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Mary Ganguli’s Slides

Mary Ganguli’s Slides. March 13 th Meeting. Mild Cognitive Impairment. A View from the Trenches. FDA’s 5 Questions. Clinical definition of MCI. Validity of MCI Diagnostic Criteria. Distinction from AD and other dementias. Appropriate outcome measures for MCI clinical trials.

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Mary Ganguli’s Slides

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  1. Mary Ganguli’s Slides March 13th Meeting

  2. Mild Cognitive Impairment A View from the Trenches

  3. FDA’s 5 Questions • Clinical definition of MCI. • Validity of MCI Diagnostic Criteria. • Distinction from AD and other dementias. • Appropriate outcome measures for MCI clinical trials. • Special design features for MCI clinical trials.

  4. Additional questions • What is MCI? • How is it similar or different to related concepts such as AAMI, CIND? • How is it related to Clinical Dementia Rating 0.5 Memory Only? • How is it similar and different to normal aging? • Is MCI a single condition? • Is MCI a homogenous condition?

  5. What is the conceptual issue in question? Clinicians are familiar with patients who do not seem either quite normal or quite demented. Typically we make – or reserve - a judgment as to whether we think they have an incipient dementing disorder. Would we all make the same judgment, given the same patient?

  6. Clinical Characterization of MCI Petersen Criteria: • 1. Memory Complaint • 2. Normal Activities of Daily Living (ADLs) • 3. Normal General Cognitive Function • 4. Abnormal Memory for Age • 5. Not Demented • (Petersen et al 1999)

  7. A. Clinical Definition of MCI Can MCI be clearly defined in a clinical setting? Translation: Can the Petersen criteria be clearly applied to patients in the clinic?

  8. 1. Memory Complaint • Must the patient complain spontaneously or can the physician elicit this complaint by questioning? • What if the patient denies memory problems? • What if there is no reliable informant? • Can patients with anosognosia have MCI?

  9. 2. Normal ADLs Assuming this includes normal Instrumental ADLs (IADLs): • Is “normality” determined by self-report? • What if there is no reliable informant? • Does it depend on the patient’s actual IADLs? • (e.g., impairment in cooking and keeping house may occur earlier than impairment in drinking beer and watching TV.)

  10. 3. Normal general cognitive function • Does this mean “normal” scores on brief mental status screening (which is the most that will happen in the average office practice)? • How will “normal” be defined? • Does it depend on age, sex, education, etc.? • Does it depend on whether or not the same patient previously had a higher score?

  11. 4. Abnormal memory for age. • Must the same standard memory test (e.g. Wechsler Memory Scale) be administered to all patients before the diagnosis of MCI is made? • Must appropriate age-norms be available on the given test? (e.g., age-norms by race, sex, and language.) • Can MCI be diagnosed without neuro-psychological testing?

  12. 5. Not Demented • How is dementia being defined? • Does this mean “not meeting DSM criteria for dementia,” i.e., not demonstrating decline in two or more cognitive domains, including memory, sufficient to interfere with social and occupational functioning?” • Does a Clinical Dementia Rating (CDR) =0.5 mean “not demented?”

  13. B. Validity of Clinical Criteria • B. Are there valid clinical criteria for the diagnosis of MCI? Translation: Do the criteria in fact measure what they purport to measure?

  14. Aspects of Validity • Face validity- “makes sense, appears valid.” • Content validity – covers the appropriate content. • Criterion-related validity: ?Concurrent validity – associated with an external, independent, gold standard criterion. ? Predictive validity – predicts certain outcomes.

  15. Face and Content Validity • Seems internally consistent, BUT • Is it too exclusive? • Is MCI always amnestic? • Can another cognitive domain be impaired in isolation?

  16. Concurrent Validity • Compared to controls, MCI subjects had greater memory loss but were otherwise similar. • Compared to mild AD patients, MCI had similar memory loss but were less impaired in other cognitive domains. • (Petersen et al 1999)

  17. Circularity vs Concurrent Validity • If MCI is defined on the basis of abnormal memory but otherwise normal cognitive and ADL function, • MCI subjects - by definition - will be worse than controls only in memory. • MCI subjects – by definition – will be better than mild AD patients only in domains other than memory.

  18. Predictive Validity MCI subjects declined at a rate intermediate between those of controls and mild AD patients. “Conversion” rate to dementia was 12% per year. (Petersen et al 1999)

  19. “Conversion” • Does “conversion” represent a change in diagnosis or primarily a change in severity of the same condition? • Who are the subjects who do not convert? • Is it only a matter of time before they all convert? • Do some of them convert to conditions other than AD?

  20. Potential Interpretations • Is MCI a separate entity? • Is MCI an intermediate stage on a continuum between normal aging and AD? • Is MCI always incipient AD? • Is MCI sometimes incipient AD and sometimes something else?

  21. C. Differential Diagnosis of MCI Can MCI be distinguished from AD and other causes of dementia? • MCI subjects had comparable memory impairment but less impairment in other domains than mild AD patients. • MCI subjects suffered less decline over time than mild AD patients. • Other Dementias – no data (?)

  22. D. Appropriate Outcome Measures for MCI Drug Trials Depends on MCI definition: Raw & change scores (stability, improvement, rate of decline) per unit time on: • Memory scores; • General mental status scores; • Other cognitive domains: attention, orientation, working memory, etc. • ADL/IADL scores; • “conversion.”

  23. Standard Features for MCI Trials • Double-blind parallel placebo-controlled; • Minimal exclusion criteria; • Adequate power to detect small effects (sample size); • Adequate length of followup; • Intent-to-treat analysis.

  24. Additional Special Features for MCI Trials? • Normal age-sex-education-matched controls not on drug (normal aging comparison group)? • Source of MCI subjects is VERY important: real world “effectiveness” trial may be needed. • Randomized start or randomized withdrawal design?

  25. Know the Enemy • First develop consensus on definition and scope of MCI; • Then examine the distribution and outcome of MCI in clinical practice and in the community at large; there may be many high-functioning persons who will, if asked, report isolated memory loss. • Then design the intervention trials.

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