New Techniques in Brain Imaging in Alzheimers Disease

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New Techniques in Brain Imaging in Alzheimers
Disease

• Susan Bookheimer Ph.D.
• Center for Cognitive Neurosciences
• UCLA School of Medicine

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Brain Imaging Approaches

• Structural MRI
• New measures
• New analysis techniques
• Functional MRI
• Early changes in function
• Prediction of outcome
• Positron Emission Tomography
• New radioisotopes

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MRI in AD

• Acquisition better scanners
• Analysis better ways of looking at the data
• Dynamic measures (vs. static)
• New types of measurements (location, thickness
  vs. size)

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Structural MRI
Comfort, claustrophobia
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New MRI ScannersHigher field strength, speed,
resolution
High Field 3 Tesla
Standard 1.5 Tesla
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Measuring Structures the Region-of-interest
Approach
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Location of Atrophy in Hippocampus
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Measuring Change in Size
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Hippocampal Circuitry
Known by tracer studies in monkeys, rats, and the
cat.
Sub
CA 1
PRC
ERC
PHG
DG
CA 3
fornix
Anterior
Posterior
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Normal Volunteer Anterior hippocampus
Normal E-4 Anterior hippocampus
Burggren et al
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APOE e3/e3
APOE e3/e4
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Cortical Thickness
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Hippocampal Circuitry
Known by tracer studies in monkeys, rats, and the
cat.
Sub
CA 1
PRC
ERC
PHG
DG
CA 3
fornix
Anterior
Posterior
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AD vs. Normal Aging Change Over Time
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MRI grey matter loss/time
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Functional MRI
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Face-Name Association Zeineh et al, Science, 2003
Distractor
Learn Face-Name Pair
Covert Name Recall
Learn
Recall
Learn
Recall
Learn
Recall
Learn
Recall
D
D
D
D
Rest
Rest
Time
7 minutes
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fMRI in normal subjects with genetic risk for
ADBookheimer, Small, et al, NEJM 2000

• Purpose use fMRI to identify changes in brain
  function prior to significant cognitive decline
  predict outcome
• APOE-3 vs E-4 extremely healthy older volunteers
  (X63.5 N30)
• Memory stress-test in cognitively normal
  elderly
• Memorize unrelated word pairs justice-club
• Memorize new faces and names

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Correct
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Group Analysis Effect of Genotype
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What if the test is easier?
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What if the test is hard, with no memory
643
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Do fMRI abnormalities in APOE-4 predict outcome?

• 2-year Neuropsychological outcome
• Diagnosis of AD
• fMRI Follow-up

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2-year outcome conversion to AD

• Seven subjects lost to illness
• 4 developed AD
• 3 other illnesses (cancer)
• All those converting to AD had APOE-4
• All others did not

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Relationship between memory decline and fMRI
change

N3
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fMRI in APOE e4 at Follow-up Maintainers gt
Decliners
Z - 6
Z - 4
Z 2
L
R
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Young Normal Volunteer
MCI
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Does treatment affect brain activity?

• Donepezil (Aricept) treatment
• 6 weeks on drug
• Memory fMRI before and after

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Donepezil Treatment- Mild AD
Pre-Treatment
Post-Treatment
Related Paired-Associate Learning vs. Rest
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PET Scanning
New Isotopes -direct measures of
amyloid -measures of neurotransmitters
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PET Positron Emission Tomography

• Uses radioactive materials to track specific
  aspects of brain function
• Add a radioisotope to something the brain uses
  glucose (18FDG) water (H2 15O)
• Neurotransmitter or precursor (dopamine,
  serotonin, etc)
• Attach to amyloid plaques

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PET Scanner
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CMRgI Abnormalities in Probable Alzheimers
Dementia
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Correlations Between APOE ?4 Gene Dose and
Reductions in Regional CMRgl (36 HM, 44 HT, 78 NC)
PF
PF
TP
TP
PC
PC
P lt 0.005
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Positron Emission Tomography (PET) Glucose
Metabolism
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PET AND GENETIC RISK FOR AD
NORMAL MEMORY
DEMENTIA
PET Imaging
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-20
-12
-18
Genetic Risk
? Lower inferior parietal metabolism in
non-demented persons with a single copy of APOE-4
Small et al, PNAS 2000 976037-6042
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Imaging Amyloid Plaques and Tangles with PET
FDDNP J. Barrio G. Small

• DDNP 1,1-dicyano-2-6-(dimethylamino)-2-naphthal
  enylpropene
• Lipophilic small molecule probe
• Fluorinated analogue (18F-DDNP) provides
  visualizations of plaques, tangles and diffuse
  amyloid

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Plaques and Tangles
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FDDNP Autoradiography
Control brain
AD brain
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FDDNP PET in AD, FTD and normal aging
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Hippocampal distribution in AD
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FDDNP in AD, MCI and NC
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DDNP and MMSE Score
10.0
7.5
Residence Time (min.)
5.0
2.5
r -0.66
0.0
0
10
25
5
15
20
35
30
MMSE
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DDNP and APOE-4 Genotype
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Relationship to cognition
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Pittsburgh Compound B PIB
From Klunk et al 2004 Annals of Neurology
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PIB and FDG Distribution
From Klunk et al 2004 Annals of Neurology
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Serotonin 1-a Receptor Mapping 18F-MPPF
18F MPPF Integration with Structural MRI
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Serotonin 1-a receptor density in AD
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18F-MPPF in AD relationship to memory
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Why is imaging important?

• Potential to detect the preclinical stage
• Treatments will more likely slow or halt, rather
  than reverse, the disease
• Identify an earlier time to intervene
• Help determine when and with whom to intervene
• Useful as a marker of change/intervention effects
• Imaging outcome measures vs. disease outcome

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Result of Treatment
Treatment
Onset
Cognitive Function
Presymptomatic stages
AD
Time
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Predicted Result of Early Treatment
Early Treatment
Onset
Cognitive Function
Presymptomatic stages
AD
Time
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Possible Result of Earlier Treatment
Improvement
Onset
Cognitive Function
Presymptomatic stages
AD
Time
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Diagnosis and Prevention in the Future
Brain Stress (MRI)
Neuron Function (PET)
Brain Aging Index
Brain Amyloid (PET)
Shrinkage (MRI)
Genetic Risk (Blood test)
Memory Scores
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Thanks!
Dr. Gary Small Dr. Jorge Barrios Dr. Vladimir
Kepe Dr. Linda Ercoli Dr. Karen Miller
Dr. Alison Burggren Meredith Braskie Dr. Paul
Thompson Kiralee Hyashi
UCLA Brain Mapping Center UCLA Center on Aging