1. Pre-Symptomatic Memory Impairment Herman Buschke, MD Einstein Aging Study (NIA AG-03949) Department of Neurology Albert Einstein College of Medicine buschke@aecom.yu.edu Semmelweis University Budapest July 20, 2009

2. Screening for Pre-Symptomatic AD need to detect memory impairment when memory is declining but is still in normal range trials of early treatment early treatment to preserve cognition prevention trials …………….

3. Memory Impairment = Low Recall ?  cannot detect early memory impairment ( when declining memory is still in normal range)  because impairment is defined by low recall, when memory impairment is severe and late

4. Memory Capacity Test (MCT)  the MCT is intended to detect early memory impairment (when declining memory is still within normal limits)  using controlled learning and cued recall to induce encoding specificity and maximum retrieval  to evaluate associative encoding shown by binding a second item to each cue

5. Overview In a sample of community-dwelling older adults, all aged with AD, 40% of the aged with aMCI, 15% of non-demented aged with normal 1st list recall, had low cognitive binding relative to their own 1st list recall. Those with low binding have lower mental status and cognitive scores and slower recall. Sperling and Rentz et al have found that MCT scores are correlated with PiB retention and can distinguish the PiB positive.

6. Controlled Learning * * Identify each item when given its Category Cue

7. Controlled Learning  shows that items are associated with their category cues  shows that individuals can produce items elicited by their category cues  induces binding of items to specific cues  assures attention to and equal processing of all items  induces deep semantic processing  induces all individuals to do the same processing  shows that the required processing was done  ensures that decreased recall is due to impaired memory  induces “Encoding Specificity” to maximize recall

8. Category Cued Recall * * Recall each item when given its Category Cue

9. Encoding Specificity “specific encoding operations performed on what is perceived determine what is stored and what is stored determines what retrieval cues are effective in providing access to what is stored” Tulving & Thomson, Psych Review, 1973, page 369 Encoding and retrieval must be coordinated.

10. Encoding Specificity retrieval depends on cues effectiveness of cues depends on what was stored what was stored depends on encoding operations performed on what was perceived

11. Encoding Specificity to maximize retrieval, acquisition & retrieval must be coordinated by controlled learning & retrieval: retrieval cues must also be present at encoding

12. Cued Recall superior to Free Recall  assures attention to and testing of all items  number of items recalled measures memory accurately  controls order of recall: all subjects recall all items in the same order equalizes the interval between learning and recall obviates need for interference before recall prevents output order interference  facilitates measurement of retrieval speed  realizes Encoding Specificity to maximize recall & recall speed

13. Controlled Learning + Controlled Recall coordinates encoding and retrieval by using the same cues for learning and retrieval induces encoding specificity which improves retrieval and discrimination of dementia * because retrieval by aged without dementia is improved more than retrieval by aged with dementia * Buschke, Sliwinski, Kuslansky, Lipton, Neurology, 1997

14. Recall with and without Encoding Specificity * * Buschke, Sliwinski, Kuslansky, Lipton, Neurology, 1997 * Effect size = mean difference / pooled sd

15. Memory Capacity Test (MCT) Using Controlled Learning and Cued Recall 1.Learn 1st list of 16 items, each from a different category 2.Cued Recall 1st list 3. Learn 2nd list of 16 new items from the same categories 4.Cued Recall 2nd list 5.Cued Recall Both Items from Both Lists 6.Free Recall Both Lists

16. MCT87 F 12yr FR=5 B=6LIST 1LIST 2BOTH 1 & 2 CATEGORY CUELearnRecallLearnRecallList 1List 2 1Reading MaterialNovelTextbook 2StateFlorida+Colorado+ 3Female NameLaura+Susan++ 4Gardener’s ToolsHoe+Rake++ + 5Human DwellingShack+Mansion+ 6CrimeRobbery+Arson++ 7ClergyPastor+Rabbi++ 8Earth FormationVolcano+Canyon+ 9Kind of DanceFoxtrot+Waltz++ 10FlowerTulip+Carnation+ 11Military TitleCaptain+General+ 12DistanceMile+Inch+ 13DiseasePlague+Measles++ + 14Elective OfficeGovernor+Mayor++ + 15HerbDill+Parsley+ 16ShipTugboatSubmarine + + Cued Recall147113

