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Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
Marilyn Albert
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Marilyn Albert

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  • 1. MCI due to AD <ul><li>Marilyn S. Albert, PhD </li></ul><ul><li>Department of Neurology </li></ul><ul><li>Johns Hopkins University </li></ul>
  • 2. Disclosures <ul><li>Consultant agreements: </li></ul><ul><ul><li>Genentech </li></ul></ul><ul><ul><li>Lilly </li></ul></ul><ul><li>Completed grants for imaging studies: </li></ul><ul><ul><li>GlaxoSmithKline </li></ul></ul><ul><ul><li>Pfizer </li></ul></ul>
  • 3. Working Group Chair: Marilyn Albert Steve DeKosky Dennis Dickson Bruno Dubois Howard Feldman Nick Fox Maria Carrillo Anthony Gamst Dave Holtzman Bill Jagust Ron Petersen Peter Snyder Tony Phelps Bill Thies Sponsored by NIA and Alzheimer’s Association
  • 4. Charge to Committee <ul><li>Develop criteria for the symptomatic pre-dementia phase of AD </li></ul><ul><ul><li>Decided to use the term ‘MCI due to AD’ as overarching concept </li></ul></ul><ul><li>Encouraged to create criteria that would be regularly re-evaluated and evolve over time as more information is acquired </li></ul>
  • 5. Goals of Committee <ul><li>Develop core set of clinical and cognitive criteria with wide application (community clinicians, tertiary care institutions, academic researchers, clinical trials) </li></ul><ul><li>Use biomarkers to increase certainty of diagnosis for use in specialized settings (academic research, clinical trials) </li></ul><ul><li>Apply current knowledge regarding biomarkers, even though it may be incomplete </li></ul><ul><ul><li>Outline areas where more information is needed </li></ul></ul><ul><ul><li>Incorporate testable hypotheses regarding prodromal phase of Alzheimer’s dementia </li></ul></ul>
  • 6. Overview <ul><li>Describe clinical and cognitive criteria for ‘MCI due to AD’ </li></ul><ul><ul><li>Describe general nature of evaluation </li></ul></ul><ul><ul><li>Outline differences from previous criteria </li></ul></ul><ul><li>Describe framework for approach to biomarkers </li></ul><ul><ul><li>Biomarkers: (1) Abeta, (2) neuronal injury </li></ul></ul><ul><li>Outline criteria for ‘MCI due to AD’ </li></ul><ul><ul><li>Four levels of certainty, depending on nature of biomarker information </li></ul></ul><ul><ul><li>Outline information that remains to be acquired in the future </li></ul></ul>
  • 7. Disease Progression Cognitive Function Progression of Alzheimer’s Disease Pre-clinical MCI due to AD AD Dementia
  • 8. Criteria for MCI due to AD Clinical Presentation – 4 criteria <ul><li>Cognitive Concern : concern about change in cognition (can be from patient, informant or skilled clinician) </li></ul><ul><li>Impairment in one or more cognitive domains : Evidence of lower performance than expected for age and education </li></ul><ul><ul><li>Episodic memory impairment most common but other domains may be affected </li></ul></ul><ul><ul><li>Cut-offs not specified (‘typically’ 1-1.5 SD) </li></ul></ul>
  • 9. Criteria for MCI due to AD Clinical Presentation – 4 criteria <ul><li>Preservation of Independence of Functional Ability : </li></ul><ul><ul><li>Mild problems with complex tasks (paying bills, cooking) </li></ul></ul><ul><ul><li>May be less efficient, take more time </li></ul></ul><ul><ul><li>Maintain independence with minimal aids </li></ul></ul><ul><li>Not demented : </li></ul><ul><ul><li>No impairment in social or occupational function </li></ul></ul><ul><ul><li>Intra-individual change may be particularly challenging to assess when seeing patient only once </li></ul></ul>
