Progression of MCI
What To Tell Your Patients
Should we worry about mild memory problems?
Alex Mitchell
Srini Malladi
Moj Feshki
Sujeeve Sanmaganatham
RCPsych AGM 2009

Healthy
(older)
Healthy
Comment:
This was the original, simple
view of cognitive impairment Dementia
in later life

The Natural History of Dementia
(Brain Volume / Intracranial Volume)
90% Pathological Burden
PRE-SYMPTOMATIC 30
MMSE
Diagnosis
PRE-CLINICAL
85%
Mild Cognitive Impairment
80%
23v24
CLINICAL
Disease Severity
Mild Dementia
75%
20v21
Moderate Dementia
70%
11v12
Death
Severe Dementia
9v10
T-10 T-5 T T+5 T+
0 10
Time in Years

Healthy
Healthy
Memory
Problems
MCI
With SMC
FTD
Comment:
This is a more sophisticated
view taking into account
grades of cognitive decline Dementia VaD
from the previous slide
AD
LBD
Mixed

Healthy
(resilient)
Healthy
No MCI
Memory but SMC
Problems
MCI
With SMC
FTD
Comment:
This is an advanced view
stratifying for subject and
objective cognitive problems. Dementia VaD
The proportion of people with
“reversible dementia” was
unclear…..now shown over
AD
LBD
Mixed

Proportion meta-analysis plot [random effects]
Reversible Dementia Bayer et al,201987
Cunha et al,301990
0.3462 (0.2420, 0.4624)
0.2364 (0.1606, 0.3268)
Freter et al,491998 0.2296 (0.1727, 0.2949)
Walstra et al,481997 0.1953 (0.1384, 0.2631)
Roberts and Caird,321990 0.1818 (0.1372, 0.2337)
• 32 Studies Massoud et al,582000 0.1475 (0.0698, 0.2617)
Katzman et al,281989 0.1250 (0.0518, 0.2407)
• 4100 cases of dementia Liu HC et al,351991 0.1091 (0.0577, 0.1828)
Hogh et al,541999 0.1038 (0.0637, 0.1574)
Erkinjuntti et al,211987 0.1011 (0.0620, 0.1533)
McMurdo et al,391993 0.0851 (0.0237, 0.2038)
Liu CK et al,381992 0.0814 (0.0334, 0.1605)
Ames et al,371992 0.0811 (0.0303, 0.1682)
Nitrini et al,421995 0.0800 (0.0352, 0.1516)
Farina et al,531999 0.0718 (0.0475, 0.1035)
Skoog et al,401993 0.0544 (0.0238, 0.1044)
Varga et al,361991 0.0533 (0.0246, 0.0987)
Livingston et al,311990 0.0465 (0.0057, 0.1581)
Sahadevan et al,551999 0.0400 (0.0110, 0.0993)
Ogunniyi et al,511998 0.0390 (0.0081, 0.1097)
Thal et al,251988 0.0387 (0.0208, 0.0653)
Van der Cammen et al,241987 0.0303 (0.0008, 0.1576)
Hedner et al,221987 0.0290 (0.0035, 0.1008)
Evans et al,271989 0.0273 (0.0057, 0.0776)
Chui and Zhang,461997 0.0273 (0.0057, 0.0776)
Burke et al,572000m 0.0270 (0.0007, 0.1416)
Von Strauss et al,561999 0.0168 (0.0062, 0.0361)
Liu CK et al,501998 0.0167 (0.0004, 0.0894)
White et al,441996 0.0133 (0.0027, 0.0383)
Philpot and Levy,231987 0.0000 (0.0000, 0.0698)
Brodaty et al,291990 0.0000 (0.0000, 0.0342)
Kua et al,471997 0.0000 (0.0000, 0.0787)
combined 0.0733 (0.0505, 0.0998)
0.0 0.2 0.4 0.6
proportion (95% confidence interval)

Simple Definition Peterson (Mayo Defn) 1997/1999/2001
1. Subjective Memory complaints
Spontaneous or affirmed?
2. Normal activities of daily living
Normal or near normal?
3. Memory impaired for age
1.5SD?
4. No dementia
Questionable dementia?
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
MCI → AD 12%/yr
100
90
80
70
Control → AD 1-2%/yr
60
100
50 90
Initial 12 24 36 48
exam Months 80
70
60
50
Initial 12 24 36 48
exam Months
Petersen RC et al: Arch Neurol 56:303, 1999

100 0
4
16
90
28
80 40
52
70
64
76
60
88
50 100
40
Comment:
30
Summary of the Petersen
(Mayo) clinic model of linear
20 decline approximating 12% per
annum.
10
0
Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9
Crude Mayo MCI Model Extrapolation

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 Type Dementia AD N=
– Follow-up 3yrs+
Classical 10x 17x 2511
– Sample n > 50
Partial 12x 9x 4644
• Expecting ?20 papers CDR 2x 10x 902
– 65 studies
CIND 5x 2x 2308
– 15 long term
– 41 medium and long AACD 6x 4x 1392
– Sample = 11,756
Comment:
Our attempt to redefine
progression in MCI

Long Term Studies 5yrs+
Annual Rate of Conversion (%)
12
Hansson et al (2007)
10
Larrieu et al (2002)
Bozoki et al (2001)
8 Dickerson et al (2007) Aggarwal et al (2005)
Visser & Verhey (2008)
6 Busse et al (2006)
Grober et al (2000)
Visser et al (2006)
Devanand et al (2007) Annerbo et al (2006)
Ishikawa & Ikeda (2007)
4
Hogan & Ebly (2000)
Ganguli et al (2004)
2
Tyas et al (2004)
Years of Observation
0
4 5 6 7 8 9 10
Triangle = Specialist Centres (clinical)
Square = Community Studies (non-clinical)

ACR
20
Medium+Long Term Studies 3yrs+
18
16
14
12
10
8
y = -5.9607Ln(x) + 16.633
6
R2 = 0.1857
4
2
Years of Observation
0
2 3 4 5 6 7 8 9 10
Triangle = Dementia
Square = Alzheimer’s disease

Long Term Studies 3yrs+
ACR to AD
All
0.10 Specialist Settings
0.09 0.09 0.09
0.09
0.08
0.08 0.07
0.07
0.06
0.06
0.05
0.05
0.04 0.04 0.04
0.04
0.03
0.02
0.01
0.00
Classical MCI Partial MCI CDR=0.5 CIND AACD

100
8
90 18
MCI-Stable 24
Recovered 31
37 20
80 Died 43
50
Dementia
57 22
70
65 19
74 17
60 16
85
14 10
9
50 100 12
8
10 7
6
40 8
5
6 4
30
3
4
20 2
2
1
10
0 0
Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 15
Advanced All Case MCI Model Extrapolation

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

Cache County Study – Clinical Value of MCI
Develop No Dementia
Dementia
MCI 55 65 45.8% PPV
No MCI 104 3042 96.7% NPV
34% (se) 98% (Sp) Prevalence =
5%

1
0.9 Post-test Probability
Baseline Probability MCI+ MCI-
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Pre-test Probability
0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

P-Tau and MCI
Develop No Dementia
Dementia
MCI with P- 132 78 63% PPV
Tau
No P-tau 31 147 83% NPV
163 225 Prevalence =
5%
81% (Se) 65% (Sp)

1.00
Post-test Probability
MCI+ P-tau+
0.90 MCI+ P-Tau-
Baseline Probability
MCI+
0.80
MCI-
0.70
0.60
0.50
0.40
0.30
0.20
0.10
Pre-test Probability
0.00
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

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.