IPA08 - What Predicts Progression of MCI to Dementia [April 2008]

What Predicts Progression of MCI to Dementia?Quantitative and Qualitative Review of 53 Studies

Alex MitchellConsultant & Hon SnR Lecturer in Liaison Psychiatry, Leicester

IPA, Dublin 2008

Introduction to Modelling Progression

Modelling Progression on MCI-DementiaD

isea

se S

ever

ity

Time in YearsT4T0 T+8

30

Severe Dementia

Moderate Dementia

Mild Dementia

MCI

Healthy

23v24

20v21

11v12

MM

SE

0

T+12

Modelling Progression on MCI-DementiaD

isea

se S

ever

ity

Time in YearsT4T0 T+8

30

MCI-ProgressiveModerate Risk

Severe Dementia

Moderate Dementia

Mild Dementia

MCI

Healthy

MCI-ProgressiveHigh Risk

23v24

20v21

11v12

MM

SE

0

T+12

The Natural History of Dementia

Time in Years

30

MCI-ProgressiveModerate Risk

MCI-ProgressiveHigh Risk

MCI-RemitterLow Risk

MCI-StableLow Risk

23v24

20v21

11v12

MM

SE

0

T4T0 T+8 T+12

Dis

ease

Sev

erit

y

Severe Dementia

Moderate Dementia

Mild Dementia

MCI

Healthy

Introduction to Predictors

Types of Predictor

• Types– Pseudo-Predictor (Marker of disease severity)

• Marked Cognitive Difficulties• Poor function• Subjective memory problems

– Transient Predictor (effects early conversion only)– Reversible vs Non-Reversible– Biological (test) vs Clinical

• Outcomes– Mortality Predictor– Loss Function Predictor– Hospitalization– Remission/Recovery– Psychiatric Complications

Classifying Predictors

Demographic

• Age• Gender• Education

Service Related

• Recruitment Setting• Education• Length of follow-up• Delay in diagnosis• Treatment• Size of study

Disease Related

• MCI Type• MCI Subtype

• Structural Imaging• Functional Imaging• CSF Studies• Genetic testing (ApoE4)• Cognitive Testing• Non-memory impairment• Depression/anxiety• Subjective Performance• Functional status

Possible Predictors

Modifiable

• Delay in diagnosis• Treatment• Depression/anxiety

Non-Modifiable

• Age• Gender• MCI Type• MCI Subtype• Recruitment Setting• Education• Length of follow-up• Structural Imaging• Functional Imaging• CSF Studies• Genetic testing (ApoE4)• Cognitive Testing• Non-memory impairment• Subjective Performance• Functional status

Disease Related Predictors

Mayo Defn 1997/1999/2001 vs Non-Mayo

1. Subjective Memory complaint

2. Normal activities of daily living

3. Objective cognitive impairmentfor age

4. No dementia

1. Subjective Memory complaint

2. Normal activities of daily living

3. Objective cognitive impairmentfor age

4. No 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 .

010433AACD

102050CIND

026402CDR=0.5

2054111Partial MCI

1351246Classical MCI

Non-SpecialistSpecialist

Non-SpecialistSpecialist

Non-SpecialistSpecialistSettings=>

MCI to VaDMCI to ADMCI to DementiaOutcome=>

4.7%(CI 4.3% to 5.2%)

4.5%(CI 4.0% to 5.1%)

5.5%(CI 4.9% to 6.2%)

3.6%(CI 3.3% to 3.8%)

3.1%(CI 2.8% to 3.4%)

5.9%(CI 5.3% to 6.5%)

All studies

Any Definition of MCI

Non-Mayo Definition

Mayo Definition


Non-Mayo Definition

Mayo Definition

Setting

Conversion to Alzheimer’s disease

Conversion toDementia

Studies conducted using the Mayo defn of MCIRR 1.9

4.7%(CI 4.3% to 5.2%)

4.5%(CI 4.0% to 5.1%)

5.5%(CI 4.9% to 6.2%)

3.6%(CI 3.3% to 3.8%)

