Progression of MCIWhat To Tell Your Patients

Alex MitchellSrini MalladiMoj FeshkiSujeeve Sanmaganatham

RCPsych AGM 2009

Should we worry about mild memory problems?

Dementia

Healthy

Healthy(older)

Comment:

This was the original, simple view of cognitive impairment in later life

The Natural History of Dementia

PRE-SYMPTOMATIC

PRE-CLINICAL

CLINICAL

Pathological Burden

Dis

ease

Sev

erit

y

Time in Years

T0

T-5 T+10

T-10 T+5

(Bra

in V

olu

me

/ In

trac

ran

ial V

olu

me)

80%

85%

90%

75%

70%

Severe Dementia

Moderate Dementia

Mild Dementia

Mild Cognitive Impairment

23v24

30

20v21

9v10

Dia

gnos

is

Dea

th

11v12

MM

SE

Dementia

Healthy

Memory Problems

MCIWith SMC

VaD

ADMixed

LBD

FTD

Healthy

Comment:

This is a more sophisticated view taking into account grades of cognitive decline from the previous slide

Dementia

Healthy

Memory Problems

MCIWith SMC

VaD

ADMixed

LBD

FTD

Healthy(resilient)

No MCIbut SMC

Comment:

This is an advanced view stratifying for subject and objective cognitive problems. The proportion of people with “reversible dementia” was unclear…..now shown over

Reversible Dementia

• 32 Studies• 4100 cases of dementia

Proportion meta-analysis plot [random effects]

0.0 0.2 0.4 0.6

combined 0.0733 (0.0505, 0.0998)

Kua et al,471997 0.0000 (0.0000, 0.0787)

Brodaty et al,291990 0.0000 (0.0000, 0.0342)

Philpot and Levy,231987 0.0000 (0.0000, 0.0698)

White et al,441996 0.0133 (0.0027, 0.0383)

Liu CK et al,501998 0.0167 (0.0004, 0.0894)

Von Strauss et al,561999 0.0168 (0.0062, 0.0361)

Burke et al,572000m 0.0270 (0.0007, 0.1416)

Chui and Zhang,461997 0.0273 (0.0057, 0.0776)

Evans et al,271989 0.0273 (0.0057, 0.0776)

Hedner et al,221987 0.0290 (0.0035, 0.1008)

Van der Cammen et al,241987 0.0303 (0.0008, 0.1576)

Thal et al,251988 0.0387 (0.0208, 0.0653)

Ogunniyi et al,511998 0.0390 (0.0081, 0.1097)

Sahadevan et al,551999 0.0400 (0.0110, 0.0993)

Livingston et al,311990 0.0465 (0.0057, 0.1581)

Varga et al,361991 0.0533 (0.0246, 0.0987)

Skoog et al,401993 0.0544 (0.0238, 0.1044)

Farina et al,531999 0.0718 (0.0475, 0.1035)

Nitrini et al,421995 0.0800 (0.0352, 0.1516)

Ames et al,371992 0.0811 (0.0303, 0.1682)

Liu CK et al,381992 0.0814 (0.0334, 0.1605)

McMurdo et al,391993 0.0851 (0.0237, 0.2038)

Erkinjuntti et al,211987 0.1011 (0.0620, 0.1533)

Hogh et al,541999 0.1038 (0.0637, 0.1574)

Liu HC et al,351991 0.1091 (0.0577, 0.1828)

Katzman et al,281989 0.1250 (0.0518, 0.2407)

Massoud et al,582000 0.1475 (0.0698, 0.2617)

Roberts and Caird,321990 0.1818 (0.1372, 0.2337)

Walstra et al,481997 0.1953 (0.1384, 0.2631)

Freter et al,491998 0.2296 (0.1727, 0.2949)

Cunha et al,301990 0.2364 (0.1606, 0.3268)

Bayer et al,201987 0.3462 (0.2420, 0.4624)

proportion (95% confidence interval)

1. Subjective Memory complaintsSpontaneous or affirmed?

2. Normal activities of daily livingNormal or near normal?

3. Memory impaired for age1.5SD?

4. No dementiaQuestionable dementia?

Simple Definition Peterson (Mayo Defn) 1997/1999/2001

Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004;256:240–6.

