MCI - Sesa

Université Catholique de Louvain
Cliniques Universitaires Saint-Luc
Les troubles cognitifs légers
(mild cognitive impairment – MCI)
Dr. Adrian Ivanoiu
Service de Neurologie
• Clinique de la Mémoire
• Centre de Revalidation Neuropsychologique

“ Alzheimer’s disease is when the
patient was older and less intelligent
than the doctor ”
British Medical Journal in 1981
(in Mariani, 2004)

Mild cognitive impairment : what are we talking about ?
epidemiological studies
Memory Clinics experience
Portrait « robot » :
memory complaints
+/- confirmed by relatives
low performer (especially on memory tasks)
preserved autonomy = not demented

Mild cognitive impairment - MCI
“those elderly subjects with mild cognitive changes but
judged to be non demented”
Flicker C, Ferris SH, Reisberg B. Mild cognitive impairment in the elderly: predictors of
dementia. Neurology. 1991 Jul;41(7):1006-9.
the Mayo Clinic conception : a risk state for future
dementia
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive
impairment. Clinical characterization and outcome. Arch Neurol 1999;56:303-308.
=> diagnostic criteria

Mild Cognitive Impairment (MCI)
MCI → AD 12%/yr
±75 % after 5 yr
Control → AD 1-2%/yr1
100
100
90
90
80
80
70
70
60
60
50
Initial 12 24 36 48
exam
Months
50
Initial 12 24 36 48
exam
Months
MCI AD
Controls AD
Petersen et al. Mild cognitive impairment. Clinical characterization and outcome. Arch Neurol 1999;56:303-308

Heterogeneity of the clinical presentation of MCI and
potential multiple etiologies
Clinical presentation
MCI
Amnestic
MCI
Multiple Domains
MCI
Single Non-memory
Domain
Possible etiologies
Degenerative
Vascular
Metabolic
Traumatic
Psychiatric
Others ?
AD
From: Winblad et al. Mild cognitive impairment - beyond controversies, towards a consensus: report of the
International Working Group on Mild Cognitive Impairment. J Intern Med. 2004 Sep; 256(3): 240-6.

New criteria : disease centered
(amnestic) MCI => full established AD
predemential => dementia
Alzheimer’s disease

Core diagnostic criteria : episodic memory impairment
gradual & progressive > 6 months
objective memory deficits => suggestive of an encoding deficit
isolated OR ass. other cognitive deficits
Supportive features : one or more
‣ medial temporal atrophy
‣ abnormal cerebrospinal fluid biomarker
‣ specific pattern of functional neuroimaging with PET
‣ proven AD mutation within the family

Preliminary question :
When starts the MCI ?
(AD ?)

Low memory & cognitive performance
‣ hereditary AD studies : 5 – 10 years
‣ epidemiological cohorts :
Framingham cohort (Elias, 2000) : > 10 ans

Patient CP
male, 73 years old, architect. No memory complaints.
1995: control for his wife with AD in a research.
MMSE 29/30; BIMC 4/28 (Nl: < 8/28)
The 1995 memory evaluation (immediate free recall of 10 words in 6 trials)
Z-sc M sec
2,5
2
1,5
1
,5
0
-,5
-1
-1,5
Ctrl âgé
Alzheimer
Patient CP
30
28
26
24
22
20
Cas CP - evolution du MMSE sur 6 ans
1st cognitive
complaints
95 98 99 00 01
dementia
MMSE (CP)
sup
inf
-2
-3 -2,5 -2 -1,5 -1 -,5 0 ,5 1 1,5 2 2,5
Z-sc M tot

Clinique de la Mémoire Saint Luc
de 1994 à 2004
age 50-79 ans : 1061 patients
‣ 46% Démences (66% Alzheimer)
‣ 11 % Autres (trauma, épilepsie etc...)
‣ 11% MCI
‣ 32% Pas déments
74 patients
31,2%
déments avérés
ou suspects

Diagnostic initial
Parmi les 74 => déments & suspects
‣ 47% => MCI
59% amnesique
12% autre domain
29% multiples domains
‣ 49% => anxio-depréssifs
‣ 4% « normaux »

Is it only a memory problem ?
- The Nun Study -
David Snowdon, epidemiologist at the University of Kentucky medical center
678 women from religious orders
Idea density in early autobiographies ≈ AD late in life
(= nb. ideas expressed / 10 words)
90 % of AD brains
13 % without AD brains
=> low density group
Snowdon, Kemper, Mortimer, Greiner, Wekstein & Markesbury (1996)

When starts Alzheimer’s disease ?
Nl
22 %
healthy
56 %
asymptomatic ? preclinical ?
An
16 %
6 %
memory only => MCI
dementia => AD
*From Braak et al. “Neuropathology of Alzheimer’s disease: what is new since A. Alzheimer? Eur Arch Psychiatry Clin Neurosci (1999)

Question :
Does the memory impairment in
amnestic MCI has anything specific ?