3.1%(CI 2.8% to 3.4%)

5.9%(CI 5.3% to 6.5%)

All studies

3.4%(CI 2.9% to 3.9%)

3.7%(CI 3.1% to 4.3%)

4.2%(CI 2.9% to 5.7%)

3.0%(CI 2.7% to 3.3%)

3.1%(CI 2.8% to 3.4%)

4.4%(CI 3.4% to 5.5%)

Community

6.5%(CI 5.8% to 7.2%)

6.9%(CI 5.7% to 8.1%)

6.0%(CI 5.3% to 6.8%)

6.7%(CI 5.9% to 7.5%)

No studies6.7%(CI 5.9% to 7.5%)

Specialist


Non-Mayo Definition

Mayo Definition


Non-Mayo Definition

Mayo Definition

Setting

Conversion to Alzheimer’s disease

Conversion to Dementia

Studies conducted in specialist settingsRR Dementia 2.2

MCI Related Syndromes as Predictors

MCI

Questionable Dementia (CDR=0.5)

CIND

AAMI/AACD

Mild Functional Impairment

Visser PJ, Verhey FRJ. Mild cognitive impairment as predictor forAlzheimer’s disease in clinical practice: effect of age and diagnostic criteria. Psychological Medicine (2008), 38, 113–122.

Relatively low Risk

0.08

0.04

0.07

0.06

0.03

0.09

0.05

0.06

0.04

0.070

0.031

0.07

0.056

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

AllSpecialist (Clinical) SettingsNon-Specialist (Population) Settings

17 12 5 9 4 5 10 4 2 2 4 46

Medium+Long Term Studies 3yrs+

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, 20040.37 RR in those with non-memory MCIvs with aMCI and multi-domain MCI.

Effect of Drugs

0.0

0.2

0.4

0.6

0.8

1.0

Probabilityof not

convertingto AD

Probabilityof not

convertingto AD

Time on MCI study (days)Time on MCI study (days)0 6m 12m 18m 24m 30m 36m0 6m 12m 18m 24m 30m 36m

DonepezilPlaceboDonepezilPlacebo

1 yr1 yr6 mo6 mo

P=0.004

P=0.04

Petersen et al (NEJM) n=769 3yrs

Donepezil

Absolute change in ventricular volume/year

Rivastigmine

Galantaminein MCI

Rate of change of brain atrophy over 24 months

Effect of Age

y = 0.0464x + 3.7916

y = 0.2039x - 6.7417

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0

20.0

60.0 65.0 70.0 75.0 80.0 85.0

ADDementia

Age at Recruitment

Rate of Conversion

Effect of Genetic Factors

0.4

0.8

0.6

1.0

0.2

Prob. Not converting to AD

Time on MCI study (days)

4002000 600 800 1,000 1,200

ApoE4 negative

P<0.0001ApoE4 positive

Apo E4 Status

Effect of CSF

Alzheimer and CSF Phospho-Tau

Andreasen N, Vanmechelen E, Vanderstichele H, Davidssson P, Blennow K. CSF levels of total tau, phospho tau and Ab42 predicts development of Alzheimer disease in patients with mild cognitive impairment. Acta Neurol Scand 2003: 107 (Suppl. 179): 47–51.

AD vs HC – P-Tau181

1541689852

833576257Test -ve

708113595Test +ve

MCIAD

Sensitivity69.8%

PPV 84.0%

Specificity83.6%

NPV 69.1%

Mitchell (2005)Meta-analysis

N=14x

MCI vs Controls – P-Tau181&231

515153362

17712156Test -ve

33832306Test +ve

No MCIMCI

Sensitivity84.5%

PPV 90.5%

Specificity79.1%

NPV 68.4%


N=11x

CSF MCI stable vs MCI progressive?

