1 Mild Cognitive Impairment: The Current Status Mild Cognitive Impairment: Mild Cognitive Impairment: The Current Status The Current Status Ronald C. Petersen, Ph.D., M.D. Mayo Clinic College of Medicine Rochester, MN Updates on Dementia Stanford University June 4, 2008 Ronald C. Petersen, Ph.D., M.D. Ronald C. Petersen, Ph.D., M.D. Mayo Clinic College of Medicine Mayo Clinic College of Medicine Rochester, MN Rochester, MN Updates on Dementia Updates on Dementia Stanford University Stanford University June 4, 2008 June 4, 2008 Disclosures Disclosures • Elan Pharmaceuticals: Chair SMC • GE Healthcare: Consultant • Elan Pharmaceuticals: Chair SMC • GE Healthcare: Consultant MILD COGNITIVE IMPAIRMENT • Conceptual framework • Epidemiology • Clinical features • Outcome • Predictors • Neuropathology • Unresolved issues • Clinical trials MILD COGNITIVE IMPAIRMENT • Conceptual framework • Epidemiology • Clinical features • Outcome • Predictors • Neuropathology • Unresolved issues • Clinical trials Prevalence of Mild, Moderate/Severe and Total Cases of Alzheimer’s Disease in the United States 2000-2050 Prevalence of Mild, Moderate/Severe and Total Cases of Alzheimer’s Disease in the United States 2000-2050 0 2 4 6 8 10 12 2000 2010 2020 2030 2040 2050 2000 2010 2020 2030 2040 2050 2000 2010 2020 2030 2040 2050 2000 2010 2020 2030 2040 2050 Cases (millions) Cases (millions) Mild Mild CP1266212-1 Mod/severe Mod/severe Delayed disease onset Delayed disease onset No therapeutic advances No therapeutic advances Delayed disease progression Delayed disease progression Both delayed disease onset and delayed disease progression Both delayed disease onset and delayed disease progression Sloane et al: Ann Rev Pub Health 23:213, 2002 Sloane et al: Ann Rev Pub Health 23:213, 2002 Time Course: AD Pathology (in situ) & Time Course: AD Pathology (in situ) & Clinical Expression Clinical Expression Pathological burden Young Presymptomatic MCI AD Time Cognitive function Pathological progression Cognitive function 40s-60s 60s–70s >70s
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1
Mild Cognitive Impairment:The Current Status
Mild Cognitive Impairment:Mild Cognitive Impairment:The Current StatusThe Current Status
Ronald C. Petersen, Ph.D., M.D.Mayo Clinic College of Medicine
Rochester, MN
Updates on DementiaStanford University
June 4, 2008
Ronald C. Petersen, Ph.D., M.D.Ronald C. Petersen, Ph.D., M.D.Mayo Clinic College of MedicineMayo Clinic College of Medicine
Rochester, MNRochester, MN
Updates on DementiaUpdates on DementiaStanford UniversityStanford University
June 4, 2008June 4, 2008
DisclosuresDisclosures
• Elan Pharmaceuticals: Chair SMC• GE Healthcare: Consultant
• Elan Pharmaceuticals: Chair SMC• GE Healthcare: Consultant
83 yo male1993 MCI 1996 1997MMSE=27 MMSE=27 MMSE=27
1999 2001 converted to AD 2003MMSE=28 MMSE=25 MMSE=22
0
25
50
75
100
0 1 2 3 4 5 6
StableStable(%)(%)
YearsYears
No atrophyNo atrophy
Mild atrophyMild atrophy
ModMod--severe atrophysevere atrophy
CP926864- 15
Boundary Shift IntegralBoundary Shift Integral
7
Scan 1
Scan 2
Boundary Boundary Shift Shift
IntegralIntegral New Neuroimaging Research
Voxel-based Morphometry
VBM VBM Normal(43) Normal(43)
vs vs AD (51)AD (51)
ADaMCI
n=88 n=51
VBMWhitwell
MCI Converter vs NonMCI Converter vs Non--ConverterConverter
0
8T score
L R 0
8T score
L R
