Reisa Sperling Preclinical Criteria Alzforum

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Reisa Sperling Preclinical Criteria Alzforum

  1. 1. Toward defining the preclinical stages of Alzheimer’s disease Recommendations from the NIA/Alzheimer’s Association Preclinical Workgroup Reisa Sperling, M.D. Center for Alzheimer’s Research and Treatment Brigham and Women’s Hospital Massachusetts General Hospital Harvard Medical School
  2. 2. Disclosures/Funding Consultant to : Janssen, Elan, Pfizer/Wyeth, Bristol-Myers-Squibb, Link, Bayer, Eisai, Roche, Avid (unpaid) Clinical Trial Site Investigator: Bristol-Myers-Squibb, Janssen, Elan, Pfizer/Wyeth, Avid Research funding from: National Institute on Aging: P01AG036694; P50AG005134 R01AG027435; K24AG035007 Alzheimer’s Association American Federation of Aging Research American Health Assistance Foundation
  3. 3. Preclinical Workgroup Reisa Sperling , Brigham and Women’s Hospital (Chair) Paul Aisen , University of California, San Diego Laurel Beckett , University of California, Davis David Bennett, Rush University Medical Center Suzanne Craft, VA Puget Sound Health Care System Anne Fagan , Washington University Takeshi Iwatsubo, University of Tokyo Cliff Jack , Mayo Clinic Jeffrey Kaye, Oregon Health Science University Thomas Montine , University of Washington Denise Park , University of Texas, Dallas Eric Reiman , Banner Alzheimer’s Institute Chris Rowe, University of Melbourne Eric Siemers , Eli Lilly and Company Yaakov Stern , Columbia University Kristine Yaffe , University of California, San Francisco Maria Carrillo, Bill Thies , Alzheimer’s Association Tony Phelps , Mollie Wagster, Marcelle Morrison-Bogorad, NIA
  4. 4. Background <ul><li>Converging evidence that the pathophysiological process of AD begins years, perhaps more than a decade, prior to the diagnosis of dementia </li></ul><ul><li>This long preclinical phase of AD provides a critical opportunity for potential intervention with disease-modifying therapy </li></ul><ul><li>Need to elucidate the link between the pathophysiological process of AD and the emergence of the clinical syndrome, and determine the best predictors of clinical decline </li></ul>
  5. 5. “ Redefining” Alzheimer’s disease <ul><li>“ Alzheimer’s disease” refers in some contexts to: </li></ul><ul><ul><li>Neuropathological criteria </li></ul></ul><ul><ul><li>Clinical syndrome, usually at the stage of dementia </li></ul></ul><ul><li>Dissociation between these connotations particularly salient as we move to earlier stages </li></ul><ul><li>Both the pathophysiological process (AD-P) and clinical symptomatology of AD (AD-C) are best conceptualized as a continuum, and may evolve in parallel but temporally offset trajectories. </li></ul>
  6. 6. Terminology for Stages of AD <ul><li>Much discussion on the optimal term for this stage of AD: </li></ul><ul><ul><li>Asymptomatic </li></ul></ul><ul><ul><li>Presymptomatic </li></ul></ul><ul><ul><li>Pre-MCI </li></ul></ul><ul><ul><li>Latent AD </li></ul></ul><ul><li>Preclinical – best captures the continuum from asymptomatic individuals to very early symptomatology but not yet meeting MCI criteria </li></ul>
  7. 7. Years Cognitive function Aging MCI AD Dementia The continuum of Alzheimer’s disease } Preclinical Asymptomatic Early symptomatic Sperling et al Alzheimer & Dementia 2011 NIA-AA Preclinical Workgroup
  8. 8. Concept of preclinical stage of disease <ul><li>Multiple examples in other diseases: </li></ul><ul><ul><li>Carcinoma in situ </li></ul></ul><ul><ul><li>Coronary artery disease detected on cardiac catheterization </li></ul></ul><ul><li>Symptoms not required to diagnose disease </li></ul><ul><ul><li>Renal insufficiency or liver cirrhosis often detected by blood test </li></ul></ul><ul><ul><li>Treatment can prevent emergence of symptoms </li></ul></ul><ul><li>Not all individuals with risk factor or early pathology will manifest symptoms </li></ul><ul><ul><li>Hypercholesterolemia/Atherosclerosis </li></ul></ul>
