Relative Risk of Progression of MCI to Dementia

Pooled and Meta-Analysis of 39 Robust Inception Cohort Studies

Alex MitchellConsultant & Hon SnR Lecturer in Liaison Psychiatry, Leicester

Moj FeshkiStR in Psychiatry

Srini MalladiConsultant in Old Age Psychiatry, Northampton

IPA, Dublin 2008

What is MCI?

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

Stages of Dementia

VI(Cortical association

areas)

All38+6-730-11Severe Alzheimer’s disease

V(Basal cortex)

Semantic MemoryVisuospatial awarenessOrientation

21-375212-20Moderate Alzheimer’s disease

III/IV(Amygdala & Thalamus)

Recognition MemorySpatial Episodic MemoryExecutive Dysfunction

13-204121-23Early Alzheimer’s disease

II(CA1 field of

hippocampus)

Verbal Episodic Memory(Delayed Recall)

1-1330.521-29Mild Cognitive Impairment

II(CA1 field of

hippocampus)

Verbal Episodic Memory (Extended Recall)

1-1220.524-29Age-Associated Memory Impairment

I(Transentorhinal

area)

No Problems01030Healthy Elderly

Braak StagingCognitive PerformanceADAS-Cog

GDSCDRMMSEStage

1. Subjective Memory complaintSpontaneous 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 .

Author (year) N Age Study Prev (%)

Graham (1997) 1800 >65 CSHA 5.3

Larrieu (2002) 1265 70-90 PAQUID 2.8

Hanninen (2002) 806 60-76 KUPIO 5.3

Lopez (2003) 2470 >75 CHS 6.0

Fisk (2003) 1790 >65 CSHA 1-3

Ganguli (2004) 1248 >65 MoVIES 3-4

Prevalence of MCI

What is the Risk of Dementia in MCI?

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

Rivastigmine InDDEX Study

Rivastigmine InDDEX Study

Cochrane Review

AChE for MCI?

Pooled Effect of Ache for MCIRR Meta-analysis (fixed effects)

ACR for MCI to Dementia by Intervention

6.3%

8.0%

9.9%

0

1

2

3

4

5

6

7

8

9

10

Drug Placebo VitE

n=4 n=4 n=1

Pooled Analysis

Pooled Analysis - Methods

• Systematic search + appraisal + extraction

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

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

4x

2x

10x

9x

17x

AD

13926xAACD

23085xCIND

9022xCDR

464412xPartial

251110xClassical

N=DementiaType

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

ACRMedium+Long Term Studies 3yrs+

Triangle = DementiaSquare = Alzheimer’s disease

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+

Weakness in Model?

• 1-2% Die per year

• 2-5% Recover per year

• ? Lost to follow-up

• => Inception vs Completer studies

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

CP1183493-10

Years after enrollment

Alive (%)

NormalsNormalsAll amnestic MCIAll amnestic MCI

P<0.0001

Mayo Data Survival (Kaplan-Mayer)

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

Extras

Non-Amnestic MCISingle Domain

Yes

Amnestic MCISingle Domain

Yes

Cognitive complaint

Not normal for age

Modest Objective Cognitive decline

Normal instrumental function

Yes

Amnestic MCI

MCI

Memory impaired? No

Non-Amnestic MCI

Single non-memorycognitive domain

impaired?

Memoryimpairment only? No

Non-Amnestic MCIMultiple Domain

No

Amnestic MCIMultiple Domain

Petersen: J Int Med, 2004

Credits / Acknowledgments

For more slides www.psycho-oncology.info/slides

Alex J Mitchell © 2008