Structural Changes in Entorhinal Cortex in Mild Cognitive Impairment and Alzheimer’s Disease:

An MRI Study

Noor Jehan Kabani

CONSORTIUM COGNITION ET VIEILLISSEMENTCONSORTIUM COGNITION ET VIEILLISSEMENT

Traitement des troubles cognitifs dans les maladies Traitement des troubles cognitifs dans les maladies neurodégénérativesneurodégénératives

Structural Basis of Dementia

Cognitive changes have a neural basis.

Magnetic resonance imaging is a non-invasive

way of studying the neural substrate.

Pathology of AD

Hierarchical Disease Progression

• Medial Temporal Lobe (Entorhinal Cortex (35); Hippocampus (27))• Anterior Temporal Cortex (38)• Inferior Temporal Cortex (20)• Middle Temporal Cortex (21)• Polymodal Association Areas

(23, 22, 39,10) • Unimodal Areas (44)• Primary or Sensory Areas (4, 18, 17)• All neocortical areas

Modified from E.Gomez

Amyloid Deposits - Neurofibrillary Tangles

•Shrinkage of gyri

• Enlargement of Lateral Ventricles

• Neuronal Death• Extensive Synapse Loss• Altered Corticocortical Connectivity

Normal Alzheimer’s Disease

Vs

Modified from E.Gomez

Other AD Brain Traits

MRI measures taken to study structural changes in AD

Volumetric Studies

Hippocampus (de Leon, 1993, 1996)

Temporal lobe cortices(Convit 1993, 2002)(Visser 2002)

So far, attempts to solve this challenge have not been entirely successful . . .

Difficulties with volumetric studies

-- contradictory results

different protocols

brain variability

-- labour intensive

Modified from E.Gomez

A major weakness

volumetric studies depend upon gross morphologicalchanges at the macroscopic level

Mild Cognitive Impairment (MCI)• transitional state between normal aging and AD

MCINormal AD

?

Modified from E.Gomez

Synaptic and neuronal degeneration at a cellular level may not be reflected in gross atrophy at the macroscopic level in the initial stages of the disease.

Rationale For This Study

Atrophic changes are not always observed in MCI subjects and even MCI subjects with no medial temporal lobe atrophy may develop AD

Our Approach

A different structural imaging parameter

MRI Magnetization Transfer (MT) (Wolff and Balaban, 1989)

Magnetization Transfer (MT)2 pool tissue model

– bulk water: MRI visible

– semi-solids: MRI invisible

– magnetization is exchanged between pools

H

H

O

semi-solid

liquid

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

H

O

H

HH

H

H

B. Pike

Macromolecules(Protiens, Lipids)

Bound pool of hydrogen

WaterFree pool of hydrogen

RF Pulse

Macromolecules(Protiens, Lipids)

Bound pool of hydrogen

WaterFree pool of hydrogen

RF Pulse

BoundFree

Macromolecules(Protiens, Lipids)

Bound pool of hydrogen

WaterFree pool of hydrogen

RF Pulse

BoundFree

Macromolecules(Protiens, Lipids)

Bound pool of hydrogen

WaterFree pool of hydrogen

RF Pulse

BoundFree

Transfer of magnetization

Macromolecules(Protiens, Lipids)

Bound pool of hydrogen

WaterFree pool of hydrogen

RF Pulse

Bound

Transfer of magnetization

Free

What does MT measurement yield?

MT allows one to indirectly study changes in myelin, protien matrices and cell membranes of the brain that are otherwise not visible using conventional MRI

METHODS

Subject Selection Criteria

• Normal Elderly: Cohort without memory complaints referred by local clinics

• MCI: DSM III (memory problems, preserved intellect, no functional disability) + duration over 6 months + 1 SD decline on explicit memory

• AD: ADRDA-NINCDS, no major depression

Subject Demographics

Normal MCI AD

n 19

11m ; 8f

33

20m ; 13f

23

14m; 9f

Age

Mean + SD

77 + 6 77 + 6 78 + 6

MMSE

Mean + SD

29 + 1 27 + 2 23 + 3

Image Acquisition

T1 T2 PD

1.5 Tesla Siemens scanner

MT MT Baseline

1.5 mm isotropic resolution

1.0 mm isotropic resolution

Image Analysis

Before AfterEstimated Field

Intensity non-uniformity correction

J. Sled

(Sled, 1998)

anterior commissure

AC-PC line

posterior commissure

VAC

Registration in stereotaxic coordinates(Collins, 1994)

L. Collins

Stereotaxic Space

J Talairach & P Tournoux, Co-planar stereotaxic atlas of the human brain, Georg Thieme, 1988

L. Collins

Accounts for differences in brain size

MTR Analysis

MT ratio image calculated

MTR = MT baseline - MT

MT baseline

MTR co-registered to T1 image

Display Software(MacDonald, 1994)

To identifying regions of interests

•Labels were painted on T1 images (1 mm resolution)

•Labels were then superimposed on the MTR images

•Volume and MTR was calculated

RESULTSPART 1

Automated Tissue Classification(Zijdenbos, 1998)

ANIMAL+INSECT

ANIMAL

INSECT

Inversenonlinear

classification

Anatomical masking

Customizedatlas

stereotaxic atlas

classified tissues L. Collins

(Collins and Zijdenbos, 1998)

Lobar Analysis

0

50

100

150

200

250

Frontal Parietal Temporal OccipitalGre

y M

atte

r V

olum

e (c

ubic

cm

) Control

MCI

DAT

**

0

50

100

150

200

250

Frontal Parietal Temporal OccipitalGre

y M

atte

r V

olum

e (c

ubic

cm

) Control

MCI

DAT

31

32

33

34

35

36

37

Frontal Parietal Temporal Occipital

Per

cen

t M

agn

etiz

atio

n

Tra

nsf

er R

atio

**

****

RESULTS

PART 2

Entorhinal Cortex And The Collateral Sulcus

Entorhinal

Perirhinal

Collateral Sulcus

0

2

4

6

8

10

12

14

Diagnosis

Ent

orhi

nal C

orte

xV

olum

e C

orre

cted

for

C

olla

tera

l Sul

cus

Var

iabi

lity

P<0.01

*

N MCI AD

29

30

31

32

33

34

Diagnosis

Perc

ent M

agne

tizat

ion

Tra

nsfe

r R

atio

0

2

4

6

8

10

12

14

Diagnosis

Ent

orhi

nal C

orte

xV

olum

e C

orre

cted

for

C

olla

tera

l Sul

cus

Var

iabi

lity

P<0.01

P<0.04 P<0.005

* *

*

N MCI AD

N MCI AD

N MCI AD

Summary

Volumetric measures were lower but no significant difference was found between MCI and normal elderly.

Summary

Volumetric measures were lower but no significant difference was found between MCI and normal elderly.

MT ratio was significantly lower in the absence of significant volumetric differences.

MTR analysis may well be a sensitive means of detecting early

structural changes indicative of incipient dementia before volumetric

changes become significant

Acknowledgements

• Consortium cognition et vieillissement (VRQ)

• Brain Imaging Center - Montreal Neurological Institute

• Geriatric unit of the Jewish General Hospital - Montreal

• Memory Clinic of the Jewish General Hospital - Montreal

• Alzheimer Society Research Foundation of Canada

• Canadian Institutes for Health Research

• Anita Shuper • Kate Hanratty • Adrienne Dorr• Anita Kar• Cinzia Gaudelli• Kathy De Sousa• John Sled• Howard Chertkow• Shelly Solomon