology 2010; 9: 119-28 Clifford R Jack Jr David S. Knopman William J. Jagust Leslie M. Shaw Paul S. Aisen Michael W. Weiner Ronald C. Petersen John Q. Trojanowski

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