Portet F, Ousset PJ, Visser PJ, Frisoni GB, Nobili F, Scheltens P, Vellas B, Touchon J . Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure. Report of the MCI Working Group of the European Consortium on Alzheimer's Disease. Journal Of Neurology Neurosurgery And Psychiatry 2006;77 (6): 714-718 .

What is the Risk of Dementia in MCI?

Comment:

Probably the first attempt to define the annual conversion rate (ACR) in MCI from 1993

Progression, Peterson, 1999

Petersen RC et al: Arch Neurol 56:303, 1999

MCI → AD 12%/yr

50

60

70

80

90

100

Initial 12 24 36 48exam Months

Control → AD 1-2%/yr

50

60

70

80

90

100

Initial 12 24 36 48exam Months

100

88

76

64

52

40

28

16

40

0

10

20

30

40

50

60

70

80

90

100

Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9

ExtrapolationCrude Mayo MCI Model

Comment:

Summary of the Petersen (Mayo) clinic model of linear decline approximating 12% per annum.

Weakness in Model?

• Problems– 1-2% Die per year– 2-5% Recover per year– 10-20% Lost to follow-up

• Need – Inception vs Completer studies– Long term studies– Class and setting stratified

Pooled Analysis - Methods

• Focus on robust studies– Follow-up 3yrs+– Sample n > 50

• Expecting ?20 papers– 65 studies– 15 long term– 41 medium and long– Sample = 11,756

4x

2x

10x

9x

17x

AD

13926xAACD

23085xCIND

9022xCDR

464412xPartial

251110xClassical

N=DementiaType

Comment:

Our attempt to redefine progression in MCI

0

2

4

6

8

10

12

4 5 6 7 8 9 10

Years of Observation

Annual Rate of Conversion (%)

Hansson et al (2007)

Bozoki et al (2001)

Visser & Verhey (2008)

Devanand et al (2007) Annerbo et al (2006)Visser et al (2006)

Ganguli et al (2004)

Tyas et al (2004)

Hogan & Ebly (2000)

Ishikawa & Ikeda (2007)

Grober et al (2000)

Larrieu et al (2002)

Dickerson et al (2007) Aggarwal et al (2005)

Busse et al (2006)

Triangle = Specialist Centres (clinical)Square = Community Studies (non-clinical)

Long Term Studies 5yrs+

y = -5.9607Ln(x) + 16.633R2 = 0.1857

0

2

4

6

8

10

12

14

16

18

20

2 3 4 5 6 7 8 9 10

Years of Observation

ACR

Triangle = DementiaSquare = Alzheimer’s disease

Medium+Long Term Studies 3yrs+

ACR to AD

0.08

0.04

0.07

0.09

0.04

0.09

0.05

0.06

0.09

0.04

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

Classical MCI Partial MCI CDR=0.5 CIND AACD

All

Specialist Settings

Long Term Studies 3yrs+

0

1

2

3

45

67

89

10

17

0

2

4

6

8

10

12

14

16

1922

20

100

85

7465

5750

4337

3124

18

8

0

10

20

30

40

50

60

70

80

90

100

Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 15

MCI-StableRecoveredDiedDementia

ExtrapolationAdvanced All Case MCI Model

MCI Concept as a “Predictor Test”MCI in Clinical Practice

Cache County Study – Clinical Value of MCI

34% (se)

104

55

Develop Dementia

Prevalence = 5%

98% (Sp)

96.7% NPV3042No MCI

45.8% PPV65MCI

No Dementia

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Pre-test Probability

Post

-test

Pro

babi

lity

Baseline Probability MCI+ MCI-

P-Tau and MCI

16381% (Se)

31

132

Develop Dementia

Prevalence = 5%

22565% (Sp)

83% NPV147No P-tau

63% PPV78MCI with P-Tau

No Dementia

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Pre-test Probability

Pos

t-tes

t Pro

babi

lity

MCI+ P-tau+

MCI+ P-Tau-

Baseline Probability

MCI+

MCI-

Summary

• MCI is not a single disease but a syndrome of convenience

• People with and without MCI may or may not decline

• The risk of dementia has been over-simplified to 10-15% ACR

• The actual risk of decline is about half this

• However other risks including early mortality can occur

• Further work is needed to map risks in SMC without MCI.