Are Subjective Memory Complaints or MCI of Clinical Significance?

Alex MitchellSrini MalladiMoj FeshkiSujeeve Sanmaganatham

Open Meeting May 2008

Should you be worried about memory problems?

Dementia

Healthy

0

10000

20000

30000

40000

50000

60000

under60

65-69 75-79 85+

Dementia prevalence

Estimated Prevalence of Dementia in Australia in 2000

Healthy

Dementia

Healthy

HealthyWith SMC

MCIWith SMC

VaD

ADMixed

LBD

FTD

Healthy

Global increase in dementia

0

50

100

150

200

250

2000 2025

mill

ions

of p

eopl

e w

ith d

emen

tia

MCIDementia

Cognitive Impairment 5X more common in the community than dementia (Unverzagt et al, 2001)

3x Audience Question MCQ

• [1] Who has no memory difficulties

• [2] Who has occasional or regular memory lapses?

• [3] Who is worried about their memory?

Regarding your memory:

3x Audience Question MCQ

• [1] Who has no memory difficulties– Most common answer in AD

• [2] Who has occasional or regular memory lapses?– Most common answer in healthy people

• [3] Who is worried about their memory?– Most common answer in MCI

• [4] Whose friends / family are worried?– Highest prediction of later decline

Answers!

Subjective complaints

Observed complaints

Clinical historyNon-quantitative

Cognitive Difficulties Scale or similar

IQCODE or similar

Objective TestsQuantitative

Patient ConcernsRelative

ConcernedClinician

Concerned

Contents=>

IQCODE

Example – Simple Complaints• I have trouble recalling

frequently used phone numbers

• I put down things and cant find them

• I forget appointments, dates or classes

• I forget errands I planned to do on my way home

• I find it hard to keep my mind on a task or job

• I forget names of people soon after being introduced

• I need to check or double check whether I locked the door, turned off the stove, etc.

• I make mistakes in writing, typing or operating a calculator

• I cannot keep my mind on one thing

• I have trouble deciding if I’ve received the correct change

• I forget to pay bills, record checks, or mail address

• I forget the date of the month

Example – Modest Complaints• I need a written list when I do

errands to avoid forgetting things• I have trouble getting out

information that’s at the tip of my tongue

• I lose my train of thoughts as I listen to somebody else

• I forgets steps in recipes I know well and have to look them up

• I forget what day of the week it is

• I leave out ingredients when I cook

• I have trouble manipulating buttons, fasteners, scissors, or both caps

• I have trouble sewing or mending

• I find it hard to keep my mind on what I’m reading

• I have to do things slowly to be sure I’m doing them right

• My mind just goes blank at times

• I forget the date of the month• I have trouble using tools for

minor household repairs

Example – Serious Complaints• I have trouble getting my keys

into a lock• I have trouble describing a

programme I just watched on television

• I don’t say quite what I mean to say

• I fail to recognize people I know• I have trouble of thinking of the

names of objects• I find it hard to understand what I

read• I miss the point of what other

people are saying

• I forget to button or zip my clothes

• I have trouble manipulating buttons, fasteners, scissors, or both caps

• I misplace my clothing• I find it hard to keep my mind on

what I’m reading• I forget right away what people

say to me• when walking or riding, I forget

how I’ve gotten from one point to another

• I have to do things slowly to be sure I’m doing them right

Special Example of Time

• What Year is it?

• What Month is it?

• What Day is it?

• What Date is it?

• What Hour is it?

• What Minute is it?

• What second is it?

Precision Difficulty

SMC Evidence Base

Might SMC be Useful for Screening?

Concepts of Screening

• Screening (possible case)– MMSE

• Case-Finding (probable case)– NINCDS-ADRDA accuracy 90%

• Severity Rating

• Gold Standard (definite case)– Pathology => disease

High accuracy

High convenience • Untrained, unassisted

• Untrained, assisted

• Trained, unassisted

• Trained, assisted

• Trained, assisted & monitored

Why Might SMC be Problematic

How to assess?

Occurrence in healthy people

Memory Complaints in the Community

0

5

10

15

20

25

30

35

40

45

50

No Diag

nosis

Anxiety

disord

ersCogn

itive d

isord

erAffe

ctive D

isord

ers

Schizo

phren

ia

Substance

Use

Adjustmen

t Diso

rders

Bassett SS, Folstein MFMemory complaints, memory performance, and psychiatric diagnosis: a community study. J Geriatr Psychiatry Neurol 1993(6) 105-111

SMC Tools• The 11x brief tools were:

• Global cognitive complaints (GCC)• Subjective memory decline scale (SMD)• Memory Assessment Clinical questionnaire (MAC-Q)• Memory self-efficacy scale (10 item version)• Subjective Memory Assessment questionnaire (SMAQ)• Everyday Memory Questionnaires – Revised (EMQ-R)• Short Memory Questionnaire (SMQ)• Cognitive Failure Questionnaire (CFQ)• Cognitive Difficulties Scale (26 item version) (CDQ26)• Memory Observation Questionnaire 2 (MOQ2)• Everyday Memory Questionnaire (EMQ)

• The 9x long tools were:

• Memory Complaint Questionnaire (MCQ)• Self Report Questionnaires (SRQ)• Cognitive Difficulties Scale (CDS)• Multiple Ability Self-Reported questionnaire (MASQ)• Memory Assessment Clinic Self Rating Scale (MAC-S)• Memory Questionnaire (MQ-P)• Memory Functioning Questionnaire (MFQ)• Inventory of Memory Experiences (IME)• Meta-memory in Adulthood (MIA)

Have You Had Memory Loss in the last year?