  • 10. Criteria for MCI due to AD Core Clinical Criteria Other Aspects of Evaluation <ul><li>Conduct usual work-up to rule out disorders other than AD: </li></ul><ul><ul><li>Medical, neurologic and psychiatric disorders that can cause cognitive decline </li></ul></ul><ul><ul><li>Summarize cardinal features of other key disorders to consider (e.g., FTLD, CJD, DLB, VaD) </li></ul></ul><ul><li>Encourage neuropsychological testing: </li></ul><ul><ul><li>Examples of brief cognitive testing for clinician </li></ul></ul><ul><ul><li>Encourage assessment of all cognitive domains, if possible </li></ul></ul><ul><ul><li>Acknowledge limitation in norms for very elderly and varying cultures </li></ul></ul>
  • 11. Criteria for MCI due to AD Core Clinical Criteria Other Aspects of Evaluation <ul><li>Evidence of progressive decline </li></ul><ul><ul><li>Encourage longitudinal assessment, when possible </li></ul></ul><ul><li>Role of genetics – special considerations </li></ul><ul><ul><li>Individuals with mutation in AD genes </li></ul></ul><ul><ul><li>Genes that increase risk for AD (ApoE) </li></ul></ul><ul><li>Emphasize that diagnosis requires clinical judgment, taking all information into account </li></ul><ul><ul><li>Re-emphasize this point in discussion of biomarkers </li></ul></ul>
  • 12. Criteria for MCI due to AD Core Clinical Criteria Minimal Differences from Prior MCI Criteria <ul><li>Concern about cognitive change can be identified by any source: </li></ul><ul><ul><li>Patient, informant, skilled clinician </li></ul></ul><ul><li>Independence of function: </li></ul><ul><ul><li>Can have evidence of functional change </li></ul></ul><ul><ul><li>Must maintain independence of function with minimal aids or assistance </li></ul></ul>
  • 13. Criteria for MCI due to AD Clinical and Cognitive Criteria Minimal Differences from Prior Criteria <ul><li>Cognitive domains impaired: </li></ul><ul><ul><li>Emphasize primary impairment is generally episodic memory </li></ul></ul><ul><ul><li>Acknowledge that other domains can be impaired </li></ul></ul><ul><ul><li>Allow for impairments in more than one cognitive domain </li></ul></ul><ul><ul><li>Do not use terms - ‘amnestic’ and ‘non-amnestic’ MCI </li></ul></ul>
  • 14. Biomarkers and MCI due to AD <ul><li>Currently intended for research only </li></ul><ul><li>Use to increase certainty that MCI syndrome is due to underlying AD pathophysiology </li></ul><ul><li>Not recommended for use in standard clinical settings </li></ul>Jagust, Fox, Holtzman
  • 15. Framework for Biomarkers <ul><li>Measures Related to Molecular Pathology of Abeta </li></ul><ul><ul><li>CSF A ß 42 </li></ul></ul><ul><ul><li>Amyloid Imaging – PiB, AV-45 </li></ul></ul><ul><li>Measures Related to Neuronal Injury </li></ul><ul><ul><li>CSF tau / phopho tau </li></ul></ul><ul><ul><li>MRI measures of structural change </li></ul></ul><ul><ul><ul><li>Hippocampal Volume </li></ul></ul></ul><ul><ul><ul><li>Medial Temporal Lobe Atrophy </li></ul></ul></ul><ul><ul><li>PET or SPECT measures of functional change </li></ul></ul><ul><ul><ul><li>FDG PET – temporoparietal topographic pattern </li></ul></ul></ul><ul><ul><ul><li>SPECT Perfusion – temporoparietal topographic pattern </li></ul></ul></ul>Change from initial draft - harmonization-
  • 16. Role of Biomarkers <ul><li>Clarify nature of underlying pathology: </li></ul><ul><ul><li>Evidence of Abeta (decreased A β 42 in CSF or increased amyloid burden on PET) strongly indicates that plaques are present </li></ul></ul><ul><ul><li>Evidence of increased tau suggests that tangles are present but is less specific (increased tau in an number of other conditions – CJD, head trauma, etc) </li></ul></ul>Amyloid angiopathy
  • 17. Role of Biomarkers <ul><li>Increase likelihood of progression from MCI syndrome to Alzheimer’s dementia: </li></ul><ul><ul><li>Measures of structural and functional change may be more useful in prediction of progression than measures that indicate AD pathology is present </li></ul></ul>
