Pre-Symptomatic Memory Impairment

Herman Buschke, MD

Einstein Aging Study (NIA AG-03949)Department of Neurology

Albert Einstein College of Medicinebuschke@aecom.yu.edu

Semmelweis University Budapest July 20, 2009

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 …………….

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

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

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.

Controlled Learning *

Category Cue ITEM

Animal SPINACH

City CELLO

Vegetable

PARIS

Musical Instrument ELEPHANT

* Identify each item when given its Category Cue

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

Category Cued Recall * Category Cue ITEM

Animal ?

City ?

Vegetable

?

Musical Instrument ?

* Recall each item when given its Category Cue

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.

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

Encoding Specificity

to maximize retrieval, acquisition & retrieval must be coordinated by controlled learning & retrieval:

retrieval cues must also be present at encoding

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

Controlled Learning + Controlled Recall

• coordinates encoding and retrievalby using the same cues for learning and retrieval

• induces encoding specificity

• which improves retrieval and discrimination of dementia *because retrieval by aged without dementiais improved more than retrieval by aged with dementia

* Buschke, Sliwinski, Kuslansky, Lipton, Neurology, 1997

Cues N Controls Cases Effect *

learn & recall 90/30 30.8 (7.6) 12.1 (6.5) 2.54

recall only 90/30 15.0 (6.4) 8.1 (5.1) 1.13

Recall with and without Encoding Specificity *

* Buschke, Sliwinski, Kuslansky, Lipton, Neurology, 1997

* Effect size = mean difference / pooled sd

Memory Capacity Test (MCT)

Using Controlled Learning and Cued Recall

1. Learn 1st list of 16 items, each from a different category2. Cued Recall 1st list

3. Learn 2nd list of 16 new items from the same categories4. Cued Recall 2nd list

5. Cued Recall Both Items from Both Lists

6. Free Recall Both Lists

MCT 87 F 12yr FR=5 B=6 LIST 1 LIST 2 BOTH 1 & 2CATEGORY CUE Learn Recall Learn Recall List 1 List 2

1 Reading Material Novel Textbook2 State Florida + Colorado +3 Female Name Laura + Susan + +4 Gardener’s Tools Hoe + Rake + + + 5 Human Dwelling Shack + Mansion +6 Crime Robbery + Arson + +7 Clergy Pastor + Rabbi + +8 Earth Formation Volcano + Canyon +9 Kind of Dance Foxtrot + Waltz + +10 Flower Tulip + Carnation +11 Military Title Captain + General +12 Distance Mile + Inch +13 Disease Plague + Measles + + + 14 Elective Office Governor + Mayor + + + 15 Herb Dill + Parsley +16 Ship Tugboat Submarine + +

Cued Recall 14 7 11 3

Study 1 ROC

AUC Specificity SensitivityList 1 +

Both 2 tru .97 .96 .85List 1alone .91 .95 .77Free

Recall .90 .94 .54

Low vs. High Binding LOW

(n = 106) HIGH

(n = 248) Age

80.8

79.4

Education (years)

13.0 *

14.5

Sex (% female)

66 %

63 %

GDS depression

.5

2.1

BIMC errors

3.1 *

1.7

WAIS IQ

97.0 *

107.1

Low vs. High Binding LOW HIGH

List 1 12.7 * 14.9

List 1 in Both 9.8 * 14.2

Binding (pairs) 4.7 * 11.7

2nd list % of 1st 36.5 % * 77.6 %

1st + true 2nd list

17.5 * 26.6

Intrusions 1.8 * 0.7

Free Recall (MCT) 7.2 * 15.1

Low vs. High Binding LOW HIGH

Free Recall (FCSRT) 24.0 * 31.4

Logical Memory

16.8 * 20.9

Category Fluency 32.2 * 37.9

Letter Fluency 29.2 * 37.0

Boston Naming 9.8 * 12.3

WAIS Vocabulary 38.0 * 46.0

Clock Drawing 12.7 * 13.6

Low vs. High Binding LOW HIGH

Digit Span (F)

5.6 * 6.0

Digit Span (B) 4.2 4.3

Digit Symbol 38.2 * 47.2

Block Design 20.4 * 24.8

Stroop Color Words 46.8 * 39.8

Trails A 68.4 * 54.5

Trails B 143.5 * 125.0

Incident Binding Impairment

Incident Binding Impairment

Low 2nd item recall with the same cue:

• Acquired

• Not due to difficulty

• Precedes impairment of 1st List recall

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;

Retrieval SpeedMCT <= 50%

(n =76)MCT > 50%

(n =298)Mean std Mean std

Age 82.0 5.16 80.1 5.23

Education 11.7 3.08 14.3 3.48

Gender 0.63 0.49 0.60 0.49

Free Recall

25.4 8.31 31.9 5.70

“MCT” = recall of both items from same cue as % of list 1 recall

Speed and Recall Correlation

MCT & aMCI Recall Time (msec)MCT

<= 50%n = 76

not MCT > 50%n =298

aMCI<= 24n =56

1860 1694 1771

not aMCI>24n=318

1733 1439 1494

1797 1469

aMCI Effect Size (not MCT > 50 %)

aMCIFree Recall <= 24

not aMCIFree Recall > 24

N RT SD N RT SD PEffectSize *

35 1694 459 263 1439 364 0.001 0.615

* Cohen’s d effect size: 95% Confidence = 0.259 – 0.971

MCT Effect Size *

MCT<= 50 %

not MCT> 50 %

N RT SD N RT SD PEffectSize *

76 1798 470 298 1469 385 0.001 0.764

* Cohen’s d effect size: 95% Confidence = 0.508 – 1.02

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 2nd 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

MCT Summary

identifies early pre-symptomatic memory impairment by low 2nd item recall relative to 1st list recallwhen declining memory is still within normal limits

detects early pre-symptomatic memory impairment in 15% of aged who still have normal 1st 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

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.

Thank You

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.”

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)