Have You Had Memory Loss in the last year?

58.5% (se)

39

55

MCI

Prevalence = 10%

79% (Sp)61% (se)

95%115124No

10%31233Yes

DementiaAbsent

DementiaPresent

St. John & Montgomery, J Geriatr Psychiatr Neurol 2003 (n=1751)

Pooled Analysis: 8x D (n=9148)

32% (se)

271

133

Mild Cases

Prevalence =8.8%

82.1% (Sp)42.8% (se)

93.7%6484461No

18.7%1494345Yes

DementiaAbsent

DementiaPresent

“Have you had memory problems”

Simple Memory Complaints

63.8

25.5

35.1

70.2

16

68.2

39.4

48.5

80.3

30.3

73.3

41.3

58

88

28

73.2

45.1

67.6

87.3

43.7

0

10

20

30

40

50

60

70

80

90

100

Forgetting where things areplaced

Unable to recall the names ofgood friends*

Unable to follow and recallconversation**

Subjective memory problems* Consider own memory to beworse than others of a similar

age**

ControlsMCIMCI=>DementiaAD (CDR1)

Lam et al. Int J Geriatr Psychiatry 2005; 20: 876–882. (n=306)

SMC Summary

• 8 studies report the rate of SMC in dementia; 7 studies reported the rate of SMC; 4 compared the rate of SMC in dementia and MCI head-to-head.

• SMC were present in about 40% of those with MCI and Dementia (relative risk 2.3).

• SMC could be used as a first stage screen to rule out healthy individuals with 90% accuracy

Theory of Diagnostic Tests

PopulationNumber ofIndividuals

Cognitive Score

Theory of Diagnostic Tests

Cognitive Impairment

Dementia

Number ofIndividuals

Optimum Cut-off value

False +veFalse +veFalse -veFalse -ve

True -veTrue -ve

True +veTrue +ve

Point of Partial Rarity?

Cognitive Score

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

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.

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

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)

Pooled + Meta-Analysis of Outcomes

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+

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

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

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

MCI-StableLow Risk

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• Vascular status

Possible Predictors

Modifiable

• Delay in diagnosis• Treatment• Depression/anxiety

• Vascular status

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

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

Disease Related Predictors

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

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

Any Definition of MCI

Non-Mayo Definition

Mayo Definition

Any Definition of MCI

Non-Mayo Definition

Mayo Definition

Setting

Conversion to Alzheimer’s disease

Conversion to Dementia

Studies conducted in specialist settingsRR Dementia 2.2

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.

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– Mean age = 71 mean MMSe = 27

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

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

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

The 3 Cities Study

• Population study in Bordeaux, Dijon and Montpellier

• MCI = 2879• Healthy = 4013

MCI-improver37%

MCI-progressive

7%

MCI-stable56%

1.14 (1.09 to 1.19)Age

1.78 (1.00 to 3.18)Anticholinergic drugs

1.95 (1.06 to 3.58)Subclinical depression

2.16 (1.31 to 3.56)Low education level

2.34 (1.38 to 3.96)ApoE4 allele

3.51 (2.09 to 5.89)IADL deficit

Women

1.16 (1.10 to 1.21)Age

2.20 (1.07 to 4.49)IADL deficit

2.26 (1.25 to 4.06)Low education level

2.84 (1.17 to 6.85)Stroke

3.15 (1.74 to 5.70)ApoE4 allele

Men

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)

• 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• TREATMENT??

Does Treatment alter the course of MCI?

0.0

0.2

0.4

0.6

0.8

1.0

Probabilityof not

convertingto AD

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

DonepezilPlacebo

1 yr1 yr6 mo6 mo

P=0.004

P=0.04

Petersen et al (NEJM) n=769 3yrs

Donepezil

Rivastigmine InDDEX Study

Galantaminein MCI

Rate of change of brain atrophy over 24 months

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

Summary – MCI and SMC

• SMC are not all equal• For mild dementia and MCI the absence of SMC is useful

• MCI is not a precise category• Most people do not convert to dementia (10years)

• MCI did not exist before (1991)– Flicker C, Ferris SH, Reisberg B. Mild cognitive impairment in the elderly: predictors

of dementia. Neurology 1991;41:1006 –1009. – 3 million cites for MCI in google

End