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