Alzheimer’s disease : an “amnestic dementia”
⇓ memory for recent events :
= episodic memory : memory for events
personally experienced in spatio-temporal context
Tulving, 1972; Schacter & Tulving, 1994; Wheeler et al., 1997; Tulving, 1999
memory impairment in early AD :
= of “hippocampal type”
Dubois & Albert. Lancet Neurol. 2004 Apr;3(4):246-8.

The most fundamental deficit in AD
a reduced capacity to learn new information
Salmon and Bondi, (1999), Kertesz and Mohs, (1999), Becker et al., (1996)
x
encoding
retrieval
test
the best predictor of future dementia
= free delayed recall
Welsh et al., 1991; Morris et al, 1991; Locascio et al, 1995; Albert, 1996; Grober
et al., 2000

x
encoding
retrieval
test
non mnesic confounding factors :
inattention, poor strategy, fatigue, low education, anxiety,
depression ...
=> apparent memory deficits
AD
Ctrls
Classical memory test
(delayed recall)
overlap
=> poor diagnostic validity

La RL/RI16 (rappel libre / indicé 16)
4 consecutive boards
x 4 items : encoded in relationship with
semantic cues (categories)
Free, then Cued recall for the remaining
items with the
same semantic cues
dentiste
dentiste
groseille
dentiste
groseille
dentiste
groseille
groseille
cuivre
cuivre
harpe
cuivre
harpe
cuivre
harpe
harpe
20 s
• which were the insects ?
• which were the fruits ?
• which were the metals ?
controlled
encoding / retrieval
conditions
AD
Ctrls
Maximise the recall +
minimise the confounding
factors
=> increases the difference
in recall by cases and
controls

La RL/RI16 (rappel libre / indicé 16)
Population
CTR
TCL
DTAlég
DTAlmod
Nombre
69
68
61
66
Âge
72(7,6)
73,4(5,8)
73,2(6,7)
72,3(7,7)
Sexe (% F)
60
53
62
67
NSC % 1/2/3 #
37/29/34
22/32/46
38/26/36
47/36/17 a,b,c
MMSE (0 – 30)
*
–
27,1(1,7)
25,7(1,3) b
20,6(2,6) b,c
Ivanoiu, Alves, Grégoire, Seron – en préparation

MCI mildAD modAD
sensitivity % / specificity %*
71/79
ou
82/68
85/92
ou
92/86
92/92
ou
95/86
* total of free recall (1+2+3)

The RI-48 Test = “Rappel Indicé 48 items”
By Ivanoiu et al., 2004; Adam et al., 2004; according to Buschke, 1997
Population
Agés
normaux
Anxiodépressifs
MCI
MA
légers
Nb
38 25 29 24
Age 71(8) 69(6) 71(6) 73(4)
MMSE
28.1(1.8) 28.7(1.3) 26.7(1.7) 23.0(2.6)
Ivanoiu et al., J Neurol, 2000 & 2005

The RI-48 Test = “Rappel Indicé 48 items”
By Ivanoiu et al., 2004; Adam et al., 2004; according to Buschke, 1997
1,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
RI 48
CERAD-recall
CERADdelayed
recall
MMSE
0,1
0,0
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0
1 - Specificity
Ivanoiu et al., J Neurol; 2005

A careful optimisation of the encoding phase = crucial
for a good discrimiation between cases and controls
=> the more encoding specificity is accentuated the
more discriminating power is increased for the diagnosis
of very mild AD

Comparison between items with low and high
encoding specificity optimisation
(a) High specificity : % items = encoded at the first trial (DCRa)
(b) Low specificity : % items = a min of two trials necessary (DCRb)

