Alzheimer’s Disease isn’t all bad.
It’s just mostly bad.
Gregory E. Alexander
University of California, Irvine
Contents
I. 
Introduction
II.  Clinical Tests
§ 
§ 
ADAS-Cog
Results
III.  Hidden Markov Model
§  Hierarchical Model
§  Results
IV.  Future Direction
2 Introduction
3 Introduction
4 Clinical Tests
ADAS
Administration Manual
for the
Alzheimer’s Disease Assessment Scale
Adapted from the Administration and Scoring Manual for the
Alzheimer’s Disease Assessment Scale,
1994 Revised Edition, Richard C. Mohs, Ph.D.
Copyright © 1994 by
The Mount Sinai School of Medicine
Present manual modified by:
Donald Connor, Ph.D
Kimberly Schafer, MS
(3/98)
A Publication of the
Alzheimer’s Disease
Cooperative Study
5 Feedback to the subject should be neutral and, usually, should not indicate whe
response was correct. Comments such as, “That’s fine” or “You’re doing w
as long as the subject is trying. If the subject specifically asks whether or not th
feedback can be given.
Clinical Tests TABLE OF CONTENTS
PAGE
Word Recall Task.................................................................... 2
Naming Task ......................................................................... 3 - 4
Commands .............................................................................. 5
Constructional Praxis ........................................................ 6 - 7
Ideational Praxis ..................................................................... 8
Orientation ............................................................................. 9
Word Recognition ............................................................ 10 - 11
Remembering Test Instructions .......................................... 12
Spoken Language Ability ...................................................... 13
Word–Finding Difficulty and Comprehension ................ 14
6 Standard Free Recall Task
The Primacy effect:
Assumed to be a function of Long-term memory (LTM)
The Recency effect:
Assumed to be a function of Short-term memory (STM)
7 ADAS-Cog Free Recall Subtest
Uses a shuffled item order over 3 study-test trials
Followed by a delayed test trial
Words as well as the shuffled order are the same for all subjects
8 ADAS-Cog Free Recall Design
Trial 1
Trial 2
Trial 3
q  Butter
q  Arm
q  Shore
q  Letter
q  Queen
q  Cabin
q  Pole
q  Ticket
q  Grass
q  Engine
q  Pole
q  Letter
q  Butter
q  Queen
q  Arm
q  Shore
q  Grass
q  Cabin
q  Ticket
q  Engine
q  Shore
q  Letter
q  Arm
q  Cabin
q  Pole
q  Ticket
q  Engine
q  Grass
q  Butter
q  Queen
Trial 4
Delay
Delayed Free Recall
Test
3 Study - Test trials & 1 Delayed Test trial
9 Data Gathered by Clinicians
205
Healthy Elderly Participants
362
Mild Cognitive Impaired (MCI) Participants
177
Early Alzheimer’s disease (AD) Participants
10 Serial Position Curves
Trial 1
Trial 2
Trial 3
Trial 4
1
1
1
1
0.8
0.8
0.8
0.8
Healthy
Healthy
0.4
0.6
0.6
0.6
0.6
0.4
0.4
0.4
0.2
0.2
0.2
0.2
0
MCI
0
1 2 3 4 5 6 7 8 9 10
0
1 2 3 4 5 6 7 8 9 10
0
1
1
1
1
0.8
0.8
0.8
0.8
MCI 0.6
0.6
0.6
0.6
0.4
0.4
0.4
0.4
0.2
0.2
0.2
0.2
0
AD
1 2 3 4 5 6 7 8 9 10
1 2 3 4 5 6 7 8 9 10
0
1 2 3 4 5 6 7 8 9 10
0
1 2 3 4 5 6 7 8 9 10
0
1
1
1
1
0.8
0.8
0.8
0.8
AD 0.6
0.6
0.6
0.6
0.4
0.4
0.4
0.4
0.2
0.2
0.2
0.2
0
1 2 3 4 5 6 7 8 9 10
Word Position in Study 1
0
1 2 3 4 5 6 7 8 9 10
Word Position in Study 2
0
1 2 3 4 5 6 7 8 9 10
Word Position in Study 3
0
1 2 3 4 5 6 7 8 9 10
1 2 3 4 5 6 7 8 9 10
1 2 3 4 5 6 7 8 9 10
Word Position in Study 1
11 ANOVA
Split-Plot Repeated Measures ANOVA of the Number of Words Recalled
in each of the Four Trials by Impairment Groups
12 Model Assumptions
Three memory states:
Unlearned state
Intermediate state
Learned state
During the study trial:
A word may make transitions into memory
storage states.
During the test trial:
Words stored in the Intermediate and Learned
state may be retrieved.
During the delayed test trial:
Only words stored in the Learned state may be
retrieved.
