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Presymptomatic Tests for AD: the Search for Mechanism...391-2 de Leon MJ, et al. Lancet.1988...
Transcript of Presymptomatic Tests for AD: the Search for Mechanism...391-2 de Leon MJ, et al. Lancet.1988...
Presymptomatic Tests for AD:
the Search for Mechanism
March 9, 2011
Barcelona, Spain
Mony de Leon
Professor of Psychiatry
NYU School of Medicine
AD phenotype
Aβ β β β and Tau
Oxidative stress and inflammation
Cellular response
Primary etiology
Phenomena
and
Pathology
Targets
Mechanistic
Targets
MCI
AD
Time
BrainHealth
Preclinical
AgeAge
Objective of Early Diagnosis
MCI
AD
Preclinical
AgeAge
Objective of Early Diagnosis
Time
BrainHealth
391-2
de Leon MJ, et al. Lancet. 1988
Percentage Cases
Age
AD (n = 203)
MCI (n = 72)
NL (n = 130)
0 1 2 3
Automated MRI Regional Boundary Shift
6-year prediction of Normal to MCI
Prediction of MCI
Accuracy
SS/SP (n=13,32)
89%
91/85%Rusinek H, de Leon, MJ et al. Radiology. 2003;229:691-696.
MESH MODELING
Thompson et al, Neuroimage 2004
3-year MRI hippocampal atrophy rate
superior inferior
Apostolova , Mosconi, de Leon et al, Neuro Biol Aging 2009NL-NL
n=10
NL-decline
n=7
ANATOMY
Annual tissue loss %
NL MCI AD1993 1997 2003
E EE
Atrophy and Metabolism10-Year decline from NL to AD
xH xxH H4
V4 4
V V
de Leon et al PNAS 2001
Automated Hippocampus Sampling7-year advanced prediction of Normal to MCI and AD
Prediction of MCI
Accuracy
SS/SP (n=25,47)
76%
82/79%
Mosconi L, de Leon MJ et al. Neurobiol Aging. 2008;29:676-692.
26%
(47)
(19)
4% /year
X
X
Estimated Earliest
Detection -11 yrs
X
X
X
LONGITUDINAL
PREDICTION
74%
BASELINE
PREDICTION
76%
2% /year
1% /year
(6)X -- NL-AD (6)
Years from Baseline
-- NL-NL (47)
-- NL-MCI (19)
0 5-5
FDG-PET for Prediction and Progression: NL Aging
10-10
Typical DB (n=55, top) and Robust DB (n=55, bottom)
Z
AD n=33 MCI n=37Effect Size
Effect Size
Typical DB Robust DB
Typical vs. Robust Normal Reference Databases
Mosconi, DeSanti, de Leon et al, J Nucl Med 2007
NL-AD (1993-2003) Post-mortem validated AD
NL
MCI
Mild AD
Mod AD
2003 CERAD definite, Braak stage C-VI
4
0
Z score
Path: AD
Mosconi, de Leon, et al Eur J Nuc Med 2009
Best Paper of the Year European Journal of Nuclear Medicine 2009
Senile or Amyloid Plaque
71 years old male65 year old male
PIB and FDGNL AD
Li , Rinne, de Leon Eur.J.Nuc.Med. 2009
Best Paper of the Year European Journal of Nuclear Medicine 2008
AD vs NL MCI vs NL
FDGAccuracy (%)
92 85
PIBAccuracy (%)
96 75
%
Agreement 94 54 ?
Dx Accuracy for FDG and PIB
Li , Rinne, de Leon Eur.J.Nuc.Med. 2008
Tangles drawn by Bonfiglio 1908
From Robert Terry
Glodzik-Sobanska L, de Leon, MJ. et al. Neurobiol Aging. 2007
CSF Analytes in Normal Aging n=78
Z-Score
Age
T-tau
P-tau231
IP
Aββββ42/40
Longitudinal memory by high and low P-tau231 in 57 NL
P<.05
Black = Low P-tau231
Red = high P-tau231
Glodzik, de Leon et al Neurobiol. Aging 2010
Longitudinal MTL-GM by high and low P-tau231 in 57 NL
Glodzik, de Leon et al Neurobiol. Aging 2010
P<.05
Black = Low P-tau231
Red = high P-tau231
MTL Gray matter Density
The Search for Mechanism
15H2O-PET EPI-ASL True-FISP-ASL
PERFUSION IMAGING PET AND MRI
MRI True-FISP Hippocampal Perfusion Imaging
MRI with rebreathing apparatus
Vasoreactivity to CO2 challenge~2% CBF change/mmHg change in CO2
Normal– N.S.
MCI– P<.05
*
Glodzik, Rusinek… de Leon et al. JCBF 2010
Hippocampal Vasoreactivity and Cardiovascular Risk
Normal– P<.05
MCI– P<.05
*
*
Glodzik, Rusinek … de Leon et al. JCBF 2010
Cortical Vasoreactivity and Cardiovascular Risk
Maternal
Paternal
Maternal and Paternal
Neither
Other
-
Parental History of AD in NL n=733
No Hx
59%
Normal cognition, MMSE 28-30Age 48-80 yrsEducation>11yrs
Paternal 10%
Maternal 27%
M+P
4%
FDG-PET in individual cases
umol/100g/min
60
30
0
FH- FHp FHm
-10 Z
Longitudinal change in NL with AD mothers
FH- (n=37)
FHp (n=9)
FHm (n=20)
+10 Z
30
35
40
45
50
55
baseline 2-yrs
CMRglc
-1%/yr-0.5%/yr
-5%/yr
30
35
40
45
50
55
baseline 2-yrs
CMRglc
-0.5%
-6.5%
-1%
Mosconi et al, Neurology 2008
CSF Biomarkers and AD Maternal History in NL
Ab42/40 IsoP
P-tau231 T-tau
FH- FHp FHmFH- FHp FHm22 14 23 22 14 23
*
*
FH- FHp FHm
FH- FHp FHm
Parietal PIB-PET Uptake in NL with Maternal History of AD
Mosconi, de Leon et al PNAS et al 2010
AD phenotype
Aβ β β β and Tau
Oxidative stress and inflammation
Cellular response
Primary etiology
Phenomena
and
Pathology
Targets
Mechanistic
Targets
Conclusions• PET and MR imaged hippocampal pathology
appears early and is progression sensitive.
• The pathology specific P-tau231 and Ab also
appear early but are not progression sensitive.
• Imaging and biomarkers may have a role in
identifying mechanisms of AD-progression by
considering energetics and vascular function.
Collaborating Scientists
• NYU
– Lidia Glodzik
– Lisa Mosconi
– Henry Rusinek
– Wai Tsui
– Elizabeth Pirraglia
– Yi Li
• Institute Basic Research
– Pankaj Mehta
• Temple University
– Domenico Pratico
• Einstein College of Medicine
– Peter Davies
• University of California L.A.
– Liana Apostolova
– Paul Thompson
• Applied Neurosolutions
– Ray Zinkowski
• Turku U. Finland
– Juha Rinne
• Sahlgrenska U. Goteborg
– Kaj Blennow
– Henryk Zetterberg
– Anders Wallin
• Cornell University- Shankar Vallabhajosula
- Stanley Goldsmith