Structural Changes in Entorhinal Cortex in

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CONSORTIUM COGNITION ET VIEILLISSEMENT Traitement
des troubles cognitifs dans les maladies
neurodégénératives
Structural Changes in Entorhinal Cortex in Mild
Cognitive Impairment and Alzheimers Disease An
MRI Study
Noor Jehan Kabani
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Structural Basis of Dementia

• Cognitive changes have a neural basis.
• Magnetic resonance imaging is a non-invasive
• way of studying the neural substrate.

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Pathology of AD
Amyloid Deposits - Neurofibrillary Tangles
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
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Other AD Brain Traits

• Neuronal Death
• Extensive Synapse Loss
• Altered Corticocortical Connectivity

• Shrinkage of gyri
• Enlargement of Lateral Ventricles

Normal
Alzheimers Disease
Vs
Modified from E.Gomez
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MRI measures taken to study structural changes in
AD
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Volumetric Studies
Hippocampus (de Leon, 1993, 1996)
Temporal lobe cortices (Convit 1993,
2002) (Visser 2002)
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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
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A major weakness volumetric studies depend upon
gross morphological changes at the macroscopic
level
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Mild Cognitive Impairment (MCI)

• transitional state between normal aging and AD

MCI
Normal
AD
?
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.
Modified from E.Gomez
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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

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Our Approach

• A different structural imaging parameter
• MRI Magnetization Transfer (MT)
• (Wolff and Balaban, 1989)

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Magnetization Transfer (MT)

• 2 pool tissue model
• bulk water MRI visible
• semi-solids MRI invisible
• magnetization is exchanged between pools

liquid
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O
semi-solid
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H
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O
H
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H
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O
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H
H
O
O
O
H
H
H
H
H
H
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H
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H
H
B. Pike
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Macromolecules (Protiens, Lipids) Bound pool of
hydrogen
Water Free pool of hydrogen
RF Pulse
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Macromolecules (Protiens, Lipids) Bound pool of
hydrogen
Water Free pool of hydrogen
RF Pulse
Bound
Free
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Macromolecules (Protiens, Lipids) Bound pool of
hydrogen
Water Free pool of hydrogen
RF Pulse
Bound
Free
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Macromolecules (Protiens, Lipids) Bound pool of
hydrogen
Water Free pool of hydrogen
RF Pulse
Bound
Transfer of magnetization
Free
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Macromolecules (Protiens, Lipids) Bound pool of
hydrogen
Water Free pool of hydrogen
RF Pulse
Bound
Transfer of magnetization
Free
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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

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METHODS
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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

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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
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1.0 mm isotropic resolution
T2
PD
T1
Image Acquisition
1.5 Tesla Siemens scanner
MT
MT Baseline
1.5 mm isotropic resolution
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Image Analysis
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Intensity non-uniformity correction
(Sled, 1998)
After
Before
Estimated Field
J. Sled
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Registration in stereotaxic coordinates
(Collins, 1994)
posterior commissure
AC-PC line
anterior commissure
VAC
L. Collins
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Stereotaxic Space
Accounts for differences in brain size
J Talairach P Tournoux, Co-planar stereotaxic
atlas of the human brain, Georg Thieme, 1988
L. Collins
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MTR Analysis

• MT ratio image calculated
• MTR MT baseline - MT
• MT baseline
• MTR co-registered to T1 image

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Display Software (MacDonald, 1994) To identifying
regions of interests
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• Labels were painted on T1 images (1 mm
  resolution)
• Labels were then superimposed on the MTR images
• Volume and MTR was calculated

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RESULTS PART 1
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Automated Tissue Classification (Zijdenbos, 1998)
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ANIMALINSECT
(Collins and Zijdenbos, 1998)
ANIMAL
Inverse nonlinear
stereotaxic atlas
Customized atlas
Anatomical masking
INSECT
classification
classified tissues
L. Collins
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Lobar Analysis
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RESULTS PART 2
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Entorhinal Cortex And The Collateral Sulcus
Entorhinal
Perirhinal
Collateral Sulcus
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Plt0.01
N
MCI
AD
39

Plt0.01
N
MCI
AD


Plt0.04
Plt0.005
N
MCI
AD
N
MCI
AD
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Summary

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

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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.

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MTR analysis may well be a sensitive means of
detecting early structural changes indicative of
incipient dementia before volumetric changes
become significant
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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