13 A Hidden Markov Model
r
Unlearned
(0)
(1-r)a
v
Intermediate
(t)
(1-r)(1-a)
(1-v)
Unlearned
Learned
(l1)
1
Intermediate
Learned
Pr ( Recall | Test )
0
t
l1
Pr ( Recall | Delayed Test )
0
0
l2
14 Model Assumptions
Memory research has shown that encoding in LTM can occur on test
trials where successful recall from STM takes place.
Ln+1
In+1
Un+1
Ln
1
0
0
In
tb
(1 – tb)
0
Un
0
0
1
A word can transition from the I-state to the L-state if it is correctly
recalled from the I-state during the test with a new transition
probability, b. (Testing effect)
15 Model Assumptions
Previous models applied to list memory experiments assumed item
homogeneity.
That assumption is very limiting for item free recall because of known
serial position effects.
Instead we assume that each of the parameters depends on the position
of the word in the study list.
16 A Hidden Markov Model
ri
(1-ri)ai
Unlearned
(0)
Intermediate
(1-ri)(1-ai)
Pr ( Recall | Test )
vi
Learned
(1-vi)
1
Unlearned
Intermediate
Learned
0
ti
l1,i
The model now contains 52 Total Parameters
17 Model Equations
The equations for the 16 response patterns for each item given the model
are a sum of products over the parameters of the model.
In fact, the model can be represented as a Multinomial Processing Tree
Model for those who know about this type of model.
First the possible sequence of states were enumerated.
Next, the probability of each enumerated state sequence is multiplied by the
probabilities of each of the item response patterns given the state sequence,
and then these are summed to give the probabilities of each response
sequence.
18 Example Equa5on The parameters are indexed by x, y and z, to illustrate the fact that the
parameters used to calculate the probability of a response sequence
given the model for a word depend on where that word was in the list
for each study trial. Pr( 0000 | M ) =rx (1 − l1,x) (1 − l1,y) (1 − l1,z) (1 − l2)
+ (1 − rx) ax(1 − tx) vy(1 − l1)2 (1 − l2)
+ (1 − rx) ax(1 − tx) (1 − vy)(1 − ty)vz(1 − l1)(1 − l2)
+ (1 − rx) (1 − ax) ry (1 − l1)2 (1 − l2)
+ (1 − rx) (1 − ax) (1 − ry) ay(1 − ty) vz (1 − l1) (1 − l2)
+ (1 − rx) (1 − ax) (1 − ry) ay (1 − ty) (1 − vz) (1 − tz)
+ (1 − rx) (1 − ax) (1 − ry) (1 − ay) (1 − rz) (1 − az)
+ (1 − rx ) (1 − ax) (1 − ry) (1 − ay) (1 − rz) az (1 − tz )
+ (1 − rx ) ax (1 − tx) (1 − vy ) (1− ty) (1 − vz) (1 − tz)
+ (1 − rx) (1 − ax) (1 − ry) (1 − ay) rz (1 − l1) (1 − l2)
19 Permuta5on Test Smith and Batchelder (2008). Model Free test of subject homogeneity
(and 95% Confidence Intervals) for the three groups
Healthy
Trial 1
2.355
Trial 2
2.500 *
Trial 3
2.353 *
Trial 4
3.457 *
(1.708, 2.110)
(1.442, 1.804)
(1.206, 1.530)
(1.594, 1.976)
MCI
2.667 *
3.326 *
(1.714, 2.014)
(1.919, 2.241)
3.497 *
(1.786, 2.090)
(1.936, 2.257)
2.253 *
2.805 *
3.636 *
2.358 *
(1.299, 1.662)
(1.680, 2.112)
(1.670, 2.102)
(0.938, 1.278)
AD
5.399 *
!
20 Hierarchical Model
570
FIG. 5C
21 D
Results A
B
Transition into LTM
1
0.9
0.8
1
0.8
0.7
0.7
0.6
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
1
2
3
4
5
6
7
Recall from STM
0.9
8
9
10
0
C
2
3
4
5
6
7
8
9
10
D
1
1
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
0
Recall from LTM (no delay) 1
Healthy
MCI
AD
Healthy
MCI
AD
Recall from LTM (w/ delay)
22 Results
The Average Parameter Values for a, v, and b.
a
v
b
Healthy
0.6645 (0.1617)
0.3921 (0.1939)
0.4581 (0.2176 )
MCI
0.5925 (0.2194)
0.1905 (0.1218)
0.4535 (0.1885)
AD
0.5452 (0.2369)
0.1940 (0.1165)
0.4419 (0.2842)
!
a – Transition into STM
v – Transition into LTM from STM
b – Transition into LTM on test trial
23 Model Fit
Bayesian p-value
Healthy
Trial 1
0.9707
Trial 2
0.9024
Trial 3
0.8293
Trial 4
0.9220
Total Sum
0.9659
MCI
0.9696
0.9696
0.9503
0.9807
0.9614
AD
0.9718
0.9887
0.9887
1.000
0.9774
!
24 Future Direction
25 That's all folks. 26