  • 18. Use of Biomarkers in Research <ul><li>Incorporation of biomarkers in diagnosis emphasizes that accumulation of amyloid is seen first and is followed by other changes (recognizing that more work needs to be done to confirm this trajectory): </li></ul><ul><ul><li>Different biomarkers provide different levels of certainty in diagnosis of MCI due to AD </li></ul></ul><ul><ul><li>Since more needs to be learned regarding biomarkers, the criteria, in essence, outline testable hypotheses regarding the levels of certainty conferred by categories of biomarkers </li></ul></ul><ul><ul><li>Can apply in academic research settings and clinical trials and determine utility of this framework </li></ul></ul>
  • 19. Diagnosis of MCI due to AD Levels of Certainty <ul><li>MCI – Core Clinical Criteria </li></ul><ul><li>MCI due to AD - Intermediate Likelihood </li></ul><ul><li>MCI due to AD – High Likelihood </li></ul><ul><li>MCI – Unlikely due to AD </li></ul>
  • 20. Diagnosis of MCI due to AD Levels of Certainty <ul><li>MCI – Core Clinical Criteria </li></ul><ul><ul><li>patient meets clinical and cognitive criteria for the MCI syndrome </li></ul></ul><ul><ul><li>biomarkers are uninformative </li></ul></ul><ul><ul><ul><li>have not been tested </li></ul></ul></ul><ul><ul><ul><li>are conflicting </li></ul></ul></ul><ul><ul><ul><li>are indeterminant </li></ul></ul></ul>
  • 21. Diagnosis of MCI due to AD Levels of Certainty <ul><li>MCI due to AD – Intermediate Likelihood </li></ul><ul><ul><li>patient meets clinical and cognitive criteria for the MCI syndrome </li></ul></ul><ul><ul><li>biomarkers are: </li></ul></ul><ul><ul><ul><li>positive for either an A β biomarker or a biomarker of neuronal injury </li></ul></ul></ul><ul><ul><ul><ul><li>consistent with one of the biomarker categories untested </li></ul></ul></ul></ul>
  • 22. Diagnosis of MCI due to AD Levels of Certainty <ul><li>MCI due to AD – High Likelihood </li></ul><ul><ul><li>patient meets clinical and cognitive criteria for the MCI syndrome </li></ul></ul><ul><ul><li>biomarkers have been tested and are </li></ul></ul><ul><ul><ul><li>positive for both an A β biomarker and a biomarker of neuronal injury </li></ul></ul></ul>Prodromal AD
  • 23. Diagnosis of MCI due to AD Levels of Certainty <ul><li>MCI unlikely due to AD </li></ul><ul><ul><li>patient meets clinical and cognitive criteria for the MCI syndrome </li></ul></ul><ul><ul><li>biomarkers have been tested </li></ul></ul><ul><ul><ul><li>Negative for both an A β biomarker and a biomarker of neuronal injury </li></ul></ul></ul>
  • 24. Future Directions Issues to be Addressed <ul><li>Standardization of biomarkers - require much more information about normative values, laboratory to laboratory variation </li></ul><ul><li>Application of biomarkers in community settings – require information about how biomarkers operate in representative populations </li></ul><ul><li>Application of biomarkers in clinical trials – use for selection of subjects and determine whether treatment alters biomarkers in expected directions </li></ul>
  • 25. Future Directions Issues to be Addressed <ul><li>Competing / Ambiguous biomarkers - lack of clarity for how to handle competing results from biomarkers (positive findings on one biomarker but negative or ambiguous findings on another) </li></ul><ul><li>Combinations of biomarkers – utility of combinations of biomarkers needs to be clarified </li></ul><ul><li>Identification of novel biomarkers that can improve diagnosis and prediction </li></ul>
  • 26. Hypothetical Model of Biomarkers in AD FDG PET Abnormal Normal Time Pre-symptomatic EMCI LMCI Dementia Function (ADL) Cognitive performance MRI hippocampal volume CSF Tau Jack et al., 2010 Amyloid imaging CSF A  42
  • 27.  

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