MCI-prog vs stable – P-Tau181&231

360211149

15213319Test -ve

20878130Test +ve

MCI-StableMCI-Prog

Sensitivity87.2%

PPV 62.5%

Specificity63.0%

NPV 87.5%


N=5x

Summary

APOE ε4 alleleTschanz et al (2006)

Sarazin et al (2007)

APOE ε4 alleleLee et al (2006)

Daly et al (2000)

Albert et al (2007)

Executive cognitive deficitsDeCarli et al (2004)

Convit et al 2000

Abstinence from alcoholSolfrizzi et al (2007)

Solfrizzi et al (2004)

functional impairment; previous strokeDi Carlo et al (2007)

Verbal fluency deficits; Behaviour at baseline; NPI apathy scoreFeldman et al (2007)

Functional impairmentTuokko et al (2003)

Wentzel et al (2001)

Stoub et al (2005)

(Grober et al 2000)

Bozoki et al (2001)

Attention deficitsDevanand et al (2007)

Aggarwal et al (2005)

Morris et al (2001)

Tyas SL (2006)

Language difficulties, visuospatial deficits. no of medicationsStorandt et al (2002)

Functional impairmentsZanetti et al (2006)

Decision making; AnxietyPalmer et al (2007)

Marcos et al (2006)

APOE ε4 alleleFleisher et al (2007)

DepressionGabryelewicz et al (2006)

Jack et al (2004)

Tabert et al (2006)

Informant reports of memory problemsFisk et al (2003)

CSF T-tau; Aβ42;rCBF in parietalHansson et al (2007)

CSF T-tau; P-Tau; Aβ42; APOE ε4 alleleHansson et al (2006)

fMRI scanningMiller et al (2007)

Temporal trendBusse et al (2006)

Ganguli et al (2004)

Temporal trendVisser et al (2006)

OthersFunctionalImaging

StructuralImaging

EducationMemory(episodic)

GlobalCognition

Gender AgeStudy

Possible Predictors

Modest (RR 1.6-2.0)

• Age• Gender• Education• Genetic testing (ApoE4)• MCI Type• Subjective Performance• Structural Imaging• Functional Imaging

Weak (RR1.1-1.5)

• Treatment• Gender• Recruitment Setting• Education• Size of study

Strong (RR 2.1+)

• Cognitive Testing (P)• Functional status (P)

• MCI Subtype• CSF Studies

• Recruitment Setting (P)• Length of follow-up

Unknown

• Delay in diagnosis/Rx• Depression/anxiety

DESCRIPA Study – Verhey, Visser et al

• 15 Countries, 24 Centres, n=881– 1yr = 753 2yr = 688 3 yr = 278 4 yr = ??– MRI data 372 CSF Data 182

• 2 Year– Progression to AD in 19%– No dementia in 78%

• Predictor Bank– Recall, MMSE, Fluency, Trails– MTA, Tau, AB– Age– BMI, alcohol

DESCRIPA - Description

• Subjects were on average 71 years old

• Mean MMSE score of 27.1.

• 50% of the patients were self-referred, 30% were referred by general practitioners, and 20% by other physicians.

• Isolated memory impairment was seen in 63% of the subjects, isolated impairment in a non-memory domain in 9%, impairments in multiple domains including memory in 22% of the subjects, impairments in multiple domains excluding memory in 6% of the subjects.

Alzheimer's and DementiaVolume 1, Issue 1, Supplement 1, July 2005, Pages 102-103

DESCRIPA, ROC Ranking

• Delayed recall 0.80• ABeta/T-Tau ratio 0.76• MMSE 0.74• Verbal Fluency 0.72• MTA 0.71• Total and P-Tau 0.69• Age 0.67• TMT B 0.68• Function 0.65• BMI 0.61• Apo E 0.57• Alcohol 0.55

• Age+MMSE+Neurop 0.76• +function 0.81• +ApoE 0.83• +MRI 0.83• +CSF 0.87

Extras

AD vs MCI – P-Tau181&231 (extrapolated)

1212362852

31356257Test -ve

901306595Test +ve

MCIAD

Sensitivity69.8%

PPV 66.0%

Specificity15.5%

NPV 17.9%

Prevalence42%


N=5x

IPA08 - What Predicts Progression of MCI to Dementia [April 2008]

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