BERG SYMPOSIUMWASHINGTON UNIVERSITY

SEPT 2003

MICHAEL W WEINER MD

CURRENT FOCUS OF MOST IMAGING RESEARCH

• Improved methods to detect treatment effects in clinical trials– Reduce sample size– Shorten length of trial

• Early detection of AD

NICK FOXUNIVERSITY OF LONDON

-0.5108

-0.1054

-8 -6 -4 -2 0 2 4 6

-0.5108

-0.1054

-8 -6 -4 -2 0 2 4 6

Time from MMSE of 23/30 (years)

Brain volume as % of intracranial volume Brain volume as % of intracranial volume vs timevs time

CLIFFORD JACK

MAYO CLINIC

Sample size estimates to detect differences equaling 50% or 25% of observed median

with 90% probability and an alpha level of 0.05 using two-sided t-tests among MCI patients

Observed median

SD (on transformed scale)

Sample size to detect effect size of 50%

Sample size to detect effect size of 25%

Hippocampus -2.55 16.13 24 102

Entorhinal cortex -5.97 72.72 21 91

Whole brain -0.63 1.91 32 130

Ventricle 3.29 0.44 16 69

CDR 0.54 0.33 311 1277

MMSE -0.47 1.31 658 2628

Neurology in review

IMAGING THE TREATMENT AND EARLY DETECTION OF AD WITH:

sMRI, pMRI, MRSI

Michael W Weiner MD

Norbert Schuff PhD

Nathan Johnson MD

Linda Chao PhD

Sample Size/Arm for 20% treatment effectOne year trial

80% power (One tail)

80% power (Two tail)

90% power (One tail)

90% power (Two tail)

ERC Rate 64 82 89 109

HP Rate 52 66 71 88

BSI_VENT 58 74 81 99 Entorhinal cortex (ERC), hippocampus (HP), ventricular BSI (BSI_VENT). Calculated from data on 20 AD subjects. Interscan interval = 1.8

AD (N=24)

CIND (N=24)

HC (N=24)

Effects of AD and CIND on Hippocampal NAA

L. Hippocampus: AD vs. HC, p=0.001 CIND vs. HC, p<0.01

R. Hippocampus: AD vs. HC, p<0.0001 CIND vs. HC, p<0.05

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Left Right

** ***

** p<0.01; *** p<0.001

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Frontal GM Parietal GM

EFFECTS OF AD AND CIND ON CORTICAL NAA

AD (N=24)

CIND (N=24)

HC (N=24)

Parietal NAA: AD vs. HC, p<0.01 CIND vs. HC, p<0.05

**

** p<0.01

P<0.05; cluster-level correction

Perfusion MRI: MCI v NCrCBF

GM concentration

Diffusion-weighted MRI and fMRI

of Aging and Dementia

Randy BucknerWashington U. St Louis Mo

YNG vs OLD YNG vs DAT OLD vs DAT

A

3.09

8.21

Z-v

alue

AGING CHANGE IN WHITE-MATTER

Head, Buckner et al., in press, Cerebral Cortex

Functional Neuroimaging

YOUNG OLD

LEFT LEFT

Logan et al, Neuron 2002

-0.20

-0.10

0.00

0.10

0.20

Do words represent living/non living: Deactivations

YOUNG OLD DAT

YOUNG OLD DATLustig et al., in press, PNAS

YOUNG OLD DAT

YOUNG OLD DAT

Functional MRI studies in early Alzheimer’s disease

Reisa Sperling, M.D., M.MSc.Brigham and Women’s Hospital

Massachusetts General Hospital

Harvard Medical School

Functional MRI - Face-Name Association Fusiform Activation

YoungControl

s

OldControl

s

MildAD

N R

+ + + + +N R

p<0.0000001

p<0.000001

p<0.00001

p<0.0001

Sperling

Test-Retest Reliability of fMRI in AD for Pharmacological studies

Sperling

SCOTT SMALLColumbia U

New York NY• Aging predominately reduces LTP in the granule

cells of the dentate gyrus;• In contrast, AD causes deficits in basal synaptic

transmission in pyramidal cells of the entorhinal cortex and CA subfields.

• Taken together, these studies suggest that AD and aging are separate and dissociable processes.