19. Study 1 ROC AUCSpecificitySensitivity List 1 + Both 2 tru.97.96.85 List 1 alone.91.95.77 Free Recall.90.94.54

20. Low vs. High Binding

24. Incident Binding Impairment

25. Low 2nd item recall with the same cue: Acquired Not due to difficulty Precedes impairment of 1st List recall

26. Retrieval Speed Retrieval speed was measured in milliseconds from onset of each cue to onset of item recall of a 16-item list with one item from each of 16 categories; each category cue was presented to elicit retrieval of the to-be-remembered item from that category, using Controlled Learning and Cued Recall, with the same cues in learning and recall, for Encoding Specificity to maximize recall and retrieval speed; Maximum recall and retrieval speed are needed to detect impairment, because impairment means that maximum performance is decreased;

27. Retrieval Speed MCT <= 50% (n =76) MCT > 50% (n =298) MeanstdMeanstd Age82.05.1680.15.23 Education11.73.0814.33.48 Gender0.630.490.600.49 Free Recall 25.48.3131.95.70 “MCT” = recall of both items from same cue as % of list 1 recall

28. Speed and Recall Correlation

29. MCT & aMCI Recall Time (msec) MCT <= 50% n = 76 not MCT > 50% n =298 aMCI <= 24 n =56 186016941771 not aMCI >24 n=318 173314391494 17971469

30. aMCI Effect Size (not MCT > 50 %) aMCI Free Recall <= 24 not aMCI Free Recall > 24 NRTSDNRTSDP Effect Size * 35169445926314393640.0010.615 * Cohen’s d effect size: 95% Confidence = 0.259 – 0.971

31. MCT Effect Size * MCT <= 50 % not MCT > 50 % NRTSDNRTSDP Effect Size * 76179847029814693850.0010.764 * Cohen’s d effect size: 95% Confidence = 0.508 – 1.02

32. Decreased Binding = Early Memory Impairment FACE VALIDITY: low 2nd list recall with the same cues ACCURACY: good sensitivity and specificity DISTRIBUTION: 100 % of aged with dementia (AD) have low 2 nd item recall COGNITIVE DEFICITS: lower mental status and cognitive scores INCIDENT IMPAIRMENT: when 1st list recall still within normal limits RETRIEVAL SPEED: slower recall BIOVALIDATION: MCT correlated with PiB retention, discriminates PiB+ 50 % of aged with MCI have low 2nd item recall 15 % of non-demented aged have low 2nd item recall

33. MCT Summary  identifies early pre-symptomatic memory impairment by low 2 nd item recall relative to 1st list recall when declining memory is still within normal limits  detects early pre-symptomatic memory impairment in 15% of aged who still have normal 1 st list recall  detecting early pre-symptomatic memory impairment provides the necessary basis for early treatment trials, early treatment to preserve cognitive function, and prevention trials

34. Disclosure Albert Einstein College of Medicine owns US Patent 7,314,444 for “Memory Assessment by Retrieval Speed” Albert Einstein College of Medicine has filed a patent application for the Memory Capacity Test Albert Einstein College of Medicine makes these tests available as a service to the research community but licenses the tests for commercial use.

35. Thank You

36. References for Controlled Learning & Cued Recall Amnestic syndrome of the medial temporal type identifies prodromal AD. Neurology, 2007; 69: 1859-1867. M. Sarazin, C. Berr, J. De Rotrou, C. Fabrigoule, F. Pasquier, S. Legrain, B. Michel, Puel, M. Volteau, J. Touchon, M. Verny and B. Dubois “Results: A total of 59 subjects converted to AD dementia. The most sensitive and specific test for diagnosis of prodromal AD was the FCSRT.” “ Conclusions: The amnestic syndrome of the medial temporal type, defined by the Free and Cued Selective Reminding Test, is able to distinguish patients at an early stage of Alzheimer disease from mild cognitive impairment non-converters.”

37. References for Controlled Learning & Cued Recall Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS–ADRDA criteria. Lancet Neurology, 2007; 6: 734-746. Bruno Dubois, Howard Feldman, Claudia Jacova, Steven DeKosky, Pascale Barberger-Gateau, Jeffrey Cummings, André Delacourte, Douglas Galasko, Serge Gauthier, Gregory Jicha, Kenichi Meguro, John O’Brien, Florence Pasquier, Philippe Robert, Martin Rossor, Steven Salloway, Yaakov Stern, Pieter Visser, Philip Scheltens “The accurate diagnosis of the episodic memory deficit of AD can be improved by use of test paradigms that provide encoding specificity. …Coordinated encoding and retrieval paradigms of this type include the free and cued recall test or similar cued recall paradigms... Reduced benefit from cueing at recall reliably identifies prodromal AD.” (p. 738)