Complaints July to September 2021 21,489 total complaints ...
LPT08 - Are Mild Memory Complaints of Clinical Significance?
-
Upload
alex-j-mitchell -
Category
Health & Medicine
-
view
769 -
download
2
description
Transcript of LPT08 - Are Mild Memory Complaints of Clinical Significance?
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