L’effet de la maladie d’Alzheimer sur la
performance à un test de mémoire
90
80
Test RL/RI 16
70
60
sujets normaux
%
50
40
30
20
10
Effet de l’âge :
- 6% tous les
10 ans
tr. cognitifs légers
Alzheimer léger
Alz. modéré
0
RLT%48
Effet de la maladie d’Alzheimer
Sujets
age 70-79
tr. cognitif léger
Alzheimer léger
Alzheimer modéré
% perf
100
64
42
30
perte%/ s. âgés
-36
-58
-70
éq.âge (-6%)
115 ans
140 ans
150 ans

A psychometric dilemma ...
A cognitive measure
The cut-off
-2SD
(2.5 pc)
is
here
MCI diagnosis
should
be here
An Nl An Nl

animal - vache
animal - cheval
animal - mouton
animal - chèvre
interférence proactive
%
,7
,65
,6
,55
,5
,45
,4
PT1 PT2 PT3 PT4
%
,8
,75
,7
,65
,6
,55
,5
,45
,4
,35
,3
,25
HC
MCI
PT1 PT2 PT3 PT4

Healthy controls vs.
MCI - all
Matched healthy controls vs.
MCI – normal performance
0
0
-,05
-,05
z-scores
-,1
-,15
z-scores
-,1
-,15
-,2
-,2
-,25
-,3
-,25
Dif PT
-,35
Dif PT
HC
MCI
p = ns
p = 0.0025

Question :
Are the CSF biomarkers useful ?

Aucun marqueur n’est actuellement en phase
d’utilisation clinique courante !
Les plus prometteurs :
Le dosage du :
β-amyloïde 1-42
protéine TAU
phosho-TAU
dans le LCR

La neuropathologie de la maladie d’Alzheimer
Plaques séniles (PS)
= peptide
β amyloïde 1-42 (Aβ-42)
Dégénéréscences
neurofibrillaires (DNF)
= protéine TAU hyperphosphorylée
Blennow K. CSF
biomarkers for
Alzheimer's disease:
use in early diagnosis
and evaluation of drug
treatment. Expert Rev
Mol Diagn. 2005
Sep;5(5):661-72.
provient du clivage de l’Amyloid
Precursor Protein (APP) = protéine
transmembranaire
APP = rôle inconnu (plasticité ?)
protéine associée au système
microtubulaire & transport
intracellulaire
surtout ds les axones

Phospho-tau
Neurofibrillary
tangles
Tau
Neuronal and
axonal damage
ß-Amyloid
β-amyloid deposition /
senile plaques
Ph
TAU
TAU
β42
disorders
with hyper
Ph TAU
CSF
all
axonal
damage
CSF
sequestration
in plaques
??
⇓ production
clearance

La méthode combinée (Seubert, 1997; Galasko, 1997)
Protéine TAU OU amyloïde Aβ 1-42
cc. trop élévée
cc. trop faible
sensibilité = 85% / spécificité = 87%
Hulstaert F, Blennow K, Ivanoiu A, et al. Improved discrimination of AD patients using beta-amyloid
(1-42) and tau levels in CSF. Neurology 1999 May 12;52(8):1555-62

Blennow K.
CSF biomarkers for Alzheimer's disease: use in early diagnosis and evaluation of
drug treatment.
Expert Rev Mol Diagn. 2005 Sep;5(5):661-72.
Review of significant studies (evidence-based approach)
Aβ42 : 6 studies (300 AD / 200 Ctrls)
sensitivity 89% / specificity 90%
TAU protein : 10 studies (800 AD / 300 Ctrls)
sensitivity 84% / specificity 91%
phTAU protein : 11 studies
sensitivity 81% / specificity 92%

Blennow K, Hampel H.
CSF markers for incipient Alzheimer's disease.
Lancet Neurol 2003;10: 605-13.
Review of significant studies (evidence-based approach)
Focus on :
mild dementia (MMSE > 23) = 7 studies
mild cognitive impairment (MCI) = 14 studies
sensitivities / specificities for Aβ42, TAU and phTAU
= similar to those found in more advanced AD
⇒ positive very early in AD
⇒ useful for early diagnosis

28 MCI / 75 AD / 38 normal aged / 17 anxio-depressed
Sensitivity (%) Specificity (%)
MCI prAD / Anx / AC
TAU protein only 50 53 94 -
Amyloid β42 only 61 64 94 -
Combination of biomarkers 86 88 76 84