  9. 9. Challenge in AD <ul><li>Do not yet have definitive evidence linking the pathologic process of AD to the emergence of clinical symptoms </li></ul><ul><li>Hypothesize that amyloid-  is an early inciting event that is necessary but may not be sufficient to cause the clinical syndrome of AD </li></ul><ul><li>Likely multiple factors which mediate the relationship between AD pathologic change and clinical manifestations </li></ul>
  10. 10. Brain and cognitive reserve ? Environmental factors Hypothetical model of AD pathophysiological cascade ? Sperling et al Alzheimer & Dementia 2011 NIA-AA Preclinical Workgroup Cerebrovascular risk factors Other age-related brain diseases Age Genetics Amyloid-  Accumulation Synaptic Dysfunction Glial Activation Tangle Formation Neuronal Death Cognitive Decline
  11. 11. Amyloid-  accumulation  (CSF/PET) Synaptic dysfunction (FDG-PET/fMRI) Tau-mediated neuronal injury (CSF) Brain structure (volumetric MRI) Cognition Clinical function Clinical Disease Stage Normal Abnormal MCI Preclinical Dementia Figure adapted from Jack et al. 2010 Sperling et al Alzheimer & Dementia 2011
  12. 12. Evidence to date from genetic- and age-at-risk cohorts <ul><li>CSF A   and PET imaging evidence of amyloid positivity in “normal” individuals associated with: </li></ul><ul><ul><li>Synaptic dysfunction on fMRI and FDG </li></ul></ul><ul><ul><li>Elevated CSF tau and phospho-tau </li></ul></ul><ul><ul><li>Cortical thinning/hippocampal atrophy </li></ul></ul><ul><li>Variable findings of decreased cognitive performance in A  + normals </li></ul><ul><li>Few studies to date suggesting increased risk of cognitive decline and progression to dementia </li></ul>
  13. 13. Caveats <ul><li>Majority of data from highly selected cohorts </li></ul><ul><ul><li>High education and socio-economic background </li></ul></ul><ul><ul><li>“ Volunteer” gene </li></ul></ul><ul><ul><li>Self-selection due to concerns about memory or family history </li></ul></ul><ul><li>Biomarkers are only “proxies” for the underlying pathologic process </li></ul><ul><ul><li>Markers of fibrillar A  may not reflect oligomeric </li></ul></ul><ul><li>Relationship between biomarkers and cognition may vary across age and genetic cohorts </li></ul>
  14. 14. Draft Operational Research Criteria for Preclinical AD <ul><li>Intended to provide a common language and framework for researchers for: </li></ul><ul><ul><li>Longitudinal natural history studies to determine whether the presence of Aβ, either in isolation or in combination with additional markers of neurodegeneration, is predictive of cognitive decline </li></ul></ul><ul><ul><li>Clinical trials of potential disease modifying agents to investigate effects on biomarker progression and/or the emergence of clinical symptoms </li></ul></ul>
  15. 15. Staging Framework for Preclinical AD
  16. 16. Operational Research Criteria for Preclinical AD <ul><li>Not intended as clinical diagnostic criteria </li></ul><ul><li>Prognostic utility of these biomarkers in individual subjects remains unclear </li></ul><ul><li>Some individuals with evidence of AD neuropathological changes will not develop clinical symptoms during life </li></ul>
  17. 17. Urgency <ul><li>Definitive studies to prove (or disprove) these hypotheses may take more than a decade </li></ul><ul><li>Need to estimate the likelihood and timeframe of progression to AD to weigh risk/benefit ratio of potential disease-modifying treatment in normal individuals </li></ul><ul><li>Secondary prevention trials in preclinical populations already in planning stages: </li></ul><ul><ul><li>Dominantly Inherited Alzheimer Network </li></ul></ul><ul><ul><li>Alzheimer Prevention Initiative </li></ul></ul><ul><ul><li>Anti-Amyloid Treatment in Asymptomatic AD (A4) </li></ul></ul>
  18. 18. Thank you Workgroup Alzheimer Association Cliff Jack Maria Carillo Paul Aisen Bill Thies David Bennett Anne Fagan Yaakov Stern NIA Eric Siemers Tony Phelps Tom Montine Molly Wagster Suzanne Craft Marcelle Morrison-Denise Park Bogorad Laurel Beckett Cerise Elliot Kristine Yaffe Neil Buckholtz Jeffrey Kaye Chris Rowe Takeshi Iwatsubo

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