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 withgood 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 bescreened 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.

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

0

20

40

60

80

100

0 20 40 60 80 100

Tru

e P

ositi

ves

(S

ensi

tivity

)

False Positives (1 − Specificity)

Alzheimer ROC curve = .97

0

20

40

60

80

100

0 20 40 60 80 100

Tru

e P

ositi

ves

(S

ensi

tivity

)

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

0

5

10

15

20

25

30

0 1 2 3

DementiaNon Dementia

Fre

quency

Number Recalled

sensitivity = .81specificity = .67

MIS Free Recall

0

10

20

30

40

50

0 1 2 3 4

DementiaNon Dementia

Fre

quen

cy

Number Recalled

sensitivity = .81specificity = .85

MIS Free and Cued Recall

0

10

20

30

40

50

0 1 2 3 4 5 6 7 8

Mis

Dementia

Non Dementia

Fre

quency

Score

Sensitivity = .81Specificity = .95

MIS and 3-Word ROC curves

0

20

40

60

80

100

0 20 40 60 80 100

3-Word

MIS

Tru

e P

ositi

ves

(Sen

sitiv

ity)

False Positives (1 − Specificity)

= .78

= .92

Barcelona MIS

Madrid ROC curve Dementia vs No Dementia Spanish-MIS ---------------------Spanish-MMSE ---------------------

1086420-2

7

6

5

4

3

2

1

0

-1

BRAAK

MIS

r = –.622

p = .003

Normal 6Path Aging 3AD 5VaD 5FTD 1DLB 1

MIS correlates with Braak stage *

* 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 specificityto 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