Screening for Alzheimer’s disease

Herman Buschke, MD
Einstein Aging Study (NIA AG-03949)
Department of Neurology
Albert Einstein College of Medicine
 Is screening needed to improve
detection of Alzheimer’s disease ?

“…nearly 75% of patients with moderate to severe

dementia are unrecognized by primary care
clinicians…” (Gifford & Cummings, Neurology,1999)

“90% of generalists determine diagnosis of dementia

by clinical impression, and 82% are confident about
their recognition of mild dementia”
(Swearer, Lester, Boudreau & Drachman,
American Neurological Association, 2002)
 Screening is needed to improve
detection of Alzheimer’s disease

we need a simple, rapid, accurate screening test with

good sensitivity and good specificity that can be used
by primary care clinicians to screen everyone at risk

an efficient screen for AD must be easy to administer,

interpret, and repeat, so that everyone at risk can be
screened regularly
 Screening Tests

Screening tests are not diagnostic tests

Screening tests select persons for diagnostic testing

Screen everyone at risk, without “pre-screening”

Repeat screening if risk persists or increases

 Screening for Alzheimer’s disease
by screening for memory impairment

Memory impairment is required for diagnosis

Memory impairment is usually the earliest sign

Screening for memory impairment is necessary

Effective screening for Alzheimer’s disease requires

an efficient screening test for memory impairment
with good specificity as well as good sensitivity
Sensitivity and Specificity
DISEASE * NO DISEASE *
100 %
80 %
60 %
40 %
20 %
SENSITIVITY SPECIFICITY

* according to the “Gold Standard”

 Screening for memory impairment

Sensitivity is necessary to detect impairment

Specificity is necessary for ethical, efficient (ppv) screening

Maximum recall is needed to detect memory impairment

because impairment means that maximum recall has decreased
Controlled Learning and Controlled Recall are needed to
• elicit maximum recall by inducing encoding specificity,
• ensure that decreased recall is due to impaired memory
Memory Impairment Screen (MIS) *

 Controlled Learning

brief delay . .

 Free Recall

 Cued Recall

* Buschke, et al., Neurology,1999

 Controlled Learning
Category Cue ITEM

Animal SPINACH

City CELLO

Vegetable PARIS

Musical Instrument ELEPHANT

 Controlled Learning

 assures attention and equal processing of all items

 induces deep semantic processing
 shows that individuals can identify items by their cues
 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
 Free Recall *
ITEMS

* recall all items in any order

 Category Cued Recall *
Category Cue ITEM

Animal ?

City ?

Vegetable ?

Musical Instrument ?

* only for items not retrieved by free recall

 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

“…. the probability of retrieval varies directly with

the compatibility of the trace and the cue, or
the stored information and the retrieval information.”

Tulving, Elements of Episodic Memory, page 249 (1985)

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

to maximize retrieval, acquisition & retrieval must

be coordinated by controlled learning & retrieval:
retrieval cues must be present at encoding
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
Recall with and without encoding specificity *

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

* Effect size = d = mean difference / pooled sd

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

MIS screening for dementia

Sample 50 dementia 433 non-dem

Age 81.4 79.3

Education (years) 11.0 12.2

Sex (% male) 34 36

Zung depression 52.3 46.2

BIMC errors 14.7 2.8

* Buschke, et al., Neurology, 1999

 Alternate Forms Reliability

• Two forms administered to 429 individuals

at beginning and end of neuropsychological evaluation

• Intra-class correlation = 0.69

• Coefficient Alpha = 0.67 for each form

 Dementia ROC curve = .94

100
True Positives (Sensitivity)

80

60

40

20

0 20 40 60 80 100
False Positives (1 − Specificity)
 Alzheimer ROC curve = .97

100
True Positives (Sensitivity)

80

60

40

20

0 20 40 60 80 100
False Positives (1− Specificity)
 Dementia Discrimination
All Dementia Positive Predictive
Value for Base Rate

MIS Sensitivity Specificity 10 % 20 % 50 %

2 0.54 0.99 0.87 0.94 0.98

3 0.74 0.98 0.78 0.89 0.97

4 0.80 0.96 0.69 0.84 0.95

5 0.86 0.91 0.53 0.72 0.91

6 0.90 0.81 0.34 0.54 0.82

 Alzheimer Discrimination
Alzheimer’s disease Positive Predictive
Value for Base Rate

MIS Sensitivity Specificity 10 % 20 % 50 %

2 0.59 0.99 0.88 0.94 0.98

3 0.80 0.98 0.79 0.90 0.97

4 0.87 0.96 0.71 0.85 0.96

5 0.92 0.91 0.55 0.73 0.92

6 0.97 0.81 0.36 0.56 0.84

MIS versus 3-Word Recall *
Sample 21 dementia 79 non-dem

Age 78.8 79.6

Education (years) 10.7 12.7

Sex (% female) 57 66

Zung depression 58.3 46.6

BIMC errors 15.8 2.9

* Kuslansky, Buschke, Katz, Sliwinski, Lipton, JAGS, 2002

 3-Word Free Recall

30
Dementia
25 Non Dementia
sensitivity = .81
20 specificity = .67
Frequency

15

10

0
0 1 2 3
Number Recalled
 MIS Free Recall

50

Dementia
40 Non Dementia
sensitivity = .81
Frequency

30 specificity = .85

20

10

0
0 1 2 3 4
Number Recalled
 MIS Free and Cued Recall
Mis
50

Dementia
40
Non Dementia
Frequency

30 Sensitivity = .81
Specificity = .95

20

10

0
0 1 2 3 4 5 6 7 8
Score
 MIS and 3-Word ROC curves

100
True Positives (Sensitivity)

80

60

40

3-Word = .78
20
MIS = .92

0 20 40 60 80 100
False Positives (1 − Specificity)
Barcelona MIS
Madrid ROC curve Dementia vs No Dementia
Spanish-MIS ---------------------
Spanish-MMSE ---------------------
 MIS correlates with Braak stage *
7

r = –.622
6

5 p = .003
4
B
R 3 Normal 6
A Path Aging 3
2
A AD 5
K 1 VaD 5
FTD 1
0
DLB 1
-1
-2 0 2 4 6 8 10

MIS
* Verghese, Buschke, Dickson, Kuslansky, Katz, Weidenheim, Lipton, JAGS, 2003
Screening Tests are Not Diagnostic Tests!

Screening tests are not diagnostic tests

Screening tests select persons for diagnostic testing

Everyone at risk should be screened

Diagnostic testing is required when screening is positive

 MIS Summary

 Screening for dementia depends on detection of memory impairment

with good specificity and positive predictive value as well as good sensitivity

 Screening requires controlled learning, controlled recall, and encoding specificity

to elicit maximum retrieval by effective cued recall

 MIS improves screening by controlled learning and controlled recall,

to maximize recall and optimize sensitivity, specificity, positive predictive value

 MIS is a simple, rapid, effective, easily administered screening test

with good specificity as well as good sensitivity for Alzheimer’s disease

 MIS is recommended by the American Academy of Neurology as a screen for AD