CSF biomarkers and cognitive measures are predictors of
evolution in mild cognitive impairment
Auriane Speth, Francis Zech, Christian JM Sindic, Xavier Seron and
Adrian Ivanoiu
Mild
cognitive impairment
Mild
Alzheimer
Disease
all stable evolving
Number 48 24 24 47
Age /years 71.0 (5.3) 70.8 (5.2) 71.2 (5.6) 71.4 (7.6)
Sex (% M) 54.2 75 33 a 38.3
Education % 1/2 # 50/50 33/67 67/33 a 60/40

Results:
The CSF Aβ42, the MMSE and the verbal
memory were predictors of an evolution towards
AD (75% of patients correctly classified)
Aβ42 = correlated with the MMSE, the Animal
Fluency and the Trail Making Test
TAU protein = correlated only with the memory
scores, independently of the outcome

Hypothesis :
CSF Aβ42 = predictor of an evolution to
AD in MCI
CSF TAU protein level = reflects the
amount of medio-temporal damage
resulting in amnesia

Question :
Are the imaging techniques useful ?

Morphological imagery markers
2
1
1. sillons plus creusés
2. ventricules plus larges
1. hippocampe plus petit
2. corne ventriculaire plus large

Homme, 72 ans, publicitaire : plainte mnésique depuis 2 ans
MCI
1999 2001
Demence légère
droite gauche

Un cas de maladie d’Alzheimer
Sœur M, une religieuse de 76 ans ...
1997
27/30
2002
6/30

Functional imagery markers
"Ever since the original reports, the PET and SPECT findings ... have been
debated in terms of diagnostic utility" (Jagust, 1999 )
"SPECT was an established technique for supporting the
clinical diagnosis of AD"
Alzheimer
Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology. Assessment of brain SPECT.
Neurology 1996;46:278-285.2.
"The dementia practice parameters : SPECT is an
optional part of the dementia evaluation"
Quality Standards Subcommittee of the American Academy of
Neurology. Practice parameters for diagnosis and evaluation of
dementia (summary statement). Neurology 1994;44:
SPECT = PET (Jagust, 1999 )

Hoffman et al., FDG PET imaging in patients with pathologically
verified dementia. J Nucl Med 2000;41; 1920-8
sensitivity / specificity of the temporo-parietal hypometabolism
(against healthy individuals) : 63 / 82 %
sensitivity / specificity of the NINCDS-ADRDA clinical criteria
(against healthy individuals) : 63 / 100 %
Kantarci & Jack. Neuroimaging in Alzheimer disease : an evidencebased
review. Neuroimage Clin N Am 13 (2003), 197-209
”there is ... evidence that diagnostic accuracy of either SPECT or PET is not
higher than the clinical criteria in AD. Nontheless, ... appear promising for
differentiating other dementia syndromes [such as ] frontotemporal dementia
and Lewy bodies dementia from AD”

In-vivo
visualisation
of amyloïd
“Pittsburgh Compound B”
Klunk et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann
Neurol. 2004 Mar;55(3):306-19.

Klunk et al. Imaging brain amyloid in Alzheimer's disease with
Pittsburgh Compound-B. Ann Neurol. 2004 Mar;55(3):306-19.
in 16 patients with mild AD and 9 controls
PIB retention increased in AD :
frontal cortex > striatum > parietal > temporal = occipital
no significant group differences between young (3) and older
controls (6)
PIB retention correlated inversely with cerebral glucose
metabolism determined with 18F-fluorodeoxyglucose

Fagan et al., Inverse relation between in vivo amyloid imaging
load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006
Mar;59(3):512-9.
brain amyloid deposition results in low CSF Abeta(42)
three cognitively normal subjects were PIB-positive with low CSF
Abeta(42)
Mintun et al., [11C]PIB in a nondemented population: potential
antecedent marker of Alzheimer disease. Neurology. 2006 Aug
8;67(3):446-52.
Four of the 41 nondemented subjects had elevated cortical BP
values and their BP values as a group were not significantly
different from the DAT subjects

Remerciements
Clinique
• Pr. Eric Constant
• Neuropsy./logopèdes
Centre Reval. Npsy. St
Luc
Faculté
• Xavier Seron
• Unités NESC & CODE
Fac Psy LLN
Doctorands
• Auriane Speth
• Bernard Hanseeuw
• Charlotte Rensonnet
Etudiants
• Marie Wertz
• Violette de Ryck