FDG PET in the Study ofCognitively Normal Persons at

Genetic Risk for Alzheimer’s Disease

Eric M. Reiman, MD

Banner Good Samaritan Medical Center

University of Arizona

Translational Genomics Research Institute

Arizona Alzheimer’s Disease Consortium

Phoenix, Arizona, USA

CMRgI Abnormalities in Probable Alzheimer’s Dementia

Number of AD Patients per Treatment Group Needed to Number of AD Patients per Treatment Group Needed to Detect an Effect with 80% Power in One YearDetect an Effect with 80% Power in One Year

Treatment Effect

20% 30% 40% 50%

Frontal 85 38 22 14

Parietal 217 97 55 36

Temporal 266 119 68 44

Cingulate 343 153 87 57

Combined 62 28 16 10

P=0.01 (two-tailed)

No adjustment for normal aging effects or subject attrition

CMRgI Abnormalities in 50-65 y.o. 4/4’s

Correlations Between APOE 4 Gene Dose and Reductions in Regional CMRgl (36 HM, 46 HT, 78 NC)

PF PFTP TP

PC PC

P < 0.005

Reg

ion

a l t

o W

ho

le B

rai n

CM

Rg

l

0.90

0.95

1.00

1.05

1.10

0 1 2

PrefrontalPrefrontal

0 1 2

ParietalParietal

0 1 2

Posterior CingulatePosterior Cingulate

0 1 2

TemporalTemporal

APOE 4 Gene Dose

P < P < 00..00050005

APOE APOE 4 Gene Dose is Correlated with Reductions in Regional CMRgl4 Gene Dose is Correlated with Reductions in Regional CMRgl

IMAGING PATHOLOGICAL PROTEINS WITH PET

Update on In Vivo Imaging of Plaques and Tangles

Gary W. Small, M.D.

University of California, Los Angeles

N

NC CN

R1

R

DDNP and F-18 DDNP

DDNPDDNP R = R R = R11 =CH =CH33

[F-18]FDDNP R = CH[F-18]FDDNP R = CH33; ; R1 = CHR1 = CH22CHCH22

1818FF

Gary Small, UCLA School of MedicineGary Small, UCLA School of Medicine

Gary Small, UCLA School of MedicineGary Small, UCLA School of Medicine

MMSE Scores vs. Residence Time (RT) ValuesMMSE Scores vs. Residence Time (RT) Values

9988776655443322

1010

2020

3030

Residence TimeResidence Time

MM

SE

MM

SE

1515

55

2525

3535

HypotheticalStages V-VIHypotheticalStages V-VI

HypotheticalStages III-IVHypotheticalStages III-IV

HypotheticalStages I-IIHypotheticalStages I-II

Shoghi-Jadid et al. Am J Ger Psychiatry 10, 24-35 (2002)

AD

Controls

Gary Small, UCLA School of MedicineGary Small, UCLA School of Medicine

Imaging Amyloid in Alzheimer's Disease

with PIBWilliam E. Klunk, MD, PhD

Laboratory of Molecular Neuropharmacology

Department of Psychiatry, Western Psychiatric Institute & Clinic

University of Pittsburgh Medical Center

[11C]6-OH-BTA-1 (PIB) Retention in Controls & AD

Uppsala University PET CentreUppsala Research Imaging Solutions AB

SUV Images

0

0.5

1

1.5

2

2.5

Brain Area

SU

V

Retention of [11C]6-OH-BTA-1 (PIB) in AD and Controls – SUV

Analysis

Uppsala University PET CentreUppsala Research Imaging Solutions AB

Correlation of [11C]6-OH-BTA-1 (PIB) Retention and rCMRglu

Uppsala University PET CentreUppsala Research Imaging Solutions AB

Parietal

R2 = 0.6695

0

0.5

1

1.5

2

2.5

0 20 40 60

rCMRglu (umoles/min/100 ml)

PIB

SU

V

SUMMARY

• Accumulating evidence that structural MRI will play a major role in– Clinical trials for AD etc– Early detection of AD

• fMRI sheds light on mechanism of cognitive impairments and compensatory response. May play a role in drug trials and early detection

SUMMARY

• Molecular imaging with PET shows exciting potential to detect amyloid, and possibly other proteins

• The future role of these methods in clinical trials and early detection remains unknown