VoxelVoxel--wise methods capture time dependent wise methods capture time dependent progression from aMCI to AD progression from aMCI to AD n = 33n = 33
MCI3 years before conversion to AD
MCI1 year before conversion to AD
ADAt time of conversion to AD
L R RL RL
3D Maps from Multiple MRI Illustrate Changing Atrophy Patterns as Subjects Progress from MCI to AD Whitwell, Jack, Brain 2007
8
NCI MCI mADNCI MCI mAD
Synapse Number and Volume Loss in CA1 in MCISynapse Number and Volume Loss in CA1 in MCI
Scheff et al: Neurol 68:1501, 2007Scheff et al: Neurol 68:1501, 2007
Syna
pses
x 1
010Sy
naps
es x
10
Syna
pses
x 1
01010
CP1307284-5
Total No. of SynapsesTotal No. of SynapsesTotal No. of Synapses40
30
20
10
0
Volu
me
(mm
3 )Vo
lum
e (m
mVo
lum
e (m
m33 ))
Total VolumeTotal VolumeTotal Volume300
200
100
0
Molecular Neuroimaging
In vivo Amyloid Imaging withPittsburgh Compound B (PIB)
N
SNH11CH3
HO
PET Imaging -[11C]6-OH-BTA-1 (PIB)
N
SN
CH3
CH3
H3C
CH
+
6 1
Histology - Thioflavin T
Amyloid Plaques
FDG and PIB in Aging and AD
AD -FDG
AD-PIB
Normal Control -PIB
PIB in Controls, MCI, ADChet Mathis, U Pittsburgh
Some MCI’s have control-like PIB retention, some have AD-like retention, and some have intermediate retention
Price et al., JCBFM 2005Lopresti et al., J Nucl Med, in press
02-310-847 06-209-892
3
2.5
2
1.5
1
0.5
0
PIB IdealizedPIB Idealized
aMCI AD
00-863-895
CN
9
02-155-940 02-310-847 06-209-892
3
2.5
2
1.5
1
0.5
0
PIB Examples PIB Examples –– full spectrumfull spectrumL
owH
igh
CN aMCI AD
00-863-895 01-873-114
CN aMCI
Cerebrospinal FluidCerebrospinal Fluid
Hansson et al: Lancet Neurol 5:228, 2006Hansson et al: Lancet Neurol 5:228, 2006
0.0
0.2
0.4
0.6
0.8
1.0
0 10 20 30 40 50 60
No
prog
ress
ion
to A
DN
o pr
ogre
ssio
n to
AD
CP1266212-4
MonthsMonths
Normal CSFNormal CSF
Pathological CSFPathological CSF
Progression to AD from MCIProgression to AD from MCI Progression Normal to MCICSF Ratio
Progression Normal to MCICSF Ratio
Li et al: Neurol 69:631, 2007Li et al: Neurol 69:631, 2007
0.0
0.2
0.4
0.6
0.8
1.0
0 10 20 30 40 50
Prop
ortio
n re
mai
ning
as c
ontr
olPr
opor
tion
rem
aini
ngPr
opor
tion
rem
aini
ngas
con
trol
as c
ontr
ol
CP1307284-4
MonthsMonthsMonths
Normal >53 yr (n=26)Normal >53 yr (n=26)Normal >53 yr (n=26)
High (n=17)High (n=17)High (n=17)
0 1 2 3 4 5 6 7 8 9
1.0
0.8
0.6
0.4
0.2
0
Predicting Progression to CDR >0Predicting Progression to CDR >0
Fagan et al: Arch Neurol 64:343, 2007Fagan et al: Arch Neurol 64:343, 2007
Prop
ortio
n re
mai
ning
CD
R 0
Prop
ortio
n re
mai
ning
CD
R 0
Prop
ortio
n re
mai
ning
CD
R 0
CP1307284-7
Time since baseline clinical assessment (yr)Time since baseline clinical assessment (yr)Time since baseline clinical assessment (yr)
CSF tau/Aβ42CSF tau/ACSF tau/Aββ4242
0 1 2 3 4 5 6 7 8 9
CSF ptau181/Aβ42CSF ptauCSF ptau181181/A/Aββ4242
<1.15<1.15<1.15
≥1.15≥≥1.151.15
<0.214<0.214<0.214
≥0.214≥≥0.2140.214
Alzheimer’s Disease Neuroimaging Initiative
ADNI
Alzheimer’s Disease Neuroimaging Initiative
ADNI
10
ADNIADNI
•• Observational study of imaging and Observational study of imaging and biomarkersbiomarkers
• Rochester– Brad Boeve– David Knopman– Eric Tangalos– Joe Parisi– Cliff Jack– Walter Rocca– Bob Ivnik– Glenn Smith– Rosebud Roberts– Shane Pankratz– Yonas Geda
• Jacksonville– Steve Younkin– Dennis Dickson– Neill Graff-Radford– Shu-Hui Yen– Todd Golde– Mike Hutton– John Lucas– Tanis Ferman– Floyd Willis